Dear Longevity Enthusiasts, As we embark on this exciting journey together, I am delighted to introduce Unlock Longevity, a space where we will explore the many dimensions of living longer, healthier, and more fulfilled lives. At Clinique La Prairie, we believe that longevity is not just about adding years to life—it’s about enhancing the quality of every moment and living with vitality and health for as long as possible! Our philosophy is rooted in a unique blend of medical science, cutting-edge technology, and, most importantly, the human capacity for empathy and care—the ability to change and to help others change. For me, longevity is a deeply personal mission. As the CEO of Clinique La Prairie, I’ve had the privilege of witnessing firsthand how innovation, science, and human connection can truly transform lives. But longevity is more than just a professional pursuit—it’s a lifestyle we embody every day. With Unlock Longevity, I want to bring you closer to this world, sharing practical insights on how to live with vitality, balance, and purpose. I understand how challenging it can be to grasp the many complex concepts that are often discussed in this field. It’s no coincidence that the most successful books on longevity today are the ones that explain these fascinating ideas in simple, clear terms. Each edition of Unlock Longevity will dive into topics that are close to my heart: from the latest scientific breakthroughs and holistic wellness practices to the evolving intersection of health and technology, and even the growing business of longevity. This journey is not just about extending life—it’s about unlocking the potential for better living, both physically and mentally. In upcoming issues, I will explore cutting-edge developments within our four pillars: medical, nutrition, well-being (including mental health), and movement. I’ll also touch on how longevity can enhance your performance in business. Together, we will unlock the keys to a life well-lived. Thank you for being part of this incredible journey. I look forward to sharing insights and discovering the transformative power of longevity with you. Yours in health and vitality, Simone Gibertoni CEO, Clinique La Prairie

Over the last few years, I have passionately studied, discussed, and shared the concepts of longevity all around the world, speaking about the incredible work our team at Clinique La Prairie does daily with our clients to help them live longer and better. Despite the immense buzz around the 'Longevity' industry—where it sometimes feels as if everyone knows what it takes to live longer and better—the numbers tell us a different story. The world, unfortunately, is not heading in the right direction. This is why I am deeply convinced that there is still much to do in spreading the concepts related to 'living better and longer,' the concepts of a holistic approach to health, and preventive medicine. Indeed, over the past five years, several industrialized countries have experienced a decline in average life expectancy, affected by various factors, including, but not limited to, the COVID-19 pandemic. Here are a few examples: life expectancy in the United States decreased significantly during the COVID-19 pandemic, due largely to virus-related deaths and complications. Other factors include a rise in deaths due to drug overdoses and poorly managed chronic conditions. In the United Kingdom, life expectancy dropped during the pandemic, with the most severe impact seen in the most disadvantaged areas, revealing long-standing health disparities. Italy and Spain saw life expectancy impacted significantly during the initial phase of the pandemic, with high mortality temporarily reducing life expectancy. We saw it clearly at Clinique La Prairie (CLP)… today, the general level of knowledge has greatly increased, and what we call 'Longevity Enthusiasts' are growing in number. But, as mentioned, the data are not just about the COVID pandemic. The rise of chronic conditions such as obesity, diabetes, and cardiovascular disease, often exacerbated by sedentary lifestyles and unhealthy diets, has contributed to declining life expectancy in many advanced countries. These risk factors increase vulnerability to various diseases and can significantly reduce quality and length of life. In the United States, more than 80 percent of the population over the age of 65 has at least one degenerative disease. In the United States, in fact, for the first time there is a possibility that the lifespan of newborn children will be shorter than that of their parents. According to the World Health Organization (WHO), more than 2 billion adults aged 18 and older are overweight, of which more than 650 million are obese. This number has been steadily increasing, with numbers nearly tripling since 1975. The most recent data suggest that over 10% percent of the world’s adult population is obese. The WHO also estimates that about 450 million adults worldwide have diabetes, up from 108 million in 1980. Another worrying statistic concerns medication use: again, in the United States, more than 60 percent of adults use at least one prescribed medication, and more than 40 percent use at least three. The situation, unfortunately, does not improve when we talk about psychological distress and mental illness: current estimates suggest that tens of millions of people in Europe (nearly 17 percent of the population) suffer from mental health disorders each year. There are several reasons for this “pandemic”: disparities in health care, pollution, socioeconomic factors. But surely the main reason for this “reverse longevity” relates to unhealthy lifestyles: an unbalanced diet, excessive alcohol consumption, smoking, and lack of physical activity contribute significantly to diseases such as obesity, type 2 diabetes, cardiovascular disease, and some cancers. This naturally leads to huge costs, direct costs of course (such as health care costs); indirect costs (such as absenteeism from work, reduced work capacity and early retirement) that affect individual and collective productivity. Last but not least, intangible costs. These costs are related to reduced quality of life, pain, and suffering associated with chronic diseases. Although not directly quantifiable in monetary terms, they have a profound impact on the well-being of individuals. In Europe alone, the cost of chronic diseases has been estimated at hundreds of billions of euros annually. While it is difficult to estimate, just one year’s overall health improvement, on average, would result in savings quantifiable in tens of trillions of dollars. So, as we can see from the data, which certainly highlight a clear trend, talking about longevity today, and how to help people live better is something necessary, even fundamental. A new approach to medicine, focused on prevention has enormous potential benefits for both the individual and society. Understanding, talking about, and investing in longevity and preventive medicine is critical to meeting the health challenges of the 21st century. Not only does it improve the health and well-being of individuals, but it also provides tangible economic benefits, reducing pressure on health care systems and contributing to a healthier and more productive society. The "Unlock Longevity" newsletter is my personal contribution to exploring, but most importantly simplifying and making accessible, the themes, techniques, and strategies related to longevity. If you believe these insights could benefit your network, feel free to share this article! This article reflects my personal views and is not intended to replace professional medical advice. Commenti

There’s always a bit of mystery around what we do at clinics like Clinique La Prairie... People often ask me, “What exactly is a longevity clinic?” Here’s a definition that I think explains clearly and simply what we do: “A longevity clinic is a specialized center focused on promoting optimal health and extending clients' healthy lifespan. It combines advanced diagnostics, cutting-edge treatments, and personalized therapies to address aging holistically. By targeting the underlying causes of age-related decline, longevity clinics aim to enhance the quality of life and empower clients to enjoy a vibrant and fulfilling existence as they age.” First and foremost, a longevity clinic specializes in aging and health, employing advanced technologies and, most importantly, a staff with specific expertise in preventive and functional medicine, as well as therapists and experts who have been specially trained. For example, these professionals often have deep experience in managing age-related diagnostics, personalized nutrition, and tailored wellness programs, ensuring a holistic approach to longevity. The power of precision medicine today goes as well to predictive systems using AI based and machine learning engines to anticipate health changes when it is still “in silent mode” by identifying micro changes in our body and allowing targeted interventions to correct health disruption empowering the doctor and the patient to avoid disease progression and enhance longevity. There are lots of impressive ready to be used solutions that are dramatically changing the way we approach health and disease. The goal is to help clients live better (this is our primary objective), and then to live longer. This speaks to the well-known difference between healthspan and lifespan. Healthspan refers to the period of life spent in good health, without chronic disease or disability. In contrast, lifespan is simply the total number of years a person lives. Today, many people spend the last years of their lives with at least one chronic condition. In fact, studies show that around 60-80% of older adults live with at least one chronic illness, underscoring the importance of extending healthspan alongside lifespan (as we discussed in Newsletter #2). We said that a Longevity Clinic “combines advanced diagnostics, cutting-edge treatments, and personalized therapies to address aging holistically”. This introduces what I call the “Longevity Circle”: diagnostics, personalized interventions, and follow-up. This process is crucial and will help us explore the fascinating world of longevity in upcoming newsletters. Diagnostics are fundamental today because they not only allow us to anticipate (prevent) but also to tailor treatments. From simpler diagnostics like blood tests or X-rays to more complex ones—genetic, epigenetic, microbiota, glycans tests—we'll explore them one by one. An in-depth diagnostic approach is essential for crafting effective, personalized interventions. At Clinique La Prairie, we've divided this approach into what we call the Four Pillars: Medical, Nutrition, Wellbeing, and Movement. This structure helps clients understand the importance of a holistic approach to longevity, and also provides clear research categories for our team and an effective way to balance our programs. While all pillars are important, we place particular emphasis on the medical aspect. The Nutrition Pillar includes 4-D advanced nutritional assessment, personalized nutrition therapy under CLP Method and longevity nutraceutical solutions. In the Wellbeing Pillar, we implement methodologies and technologies—some of which are exceptionally innovative—to reduce chronic stress and empower mental and cognitive health. Finally, in the Movement Pillar, we use the science of Sports Medicine to give a strong scientific angle with simple, personalized, and actionable protocols. This concept is so important to us that we’ve incorporated it into the design of our new centres. Our Health Resorts feature a “Longevity Plaza” where clients can physically access the Four Pillars. It’s a way of representing, in the real world, how life should be after leaving the clinic—balanced across the Four Pillars in a holistic way. Contenuto dell’articolo Clinique La Prairie Anji Resort But what do we mean by personalized intervention? Let me give a simple example, which helps illustrate the concept of "personalization." Imagine a client on a detox program wondering if they can still enjoy their usual two or three cups of coffee a day. The standard answer would typically be “no.” However, genetic tests offer a personalized approach. These tests analyse specific genes like CYP1A2 and ADORA2A, which determine how quickly you metabolize caffeine and how sensitive you are to its effects. Biologically, the human body takes around 6h to eliminate the amount of caffeine in one single coffee if you are a normal/standard metabolizer. On the other hand, individuals with a slow-metabolizing variant of CYP1A2 are more likely to experience negative side effects like high blood pressure or insomnia as caffeine persist longer in the body after ingestion. These individuals will need to avoid coffee consumption after 3pm in order to not overlap with their sleep schedule and to not exceed two coffees a day. Other genes, like ADORA2A, influence sensitivity to caffeine’s stimulating effects, affecting factors such as sleep and anxiety levels. This can only be understood with a genetic test: it's a simple example but imagine what it means in a complete diagnostic process including your pharmacogenetics profiling for all the drugs you might need to take and you are not compatible with. We may all seem superficially the same, but we are profoundly different! A 'standard' approach can only deliver limited results! Follow-up is crucial for measuring results and fine-tuning interventions. Personalized follow-up is why we’ve established “Longevity Hubs” in major cities as part of our ecosystem. While a week at a clinic can be life-changing, consistent application of these methods—and methodological consistency—is essential! Finally, in the definition I provided at the beginning, we mention "addressing the root causes of age-related decline." We will explore these in detail in future newsletters (in the next edition, we’ll discuss inflammation, for example). We’re talking about genomic instability, telomere attrition, mitochondrial dysfunction, cellular senescence, chronic low-grade inflammation, loss of proteostasis—many terms that can be hard to understand, but we’ll explain each one. For now, it’s enough to say that aging is a complex and multifactorial phenomenon, influenced by various cellular and molecular processes. These factors accelerate functional decline and increase vulnerability to age-related diseases. In future editions, we’ll explore each component of this ‘Longevity Circle,’ diving into the most sophisticated diagnostic and intervention techniques. But, ultimately, the key is creating real, lasting change in people’s lives! The "Unlock Longevity" newsletter is my personal contribution to exploring, but most importantly simplifying and making accessible, the themes, techniques, and strategies related to longevity. If you believe these insights could benefit your network, feel free to share this article! This article reflects my personal views and is not intended to replace professional medical advice. Commenti

For centuries, scientists have understood inflammation as the body’s natural response to injury or infection. It is the redness, swelling, heat, and pain we experience when our bodies fight. As research on aging has progressed, scientists have noticed a curious phenomenon. Many age-related diseases, such as heart disease, Alzheimer’s and arthritis, share a common thread: chronic low-grade inflammation, even in the absence of apparent infection or injury. Scientists like Dr. Claudio Franceschi, a pioneer in inflammaging research, began meticulously studying the hallmarks of this chronic inflammation. They observed the persistent activation of the immune system, the overproduction of inflammatory molecules such as cytokines, and the gradual decline in the immune system’s ability to self-regulate. In 2004, TIME magazine published a groundbreaking article entitled “The Secret Killer”, which sounded an alarm about the underestimated threat of chronic low-grade inflammation and inflammaging. This article highlighted how such inflammation could be the insidious root of multiple serious chronic diseases, from cardiovascular diseases to conditions such as cancer and diabetes to neurodegenerative diseases. The article opened a new perspective on global health, showing how a necessary and protective physiological process could turn into a dangerous contributor to chronic disease when it lost its transient nature and became persistent. Chronic low-grade inflammation, called inflammaging, is thus a slow and progressive systemic increase in the production of pro-inflammatory components, among other mediators of the immune system, in the absence of overt inflammatory disease or infection. Chronic low-grade inflammation, unlike the acute inflammatory response that is immediate and localized, is a devious process that can remain hidden in the body for years without obvious symptoms, making early diagnosis and prevention a real conundrum. This insidious phenomenon of chronic inflammation can be compared to the metaphor of the boiled frog, which does not notice the gradual rise in water temperature until it is too late. Similarly, chronic inflammation develops and worsens over time so gradually that it often goes unnoticed until serious complications emerge, making the fight against it especially difficult. Chronic inflammation and the immune system, in particular, are closely interconnected in a complex process that intensifies as we age. During this process our bone marrow, which is like a blood cell factory in our bodies, begins to change the way it produces these cells. Normally, it produces two main types of cells: myeloid cells and lymphoid cells. Myeloid cells help fight infection quickly and are part of our basic immune defense. Lymphoid cells, such as T- and B-lymphocytes, are more specialized and help fight specific germs or infections and remember them so they act quickly if they return. As we age, the bone marrow tends to produce more myeloid cells than lymphoid cells. This imbalance can make our immune system less effective in protecting us from new infections or diseases. This change in blood cell production, along with the general increase in inflammation in the body, contributes to what we call immunosenescence, which is basically the aging of our immune system. As the immune system ages, it is no longer as good at recognizing and eliminating threats, such as viruses. This makes older people more vulnerable to infection and disease. Many hypotheses have been formulated about the causes of chronic inflammation, including incomplete immune resolution, latent chronic viral infections, increased intestinal permeability, imbalances in endogenous microflora, visceral adiposity, the accumulation of senescent cells due to cell damage (which we will discuss later), and antagonistic pleiotropy (antagonistic pleiotropy shows us how nature can make trade-offs, with some genes being a kind of “double-edged sword” - useful in one period of life, but potentially harmful in another). One thing that is certain, though, is that diet plays a crucial role in modulating inflammation in the body. Some foods can promote inflammation, while others can help reduce it. A poor diet, especially one rich in ultra-processed foods, saturated fats, refined sugars, and excess calories, can contribute significantly to the onset and maintenance of chronic low-level inflammation. Let’s begin by introducing some concepts related to foods that can help us reduce inflammation, the function of the microbiota (which we will look at in more detail later), and finally the glycemic index (The glycemic index or GI is a measure that indicates how quickly a food can raise blood sugar levels after being consumed. Foods are ranked on a scale from 0 to 100, with pure glucose having a value of 100 as a reference). We have pro-inflammatory foods: foods such as processed red meat, fried foods, refined sugars and trans fats are known for their potential to increase inflammation. An excessive intake of omega-6 fatty acids, typically found in vegetable oils such as corn and soybean oils, compared to omega-3s, found in large amounts in fatty fish such as salmon and sardines, can promote a pro-inflammatory state (omega-3s are known for their anti-inflammatory properties). A diet low in fiber can have a negative impact on the health of the gut microbiota, which plays a crucial role in regulating inflammation. A healthy microbiota helps maintain the integrity of the gut wall and regulate inflammation; a diet low in fiber can impair these functions. In contrast, a diet rich in fruits, vegetables, nuts, seeds, and whole grains, which are abundant sources of antioxidants and anti-inflammatory nutrients such as vitamins, minerals, and phytochemicals, can help reduce inflammation. Finally, foods with a high glycemic index, such as white bread, sweet snacks, and sugary drinks, can cause rapid spikes in blood sugar, which in turn can trigger inflammatory reactions. Although there are no absolutely precise specific statistics quantifying the “longevity potential” related solely to an anti-inflammatory diet, it is widely recognized that foods that reduce inflammation can contribute to a longer and healthier life by reducing the risk of many chronic diseases. We will then see how many other lifestyle factors, such as sleep and movement (the health of our muscles for example) and stress can influence chronic inflammation. But how can we measure our level of “Inflammaging”? Assessing the state of inflammation requires a multifactorial approach that considers a variety of indicators and individual factors. Medical advice is critical in interpreting the results and determining the most appropriate plan of action. Although biomarkers such as C-Reactive Protein (CRP), Interleukin-6 (IL-6), Tumor Necrosis Factor-alpha (TNF-α), Fibrinogen, and Klotho offer valuable cues for assessing the inflammatory state, it is critical to consider them within a broader clinical framework to gain a complete understanding. Measuring biomarkers repeatedly over time, rather than a single measurement, may provide more useful information about the course of inflammation. This longitudinal approach helps distinguish between chronic low-grade inflammation, which is characteristic of aging, and acute inflammation due to an infection or other transient event. We will then see how there are “broader” markers of immunosenescence that assess the aging of immune cells and their ability to respond to inflammation. In coming articles I will delve further into the link between physical activity and inflammation; the physiological, not to mention psychological benefits of exercise cannot be understated. The "Unlock Longevity" newsletter is my personal contribution to exploring, but most importantly simplifying and making accessible, the themes, techniques, and strategies related to longevity. If you believe these insights could benefit your network, feel free to share this article! This article reflects my personal views and is not intended to replace professional medical advice. Commenti

Meditation isn’t a passing trend. While elements of this practice—like so much of Eastern philosophy—have been adapted for the West, dismissing it as a fleeting “New Age” fad is a mistake. Decades of scientific research have demonstrated meditation’s profound effects on mental, physical, and mind-body health connections. Today, I want to dive into this practice, which I’ve been engaging in for over six years and has brought immense benefits to my life. Meditation is an ancient art: some of the earliest written records of meditation date from circa 1,500 BC India. Over the centuries, it spread to neighboring Asian countries. Some of the first written records of some form of meditation in the west come from Philo of Alexandria, who had written about "spiritual exercises" involving attention and concentration. Meditation has gradually found its place in Western culture, though it has taken time to reach the level of mainstream acceptance we see today. Contenuto dell’articolo So, what does meditation look like in the West? In essence, it’s a practice that fosters self-awareness, deepening our understanding of individuality across physical, emotional, and psychological dimensions. Today, techniques like meditation and mindfulness are widely practiced and continue to attract growing interest from the global scientific community due to their potential benefits for mental and physical health. The field of meditation research, particularly involving mindfulness and related interventions, began gaining momentum in the 1990s. By 2016, there were already over 4,000 scientific articles on meditation, reflecting a significant rise from earlier decades. While earlier mentions of meditation were rare, recent years have seen a marked increase in research, with hundreds of articles published annually on the topic, largely due to growing interest in its therapeutic applications across mental health, chronic pain, and stress management. Scientific research has demonstrated that meditation and mindfulness are effective in treating stress, anxiety and depression, three of the main psychosomatic ills of current times. Clinical research points to excellent results also in treating other conditions, like post-traumatic stress syndrome, panic attacks and obsessive-compulsive disorder. Meditation has also been shown to lead to a decrease in cortisol (the hormone responsible for stress and anxiety) and testosterone levels (responsible for aggressiveness), with related positive effects on nervousness, insomnia and hyperactivity, among others. It has also been shown that the practice of meditation can lead to the release of greater quantities of hormones like endorphin, serotonin and dopamine, which "govern" positive feelings like satisfaction, physical pleasure and enthusiasm, thus helping promote a feeling of well-being. By reducing the load on the sympathetic nervous system, meditation helps to relieve muscular, nervous and psychological tension, all the while improving the functioning of the parasympathetic nervous system, leading to a lower heart rate, with positive effects on the cardiac system's functioning. Through meditation, which enhances our ability to think clearly and concentrate, we can improve our ability to perceive the feelings of those around us. This leads to improved understanding at all levels, facilitating relations between work colleagues and family members, for example. Meditation acts also on the brain: other research, by Sara W. Lazar and her colleagues at Harvard University and carried out on people who practice various forms of meditation, shows this activity can actually alter the brain's function and structure. For example, in those who have practiced mediation over many years, the volume of the areas responsible for coordinating memory and complex actions increases while the volume of the amygdala, which manages fear, was seen to decrease. This body of work highlights the brain's plasticity and the possibility of using meditation to actively influence brain structure and function over time, as noted in publications by Harvard Medical School and Massachusetts General Hospital. Meditation's benefits have been successfully "translated" into a variety of psychological therapies, including the widely acclaimed Mindfulness-Based Stress Reduction (MBSR) program, pioneered in the 1980s by doctor Jon Kabat-Zinn, who developed the practice at the University of Massachusetts Medical School and is credited with having made it popular in the West. Other applications include combating depression: In the early 2000s, clinical psychologist John Teasdale (University of Cambridge) - a pioneer in cognitive therapy in the UK and a founder of the Mindfulness-based Cognitive Therapy (MBCT) - and cognitive psychologist Zindel Segal (University of Toronto) - another co-founder of MBCT - gave patients who had suffered three previous bouts of depression six months of mindfulness and cognitive therapy. This group witnessed a 40 percent reduction in the risk of relapse over the following year, compared to a control group. Aside from its psychological benefits, scientists have researched the physical effects of meditation, also. And there are many. Over the past 15 years, the three mostly widely practiced forms of meditation have been analyzed with the most recent brain imaging technologies and the connection between meditation and the brain's functions have begun to emerge clearly, for example in its ability to impact how the body perceives physical pain. Research led by Fadel Zeidan at Wake Forest University has shown that meditation can significantly reduce the perception of pain, even outperforming morphine in some cases. In one study, brief meditation sessions were able to reduce pain intensity by up to 57%, this is substantial in relation to typical analgesics. Zeidan's team also discovered that mindfulness meditation achieves this analgesic effect without engaging the brain's opioid receptors, indicating that it operates through a unique neural pathway, distinct from traditional pain medications Contenuto dell’articolo Its use in combating inflammation is also scientifically proven. Steven Cole, a genomics researcher at the University of California, Los Angeles (UCLA), conducted a study on people aged 45 to 85 to determine whether meditation could help reduce the feeling of solitude in older people - a condition that can increase the risk of heart disease, Alzheimer's and depression, among others. Over the eight-week duration of the trial, Cole studied a group of people who carried out one two-hour MBSR session a week and a half-hour of meditation each day. The findings were revelatory: patients who meditated regularly said they felt less lonely and suffered from fewer inflammations in their bodies. It also appeared that meditation had a positive effect on the body's immune system. In another study, David Creswell, Associate Professor in Psychology at Carnegie Mellon University's Center for the Neural Basis of Cognition, asked 24 HIV-positive subjects to follow a meditation regimen for eight weeks. At the end, the group witnessed a lesser reduction in CD4T lymphocyte cells - a key component of the immune system's "control" mechanisms that are hard hit by the HIV virus - than experienced by the members of a control group. Even in combating lesser ailments, meditation appears to be important: in a study on some 50 patients, Bruce Barrett, a professor at the University of Wisconsin's School of Medicine and Public Health, found that those who meditated on average almost 50 percent fewer days off from work due to respiratory infections - which lasted less and whose symptoms were lighter - compared to those who did not meditate. Even those suffering from hypertension can find respite. In a study on 60 patients suffering from hypertension, coordinated by Randall Zusman, the hypertension program director at Massachusetts General Hospital, the 40 who followed a meditation therapy saw their high blood pressure condition improved so much that their medications were cut significantly. The reason is mostly a question of physics: meditation leads to the production of nitric oxide, which dilates the blood vessels, leading to a decrease in blood pressure. Another from of meditation – Transcendental Meditation (TM) – has also been the subject of hundreds of scientific studies, which have proven its benefits. This form of meditation - practiced in two, 20-minute sessions every day - was developed by Maharishi Mahesh Yogi in India, in the 1950s. Yogi also founded the Transcendental Meditation movement, which survived his death, in 2008, and remains active. Transcendental Meditation helps practitioners easily achieve a state of inner peace and – as with other forms of meditation – is considered highly effective in combating stress and anxiety as well as helping improve brain functionality and cardiovascular health. A 2013 statement from the American Heart Association said that TM could be considered as a treatment for hypertension, although it said other treatments could be equally or more effective. Meditation, therefore, offers real benefits to its practitioners - no matter what their age or physical condition. But while the benefits are increasingly clear, there are still some things that need to be better understood. Experts warn that it is still early days, in terms of the science: there is still much need for research, to acquire more detailed understanding of the discoveries so far made, to learn of any possible negative side effects of meditation and also to understand what the most appropriate length of a meditation session is and how to adapt it to the specific needs of each individual. Meditation isn’t just a practice—it’s a powerful path to well-being, resilience, and inner peace. Imagine if there were a pill that could do everything meditation does. At conferences, I often say that if people could buy such a pill, they would pay thousands of euros! Yet, all it really takes is dedicating two sessions of 20 minutes a day to this practice, and still, so few commit to it. The research is clear: meditation can transform not only our mental and emotional health but our physical health as well. And the best part? Just a few minutes a day is enough to start seeing benefits. So why not give it a try? Each session is an investment in a healthier, more centred you. Commenti

One of the most common questions that we receive about longevity is the research foundation we rely on to define strategies that can help us live better and longer. In fact, there are two questions I am often asked, and I’d like to address them in this newsletter: Why are there no specific medications for longevity? And if there aren’t any, what are the recommendations for living longer based on? To answer these questions, we need to introduce a few concepts that might seem complex but are essential to understand. Let’s start with the first question: Why don’t longevity medications exist? The approval process for a new drug is highly complex, and understanding this process helps explain why it’s so challenging to develop drugs that claim to “work” on longevity. Medical research for new treatments follows a rigorous pathway divided into multiple phases, each with a specific goal. First, we have preclinical studies: these represent the initial phase of research on new drugs or treatments, conducted before testing on humans to evaluate safety and efficacy. These studies take place in laboratories and are divided into two categories: in vitro (on isolated cells or tissues, to observe effects at a cellular or molecular level) and in vivo (on non-human animals, to assess how the treatment interacts within a complete organism). Once the preclinical studies are complete, the process moves to clinical trials, which unfold over three main phases, each with a distinct purpose. Phase 1 focuses on safety. A small group of participants, usually between 20 and 100 healthy volunteers or individuals with the condition being studied, receive a low dose of the treatment. This phase aims to ensure that the treatment is safe for humans and helps identify the optimal dosage. If Phase 1 is successful, the treatment progresses to Phase 2. Here, researchers look more closely at the treatment’s effectiveness while continuing to monitor safety. The number of participants increases: this phase helps confirm whether the treatment shows real benefits and provides more data on any side effects. The results from Phase 2 also guide the correct dosage for the next phase. Phase 3 is where the treatment is tested on a much larger scale. This phase typically involves several hundred to thousands of patients (between 1,000 and 3,000). Participants are randomly assigned to receive either the new treatment, a standard treatment, or a placebo. This setup, known as a randomized controlled trial (RCT), helps determine whether the new treatment is genuinely effective by comparing it directly with existing options. The data collected in Phase 3 are essential for proving the treatment’s safety and effectiveness, enabling it to be reviewed and approved by regulatory agencies like the FDA. The process of a randomized controlled trial (RCT) begins with carefully selecting participants who fit the specific characteristics needed for the study. For instance, if a new diabetes medication is being tested, the trial would recruit people diagnosed with diabetes who are willing to participate. Once the participants are chosen, they’re divided randomly into groups. This random assignment is what makes the study “randomized,” ensuring that each group is similar in most ways except for the treatment they receive. Randomized Controlled Trials (RCTs) are widely regarded as the gold standard in clinical research. By randomly assigning participants to either the intervention group or the control group, RCTs minimize bias and allow researchers to establish a clear cause-and-effect relationship between an intervention and its outcomes. This rigorous design helps ensure the reliability and validity of results, making RCTs essential for assessing the efficacy and safety of new treatments, therapies, and preventive measures. Finally, after the study is complete, researchers compare the results between the two groups. They look to see if those who received the new treatment showed real, measurable improvements compared to the control group. This comparison is crucial in determining whether the new treatment is effective and safe. Contenuto dell’articolo However, when it comes to longevity research, relying solely on RCTs becomes challenging. Studying the effects of treatments on lifespan requires observing outcomes over decades—sometimes 50 or 60 years, making it nearly impossible to conduct a realistic study within our lifetime. Additionally, both aging research and longevity itself often involves multiple factors, like diet, exercise, medications, and supplements, which work together in complex ways that make it difficult to measure the direct impact of any single intervention in one lifespan.[IG1] Another significant challenge in developing longevity-focused treatments is the lack of universally accepted biomarkers that can accurately measure aging, or the effectiveness of a treatment designed to slow it down. This is why regulatory agencies like the FDA in the United States, the EMA in Europe, and Swissmedic in Switzerland currently do not approve drugs solely intended to extend lifespan. These agencies focus on treatments that address specific diseases with clear diagnostic criteria, rather than on aging as a general process. Aging is not considered a medical condition or disease, and therefore does not qualify as a direct target for drug approval. So, if there aren’t direct medications for longevity, how do we define the best strategies, therapies, and interventions for a longer and healthier life? Here’s how we determine what might truly help us live better and longer. One approach is to study populations that naturally live long and healthy lives, such as those in Blue Zones—regions of the world with a high number of centenarians. Researchers analyze common factors among these people, like diet, lifestyle, and social connections, to identify habits and conditions linked to longevity. By observing these communities without interfering, scientists can gain insights into practices that promote healthy aging, providing valuable guidance for other cultures and lifestyles. It is important to note that recent research has cast doubts on the accuracy of some of the data collected in said Blue Zones and on the world’s oldest people and extreme patterns of longevity. Another method involves studying aging biomarkers, which are biological indicators that reflect a person’s biological age, like telomere length or levels of inflammatory proteins. Instead of following people for a lifetime, researchers monitor these biomarkers over shorter periods to assess the potential effects of treatments. This approach allows them to gather data on anti-aging effects without waiting decades for changes in lifespan. While there isn’t yet universal agreement on the most reliable biomarkers, this research offers a practical way to measure aging in the short term. Short-lived animals, such as mice, worms, and fruit flies, also serve as valuable models for longevity research. These animals share many biological processes with humans and have short lifespans, which allows scientists to study the effects of anti-aging treatments throughout their entire lives within a manageable timeframe. Studies on animals have highlighted promising interventions, like calorie restriction and certain compounds such as rapamycin or metformin, that seem to extend lifespan. Although these findings don’t always directly [IG2] apply to humans, they provide important clues for further research. Computational models and artificial intelligence (AI) are also becoming crucial in longevity science. With these tools, researchers can analyze vast genetic and clinical datasets, simulate the aging process, and predict how different treatments might impact it. In addition, some anti-aging strategies can be evaluated through shorter-term human studies, focusing on measurable changes in health markers like cardiovascular function or inflammation levels. For example, researchers can test how a specific diet or supplement affects inflammation or oxidative stress markers over weeks or months. Epidemiological studies offer another perspective by analyzing large population groups to identify associations between certain habits and longevity. Unlike randomized trials, these studies don’t alter variables directly, but they reveal patterns—such as the link between physical activity and longer life—that offer valuable guidance. Meta-analyses, which combine the findings of multiple studies, provide even clearer and more reliable insights into which interventions work best across different populations and settings. Finally, regenerative biology and medicine explore ways to repair or replace damaged cells and tissues. Although still experimental, techniques like cell therapy and tissue engineering hold exciting potential for slowing or even reversing some aging processes. While these methods don’t aim to extend lifespan directly, they focus on enhancing quality of life and health in older age. As aging is multifactorial so too is the approach to longevity. Together, these approaches create a comprehensive framework for understanding and developing strategies to support a longer and healthier life. The "Unlock Longevity" newsletter is my personal contribution to exploring, but most importantly simplifying and making accessible, the themes, techniques, and strategies related to longevity. If you believe these insights could benefit your network, feel free to share this article! This article reflects my personal views and is not intended to replace professional medical advice.

When people ask me why longevity has become "trendy" today, I believe there are five key developments that have contributed to its growing popularity. First and foremost is the aging population. We live in a world where more people are reaching advanced ages, which has opened up extraordinary opportunities not only in traditional medicine but also in what we might call elective medicine. The business and investment sectors have recognized enormous potential here. Their entry into this field has led to significant technological advancements, particularly in diagnostics. As we've discussed in previous newsletters, diagnostics have evolved tremendously, enabling breakthroughs that were unimaginable just a few years ago. Then came an unexpected event: COVID-19. While the pandemic brought global challenges, it profoundly impacted people's awareness of their own health. COVID taught many how much they can influence their well-being, introducing the general public to concepts that were previously little known, such as the "immune system," along with more specific terms like "genetics" and "epigenetics." The final and most crucial step in this journey, while all this was happening, has been the profound understanding of 2 important layers of human biology; genetics and epigenetics. We've begun to understand that we are not entirely bound by our genetic makeup and that, through our daily choices, we can influence how our genes are expressed. When it comes to genetics and epigenetics, this represents the most significant revolution in recent years. I recall an interview I conducted several years ago with a renowned geneticist. I asked the expert how much of our health is influenced by our genetics? This was only ten years ago, and she confidently responded that genetics was undoubtedly the most crucial factor. It's widely accepted that genetics accounts for, at most, 20-30% of our health outcomes. So, what exactly is impacting in such significant way our health traits? Well, epigenetics - the mechanisms that are profoundly shaping our health in response to environmental and lifestyle factors. On this topic, I feel it's essential, as always, to stay true to the mission of this newsletter: simplifying complex concepts for better understanding. It's important to make a clear distinction between genetics and epigenetics. Whenever I speak in public, I always ask the audience whether this concept is clear to them, and even today, I still see many hands raised, signaling that the difference between genetics and epigenetics remains unclear to many. First of all, let's dive into the fascinating concept of the human genome. The human genome refers to the complete set of hereditary genetic information necessary to build and operate the human body. Within the genome lies all the information that enables us to live, think, move, and act. This genetic information is stored in our DNA, primarily located in the cell's nucleus. DNA contains instructions encoded in its sequence of nitrogenous bases, which guide the synthesis of proteins. Therefore, gene expression is the process by which the information encoded in a gene is used to produce a protein or RNA molecule. It is how genetic instructions are "read" and translated into the building blocks that allow cells and organisms to function. In 2003, the Human Genome Project revealed key insights about our DNA. Humans have approximately 20,000 genes and share 99.9% of their genetic makeup, with only 0.1% difference (about 3 million genetic "letters") accounting for variations, known as genetic polymorphisms. These are differences in the genetic code that can influence traits or susceptibility to diseases. Complex diseases and traits — like diabetes, heart disease, or obesity — are shaped by a combination of genetic variants and environmental factors, such as lifestyle and behavior. Whether a complex disease develops depends on the balance between risk factors and protective factors, which can be genetic or environmental or both in origin. Contenuto dell’articolo When it comes to the environment, let’s unlock the incredible science of Epigenetics. Epigenetics, means ‘on top of’ genetics. It studies the mechanisms that affect how our genes behave, investigating the regulatory mechanisms of gene expression. In simpler terms, epigenetics acts like a control system, deciding which genes should be turned on, off, or adjusted in a specific cell. Epigenetic changes occur through processes like DNA methylation, histone modification, and RNA-associated regulation, which alter how genes are expressed and are highly influenced by factors like diet, stress, pollution, and exercise. Importantly, Epigenetics is closely linked to wellbeing, aging and diseases, and are affected by our environment and lifestyles. Imagine your genetics as the script of a play. This script contains all the characters, dialogues, and stage directions—the complete storyline written by the playwright. It represents your DNA, the fixed instructions that outline the potential of the performance. Now, think of epigenetics as the director's interpretation and the actors' performances. While the script provides the foundation, the way the director chooses to bring it to life can vary immensely. The director decides which scenes to emphasize, which emotions to highlight, and how the actors should portray their characters. The actors add their own nuances, timing, and expressions to the roles. In this metaphor, the script (genetics) remains the same, but the actual performance (epigenetics) can differ each night depending on various factors like the director's vision, the actors' choices, and the audience's reactions. This means that even with the same script, the play can be a comedy, a tragedy, or anything in between, based on how it's executed. In practical terms, while your genetic code provides the foundational script, your lifestyle choices—such as diet, exercise, stress management, and sleep—are like the director's and actors' decisions that shape how that script is brought to life. Epigenetics is the dynamic process of interpreting and expressing the script, ensuring the performance resonates with the environment and circumstances. Remarkably, the epigenome can be modified, allowing us to slow down the aging clock—or even turn it back—through a growing arsenal of discovered and developing molecules. These include polyphenols, sirtuin activators, senolytics, senotherapeutics, and much more. Your epigenetic and genetic makeup go hand-in-hand, and while we can’t change our genetics, epigenetic is dynamic and modifications can actually affect how your genes are expressed along with your aging process. For example, genes can double the risk of heart disease, but a good lifestyle cuts it in half. But how did we come to understand whether our traits are influenced more by genetic or environmental factors? Among the most fascinating studies on this topic are those conducted on identical twins, who are unique in nature as they share the exact same DNA. Genetically speaking, identical twins are essentially clones, resulting from the fertilization of a single egg by a single sperm. At a later stage, the primitive cellular mass divides into two smaller masses, each with identical DNA but destined to develop into two separate individuals. Unlike identical twins, fraternal twins do not share the same DNA because they originate from different eggs fertilized by different sperm. Twin pairs typically grow up in the same environment, sharing the same family and often interacting with the same social circles. However, there's a key distinction: while identical twins share 100% of their DNA, fraternal twins share only about 50%. Studies on twin pairs have revealed a heritability coefficient of approximately 0.20 to 0.30. These findings, first observed in studies conducted in the late 1800s, have been confirmed by more recent research. Such studies have been instrumental in highlighting the interplay between genetic and environmental factors in shaping who we are. In the case of life expectancy, a heritability coefficient ranging between 0.15 and 0.30 indicates that a significant portion of the differences between individuals is driven by non-genetic factors. Another study, promoted by Calico—a Google-affiliated company whose name stands for California Life Company—further confirmed that the heritability of life expectancy is minimally influenced by genetic makeup. In other words, life expectancy is largely independent of our genetic inheritance. What's fascinating is how much your lifestyle influences this "performance." Various lifestyle factors have been identified as capable of altering epigenetic patterns. These include your diet, physical activity, body weight, and exposure to harmful substances such as tobacco or alcohol. Environmental factors like pollution, stress, and even sleep quality also play a significant role. Other influences include exposure to UV radiation, chronic inflammation, chemical contaminants in food or water, and even social interactions or mental health. Each of these factors can influence how your genes are expressed, effectively "rewriting" parts of your epigenetic score in ways that can either enhance health or increase the risk of disease. This underscores the incredible importance of everyday choices in shaping your long-term health and well-being. Another fascinating study, published in BMJ Evidence-Based Medicine by researchers from the University of Edinburgh and Zhejiang University, explored the combined effects of genetics and lifestyle on human lifespan. Using data from over 353,000 participants in the UK Biobank cohort, the study revealed that while genetics plays a role in longevity—accounting for roughly 20-30%—modifiable lifestyle factors have a far greater impact. Key lifestyle factors identified included smoking, alcohol consumption, physical activity, body weight, sleep duration, and diet. Most notably, the study highlighted that adopting healthy behaviours can significantly mitigate genetic risks associated with shorter lifespans. In other words, even those with less favorable genetic profiles can improve their longevity through proactive lifestyle choices. The findings emphasize that genetics is not destiny. Lifestyle factors such as avoiding smoking, staying active, maintaining a balanced diet, optimizing sleep, and limiting alcohol are powerful tools for influencing the aging process and consequently our longevity. This research highlights the vital impact of daily habits on our well-being and presents an empowering perspective: we have more control over our health and aging than we ever thought possible. In other words, we can actively regulate or “manipulate” the way we age and enhance healthspan by using strategic and personalized interventions. Now that we've clarified the difference between genetics and epigenetics, in the next newsletter we will explore the power of genetic and epigenetic screening. These tests are an integral part of Phase 1 in our longevity cycle, which, as a reminder, consists of diagnostics, interventions, and follow-up. The "Unlock Longevity" newsletter is my personal contribution to exploring, but most importantly simplifying and making accessible, the themes, techniques, and strategies related to longevity. If you believe these insights could benefit your network, feel free to share this article! This article reflects my personal views and is not intended to replace professional medical advice. Commenti

Every day, new information emerges about GLP-1 Receptor Agonists—some overwhelmingly positive, others raising critical concerns. These drugs are rapidly becoming some of the most talked-about treatments in medical history. But what exactly are GLP-1 Receptor Agonists, and why are they causing such a stir? GLP-1 Receptor Agonists mimic the natural hormone glucagon-like peptide 1 (GLP-1), which has been used for decades in diabetes treatment. Today, these medications—marketed under brand names like Ozempic, Wegovy, and Mounjaro—are gaining immense popularity, especially in the United States (though not exclusively, of course). Initially developed for diabetes management, these drugs have since demonstrated potential benefits for conditions such as obesity, cardiovascular disease, and even neurodegenerative disorders. The versatility of GLP-1 drugs is one of the reasons behind their rapid rise in use. For instance, in April 2023, the GLP-1 agonist tirzepatide (Mounjaro) showed promising results for treating conditions such as sleep apnea and breathing disorders. Additionally, evidence suggests that GLP-1 drugs may help reduce the risk of chronic kidney disease, with ongoing trials exploring their potential for managing liver disease, substance use disorders, and addictions. Obese patients using these medications report fewer heart attacks and strokes, benefits that appear independent of the amount of weight lost. In one notable study involving over 17,600 overweight participants from 40 countries, those taking semaglutide lost an average of 10% of their body weight and experienced a 20% reduction in serious cardiovascular events. Let’s simplify how these drugs work. GLP-1 is a short-lived hormone released in the gut after eating. Once in the bloodstream, it performs several vital functions: · Regulating blood sugar by stimulating insulin release and suppressing glucagon production. · Slowing gastric emptying, which promotes a feeling of fullness. · Acting on the brain's hypothalamus to regulate hunger, satiety, and reward pathways linked to cravings. Contenuto dell’articolo This mechanism explains why GLP-1 drugs are highly effective in reducing appetite and aiding weight loss. But why are we discussing this drug in a newsletter about longevity? Well, not only because obesity and cardiovascular diseases are strongly linked to mortality, but also because these drugs have shown powerful anti-inflammatory properties! Their anti-inflammatory properties play a crucial role in mitigating chronic diseases. GLP-1 drugs lower levels of inflammatory molecules, such as cytokines, which are known to drive aging and age-related illnesses. This reduction in inflammation may also contribute to secondary benefits, such as improved skin health, relief from arthritis, and better kidney and liver function. One of the most exciting avenues for GLP-1 drugs is their potential use in combating neurodegenerative diseases. Recent research published in the British Medical Journal analyzed data from over 110,000 adults in the Korea National Health Insurance Service Database. The study found that patients taking diabetes medications, including GLP-1 agonists, experienced a significant reduction in the risk of developing dementia, including Alzheimer’s disease and vascular dementia. Although this study initially focused on SGLT2 inhibitors—a different class of diabetes drugs—the findings suggest a shared potential for GLP-1 drugs due to their anti-inflammatory and neuroprotective effects. These properties make GLP-1 agonists promising candidates for further research into conditions like Alzheimer’s and Parkinson’s disease. Unsurprisingly, GLP-1 drugs have ignited a massive business boom. Originally designed for diabetes management, their expanding applications for weight loss, cardiovascular health, and neurodegenerative diseases have positioned them at the forefront of modern medical innovation. A report by the Financial Times highlights the staggering market potential of these drugs, projecting that their sales could reach $150 billion by 2030. With over 100 million Americans and 1 billion people globally affected by obesity, the demand for these medications is immense. Pharmaceutical giants like Eli Lilly and Novo Nordisk are investing billions in research and development to dominate this market. However, this unprecedented growth has also sparked debates about affordability and accessibility. In the United States, lawmakers are considering proposals to expand access to GLP-1 drugs—a move that could cost healthcare systems tens of billions of dollars annually. While GLP-1 drugs hold incredible promise, their rise has been accompanied by an "Instagram effect." Social media platforms are flooded with testimonials and influencer posts promoting these medications as miraculous weight-loss solutions. This portrayal risks trivializing their medical purpose, encouraging misuse, and spreading misinformation about their capabilities and limitations. Additionally, the growing hype has fueled a surge in illegal imports. A recent confiscation by Swiss customs authorities revealed that a significant portion of smuggled goods consisted of weight-loss drugs, including GLP-1 agonists. This highlights the need for better public education on the proper use of GLP-1 drugs, as well as stricter enforcement to combat illegal imports. What are the side effects of GLP-1 drugs (besides the fact that their efficacy depends on continued use)? Reported side effects include nausea, vomiting, diarrhoea, and constipation. In more serious cases, users have experienced gallbladder issues such as gallstones. Additionally, there are concerns about rare risks, including pancreatitis and a potential link to thyroid tumors observed in animal studies, though this remains unconfirmed in humans. Another significant concern is the loss of muscle mass that sometimes accompanies weight loss. This can lead to complications such as balance issues, reduced mobility, and sagging skin. To mitigate these effects, it is essential to combine GLP-1 treatments with resistance training, a protein-rich diet, and other lifestyle interventions. GLP-1 drugs represent a groundbreaking leap in treating obesity, diabetes, and related conditions. However, their success depends on responsible use, patient education, and a comprehensive approach that integrates medication with sustainable lifestyle changes. On their ability to improve obesity in the long term, I remain astounded by the fact that, despite all the medications we have, the prevalence of diabetes has doubled globally in the past 30 years. The Lancet recently reported that diabetes rates rose from 7% in 1990 to 14% in 2022. This trend underscores that while medications like GLP-1 drugs can be powerful tools, they must be part of a broader strategy that includes lifestyle changes, prevention, and public health education. As their popularity continues to soar, it’s crucial to ensure that GLP-1 drugs are seen not as a "magic potion" but as one tool among many in the pursuit of better health. Only by combining these treatments with a focus on prevention, physical activity, and balanced nutrition can we hope to address the global challenges of obesity and chronic disease effectively. The "Unlock Longevity" newsletter is my personal contribution to exploring, but most importantly simplifying and making accessible, the themes, techniques, and strategies related to longevity. If you believe these insights could benefit your network, feel free to share this article! This article reflects my personal views and is not intended to replace professional medical advice. Commenti

Welcome to the latest edition of Unlock Longevity, where science meets inspiration to empower healthier, longer lives. I’d like to introduce the first issue in a special series of newsletters that is brought to you in collaboration with the Scientific Committee of Clinique La Prairie. Together, we delve into groundbreaking research and innovations that are shaping the future of healthy aging. The Clinique La Prairie Scientific Committee brings together world-renowned researchers and clinicians, whose expertise spans diverse fields such as medicine, nutrition, biochemistry, immunology, genetics, and pharmacology. This series takes the form of exclusive interviews between myself and the experts on the Scientific Committee. Through these conversations, we will uncover the cutting-edge science and personal insights driving their pioneering work. Our first contributor is Dr. Justin Carrard, a Sport and Exercise Physician and accomplished researcher at the Department of Sport, Exercise and Health at the University of Basel, Switzerland. Dr. Carrard’s research focuses on the metabolic determinants of healthy aging and active living. Passionate about the power of exercise to enhance longevity, treat chronic diseases, and prevent injuries, he brings invaluable insights into topics like lipid metabolism, overtraining, and musculoskeletal health. In the coming weeks, you can look forward to an array of enlightening articles that marry the rigor of scientific discovery with practical applications for your health journey. Can you give us an overview of the overall benefits of regular physical activity on both physical and mental health? Regular physical activity improves physical and mental health globally by strengthening muscles and bones, boosting immune function, reducing the risk of chronic cardiometabolic diseases, and reducing stress, anxiety, and depression while improving mood and cognitive function. Why is exercise often said to be "better than medicine" when it comes to promoting long-term health and longevity? Exercise is considered one the most potent medicines because it simultaneously acts on different body systems, while drugs usually act on a few specific sites of the body (called receptors). How much physical activity should an average person aim for each week to achieve minimum health benefits? The World Health Organization recommends that adults aim for a minimum of 150–300 minutes of moderate-intensity aerobic activity or 75–150 minutes of vigorous activity per week, along with strength training exercises twice weekly. Are resistance or weight training exercises as important as aerobic exercises? Why? Both aerobic (endurance) and strength training are essential and should be done as they act differently on the body. For instance, endurance and strength training tend to reduce blood glucose levels using different (synergic) ways. What are some generic but effective exercise tips you can share for beginners? Start slow and focus on consistency rather than intensity. Choose activities you enjoy, set realistic goals, incorporate rest days, and gradually increase duration and intensity as your fitness improves. What is cardiorespiratory fitness, and why is it considered a critical component of overall health? Cardiorespiratory fitness refers to the ability of the lungs, heart, blood vessels and muscles to deliver and use oxygen to produce energy during exercise. This is arguably one of the most potent proxy (markers) we have globally, and the American Heart Association even recommends assessing it as a new vital sign in clinical practice. What are the specific benefits of improving cardiorespiratory fitness, particularly as it relates to longevity? Improving cardiorespiratory fitness reduces the risk of developing chronic diseases, the mortality linked to specific diseases (e.g. cardiometabolic diseases or cancer) and the global mortality. Ultimately, being fitter enables one to live a longer and healthier life. Is there scientific evidence linking regular physical activity to increased lifespan or reduced age-related risks? Yes, there is plenty of scientific evidence demonstrating that being regularly physically active leads to a lower risk of developing a chronic disease and dying of such a disease. In addition, unfit people who become fit reduce their risk. Why is VO2max such an important metric in assessing fitness levels and longevity? VO2max is used to assess cardiorespiratory fitness, and both terms are often used interchangeably. It reflects the body's capacity to uptake, transport, and use oxygen to produce energy to exercise. As written above, it is a crucial global health and longevity marker. Can you explain in simple terms how VO2max works and how it reflects a person's health and performance potential? VO2max is the maximum amount of oxygen the body uses to produce energy and, therefore, movements. It reflects the ability of the lungs, heart, blood vessels and muscles to deliver and use oxygen to produce energy during exercise. Does exercise intensity influence VO2max, and if so, how? Regular bouts of high-intensity exercise, for instance, under the form of high-intensity interval training, can lead to a significant improvement of VO2max. On average, VO2max can be increased by 10-20% with adequate training, the rest being genetically determined. How does exercise intensity impact mortality and longevity? Is there a "sweet spot" for maximizing benefits without overtraining? Following the WHO recommendations regarding physical activity is a safe method to improve one's health and optimize longevity. It has been shown that doing twice as much as the WHO recommendations leads to even more health benefits. However, it is possible to train too much and land in a state of chronic fatigue, which is called either non-functional overreaching or overtraining syndrome. The difference between syndromes lies mainly in the time needed to fully recover, with overtraining syndrome needing months to sometimes even years to recover. However, it is essential to remember that these syndromes remain relatively rare and affect very ambitious sportspeople who train a lot. In our modern societies, most people have the opposite problem, i.e. they don't move enough. How would you design the ideal HIIT training session for someone who is relatively healthy but has limited time? There is no one-size-fits-all HIIT protocol, but rather general principles to follow. A good start could be to repeat six times 1 minute of intensive exercise with 1 minute of rest in between. With time, the number of repetitions can be increased. What should the ultimate goal of a well-structured HIIT program be in terms of health and fitness outcomes? The idea of HIIT is to spend more time on the training volume close to the intensity reached at VO2max, thereby optimizing the effect of training in a limited amount of time. The ultimate goal is to improve VO2max, well-being and healthspan. Can you explain the difference between active recovery and passive recovery? How do you determine which is more appropriate? Whether the recovery should be passive or active in a HIIT session depends on the recovery duration between two intensive bouts. It is usually recommended to do an active recovery for a recovery period longer than 2-3 minutes. This enables maintaining the heart rate at a certain level during the recovery and, therefore, reaching the desired heart rate range during the next intensive bout. On the contrary, short periods of recovery (less than 2 minutes) should instead be passive to give the body time to recover to be ready for the next intensive bout. For busy professionals who struggle to find time, can you suggest a 30-minute workout routine that maximizes health benefits while being time-efficient? A balanced 30-minute routine could include 5 minutes of dynamic warm-up, 20 minutes alternating between 1-minute high-intensity effort and 1 minute of passive recovery (walking), and 5 minutes of cool-down (low-intensity jogging). Is it true that as we age, we need to be more cautious about the intensity of our HIIT workouts? As we age, VO2max tends to lower, and it is indeed wise to adapt a HIIT session to the current state of VO2max (or fitness). So, the absolute intensity could be lowered, but the relative intensity in terms of percentage of VO2max would remain relatively similar. How much rest or recovery time should there be between HIIT sessions to avoid injury or overtraining, especially for older adults? Allow 48 hours of relative rest between HIIT sessions to ensure adequate recovery and reduce the risk of fatigue or injury. With relative rest, it is meant not to train at a high intensity in this period. However, low-intensity training can be done. What are your thoughts on hypoxic training (training in reduced oxygen conditions)? Hypoxic training can improve endurance and repeated sprint capacity by adapting the body to function with reduced oxygen availability. Still, it should be done cautiously and under supervision, especially for untrained individuals. Can you explain what hypoxic training is and how it might benefit someone looking to improve their endurance or health outcomes? Hypoxic training involves exercising or living in environments with reduced oxygen availability to enhance physical performance and adaptation. There are two main types of hypoxic training: Live High, Train High: Individuals consistently live and train at high altitudes, exposing themselves to low oxygen levels. This approach stimulates the production of red blood cells and haemoglobin, improving oxygen-carrying capacity. Live High, Train Low: Participants live at high altitudes to benefit from hypoxic adaptation but train at lower altitudes where oxygen is sufficient to maintain high-intensity performance. This method combines physiological adaptation with optimal training intensity. Hypoxic training creates an oxygen deficit, prompting the body to produce more erythropoietin (EPO), stimulating red blood cell production. This increases oxygen delivery to muscles during exercise. It also enhances mitochondrial efficiency, vascular growth, and aerobic capacity. While hypoxic training improves endurance, its effectiveness depends on the duration, intensity, and individual's baseline fitness. Elite athletes widely use it, but it requires careful management to avoid fatigue or health risks. Are there specific populations or age groups that might benefit more from hypoxic training? Athletes preparing for endurance sports or high-altitude events and individuals looking to improve cardiovascular efficiency may benefit most from hypoxic training. There is also growing data showing that some patients (for instance, with obesity) could benefit from hypoxic training. For someone who is just starting out or is intimidated by intense exercise, what's a simple, realistic way to get started and build consistency? Start with low-intensity activities like walking or light yoga, set small and realistic goals, establish a consistent schedule, and gradually progress as your confidence and stamina build. The "Unlock Longevity" newsletter is my personal contribution to exploring, but most importantly simplifying and making accessible, the themes, techniques, and strategies related to longevity. If you believe these insights could benefit your network, feel free to share this article! This article reflects my personal views and is not intended to replace professional medical advice.

There is a deeply rooted belief that guides us at Clinique La Prairie: the importance of a medical approach to longevity. Let me explain further: in a longevity landscape often dominated by miraculous solutions and fantastical promises, we firmly believe that having 50 doctors who keep us grounded and ensure we always follow a scientific, evidence-based approach is essential. (Let me remind you of CLP's four pillars of longevity: Medical—first and foremost, Nutrition, Wellbeing, and Movement). Too often, the pursuit of sensational solutions leads us to forget the fundamentals of longevity. This is why I am delighted to introduce Dr. Adrian Heini. An FMH Specialist in Internal and General Medicine, as well as a Specialist in Preventive Medicine. With over twenty years of service at the Clinique and since 2020, as our Medical Director, leading our Medical Pillar with vision and dedication, Adrian brings invaluable expertise to the conversation. With him, we will discuss Traditional Biomarkers and Longevity. It’s a perfect opportunity to remind ourselves how essential “traditional medicine” and the tests typically performed in a thorough, routine check-up remain as part of any longevity process. 1. Adrian, what are "traditional" biomarkers, and why are they important in assessing health and longevity? Traditional biomarkers are measurable indicators used in medicine and biology to assess health, diagnose diseases, or monitor the effects of treatments. These biomarkers are often found in blood, urine, or other body fluids and provide information about the body's physiological state. Examples can be cholesterol levels and blood sugar for cardio metabolic risk. Liver and kidney function for an appreciation of elimination potential and others. 2. How do traditional biomarkers differ from newer ones, such as genetic or epigenetic biomarkers? Traditional biomarkers have long been the cornerstone of medical diagnostics, offering extensively studied and validated indicators of health and disease across large populations. Their reliability and acceptance have made them a standard in clinical practice. However, newer biomarkers, such as genetic and epigenetic ones, are redefining our approach to predicting and understanding health. These innovative markers have the potential to identify risks and events far earlier than traditional methods, paving the way for more personalized and preventative care. At Clinique La Prairie, we are at the forefront of these medical advances, integrating the latest scientific developments into our holistic approach to health and longevity. While these newer biomarkers are not yet widely established in clinical practice and still require validation in large-scale patient cohorts, we believe they are critical. What is considered novel today will soon become the norm, and we are committed to leading this transition, ensuring our clients benefit from cutting-edge tools to enhance their health and well-being. 3. Which blood biomarkers are most relevant to predicting longevity and overall health? In my opinion, it is a mix of traditional markers and novel markers, such as antioxidant profiles and epigenetic parameters. 4. Can you explain the significance of commonly measured markers such as cholesterol, triglycerides, and glucose levels in relation to aging? Markers such as cholesterol, triglycerides, and glucose levels are critical indicators of metabolic health and play a significant role in the aging process. When these markers are elevated, they often signal the presence of metabolic syndrome—a condition characterized by visceral fat accumulation, high blood pressure, high cholesterol, and insulin resistance. Metabolic syndrome is strongly linked to an increased risk of comorbidities, including diabetes, cardiovascular diseases, and liver disorders, all of which accelerate aging and contribute to overall decline in health. 5. What role do inflammation markers, such as C-reactive protein (CRP), play in assessing age-related diseases? CRP reflects the inflammatory state - it has a predictive value within the very low range (you need to dispose of the high-sensitive CRP test). If CRP is high, an acute infection is usually present. 6. Are there specific markers in blood work that can indicate early signs of chronic diseases such as cardiovascular disease or diabetes? To detect early stages of chronic diseases like cardiovascular disease or diabetes, specific blood markers are particularly valuable. For instance, an insulin sensitivity test (HOMA) helps assess insulin resistance, which is a key precursor to diabetes. Additionally, high-sensitivity C-reactive protein (hsCRP) is a marker of inflammation that can signal early cardiovascular risk. Looking ahead, ceramides—a type of lipid—are emerging as a potentially more precise indicator of cardiovascular health compared to the traditional cholesterol profile and may become a standard biomarker in the near future. 7. Why is chronic inflammation often referred to as a hallmark of aging? Because we know now that low-grade inflammation represents stress to the cell and decreases the body potential to clean for senescent cells (waste); in turn, senescent cells release inflammatory substances. 8. Which traditional tests can measure systemic inflammation, and how can they inform longevity strategies? High sensitivity CRP is one, but we need tests that are earlier precursors of chronic inflammation: We use the genetic profile of an individual to know the genetic predisposition of patients, we also use an epigenetic stress test ( that can favorably or negatively evolve) other standard methods are currently developed. 9. What is the role of radiology in longevity assessment? Radiology plays a critical role in longevity assessment by aiding in both disease prevention and the identification of degenerative changes in the body. Through advanced imaging techniques such as ultrasound, CT scans, and MRI, radiology allows for early screening of diseases and the detection of age-related degeneration in structures like bones, joints, and brain morphology. This early identification helps implement timely interventions to preserve health and improve longevity outcomes. 10. Can imaging techniques, such as CT scans, MRIs, or DEXA scans, provide insights into aging-related changes in the body? CT scanning would detect lung diseases, tumors and vascular pathologies; DEXA scans can identify osteoporosis, but also changes in body composition, that closely relate to aging. MRIs can identify grey and white matter degeneration and atherosclerotic vessel modifications. 11. How does bone density testing relate to longevity, particularly in aging populations? Bone density testing, such as DEXA scans, assesses bone mineral density to identify risks for osteoporosis and fractures, which are critical concerns in aging populations. Low bone density increases the likelihood of fractures, particularly hip fractures, which are associated with decreased mobility, higher morbidity, and shorter lifespan. Maintaining strong bones through early detection and interventions like diet, exercise, and medications can significantly enhance quality of life and longevity 12. How important are tests like blood pressure monitoring, electrocardiograms (ECG), or cardiac imaging in assessing long-term health risks? Cardiological assessments, such as blood pressure monitoring, electrocardiograms (ECG), and cardiac imaging, are essential for screening and monitoring cardiovascular health. Given that cardiovascular disease is one of the leading age-related morbidities, these tests play a vital role in early detection, risk assessment, and ongoing management of heart-related conditions, helping to mitigate long-term health risks and improve overall longevity. 13. Which biomarkers are most reflective of a person’s nutritional status, and how do they relate to longevity? In clinical nutrition, biomarkers such as albumin are commonly used to detect malnutrition. However, when evaluating optimal nutritional status for disease prevention and longevity, a more comprehensive approach is needed. At our clinic, we assess a combination of biological profiles, including antioxidant potential, heavy metal levels, and fatty acid composition. These markers provide valuable insights into nutrient balance, oxidative stress, and potential toxic exposure, all of which are critical for promoting long-term health and longevity. 14. How can markers such as vitamin D levels provide insight into a person’s health and aging trajectory? Markers such as vitamin D levels, particularly vitamin D3, offer valuable insights into a person’s overall health and the challenges associated with aging. While vitamin D is not a direct marker of longevity, it is a critical indicator of health that highlights potential vulnerabilities, particularly in older populations. Vitamin D3 is essential for bone health, playing a key role in calcium absorption and bone mineralization. Deficiencies can accelerate conditions like osteoporosis and increase the risk of fractures, which significantly impact mobility and quality of life in aging individuals. In terms of muscle function, adequate vitamin D levels support muscle strength and help reduce the risk of falls, a major cause of injury and hospitalization in older adults. Furthermore, vitamin D is crucial for a well-functioning immune system, aiding in the fight against infections and helping to reduce inflammation—one of the primary drivers of aging and chronic disease. 15. How often should these traditional biomarkers be monitored to ensure early detection of potential age-related health risks? Once a year would be optimal. 16. Are there age-specific thresholds for these markers, or should they be personalized for each individual? Both age-specific thresholds and personalized approaches are important for biomarkers. While age-based ranges account for physiological changes, individual factors like genetics, lifestyle, and health conditions require tailored targets to optimize health and longevity. 17. Do you think traditional biomarkers will continue to play a significant role in longevity science, or will they be gradually replaced by newer technologies? Yes! 18. For someone aiming to improve their longevity, what are the key blood tests or radiological assessments you would recommend as a starting point? For someone aiming to improve their longevity, the focus should be on comprehensive assessments that provide insights into overall health, early detection of potential risks, and prevention of chronic diseases. As a starting point, the following blood tests and radiological assessments are recommended: Key Blood Tests: Complete Blood Count: Provides an overview of overall health and can detect infections, anemia, and immune system issues. Lipid Panel: Assesses cholesterol levels to evaluate cardiovascular health. Fasting Blood Glucose: Monitors blood sugar levels and assesses risk for diabetes and metabolic syndrome. Liver and Kidney Function Tests: Evaluates organ health and detects early signs of dysfunction. Vitamin D Levels: Identifies deficiencies that can affect bone health, immune function, and inflammation. Inflammatory Markers: Indicates levels of chronic inflammation, a key driver of aging and chronic disease. Thyroid Panel: Screens for thyroid dysfunction, which can impact metabolism and energy levels. Hormonal Profile: Monitors hormonal balance, which is crucial for energy, mood, and aging. Nutritional and Mineral Levels: Assesses nutritional deficiencies that can affect energy, cognition, and cellular repair. Oxidative Stress Markers: Evaluates oxidative damage and antioxidant capacity. Genetic and Epigenetic Markers: Helps identify predispositions to certain diseases and the biological age of cells. Radiological Assessments: Body Composition Analysis: Evaluates muscle mass, fat distribution, and overall body composition, which are key indicators of metabolic health. Assesses bone health and identifies early signs of osteoporosis. Carotid Intima-Media Thickness: Screens for early signs of atherosclerosis and cardiovascular disease. Low-Dose Chest CT: Detects early signs of lung abnormalities or cancer. MRI of the Brain: Identifies early structural changes that could signal neurodegenerative risk. In addition to blood tests and radiological assessments, functional tests provide dynamic insights into how well the body is performing and adapting, offering a deeper understanding of overall health and longevity. These tests and assessments provide a comprehensive baseline for understanding one’s health and potential risks. At Clinique La Prairie, we emphasize a tailored approach, ensuring these diagnostics align with individual health profiles, lifestyle, and longevity goals. Regular monitoring and follow-ups based on these results can guide personalized strategies to optimize health and extend both lifespan and healthspan. Many thanks to you Adrian! The "Unlock Longevity" newsletter is my personal contribution to exploring, but most importantly simplifying and making accessible, the themes, techniques, and strategies related to longevity. If you believe these insights could benefit your network, feel free to share this article! This article reflects my personal views and is not intended to replace professional medical advice.

As we prepare to take a pause for the Christmas holidays, I am delighted to share a captivating scientific article recently published by Clinique La Prairie’s Innovation Team, in collaboration with our Scientific Committee. You will find the full article and references at the end of this newsletter. The research addresses a subject that is both vital and often underestimated: longevity and brain health. Titled “Maintaining Brain Health Across the Lifespan”, this publication explores the intricate factors that govern brain well-being, offering valuable insights into the steps we can take to preserve its vitality over time. Notably, this groundbreaking work laid the foundation for our Brain Potential Program, a pioneering offering that remains at the forefront of global innovation, reflecting Clinique La Prairie’s ongoing commitment to advancing science and health. The human brain is an extraordinary organ—a sophisticated network of billions of neurons and trillions of connections that orchestrate our every thought, emotion, and action. It shapes our memories, drives our creativity, and enables us to solve problems, adapt to challenges, and interact meaningfully with the world around us. Thanks to its unique ability for neuroplasticity, the brain continually reorganizes and strengthens itself in response to learning, lifestyle, and environment, embodying one of nature’s most impressive feats. Our team draws on Gorelick et al.’s definition of brain health as the “optimal capacity to function adaptively in the environment,” which encompasses three essential domains: Thinking, Moving, and Feeling. Aging, often associated with cognitive decline, need not be synonymous with brain deterioration. The concept of Optimal Aging emphasizes the preservation of cognitive function and the absence of disease, even as we grow older. Central to this idea is Cognitive Reserve—the brain’s remarkable ability to adapt to age-related changes or damage by accessing alternative networks or pathways. This explains why individuals with similar levels of brain pathology, such as Alzheimer’s, can experience vastly different degrees of cognitive impairment. Cognitive Reserve is built throughout life and influenced by key factors, such as education and lifelong learning, which strengthen cognitive resilience; mental and social engagement, like puzzles, reading, or mastering new skills; physical exercise, which supports neuroplasticity and vascular health; and healthy lifestyle choices, including proper nutrition, sufficient sleep, and stress management. The more Cognitive Reserve we accumulate, the better equipped our brain is to withstand the challenges of aging. Over a lifetime, the brain undergoes profound changes at the molecular, cellular, and systemic levels. These processes, often referred to as the “hallmarks of brain aging,” include energy production issues in cells (mitochondrial dysfunction), DNA damage, inflammation, difficulties clearing cellular waste, and impaired oxidative stress response. Together, these mechanisms pave the way for neurodegenerative diseases, characterized by the buildup of abnormal proteins—such as amyloid-beta and tau—in critical memory regions like the hippocampus. The glymphatic system, which removes waste from the brain during deep sleep, plays a crucial role here. When this system falters—often due to poor sleep or cardiovascular problems—the brain becomes less efficient at clearing these harmful proteins, accelerating neurodegeneration. Structural changes also occur as we age: grey and white matter volume gradually decrease, especially after age 50, with pronounced losses in regions vital to memory, learning, and executive function. These changes often correspond to declines in processing speed, working memory, and executive abilities, while crystallized intelligence—skills like vocabulary and general knowledge—remains largely stable. To maintain brain resilience and slow the aging process, the LiMEE framework introduces a holistic, science-backed approach. It focuses on Lifelong, Modifiable, Endogenous, and Exogenous factors, highlighting five core principles: risks like poor diet, inactivity, and chronic inflammation compromise brain health; their impact is cumulative over a lifetime; greater exposure leads to greater risk; addressing these risks through preventive strategies preserves brain vitality; and, finally, these mechanisms interact, creating an interconnected web of influences. Among these factors, nutrition stands out as one of the most influential. Diets rich in anti-inflammatory foods—such as fruits, vegetables, whole grains, nuts, and oily fish—are linked to better cognitive performance and lower dementia risk. Conversely, processed foods, refined sugars, and excess red meat provoke low-grade inflammation, a key driver of brain aging. The Mediterranean diet, with its emphasis on plant-based foods, fish, and olive oil, has been shown to enhance cognitive function and reduce Alzheimer’s risk. Polyphenols from sources like green tea and spices such as turmeric may further offer neuroprotective effects, reducing oxidative stress and slowing age-related brain changes. We will deep dive on Neuronutrition in a future newsletter. Physical activity is equally powerful in promoting brain health. Regular exercise improves blood flow, strengthens brain regions involved in memory, and enhances cognitive performance. Evidence from the UK Biobank study shows that walking 10,000 steps daily can reduce dementia risk by up to 50%. Physical activity also promotes better sleep and supports the glymphatic system’s waste-clearing processes, further protecting the brain. Sleep, an often-overlooked pillar of brain health, is essential for waste clearance and overall brain function. As we age, sleep patterns shift, with lighter, shorter sleep becoming more common. Poor sleep quality impairs the glymphatic system and increases amyloid-beta accumulation, contributing to cognitive decline. Addressing sleep disorders, such as sleep apnea, improves not only cognitive health but also overall well-being. Lastly, cardiovascular and metabolic health play a decisive role in brain aging. Conditions like hypertension, obesity, and diabetes accelerate cognitive decline, as they weaken the blood-brain barrier and create an environment conducive to chronic inflammation—often described as “inflammaging”. However, targeting these risks through lifestyle changes or medical interventions can significantly “turn back the clock” on brain health, reducing the burden of cognitive decline. A wide range of factors—both within our bodies and in our surroundings—influence brain health. Genetics, age, and socioeconomic conditions all matter, as do environmental elements like pollution and stress. Many of these problems—such as high blood pressure, obesity, poor sleep, and inflammation—are connected to the LiMEE factors: nutrition, physical activity, sleep, cardiovascular health, and immune health. Together, these risks can speed up brain aging and weaken cognitive function. For instance, socioeconomic disadvantage and stress can lead to unhealthy habits or poor sleep, which, in turn, raise cardiovascular risks and inflammation. Pollution can also damage the brain by triggering inflammation and accelerating cognitive decline. Understanding these links helps us see why a one-size-fits-all approach doesn’t work; different people face different challenges. On the bright side, we now have tools to better measure how lifestyle factors—like activity levels and sleep—change over time, thanks to wearable devices and continuous monitoring. This data makes it easier to design truly personalized, long-term interventions to protect the brain. Evidence supports the idea that combining multiple strategies—improving diet, staying active, managing cardiovascular risks, boosting immune health, and ensuring good sleep—can work better than addressing just one issue. Multimodal interventions, tested in large clinical trials like FINGER, PreDIVA, and MAPT, show promise in preventing cognitive decline when tailored to individual needs. In short, focusing on the LiMEE factors and approaching brain health from every angle allows us to prevent problems, maintain cognitive vitality, and promote healthy aging. The hope is that, by identifying and addressing multiple risks at once, we can keep our brains stronger and more resilient over the long haul. This exceptional work from the Clinique La Prairie Innovation Team and our Scientific Committee exemplifies our unwavering dedication to pioneering science and health. It lights the path toward a future in which each of us can aspire to enjoy a sharper, more resilient mind throughout our lives. For those eager to explore this further, you can access the full study here: Maintaining Brain Health Across the Lifespan. Wishing you all a joyous holiday season and a bright start to the New Year! The "Unlock Longevity" newsletter is my personal contribution to exploring, but most importantly simplifying and making accessible, the themes, techniques, and strategies related to longevity. If you believe these insights could benefit your network, feel free to share this article! This article reflects my personal views and is not intended to replace professional medical advice. Commenti

As we begin this new year, I’d like to take a moment to wish you a happy, healthy, and fulfilling 2025! May it be a year filled with well-being, growth, and opportunities to thrive. Nutrition has always been a cornerstone of Clinique La Prairie’s holistic approach to health. In this edition of Unlock Longevity, we delve into the profound impact that nutrition has on both longevity and overall well-being. In this chapter of our journey into longevity, we explore how nutrition directly influences Brain Health. Over the past three years, this has been a pivotal focus of our research, culminating in the launch of our groundbreaking Brain Potential program. I firmly believe it to be the most advanced program in the world for diagnosing and addressing brain health. I had the privilege of speaking with Dr. Giorgia Grisotto, a member of CLP’s Nutritional Team and a PhD in the field, who graciously shared her insights on how dietary choices can unlock a healthier, more vibrant, and longer life. Our conversation unpacks the fascinating science behind nutrition, emphasizing the critical connection between the gut and the brain.Giorgia highlighted the role of key nutrients in enhancing cognitive and immune health, and provided practical guidance on achieving balance and focus through mindful eating. She also shared her perspective on the transformative benefits of plant-based eating, the importance of anti-inflammatory foods, and the role of advanced nutraceuticals in combating aging at the cellular level. Through this dialogue, my hope is to inspire you to view food not merely as sustenance, but as a vital tool for achieving longevity, resilience, and optimal brain health. Together, let’s unlock the power of nutrition to transform how we live, age, and thrive. Starting with the microbiota: why is it so important when we talk about brain health? Microbiota refers to the living microorganisms present in a specific environment, such as the oral cavity or gut. In contrast, the microbiome encompasses the collective genomes of all microorganisms in that environment, including the microbial community itself, as well as their structural components, metabolites, and surrounding environmental conditions. The human gastrointestinal tract harbors a vast microbial community, comprising approximately 100 trillion microorganisms. The human microbiome plays a critical role in health and disease. Recent advances have demonstrated that the human microbiota is deeply involved in nutrient extraction, metabolism, and immune function. Researchers are increasingly investigating what constitutes a "healthy" gut microbiota and its connection to host physiological processes, such as the intricate interplay between the gut and the brain. Growing evidence from clinical and preclinical studies highlights the possible role of gut microbiota in the development of neurodegenerative diseases. This has spurred interest in exploring the link between gut microbiota and degenerative disorders, aiming to uncover potential therapeutic strategies for these challenging conditions. Nowadays, further studies are needed to understand the intricate mechanisms behind. Explain how foods stimulate neurotransmitters and which neurotransmitters should we aim to stimulate in the morning versus the afternoon? The food we consume provides the precursors necessary for neurotransmitter synthesis. In the morning, it is beneficial to support the production of acetylcholine and dopamine, which enhance cognitive functions such as memory, concentration, attention, and energy, helping us begin the day optimally. In the afternoon, it is advantageous to promote the synthesis of neurotransmitters like serotonin and gamma-aminobutyric acid (GABA), which are associated with relaxation and calming effects, ultimately contributing to better sleep quality. What foods do you recommend for the morning and afternoon? In the morning, I recommend consuming foods that supply the precursors choline and tyrosine, essential for producing the neurotransmitters acetylcholine and dopamine, respectively. Foods rich in choline include eggs, fresh salmon, dried shiitake mushrooms, soybean sprouts, wheat, and seeds. For tyrosine, options include cheese, milk, yogurt, nuts, goji berries, and avocado. Whether you prefer a savory or sweet breakfast, you can support the production of both neurotransmitters. In the afternoon or evening, I suggest foods that provide the precursors tryptophan and glutamic acid, which aid in synthesizing the neurotransmitters serotonin and GABA, respectively. Tryptophan-rich foods include spinach, sweet potatoes, kale, broccoli, prunes, kiwi, and mango, while glutamic acid can be found in tofu, all types of beans, grapefruit, and dried figs. Certain foods, such as eggs, are versatile and can stimulate the production of multiple neurotransmitters. How do you suggest balancing a plate to maintain focus and performance throughout the day? A balanced diet is based on the proper intake of macronutrients (proteins, carbohydrates, and fats) and micronutrients in every meal. The plate should consist of 50% vegetables (cooked or raw), 25% low-inflammatory proteins (e.g., fish, seafood, white meat) , and 25% carbohydrates, preferably whole grains. A healthy snack is recommended, but the distribution of meals largely depends on the individual’s lifestyle and needs. Staying hydrated is essential, and reducing the intake of sugar, processed products, alcohol, and salt is highly advised for maintaining a healthy and balanced diet. Why does CLP recommend a vegan dinner in the evening? Clinique La Prairie promotes a vegan diet (plant-based proteins such as legumes) to provide the body with high-quality nutrients that are highly anti-inflammatory and antioxidant. These nutrients support the body's internal repair processes that occur during the night and stimulate the production of the neurotransmitter GABA, thereby promoting better sleep quality and quantity. What are the "good fats" you suggest incorporating into a diet? For "healthy fats," we recommend incorporating vegetable oils in moderate quantities (20-30g/day per person) due to their several functions such as source of energy, constitution of membrane cells, participation in the nervous system and involved in the operating of the immune and hormonal system. Depending on the oil's use (temperature and cooking time), we suggest the best oil to use in the kitchen. Additionally, nuts and seeds are essential allies for our well-being, as they are rich in nutrients like selenium, magnesium, zinc, and vitamins. However, be careful not to overdo the portions! We do not recommend processed (liquid/solid) fats or animal fats due to their inflammatory impact on the body. Which antioxidant-rich foods do you recommend? There are various antioxidant-rich foods, including chia seeds, goji berries, dark chocolate (>75%), red fruits, as well as plenty of fruits and vegetables. What are the key nutrients that protect neurons? Several nutrients act as protectors for our neurons, primarily through their strong antioxidant properties and immune-boosting effects. Zinc is crucial for the proper development and function of immune cells, aiding immune responses by promoting the production of antibodies and cytokines. Magnesium enhances immune cell activity and contributes to antioxidant defense mechanisms. Selenium plays a key role in producing enzymes that guard against oxidative stress and support immune functions. Omega-3 fatty acids contribute to various protective mechanisms, including those related to cardiovascular health, neurodevelopment, neurodegenerative diseases, and chronic conditions. Additionally, vitamins C, D, and E are essential for regulating immune responses, combating oxidative damage, and stimulating antibody production. What spices and herbs do you recommend, and why? Spices and herbs are highly recommended for their numerous health benefits. Depending on your taste preferences, you can choose from options like black pepper, cayenne, chili pepper, cinnamon, cloves, fennel seeds, fenugreek, holy basil, garlic, ginger, mustard seeds, peppermint, rosemary, sage, and turmeric. To enhance their absorption and effectiveness, consider applying heat, using oil, or blending them into your dishes! Is it important to use spices and herbs instead of salt? First of all, reducing the use of salt is important for our health. To flavor dishes, you can use spices and herbs of your choice. They also have healing properties, such as anti-inflammatory, antioxidant, antibacterial, and anti-mutagenic effects. They are not only great for taste but also beneficial for our health! Why is it important to stimulate the immune system? The immune system – and its innate or adaptive defense mechanisms – is the body’s defense system against foreign agents. It is made up of various cells with different functions and circulating molecules that work together to recognize and eliminate foreign agents, such as bacteria, parasites, fungi, viruses, and cells infected by pathogens. Our immune defenses are ready to act in case of emergency, implementing defense systems to protect the body and restore internal balance. A weak immune system leads to dysfunction in the body’s protective defenses, resulting in bacterial, viral, or fungal infections. The causes are numerous, but maintaining a healthy lifestyle helps reduce the risk of weakening the immune system and becoming more susceptible to pathogens. Are there studies indicating which foods can help delay neurodegenerative diseases? Neurodegenerative diseases are marked by the gradual loss of neuronal function in the brain, leading to cognitive decline and motor dysfunction. While multiple factors contribute to these conditions, nutrition appears to play a significant role in their onset and progression. Research indicates that malnutrition and a low body mass index (BMI) are linked to an increased risk of dementia and higher mortality rates. The Mediterranean diet, nutritional support, and calorie-controlled diets may help protect against cognitive decline, Alzheimer's disease, and Parkinson's disease, while malnutrition and insulin resistance are notable risk factors. Additionally, malnutrition disrupts the gut-microbiota-brain axis, which can intensify the neurodegenerative process. While omega-3 and omega-6 fatty acids, along with vitamin supplementation, seem less effective in preventing neuronal degeneration, insulin activity is identified as a key factor in maintaining brain health. Malnutrition remains strongly associated with a higher risk of dementia and mortality. Ongoing studies are investigating these relationships, and further research is needed to validate and expand upon these findings. Which supplements do you recommend for brain health? Cognitive decline begins physiologically around the age of 30. Maintaining a healthy lifestyle is the first line of defense to protect the brain environment and neurons (brain cells) from both endogenous and exogenous damage. Today's hectic lifestyle exposes us to greater risk factors, accelerating inflammatory and oxidative processes and disrupting internal homeostasis at all levels: molecular, cellular, tissue, and organ systems. The brain is a highly sensitive and fragile organ that must be safeguarded with a healthy lifestyle and targeted, effective supplementation. Generic supplements (e.g., omega-3, zinc, magnesium) are undoubtedly important allies, but the new generation of long-term supplements that address many of the 12 hallmarks of aging, such as Clinique La Prairie Holistic Health Supplements, are essential. Age-Defy is certainly a comprehensive supplement that, thanks to its wide range of nutraceuticals, works effectively and specifically against oxidative stress in all cells—brain and non-brain cells—chronic inflammation, which over time is linked to degenerative chronic diseases, and molecular-level cellular protection. Holistic Health Supplements become an indispensable daily support that we can no longer do without! The "Unlock Longevity" newsletter is my personal contribution to exploring, but most importantly simplifying and making accessible, the themes, techniques, and strategies related to longevity. If you believe these insights could benefit your network, feel free to share this article! This article reflects my personal views and is not intended to replace professional medical advice. Commenti

In this newsletter I want to talk to you about a central topic in the world of longevity, which I am sure you have heard a lot about: stem cells. Before, however, I delve into the efficacy of treatments for them - a topic I will address in future newsletters - I want to focus on one key thing: understanding what stem cells are exactly and, above all, what the different types of stem cells are. This first step will help us better understand the applications and interventions that revolve around these extraordinary protagonists of regeneration. To understand stem cells, we must first consider a crucial fact: our body loses cells all the time. Some cells become 'zombies' (as we have seen before), others commit suicide in a process called apoptosis, and still others become detached from our body or are eliminated by the immune system because they behave suspiciously, as happens with cancer cells. Consequently, depending on the organ, our cells are constantly regenerating. For example, the uppermost layer of the intestinal walls renews itself every four days, while skin cells change every 10-30 days. Some cells regenerate less frequently, but most of our body is involved in a continuous cycle of cell renewal. Fortunately, this regenerative process is made possible by specialised cells: stem cells. It is they who enable us to regenerate tissue and keep our bodies 'new' even when existing cells are lost or damaged. So, as we have seen, stem cells are crucial because they determine the organism's ability to regenerate itself. However, as with many other mechanisms we have explored in previous newsletters, as the years go by, stem cells gradually lose their effectiveness. They become less efficient at replacing lost cells, thus compromising our body's regenerative capacity. Well! Now that we understand what stem cells are, let's make a first distinction between Totipotent, Pluripotent and Multipotent stem cells. Sounds complex... follow me! Imagine you are at the beginning of life: everything starts with a single cell, the zygote. This cell is extraordinary because it can do anything: this is a totipotent stem cell: it has the potential to create not only all the cells in the human body, but also those needed to build the placenta, which nourishes and protects the embryo during development. Contenuto dell’articolo Embryonic stem cells can differentiate into any type of cell of the body. Figure created with BioRender. As life progresses, cells begin to specialise. Some become pluripotent stem cells. These cells, although they have lost some of their 'omnipotence', are still extremely versatile. Pluripotent cells can create almost any type of cell in the human body, but can no longer form the placenta. We will return to the subject of pluripotent stem cells and induced pluripotent stem cells (iPSCs) later. Finally, as development progresses, the cells specialise further. Here, meet the multipotent stem cells, which are like highly specialised craftsmen. They can only create a certain type of cell, remaining within their 'family'. For example, in the bone marrow there are multipotent cells that only produce the various types of blood cells. However, they cannot become neurons or skin cells: their task is well defined. Thus, adult stem cells are multipotent. A specific type of adult stem cells are mesenchymal stem cells (MSCs). These cells, initially discovered in bone marrow, are also found in other tissues such as adipose tissue. MSCs are known for their ability to transform into cells that form bone, cartilage, muscle and adipose tissue. They also play an important role in controlling inflammation and modulating the immune system, making them promising for regenerative therapies and the treatment of autoimmune diseases. This detail is important because in the field of longevity we will hear a lot about this type of cells! So, we repeat: adult stem cells include all types of stem cells found in adult tissues and play a key role in tissue maintenance and repair. Among them, mesenchymal stem cells represent a specific subgroup, specialised in generating mesenchymal tissues such as bone, cartilage and fat. These cells also have a unique function in modulating inflammation and immunity. But where do we find these precious 'cells'? Well, they have several 'operating bases' in our bodies. One of the main ones is the bone marrow, that spongy substance found inside our bones. It is a bit like their headquarters, where a large quantity of stem cells reside, ready to intervene if needed. To harvest them, a puncture is made, usually in the pelvic bone, a procedure that can cause some discomfort but is performed under anaesthesia. Another source, less rich but still important, is peripheral blood. Normally, there are only a few in the blood circulating in our veins, but we can 'persuade' them to leave the bone marrow and enter the bloodstream through specific drugs. It is like giving them a 'green light' to go on a mission. Once in the blood, they are collected in a procedure similar to a donation. Then there is a very special source, available only at birth: the umbilical cord and placenta. The blood contained in these tissues, which nourish the baby during pregnancy, is rich in stem cells, especially those that produce blood cells. Finally, another interesting source is adipose tissue, i.e. fat. Here too we find stem cells, which can be extracted by liposuction or other less invasive techniques. Therefore, when discussing stem cells, it is common to mention their harvesting from adipose tissue or bone marrow. When it comes to stem cell transplantation, it is essential to distinguish between two main types: autologous and allogeneic. The main difference lies in the origin of the cells. In autologous transplantation, the stem cells come from the same patient who will receive them. Imagine that the patient is both the donor and the recipient. The cells are taken from thier body, usually, as we have seen, from bone marrow, peripheral blood or, in some cases, adipose tissue. After harvesting, the cells may be processed in the laboratory to purify them or to select specific cell types. Subsequently, these cells are re-infused into the patient. The great advantage of autologous transplantation is that there is no risk of rejection. In allogeneic transplantation, on the other hand, the stem cells come from a donor other than the patient ('Allo' means 'other', so these cells come from another person, a donor): in this case we may have problems with rejection. This is because, unlike autologous cells, allogeneic cells may be recognised by the body as foreign, as if they were 'bricks' of a different type. Unlike haematopoietic cells, mesenchymal stem cells (MSCs) have a significantly lower risk of rejection. This is due to their immunomodulatory properties, which allow them to suppress the recipient's immune response. OK! We have seen the most important concepts... all that remains is for me to tell you about induced pluripotent stem cells, abbreviated to iPSCs. But what are they? iPSCs are stem cells created in the laboratory from 'common' adult cells, such as skin or blood cells. Imagine you have a specialised adult cell, e.g. a skin cell that has the specific task of protecting your body. Thanks to a special 'reprogramming' technique, scientists are able to turn this adult cell back to a 'younger' and more versatile state, transforming it into a pluripotent stem cell, i.e. one that is capable of differentiating into many types of cells in the body. This incredible reprogramming process was discovered by Japanese researcher Shinya Yamanaka and his team in 2006. Yamanaka discovered that by introducing specific genes, called 'transcription factors', into adult cells, it was possible to 'reset' them back to a pluripotent state. It is as if he had found a 'switch' capable of turning back the cells' biological clock. For this revolutionary discovery, Yamanaka received the Nobel Prize in Medicine in 2012. In summary, iPSCs are pluripotent stem cells artificially generated from adult cells thanks to Yamanaka's discovery. Without going into further details, we can say that iPSCs offer enormous potential, but for their large-scale application, certain challenges related to safety, efficiency, cost and the complexity of differentiation must be overcome. I would like to conclude by listing some factors on why stem cells are so important for longevity research (a short selection of the main ones): High Expansion Potential Stem cells are able to divide numerous times, generating new cells identical to themselves. This ability is essential to generate large numbers of cells for therapeutic and research purposes. Plasticity or Multipotent Differentiation They are able to transform themselves into different types of specialised cells, depending on the context and stimuli. This makes them useful for repairing or regenerating different types of tissues and organs. Migration Capability Stem cells can migrate to damaged or inflamed areas of the body, guided by chemical signals released by injured tissues (a mechanism known as 'homing'). Transfer from Laboratory to Patient Stem cells can be cultivated, manipulated and stored in the laboratory and then safely administered to the patient, either by local or systemic injections. Anti-Inflammation Properties Some stem cells can release biochemical factors that reduce inflammation in damaged tissues, enhancing healing. Secretion capacity of bioactive factors Stem cells release cytokines, growth factors and other chemical signals that stimulate the regeneration of surrounding tissues and recruit other repair cells. Versatility in Tissue Types They are compatible with different tissue types. Stem cells can be used to repair skin, muscle, cartilage, bone, heart, liver, brain and many other organs. Anti-Aging Potential Stem cells can help counteract the effects of ageing by improving skin quality, tissue regeneration and organ function (we will see how many studies still need to be confirmed on this subject!). In conclusion, stem cells represent one of the most fascinating and promising topics in the landscape of longevity and regenerative medicine. Through their extraordinary ability to regenerate tissues, reduce inflammation and potentially slow down certain processes of ageing, they are opening up new frontiers in science and health care. However, as we have seen, there are still many challenges ahead! Stem cells teach us that our bodies possess an extraordinary potential for self-regeneration, which we can learn to sustain and improve through research and science. As practical applications continue to evolve, it is clear that the future of medicine, and perhaps of our own longevity, will also pass through the understanding and conscious use of these extraordinary 'cells of life'. In future newsletters we will delve into some of the more practical and concrete aspects related to stem cells, such as available treatments, current limitations and future perspectives. The journey towards a better understanding of longevity has just begun, and I am excited to continue exploring it with you. The "Unlock Longevity" newsletter is my personal contribution to exploring, but most importantly simplifying and making accessible, the themes, techniques, and strategies related to longevity. If you believe these insights could benefit your network, feel free to share this article! This article reflects my personal views and is not intended to replace professional medical advice. Commenti

Touch—a seemingly simple act—has profound and transformative effects on our physical, emotional, and mental well-being. In this exclusive newsletter, we explore the science, benefits, and untapped potential of therapeutic touch. This essential concept falls under our Wellbeing Pillar at Clinique La Prairie and highlights the transformative role of therapeutic massage. Despite its profound benefits, therapeutic touch remains underappreciated, and I am happy to bring this discussion to light by sharing an inspiring interview with Hicham Ahyoud, one of our exceptional therapists at Clinique La Prairie. Hicham’s journey into the world of wellness is nothing short of extraordinary. Born in Marrakech, Morocco and raised in France, he began his career with studies in wellness, which laid the foundation for his expertise. Seeking to deepen his knowledge, he travelled to China, immersing himself in the wisdom of traditional Chinese medicine and the power of natural healing. This transformative experience enriched his approach and philosophy. Upon returning to France, Hicham earned the prestigious title of MOF (Meilleur Ouvrier de France), also known as "Best Hands of France," a remarkable recognition of his dedication to excellence. The Power of Touch—a cornerstone of holistic health that not only addresses stress but also contributes to longevity and overall well-being. Whether you’re curious about the science behind touch or its role in fostering physical and emotional balance, I’m confident this conversation will inspire you to discover the profound potential of therapeutic touch in enhancing your health and vitality. Let’s dive in! Hicham, What is Therapeutic Touch, and Why is it So Important? Therapeutic touch is more than just a manual therapy; it’s a holistic approach that engages the body’s systems to promote optimal well-being. This practice works on multiple levels: reducing stress, improving circulation, releasing endorphins, and strengthening the mind-body connection. The sensory receptors in our skin send powerful signals to the brain, triggering the release of neurochemicals like oxytocin and serotonin, which create an internal cascade of relaxation and regeneration. Beyond physical benefits, therapeutic touch addresses emotional and psychological balance, making it a cornerstone of holistic health. Unlike verbal or pharmacological therapies, touch establishes direct contact with the body, engaging millions of sensory receptors in the skin. This connection generates an immediate response in the nervous system, fostering deep relaxation, empathy, and emotional calm. The unique bond between the skin and brain—both originating from the same embryonic layer—amplifies its effects, making touch a relational and biological therapy like no other. How does therapeutic touch influence the nervous system? Hicham Ahyoud: Therapeutic touch has a profound impact on both the central and autonomic nervous systems. One of the key mechanisms is the activation of the vagal nerve, which is a cornerstone of the parasympathetic nervous system. This activation induces deep relaxation, reduces blood pressure, and promotes a sense of calm. Touch also calms the amygdala, the part of the brain responsible for processing stress and fear. This helps ease anxiety and reduces emotional reactivity. Additionally, therapeutic touch triggers the release of oxytocin, often called the “trust hormone,” which promotes well-being and counters the effects of stress. Finally, touch can block pain signals through a mechanism called the "gate control theory," modulating how we perceive pain. Together, these effects create harmony within the body and mind. Contenuto dell’articolo Can touch contribute to emotional balance? Hicham Ahyoud: Absolutely. Caring touch goes beyond just reducing stress—it actively cultivates emotional stability. By stimulating the parasympathetic nervous system, touch lowers cortisol levels while increasing serotonin, endorphins, and oxytocin. These chemicals work together to improve mood, foster feelings of trust and connection, and reduce anxiety. For instance, therapies like reflexology or cranial massage are especially effective at promoting emotional balance. Regular sessions can even help alleviate symptoms of depression and insomnia, creating a sense of overall well-being. What role does touch play in mental health? Hicham Ahyoud: Touch is an essential tool for improving mental health. It reduces stress and anxiety by lowering cortisol levels and stimulating oxytocin production. At the same time, it encourages the release of serotonin and dopamine, which are crucial for regulating mood and alleviating depressive symptoms. Another significant benefit is the way touch strengthens social bonds. It fosters trust and attachment, reducing feelings of isolation—a major risk factor for mental health challenges. Additionally, touch improves sleep quality by inducing relaxation and stimulating melatonin production, both of which are essential for recovery and overall well-being. Can therapeutic touch slow down the aging process? Hicham Ahyoud: Yes, touch can absolutely contribute to slowing down the aging process. By reducing stress and protecting telomeres—the protective ends of our chromosomes—it helps preserve cellular integrity. Touch also improves circulation and tissue regeneration, promoting better collagen production and skin elasticity. Additionally, therapeutic touch reduces chronic inflammation, a key driver of aging, and strengthens the immune system. By enhancing emotional well-being and combating social isolation, touch addresses both the physical and psychological factors associated with aging. How does touch balance the endocrine and immune systems? Hicham Ahyoud: Touch plays a unique role in harmonizing the body’s endocrine and immune systems. It reduces cortisol, the stress hormone, while boosting levels of oxytocin, dopamine, and serotonin. This creates a balanced hormonal environment that supports overall well-being. From an immune perspective, touch lowers inflammatory markers like IL-6 and boosts natural killer (NK) cell activity, which enhances the body’s ability to fight infections and abnormal cells. By reducing stress and inflammation, touch also eases the immune system’s workload, allowing the body to focus on regeneration and repair. What are practical ways to incorporate therapeutic touch into daily life? Hicham Ahyoud: There are many simple ways to make touch a part of your routine: Schedule regular professional massages or energy-healing sessions to relieve tension and improve circulation. Practice self-massage techniques at home for areas like the neck, shoulders, or hands. Strengthen emotional bonds by hugging loved ones or holding hands—it’s a small act with a big impact. Engage in tactile activities like yoga, tai chi, or pottery to deepen your connection with your body. Use mindful touch during meditation or relaxation, gently stroking your arms or hands to increase body awareness and reduce stress. Incorporating these practices into your life can transform your physical, emotional, and mental well-being, helping you unlock the full potential of therapeutic touch. Thanks to Hicham! The "Unlock Longevity" newsletter is my personal contribution to exploring, but most importantly simplifying and making accessible, the themes, techniques, and strategies related to longevity. If you believe these insights could benefit your network, feel free to share this article! This article reflects my personal views and is not intended to replace professional medical advice. Commenti

Aging is a universal process, yet understanding its mechanisms remains one of the most complex and fascinating challenges in science. In the next three editions of this newsletter, we’ll explore The Hallmarks of Aging—a groundbreaking framework that provides insight into the key drivers of aging and its biological underpinnings. These concepts may seem intricate, but they are essential to understanding how and why we age, and they hold the key to unlocking longevity. So stay with me as we dive into the most important research ever conducted on aging. In 2000, researchers Douglas Hanahan and Robert Weinberg published a groundbreaking article entitled ‘The Hallmarks of Cancer’ in the journal ‘Cell’. This work profoundly influenced the field of cancer research by providing a conceptual framework for understanding the transformations necessary for a normal cell to become cancerous. The original 2000 article identifies six fundamental characteristics, or ‘hallmarks’, that cancer cells must acquire during the process of tumorigenesis. In 2013, ‘The Hallmarks of Aging’ was published in the journal ‘Cell’ by authors who sought to emulate Hanahan and Weinberg’s pioneering approach in the context of aging. This article had a significant impact on the field of gerontology and the biology of aging, as it provided a similarly revolutionary framework for understanding the biological mechanisms that drive the aging process. Just as ‘The Hallmarks of Cancer’ categorized and summarized the fundamental characteristics of cancer cells, so ‘The Hallmarks of Aging’ outlined the key processes that contribute to the biological deterioration associated with age. The 2023 study, “Hallmarks of Aging: An Expanding Universe”, introduced three new hallmarks to the original nine from 2013. The goal of the new study was not just to add more hallmarks for the sake of completeness but to reflect the most up-to-date scientific understanding of aging. The 2 studies identified then 12 “hallmarks” that are considered determinant contributions to aging, classified into three main categories: primary, antagonistic, and integrative. Primary Hallmarks (Drivers of Damage) These are the underlying causes of cellular damage and the direct drivers of aging. 1. Genomic Instability: Accumulation of DNA damage caused by replication errors, radiation, chemicals, and viruses, leading to compromised cellular function. 2. Telomere Shortening: Telomeres, the protective “caps” at the ends of chromosomes, shorten with each cell division, eventually triggering cellular senescence and contributing to age-related diseases. 3. Epigenetic Alterations: Changes in how genes are regulated (without altering the DNA sequence itself), disrupting normal cellular functions and contributing to aging. 4. Loss of Proteostasis: Decline in the cell’s ability to maintain correctly folded and functional proteins, resulting in the accumulation of toxic or dysfunctional proteins. 5. Disabled Macroautophagy: Originally considered a subset of proteostasis, it now stands independently due to its broader implications on aging, such as its role in organelle turnover and cellular waste management. This hallmark was added in the 2023 study Contenuto dell’articolo Antagonistic Hallmarks (Responses to Damage That Can Become Harmful) These are initially protective responses to damage, but they can become harmful when dysregulated or chronic, contributing to aging. 6. Deregulated Nutrient Sensing Energy-regulating systems, like insulin signaling and mTOR pathways, become less efficient with age, leading to metabolic and cellular imbalances. 7. Mitochondrial Dysfunction: Mitochondria, the cell’s “power plants,” become less efficient with age, producing less energy (ATP) and more reactive oxygen species (ROS), which exacerbate cellular damage 8. Cellular Senescence: Damaged cells stop dividing as a protective mechanism but begin to release inflammatory signals, creating a pro-inflammatory environment that harms surrounding tissues. Integrative Hallmarks (Consequences of Accumulated Damage) These arise as a result of the accumulated damage caused by primary and antagonistic hallmarks, leading to systemic dysfunction and impaired regeneration. 9. Stem Cell Exhaustion: Stem cells, which are critical for tissue repair and regeneration, decline in both quantity and function, limiting the body’s ability to repair itself. 10. Intercellular Communication Changes: Altered signaling between cells leads to chronic inflammation and compromises the overall function of tissues and organs, exacerbating age-related decline. 11. Chronic Inflammation: While previously integrated under altered intercellular communication, its independent categorization reflects the growing recognition of inflammation’s systemic impact on aging and age-related diseases. Added in 2023 study. 12. Dysbiosis: This hallmark emphasizes the critical role of the microbiome in aging, highlighting the effects of microbial imbalance on systemic health and longevity. (Added in the 2023 study.) The hallmarks of aging were identified using three key criteria, ensuring that these processes are central to the biology of aging and not just incidental phenomena. 1. Hallmarks must occur during aging: This means that the hallmark processes are present and active as organisms grow older. They should not just appear sporadically or under specific conditions but must be consistently observed as part of the aging process across different tissues, systems, and organisms. For example, genomic instability (accumulation of DNA damage) and telomere shortening are seen universally as individuals age. 2. Their forcing must accelerate aging: If these processes are artificially enhanced or exacerbated, they should speed up the aging process. For instance, if we experimentally increase DNA damage or induce mitochondrial dysfunction, the organism should exhibit signs of premature aging, such as reduced physical function, shorter lifespan, or earlier onset of age-related diseases. 3. Their reduction must increase “longevity”: Conversely, mitigating or reducing the effects of these hallmarks should lead to increased healthspan (the period of life spent in good health) or lifespan. For example, if interventions repair DNA damage, improve mitochondrial function, or maintain telomere length, organisms should show delayed aging, extended vitality, and improved overall longevity. This hallmark is the one which is most difficult to prove. Contenuto dell’articolo Understanding “Hallmarks” will enable us to introduce some fundamental concepts in the field of longevity. Let's start with “genomic instability”: we have already talked about DNA. DNA is the genetic material found inside our cells. It is like a long code made up of four “letters” called nucleotides. These letters combine into specific sequences to create our genes, which determine everything from the color of our eyes to the way our organs function. As we have seen, DNA is like the instruction manual for our lives. It contains all the code we need to build and maintain our bodies. But like any other manual, it wears out and gets damaged over time. This, precisely, is what we call genomic instability, one of the main hallmarks of aging. Throughout our lives, DNA is constantly bombarded by agents that can damage it. These agents can be: External environmental factors: such as ultraviolet radiation from the sun, toxic chemicals and cigarette smoke. Internal errors: which occur during DNA copying when cells divide or due to malfunctions in DNA repair systems. Our cells have DNA repair systems that work to correct these errors. However, these systems are not perfect, and as we age, they become less efficient. As a result, DNA damage accumulates over time, leading to what we call genomic instability. Genomic instability is a serious problem because DNA damage can cause genetic mutations. Mutations can alter cell function in several ways, including cell death or senescence. In general, cells with a high level of DNA damage can deteriorate more rapidly, contributing to a general decline in tissue and organ function. And we must not forget viruses: viruses can attack host cell DNA by integrating their own genetic material into the cell’s DNA (integration), causing mutations through indirect damage, or leading to cell destruction during the production of new viruses. Some viruses can increase levels of reactive oxygen species (ROS) within cells. These chemically reactive compounds can damage DNA, proteins, and lipids, contributing to genomic instability. The chronic inflammation we have already discussed induced by persistent viral infections can also promote genomic instability. If the repair systems do not function properly, DNA damage may not be effectively corrected, leading to an accumulation of mutations. In summary: “Genomic instability” refers to the damage that DNA accumulates over time due to external factors like UV radiation and smoking, or internal errors during cell division. Although cells have repair systems, these become less efficient with age, leading to mutations, cellular malfunction, and an overall decline in tissue function. The second “Hallmark” and Telomeres Well, now we have to talk about “telomeres” another fundamental concept if we want to understand aging and longevity. Our second “hallmark.” Inside every cell is a dark area called the nucleus (the “brain of the cell”). Simplifying, let's say that inside the nucleus are scattered filamentous structures (kind of like a plate of spaghetti) called chromatin. But when cells are about to duplicate, these “spaghetti” compact into what are called “chromosomes,” that is, the “spaghetti” come together into X-shaped sticks. Chromosomes are nothing more than twisted DNA. Since the two chromosome rods are siblings (one comes from the male parent, the other one from the female parent), and were created precisely to allow the cell and DNA to duplicate, telomeres act as protective “caps” for the chromosomes, preserving the stability of the genome. Without telomeres, the ends of chromosomes could be damaged during cellular processes. In short, telomeres ensure that in duplication, DNA is not “ruined.” However, the duplication mechanism causes telomeres to “wear out” a little bit with each new cell... Over time and with successive cell divisions, telomeres become progressively shorter. This shortening is one of the factors that contribute to the process of cell aging and to limiting the number of times a cell can divide. In fact, when telomeres shorten and reach a critical length, a DNA Damage Response (DDR) is triggered. Cells stop dividing and become senescent. Cellular senescence is a process in which cells stop proliferating but remain metabolically active. Cells begin to produce and release molecules that cause inflammation, creating a pro-inflammatory state in the surrounding environment (back to inflammation). Imagine leaving garbage in our house every day.... You will have a picture of senescent cells! Telomere shortening has been associated with age-related diseases such as cardiovascular disease, type 2 diabetes, and some cancers. But what can be done to counter telomere shortening? In preclinical research, one of the main strategies to combat telomere shortening is to activate the enzyme telomerase. This enzyme has the specific task of maintaining telomere integrity by adding DNA sequences to the ends of chromosomes, thereby compensating for the natural shortening that occurs during cell replication. Activation of telomerase can potentially slow, stop or even reverse telomere shortening, offering a possible pathway to mitigate cellular aging and age-associated diseases. In addition, telomere length is considered a “biomarker” for understanding how much our bodies are aging (a Spanish company “Life-Length” has been working on this issue for several years). Telomere length is thus considered a reflection of a person’s biological age, which may differ from chronological age. But what is biological age? Biological age refers to how rapidly body tissues and cells are aging, which can be influenced by genetics, lifestyle, disease, and environment, as we have seen. Telomeres are therefore considered a “biomarker”- actually only partially! For a biomarker to be defined as such there are well-defined criteria that must be met (like “hallmarks,” as we have seen): it must be predictive of longevity better than registry age (if not, what would be the point?), correlated with mechanisms that contribute to aging but not to a specific disease, and other factors. Not everyone agrees that telomeres meet these criteria in order to call them an accurate “marker” of longevity. In summary, Telomeres are protective caps at the ends of chromosomes that ensure DNA remains intact during cell division. However, with each division, telomeres shorten, and over time, this leads to cellular aging and senescence, where cells stop dividing but remain active, often causing inflammation in surrounding tissues. In the next edition of this newsletter, we will continue our journey through the hallmarks of aging. Stay with me as we unravel the science of longevity, one hallmark at a time. The "Unlock Longevity" newsletter is my personal contribution to exploring, but most importantly simplifying and making accessible, the themes, techniques, and strategies related to longevity. If you believe these insights could benefit your network, feel free to share this article! This article reflects my personal views and is not intended to replace professional medical advice.

In the last edition of this newsletter, we introduced the groundbreaking study The Hallmarks of Aging, highlighting its significance in understanding the biological mechanisms of aging. We provided an overview of the 12 hallmarks and their classification into primary, antagonistic, and integrative categories. Additionally, we focused on the first two hallmarks—genomic instability and telomere shortening—explaining how DNA damage and the progressive erosion of chromosome-protecting telomeres drive cellular aging and dysfunction. These foundational concepts set the stage for understanding the intricate processes that contribute to aging and pave the way for exploring strategies to mitigate its effects. In this second edition, we will continue our journey by diving into the next hallmarks, further uncovering the science behind longevity. Let’s now talk about… “Epigenetic Alterations” (3rd Hallmark). We’ve already talked about epigenetics and described it as the “layer above genetics.” If DNA is the instruction manual for building and maintaining our bodies, epigenetics is like the system that decides how and when these instructions are used. It doesn’t change the DNA code itself but influences how the genes in the code are turned on or off. In simpler terms, epigenetics controls whether a gene is “active” or “silent.” Think of it as a dimmer switch for a light bulb: it doesn’t remove the bulb (the gene) but controls how brightly it shines (how much it’s expressed). Epigenetic mechanisms can occur as : DNA methylation, chromatine structure, histones modificationsand non-coding RNAs. These mechanisms are critical regulators of gene expression and play an essential role in the aging process. Epigenetic alterations occur when this regulatory system starts to go wrong with age. These changes can disrupt the way genes are expressed, leading to errors in how cells function. For example some genes that should stay “off” are mistakenly turned “on or Important genes that should be “on” for repair and protection might be switched “off.” (A more accurate explanation would be to say that the patterns of epigenetic marks become disrupted, leading to dysregulation of gene expression). This dysregulation in gene expression affects how cells operate, how tissues repair themselves, and how the body responds to stress and damage. Over time, it contributes to the aging process and increases the risk of age-related diseases. One key example of epigenetic alterations is DNA methylation, an incredible process that helps regulate gene activity. Methylation is fundamental during development, since it silences genes whose expression is no longer needed. DNA methylation is a stable and heritable epigenetic mechanism, and it refers to the addition of a methyl group to a CpG dinucleotide sequence and affects how accessible genes are to transcription proteins. Therefore, highly methylated DNA stays tightly wound around histones (proteins attached to DNA structure), preventing gene transcription. Low methylation loosens the coils and make the DNA accessible to RNA polymerase, allowing gene transcription. Many of these aging-related changes in methylation are environmentally related, such as nutrition, tobacco, stress, and pollution. With aging, changes in DNA methylation accumulate, and these changes have been associated with genomic instability and with a number of non-communicable disorders, including cardiovascular diseases and cancer. In fact, aging has been associated with general decreases in DNA methylation. Global DNA methylation provides a comprehensive overview of the methylation state of the epigenome, and it has been associated with vulnerability to diseases and accelerated aging. The “loss of proteostasis” is the 4th Hallmark. In this hallmark, we talk about proteins, essential for almost all cellular functions. Without proteins, our bodies could not grow, repair, or function properly. Proteins are fundamental to the health and maintenance of all living organisms, influencing everything from physical structure to critical biological functions. Proteostasis, or protein homeostasis, is the system through which a cell regulates the production, folding, transport, and degradation of proteins. Again, to simplify, we can say that when there are errors in the functioning of this mechanism (either because proteins do not fold correctly, or because autophagy—which should eliminate damaged proteins—does not work, for example), "toxic" protein waste can accumulate, leading to diseases. This hallmark introduces a substance that is frequently discussed today in relation to longevity: rapamycin. In 1972, a group of Canadian scientists, led by the enterprising microbiologist Suren Sehgal, embarked on a bold scientific expedition that would take them to the remote corners of the world, to Easter Island, also known as Rapa Nui. This island, famous for its enigmatic moai, the giant stone statues, was surrounded by mystery and allure, but for Sehgal and his team, the true treasure lay hidden in its volcanic soil. The mission's goal was simple but ambitious: to search for new microorganisms in the island’s soil that might have useful properties, particularly antimicrobial ones. After days of exhausting research under the relentless sun and among the windy hills of Rapa Nui, the team collected soil samples they hoped contained undiscovered microorganisms. Once back in Canada, with their precious samples secured, they began the arduous task of isolating and cultivating the microorganisms present in the soil samples. Among them, one particular bacterium, called Streptomyces hygroscopicus, caught their attention for its extraordinary ability to produce a substance never seen before. This substance showed not only antifungal activity but also potential immunosuppressive and anti-tumor properties. It was an exciting discovery that could have profound medical implications. The new compound was named "rapamycin" in honor of Rapa Nui, the island that had hosted their research. Rapamycin is a drug that blocks the action of a very important protein called mTOR, which is essential for many cellular functions such as cell growth, division, and survival. mTOR is part of two groups of proteins, known as mTORC1 and mTORC2, which help the cell regulate these functions. One of the functions of mTORC1 is to regulate autophagy, the process by which cells "clean" themselves by eliminating damaged proteins and other cellular debris. When rapamycin inhibits mTORC1, it increases autophagy, improving the cell’s ability to clean itself. This helps prevent the accumulation of damaged proteins that can cause diseases and impair cell function, especially when they are under stress or damaged. Is in fact now time to deep dive on autophagy… Contenuto dell’articolo Photo by Stephanie Morcinek on Unsplash In the new “Hallmarks” study of 2023 Disabled Macroautophagy is was introduced (the 5th Hallmark). Originally considered a subset of proteostasis, it now stands independently due to its broader implications on aging, such as its role in organelle turnover and cellular waste management. Macroautophagy, often referred to simply as “autophagy,” functions as the body’s natural recycling system. Within our cells, it acts like a dedicated clean-up crew, breaking down and reusing damaged components such as old proteins and malfunctioning organelles (the tiny structures that perform vital functions within cells). It’s essentially the cell’s way of taking out the trash and repairing itself to maintain optimal health. However, as we age, this recycling system begins to falter. When macroautophagy slows down or becomes “disabled,” cellular “junk” starts to accumulate. This includes damaged mitochondria—the organelles responsible for energy production—and other waste products that the cell can no longer eliminate effectively. This build-up of clutter interferes with the cell’s normal functions, contributing to cellular aging and diminishing the ability of tissues and organs to work properly. When macroautophagy is impaired, the resulting waste accumulation triggers a cascade of problems. These include inflammation, reduced cellular energy, and even cell death. Understanding and addressing these dysfunctions could pave the way for therapies that boost or restore this recycling system, offering hope for slowing aging and mitigating age-related diseases. In essence, macroautophagy is like your cell’s personal “Marie Kondo,” keeping everything tidy and functional. When this system fails, cellular clutter takes over, causing significant disruptions that underscore the aging process. The 6th "hallmark" of aging, is the “deregulation of nutrient sensing”. Cells have specialized mechanisms for detecting the presence of nutrients like glucose, amino acids, and lipids. These mechanisms include signaling pathways such as those mediated by insulin/IGF-1, mTOR, and AMPK. These pathways regulate essential cellular responses such as protein synthesis, energy metabolism, and autophagy. In summary, nutrient-sensing deregulation is a fundamental aspect of aging that affects the cell’s ability to effectively manage nutrients and energy. We can encounter issues like glucose not being effectively absorbed, leading to high blood sugar levels and metabolic problems such as type 2 diabetes. We can have issues related to excessive growth due to mTOR (as previously discussed), and we can have problems related to AMPK. I want to focus on this mechanism because it is another key term in longevity. AMPK is an important protein in our cells that helps manage energy. AMPK acts like an energy switch. When a cell has low ATP levels (the main energy source for cells), AMPK is activated. This signals to the cell that it is running low on energy. Once activated, AMPK helps stimulate the production of more energy: it activates various processes that increase ATP production, thus providing more energy to the cell. AMPK also helps promote autophagy, the process by which the cell cleans and recycles parts of itself that are damaged or no longer needed. It’s as if the cell performs a kind of "spring cleaning" to improve its efficiency and health. Needless to say, the combination of reduced energy production and decreased cellular cleaning can lead to accumulated damage in cells. We should remember this mechanism because fasting is closely linked to AMPK activation, and this connection plays a key role in the health benefits often associated with intermittent or prolonged fasting. 7th hallmark: Mitochondrial Dysfunction—a critical player in the aging process. Mitochondrial dysfunction is one of the critical hallmarks of aging, highlighting the vital role of mitochondria in maintaining our cellular health and overall vitality. Mitochondria are complex organelles, containing their own DNA and composed of a double membrane. These tiny, bean-shaped structures within our cells are responsible for producing ATP (adenosine triphosphate), the primary energy currency of the body. Every cellular process requiring energy, from brain activity to muscle contractions, relies on the ATP generated by mitochondria. It is not only mitochondrial function that plays a role in aging, but also mitochondrial form. Mitochondria are constantly dynamically rearranging and degrading via the processes of fission, fusion and mitophagy. Mitochondria, besides being the “cellular powerhouse,” provide metabolic intermediates that are used as substrates for epigenetic modifications and chromatin remodeling, thus, driving cell fate decisions during differentiation. Moreover, mitochondrial fitness and mitochondrial quality control mechanisms are closely related to cellular function, and impairment of these mitochondrial properties associates with aging. As we age, mitochondria lose their efficiency, producing less ATP and leading to a significant decline in cellular energy levels. This reduction in energy impacts the functioning of tissues and organs, contributing to the progression of aging and age-related diseases. Interestingly, the brain and muscle are among the organs with the highest mitochondrial content per cell, reflecting their substantial energy demands. Mitochondrial dysfunction in these tissues is closely linked to aging processes, contributing to declines in cognitive and muscular functions. One of the key factors in mitochondrial dysfunction is the role of Reactive Oxygen Species (ROS), chemically reactive molecules generated as byproducts of mitochondrial energy production. In young and healthy cells, ROS serve an important purpose, acting as signaling molecules that help cells respond to stress and maintain balance. However, with age, the accumulation of ROS shifts from being beneficial to harmful. Elevated ROS levels can damage cellular components, including DNA, proteins, and lipids, exacerbating mitochondrial dysfunction and accelerating aging. The relationship between ROS and aging is complex. While in some cases ROS can promote cellular resilience, in older cells, they tend to worsen the pathological state, leading to further deterioration. This creates a vicious cycle: dysfunctional mitochondria produce more ROS, which in turn causes further damage to the mitochondria and other parts of the cell. This feedback loop not only reduces mitochondrial efficiency but also disrupts essential cellular processes, including metabolism, inflammation regulation, and signaling. These disruptions are closely linked to various age-related conditions such as cardiovascular diseases and neurodegenerative disorders. I will dive deeper into mitochondria and their role in aging in an upcoming newsletter, featuring insights from a leading expert. Mitochondria are just one piece of the puzzle. Aging is a complex biological journey shaped by multiple interconnected factors. In the next part of our our journey through the hallmarks of aging, we will dive into the fascinating world of Cellular Senescence, where damaged cells lose their ability to divide but continue releasing inflammatory signals, disrupting tissue function. We will also uncover the impact of Stem cell Exhaustion, a process that limits the body’s ability to regenerate and repair itself over time. Beyond this, we will explore how aging disrupts Intercellular Communication, accelerating tissue dysfunction, and how Chronic Inflammation acts as a silent force fueling age-related diseases. Lastly, we will examine the role of Dysbiosis, where imbalances in the gut microbiome influence immunity, metabolism, and overall longevity. Understanding these final hallmarks is key to unlocking the future of healthy aging. Stay tuned! The "Unlock Longevity" newsletter is my personal contribution to exploring, but most importantly simplifying and making accessible, the themes, techniques, and strategies related to longevity. If you believe these insights could benefit your network, feel free to share this article! This article reflects my personal views and is not intended to replace professional medical advice.

In this third part of the newsletter, we continue our exploration of the Hallmarks of Aging, diving deeper into the mechanisms that shape the aging process. Aging is a complex biological process driven by key mechanisms identified in The Hallmarks of Aging, a groundbreaking framework inspired by The Hallmarks of Cancer. Originally published in 2013 and updated in 2023, this model classifies 12 hallmarks into three categories: Primary (damage drivers), Antagonistic (responses that turn harmful over time), and Integrative (systemic consequences of accumulated damage). In the first part of this journey, we explored Genomic Instability—the accumulation of DNA damage leading to cellular dysfunction—and Telomere Shortening, where protective chromosome caps erode, triggering cellular senescence and inflammation. In the second part of the “hallmarks” newsletters, we delved deeper into the intricate mechanisms that shape the aging process, uncovering five more hallmarks that play a critical role in longevity. We began with Epigenetic Alterations, the subtle yet powerful shifts in gene regulation that accumulate over time, influencing how our cells function and respond to stress. From there, we explored Loss of Proteostasis, where the body’s ability to maintain and manage proteins falters, leading to the buildup of toxic or misfolded proteins that disrupt cellular health. Our journey then took us to Macroautophagy, the essential cellular recycling process that clears out damaged components. With age, this system slows down, allowing waste to accumulate and impairing the body's ability to renew itself. We also examined Deregulated Nutrient Sensing, where the once finely tuned mechanisms that regulate energy and metabolism become less efficient, contributing to metabolic imbalances and age-related diseases. Finally, we uncovered the profound impact of Mitochondrial Dysfunction, a hallmark that affects the very core of cellular energy production. As mitochondria deteriorate, they produce less energy and more harmful reactive oxygen species, setting off a cycle of damage that accelerates aging. With each hallmark we explore, the bigger picture of aging becomes clearer. In this edition, we will complete the journey by examining the final five hallmarks—revealing how cellular senescence, stem cell exhaustion, disrupted intercellular communication, chronic inflammation, and dysbiosis all contribute to aging. The 8th hallmark of aging is “cellular senescence”, a process triggered by factors like genomic instability, telomere dysfunction, and mitochondrial damage—all hallmarks we’ve discussed before. This hallmark, known as an “antagonistic hallmark,” represents a key mechanism in the biology of aging. Cellular senescence has been extensively studied by Judith Campisi at the Buck Institute in California, an institution founded in 1999 (now under the leadership of my friend Eric Verdin), where her research has provided invaluable insights into its role in aging and longevity. Contenuto dell’articolo Cellular senescence appears as a response to stress. When the quantity of senescent cells reaches a certain threshold, the immune system fails to eliminate them, triggering persistence and accumulation of cellular senescence. Moreover, their tissue destructive SASP produces a pro-inflammatory environment that induces secondary senescence, or the transformation of healthy cells into senescent. Figure inspired by (Gasek et al., 2021) and created with BioRender. As we’ve previously discussed, senescent cells are those that have entered a state of “altered” metabolism. These cells are still alive but unable to perform their normal functions. They can be easily recognized under a microscope due to their distinct characteristics: they appear enlarged, misshapen, and irregular. Senescent cells also display shortened telomeres, damaged DNA, and the activation of specific genes, such as INK4 and ARF. In laboratories, scientists can identify senescent cells using a specific enzyme that “stains them blue”, making them easier to study. Senescence serves an important purpose in health. It is, at its core, a protective mechanism designed to safeguard the body and to accelerate healing. When cells become damaged or dysfunctional, senescence halts their division, preventing the proliferation of potentially harmful cells, such as those that could become cancerous. Afterwards, the immune cells clears them, stimulating tissue repair. In this way, senescence functions as a critical safeguard for the organism, ensuring that damaged cells do not threaten overall health. However, senescence also has a darker side. Judith Campisi’s research has revealed that when the immune system cannot effectively clear these senescent cells, they accumulate in tissues, where they start secreting inflammatory molecules. This condition, known as the Senescence-Associated Secretory Phenotype (SASP), creates a pro-inflammatory environment that, in turn, can turn other healthy cells senescent. While senescence initially acts as a protective mechanism, the buildup of these cells and the inflammation they cause can disrupt tissue health, accelerate aging, and contribute to a variety of age-related diseases. This chronic, low-grade inflammation, often referred to as inflammaging, is a major driver of aging and degenerative conditions. Contenuto dell’articolo Schema of cellular senescence and the SASP. Figure created with BioRender. As we have discussed, research into cellular senescence is now focused on developing interventions that could mitigate its negative effects. Preclinical studies are exploring the use of senolytic and senomorphic drugs: · Senolytics: Substances that aim to eliminate senescent cells. · Senomorphics: Drugs that modify the behavior of senescent cells without eliminating them by reducing their secretion of harmful substances. We will encounter these two terms (senolytic and senomorphic) many times, as several compounds are being developed in the field of longevity with these objectives. In 2021, a team of Italian researchers led by Fabrizio d'Adda di Fagagna, from IFOM in Milan and IGM-CNR in Pavia, published a study in EMBO Reports that explores a new dimension of aging and its relationship to susceptibility to SARS-CoV-2, the virus responsible for the COVID-19 pandemic. The team found that telomere shortening and DNA damage, both of them mechanisms of aging, can increase the expression of angiotensin converting enzyme 2 (ACE2) in the lungs, which is the receptor used by the coronavirus to enter into the cells. This finding may explain why some people are more prone to suffer from severe symptoms from COVID-19. Once again, everything is connected!!! In summary, cellular senescence is a fascinating yet complex hallmark of aging. While it begins as a beneficial process to prevent damaged cells from dividing, the accumulation of these cells and their inflammatory effects pose significant challenges to tissue health and longevity. The 9th Hallmark of Aging is the exhaustion of stem cells, which are the body’s “repair system.” Stem cells are special cells that can divide and transform into various types of cells needed to regenerate and maintain our tissues. As we age, the quantity and functionality of these stem cells decline. This means the body loses its ability to effectively repair damage, regenerate tissues, and respond to injuries or diseases. For example, fewer functioning stem cells can lead to slower wound healing, weaker muscle regeneration, and a reduced ability to replenish blood cells or immune cells. In addition to these changes, aging also changes the environment where these stem cells are located, which are called “niches”. Some niches, such as the stem cell niches located in the brain or in the bone marrow, become pro-inflammatory, triggering mechanisms of cellular senescence amongst stem cells. This decline in stem cell activity is a major contributor to the aging process, as it limits the body’s capacity to maintain and restore itself over time. I have explored already the role of Stem Cells in the 13 Issue, where we discovered that the role of stem cells has become a cornerstone in today’s longevity research. The 10th Hallmark of Aging is altered intercellular communication, which essentially summarizes and connects the effects of all the previous hallmarks. It highlights how aging impacts the way cells, tissues, and organs communicate with one another, leading to systemic dysfunctions. As cells accumulate damage over time—whether due to genomic instability, mitochondrial dysfunction, or telomere shortening—their ability to send and receive accurate signals becomes impaired. This hallmark is closely tied to chronic inflammation (Hallmark 11), often referred to as “inflammaging,” which is triggered by damaged cells that release harmful inflammatory molecules. We’ve already touched on chronic inflammation in Unlock Longevity Issue 4. This pro-inflammatory state disrupts communication between tissues and organs, contributing to aging on a systemic level. For instance, if a primary organ, such as the pancreas, loses its ability to produce essential hormones due to tissue degeneration, this will inevitably affect secondary organs and systems that depend on those hormones. Aging, therefore, is not just a localized process—it is deeply systemic. Interestingly, research shows that reversing damage in one area can have cascading benefits for other parts of the body. An example often cited—though ethically controversial—is parabiosis, an experiment in which the circulatory systems of two animals, one old and one young, are connected. This procedure has shown that the older animal can experience tissue rejuvenation due to factors in the younger animal’s blood, reinforcing the idea that aging is influenced by systemic signals. The last hallmark of aging, Dysbiosis, or microbial imbalance, highlights the critical role of the gut microbiome in systemic health and longevity. These new hallmarks reflect the evolving understanding of aging as a deeply interconnected process that involves not only our cells but also the ecosystems within us, or our hosts. I look forward to dedicating a future newsletter entirely to the microbiome—a fascinating and increasingly discussed topic in the field of longevity. So, I know these three newsletters have been a bit complex, but bravo for following along on this journey! Aging is a deeply intricate process, and together, we’ve explored the biological hallmarks that shape how we grow older. From genomic instability to telomere shortening, epigenetic alterations, loss of proteostasis, disabled macroautophagy, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, altered intercellular communication, chronic inflammation, and dysbiosis, we’ve touched on the key mechanisms driving aging and how they connect to longevity science. Understanding these hallmarks gives us a powerful foundation—not just to appreciate the science, but to make informed choices about health and longevity. There’s still so much to discover, and I’m excited to continue exploring it with you! The "Unlock Longevity" newsletter is my personal contribution to exploring, but most importantly simplifying and making accessible, the themes, techniques, and strategies related to longevity. If you believe these insights could benefit your network, feel free to share this article! This article reflects my personal views and is not intended to replace professional medical advice.

I’m delighted to share this exclusive interview with Dr. Serge Rezzi, a renowned expert in nutritional biochemistry. Currently serving as the CEO of the Swiss Nutrition and Health Foundation (SNHf) in Epalinges, Switzerland, Dr. Rezzi has dedicated his career to advancing our understanding of nutrition, metabolism, and health optimization. With a distinguished background that includes key roles at the Swiss Vitamin Institute and the Nestlé Institute of Health Sciences SA, his expertise spans nutritional status, metabolomics, and personalized health strategies. In this conversation, he shares his perspective on the evolving role of supplementation in longevity, offering valuable insights into what truly makes a difference when it comes to optimizing health for the long term. In recent years, the supplement market has seen unprecedented growth. In your opinion, what are the main factors driving this trend? Is it primarily consumer demand for preventive health, advancements in science, or effective marketing strategies? The main factor is from my point of view the increasing health consciousness of people and this combined with modern lifestyle and nutritional habits that do not systematically warrant adequate intake of nutrients and essential nutrients in particular such as vitamins, trace elements or long chain fatty omega-3 acids. The aging of the population also invites for considering dietary supplements as a way to cope or at least delay ageing associated-physiological processes and increased needs for specific nutrients that may improve wellbeing. So, I would say that this would be first the increase demand for preventive health. Of course, marketing strategies also amplifies a market growth often using, and unfortunately I would say, overpromises or claims that are not substantiated with strong scientific evidence. There is a clear gap for quality science to support health relevance of dietary supplements in general. Supplements are often divided into two categories: those designed to address specific nutritional deficiencies and those formulated to enhance overall health and well-being. Could you clarify the differences between these two approaches and their respective roles in health management? Supplements for Specific Nutritional Deficiencies are intended to meet distinctive nutritional requirements that have been well defined for given physiological or clinical conditions. The aim is therefore to correct well characterised deficiencies related to specific vitamins, minerals, or other essential nutrients. Those supplements or medical nutrition products are prescribed by healthcare professionals based on clinical assessments or diagnostic tests. Examples include iron supplements for anemia or vitamin D for those with limited sun exposure. Supplements for Overall Health and Well-being are general-purpose formulations aiming at supporting and enhancing overall health. Classical examples include OTC products that contain a broad spectrum of vitamins, minerals, and other beneficial biologically active compounds. Those products are consumed as a proactive preventive measure (primary prevention for instance) by health-conscious people who want to secure optimal nutrient intake that are believed to optimize health status often as part of a holistic health approach including healthy lifestyle and diet. While healthcare professional can or should be used to guide such supplement recommendation, many people actually consume such products following a “self-medication” approach with usually a lack of strong scientific evidence. In your expert opinion, what defines a high-quality supplement? Is it the sourcing of ingredients, the bioavailability, the clinical evidence backing its claims, or all of the above? Could you provide an example of a supplement that embodies these principles? What defines a high-quality supplement is a warranty of good quality raw materials that ideally should be independently controlled for quality and of course the availability of clinical evidence backing needs for specific nutrients. A large proportion of dietary supplements show important non-compliance issues. Specifically, it is known that many supplement products on the market do not contain what their label indicate. Independent testing has shown that for instance many micronutrients such as vitamins, minerals and trace elements do not reach the levels announced on the product labels. The root causes of this situation that confuse the consumer but also the possible health benefits of supplements are multiple. First, these causes include the absence of rigorous and mandatory testing and approval processes from the regulatory framework. Second, lack of manufacturing consistencies or standardization leads to substandard production practices and quality control that impact product quality. There is also an inherent ingredient variability, particularly when nutrients are obtained from natural source. Third, there are stability concerns during shelf life of the products with significant impact on nutrient loss (omega-3 fatty acids for instance) but also potentially with generation of unfavourable nutrient byproducts (oxidized molecules). All these factors together with a clear emphasis of company marketing on overpromising claims contribute to a situation where consumers are left with a proliferative product offering with variable quality, lack of independent control and demanding regulatory framework and not to forget, an obvious of scientific evidence for the health benefits of consuming dietary supplements. Your quality control studies have highlighted that many supplements on the market fail to meet their label claims. Can you explain the extent of this issue and how it impacts consumer trust and health outcomes? Possible root causes of product compliance issues were previously introduced. It is estimated, based on studies on vitamins and mineral supplements that at least 40% of the products do not fulfil their composition as declared on their labels. Independent studies to highlight this issue are increasingly conducted to raise consumer awareness. As per today, we see the independent testing and certification as the key to achieve consumer trust and this irrespective of the brands. Given your findings, is it possible that some nutrient deficiencies in individuals who regularly take supplements could stem from poor-quality products rather than dietary insufficiency? If so, what steps can consumers take to avoid this problem? I think it is highly possible that some dietary supplements may fail to adequately correct nutritional deficiencies due their intrinsic quality. This makes total sense when one realizes that posology (dose and frequency of supplement intake) is first driven by the declared nutrient composition. If the composition is not as expected, how can a supplement effectively correct nutritional deficiencies ? How important is the origin and quality of raw materials in determining the effectiveness and safety of a supplement? For instance, are there significant differences in efficacy between synthetic ingredients and those derived from natural sources? The control of the quality throughout the value chain is very important to warrant the compositional quality of the dietary supplement. This begins with a proper selection of the provider of raw materials as well as the definition of a quality system that enables to keep composition under control. This is also important to avoid contamination with undesired substances that may exhibit detrimental effects on health. The use of synthetic ingredients enables an easier control on the ingredient composition and stability. Natural ingredients are more desired by consumers but prone to inherent variability from collection to storage to formulation. The differences between natural and synthetic nutrients such as vitamin C for instance has triggered lot of debate. Natural substances are perceived to be more effective than synthetic by consumer, however if despite the origin the molecule is strictly identical the effect should be the same. Nevertheless, natural substances often carry other molecules that may synergise with the effect of the searched molecule, and in such situation, effect might be different between natural and synthetic ingredients. Many consumers are unaware of the vast differences in quality among supplements. For example, curcumin is often sold in varying grades of purity and bioavailability. How can companies address this knowledge gap and educate consumers about the benefits of investing in higher-quality supplements, despite the higher cost? Companies could increase their transparency on the quality of their ingredients and products making available all proof of quality controls on a regular basis. A powerful approach to gaining transparency and trust with consumers is to opt for independent testing and certification processes to ascertain the compositions (including the origin) of the ingredients and the products. Marketing strategies could leverage the use of independent quality testing to create a competitive gap with products that are not of the same quality. If superior quality can be demonstrated higher cost can be accepted by consumers. Regulatory frameworks for supplements vary widely across countries. Do you think stricter regulations and standardizations are necessary to ensure product safety and efficacy? Or would they stifle innovation in the industry? A more demanding regulatory framework will help better quality and safety of products on the market. Standardization of manufacturing practices across different countries will take lot of time, efforts and is unlikely to be a realist option. In the absence of such regulatory evolution, companies can still play the transparency with consumers opting for independent quality control and certification processes. I believe that this would trigger innovation in the supplement industry as for the time being most of the products follow a rather “me too” strategy with little if no differentiation on scientifically proven quality and efficacy. As personalized nutrition becomes more prominent, how do you see the role of supplements evolving? Could we move towards bespoke formulations tailored to individual genetic, lifestyle, and health profiles, and what challenges would that present for manufacturers and consumers alike? Personalisation, if not rather stratification (formulations addressing the needs of groups of people), is an important trend in the growth of dietary supplements. Formulations tailored for specific lifestyle, just taking cooking habits or sport activity for instance, or even genetic background will become increasingly wanted and popular. The challenges hampering a broad dissemination of value propositions for personalization of dietary supplements are multifaceted. First and foremost, industry is designed to manufacture highly standardized formulations possibly for the greatest number of consumers at the minimal cost. In such a system, increasing the number of stock keeping units (SKU) remains an unfavourable option. Second, personalisation of an offer implies to categorize consumers for customization. In the case of dietary supplements this means the ability to perform accurate diagnostics of nutritional status to set the personalized offer but also and above all to monitor for efficacy. A key challenge for manufacturers remains to manage with efficiency two businesses (manufacturing of supplements and diagnostic business) that are very different in essence. For the consumers, the challenge will be to trustworthy adhere to a supplement personalization program and this is where having strong scientific evidence becomes crucial. Given the widespread use of dietary supplements, do you believe they should play a role in public health initiatives? For example, could supplements targeting specific nutrient gaps (like vitamin D or omega-3) be used to complement traditional healthcare approaches on a population level? I strongly believe in the role of balanced and varied diet with foods having relevant nutrient density is key for primary (prevention of disease) and secondary (management of risk factors) prevention in public health initiatives. In such a context, there should be not much space left for dietary supplements as diet would provide all necessary macro- and micronutrients to people. However, it is not always possible to reach 100% of nutritional adequacy depending on where people live, their socioeconomic status, their health status… Dietary supplements have thus a role to play in reaching nutritional adequacy but at the conditions that their quality is well under control and that scientific data can support their use for maintaining health bodily functions throughout life. One could start indeed by targeting specific nutrients gaps in childhood for instance or in advanced age. Lastly, what advancements or innovations in supplement development are you most excited about? Are there particular ingredients, delivery systems, or technologies that you believe will shape the future of the supplement industry? I am intrigued by finding biomimetic solutions to increase nutrient stability and bioavailability. Encapsulation techniques have shown their ability to improve absorption and control of time release of nutrients. I think that there is an untapped area of agricultural or industrial side streams that one could leverage for production of dietary supplements. Microalgae, microbial or fungal fermentation also offer a broad reservoir of nutrients with the possibility to drive the production of specific nutrient formulations. Finally, AI may have a role to play to design personalized nutrition programs leveraging the exposome, genome and metagenome spaces of individuals. This will hopefully remain under the control of healthcare professional well educated in food and nutrition sciences. The "Unlock Longevity" newsletter is my personal contribution to exploring, but most importantly simplifying and making accessible, the themes, techniques, and strategies related to longevity. If you believe these insights could benefit your network, feel free to share this article! This article reflects my personal views and is not intended to replace professional medical advice.

Intermittent fasting has taken the health world by storm, but it’s far from a modern trend. From religious rituals to survival instincts, fasting has been embedded in human history for centuries. Today, science is uncovering its potential as a powerful tool for metabolic health, longevity, and disease prevention. But is it truly the key to better health, or just another passing craze? Unlike traditional dieting, intermittent fasting isn’t about what you eat—it’s about when you eat. Intermittent fasting is an eating strategy that alternates between fasting and regular eating periods. Unlike caloric restriction, which mandates a continuous reduction in food intake, intermittent fasting allows periods of normal eating, often leading to spontaneous reductions in overall calorie consumption without strict rules. The most common intermittent fasting methods include time-restricted eating, alternate-day fasting, twice-per-week fasting, and periodic fasting. This process shifts the body’s fuel source to ketones, which offer a stable, muscle-preserving energy supply and stimulate cellular repair and stress resilience. This natural adaptation allows the body to use stored energy efficiently and maintain vital functions during food scarcity. As a result, intermittent fasting has shown multiple health benefits, including reductions in body weight, blood glucose, and fasting insulin levels. However, while animal studies suggest possible life-extending effects, these have not yet been proven in humans. Ever wonder why skipping meals can sometimes leave you feeling sharper and more energized? The answer lies in your metabolism. When you fast, your body transitions from burning glucose (sugar) to burning fat, producing molecules called ketones. This shift, known as the “G-to-K switch” (glucose to ketones), typically happens after 12-24 hours of fasting. It allows the body to tap into fat stores for energy while preserving muscle mass and stimulating cellular repair. Contenuto dell’articolo This bioenergetic challenge is closely dependent on physical activity levels, since the switch occurs faster in individuals with high levels of physical activity. When the G-to-K switch is active, there is an increase in circulating ketones, ghrelin, and myokines, while glucose, leptin, insulin, and pro-inflammatory cytokine levels remain low. Autophagy and DNA repair pathways are also enhanced. During these energy-demanding conditions, cells experience a decrease in mammalian target of rapamycin (mTOR) pathway activity and overall protein synthesis (we have already talked about mTor many times now! You should be familiar…). Together, these pathways increase the cellular resilience to stress and support reparation and recycling of damaged cellular components. Research by Dr. Valter Longo and others has shown that this metabolic switch triggers profound benefits: inflammation decreases, insulin sensitivity improves, and cellular resilience strengthens. Fasting also activates autophagy, a self-cleaning process where cells remove damaged components, reducing the risk of chronic diseases. Studies suggest that intermittent fasting can help regenerate the immune system by stimulating the production of new white blood cells. Periodic fasting has been shown to reprogram stem cells and enhance immune balance, a promising discovery for aging and disease prevention. If weight loss, better blood sugar control, and improved cholesterol levels are on your radar, intermittent fasting might be worth considering. Research indicates that it can lower body fat, boost HDL (good) cholesterol, and reduce LDL (bad) cholesterol. Additionally, fasting has been linked to lower fasting glucose and insulin levels, which may help prevent type 2 diabetes. However, some reviews caution that more high-quality studies are needed to confirm these effects in humans. Fasting may also be a heart-healthy habit. Studies suggest it can help lower blood pressure and improve cardiovascular function. A 2024 study found moderate-to-high evidence supporting the role of intermittent fasting in reducing both systolic and diastolic blood pressure. Animal studies have even suggested it could enhance heart function, though further human trials are required. Despite the promising benefits, intermittent fasting isn’t a magic bullet—and it’s not for everyone. Some observational studies link skipping breakfast (a form of time-restricted eating) to increased cardiovascular risk. However, experts argue this could be due to unhealthy lifestyle factors rather than fasting itself. Another hot debate is whether intermittent fasting is truly superior to traditional caloric restriction. Some research suggests the benefits of fasting stem from an overall reduction in calorie intake rather than the fasting period itself. A study in mice found that while intermittent fasting extended lifespan by 11%, a 20% calorie restriction resulted in an 18% increase, and a 40% restriction led to a 36% increase. In human trials, some studies show similar metabolic improvements between fasting and consistent calorie restriction, raising questions about which strategy is more effective. Additionally, longer fasting periods (2-5 days) should be approached with caution. Without proper supervision, extended fasting can lead to nutrient deficiencies, dangerously low blood pressure, and excessive weight loss. Certain groups—including children, pregnant women, and older adults with frailty—should avoid strict fasting protocols. There’s also a lot of buzz around the “fast-mimicking diet,” conceived by Dr. Valter Longo. Let’s take a brief look at what it entails. This approach aims to replicate many of the beneficial metabolic effects of extended fasting—such as enhanced cellular repair, reduced inflammation, and improved insulin sensitivity—without requiring complete abstinence from food. Typically followed for about five days, it focuses on a low-calorie meal plan that limits protein and simple carbohydrates while incorporating healthy fats. By lowering levels of insulin-like growth factor 1 (IGF-1) and inducing mild ketosis, the fast-mimicking diet triggers mechanisms like autophagy and DNA repair while preserving muscle mass and ensuring essential nutrients are still provided. Intermittent fasting is an exciting and evolving area of health science, with potential benefits for metabolism, immunity, and cardiovascular health. However, there is no universal solution—what works for one person may not work for another. The key is personalization, ensuring that fasting aligns with an individual’s lifestyle, health status, and nutritional needs. Regular monitoring of metabolic indicators, such as blood glucose, ketones, and inflammatory markers, would help optimize fasting protocols for safety and effectiveness. As research continues, intermittent fasting remains a fascinating tool for health optimization, but it should always be approached with knowledge and balance. So, is intermittent fasting the future of health, or just another diet trend? The answer likely lies somewhere in between—but one thing’s for sure: the science is worth watching. For those interested in delving deeper into the scientific studies on intermittent fasting, here is a list of key references: Allaf, M. et al. (2021). Intermittent fasting for the prevention of cardiovascular disease. Cochrane Database of Systematic Reviews. Chen, H. et al. (2020). Association between skipping breakfast and risk of cardiovascular disease. Clinical Nutrition. Cheng, C.-W. et al. (2014). Prolonged fasting reduces IGF-1/PKA and promotes hematopoietic-stem-cell-based regeneration. Cell Stem Cell. Colman, R. J. et al. (2009). Caloric restriction delays disease onset and mortality in rhesus monkeys. Science. Di Francesco, A. et al. (2024). Dietary restriction impacts health and lifespan in mice. Nature. Liang, Y. et al. (2018). Caloric restriction and longevity: A meta-analysis. Scientific Reports. Liu, D. et al. (2022). Calorie restriction with or without time-restricted eating in weight loss. New England Journal of Medicine. Longo, V. D. et al. (2021). Intermittent fasting, longevity, and disease. Nature Aging. Longo, V. D., & Mattson, M. P. (2014). Fasting mechanisms and clinical applications. Cell Metabolism. Mattson, M. P. et al. (2018). Intermittent metabolic switching and brain health. Nature Reviews Neuroscience. Prisco, S. Z. et al. (2021). Intermittent fasting enhances right ventricular function in pulmonary hypertension. Journal of the American Heart Association. Santos, H. O. et al. (2022). Intermittent fasting, chronobiology, and metabolism. American Journal of Clinical Nutrition. Sun, M.-L. et al. (2024). Intermittent fasting and health outcomes: A systematic review. EClinicalMedicine. Teong, X. T. et al. (2023). Intermittent fasting and diabetes prevention. Nature Medicine. These references provide further insights into the latest research and ongoing debates on intermittent fasting. The "Unlock Longevity" newsletter is my personal contribution to exploring, but most importantly simplifying and making accessible, the themes, techniques, and strategies related to longevity. If you believe these insights could benefit your network, feel free to share this article! This article reflects my personal views and is not intended to replace professional medical advice.

Last week, an important new study published in the scientific journal Nature Medicine significantly confirmed our understanding of aging and longevity. Environmental and Genetic Architectures of Aging and Mortality by Austin Argentieri and colleagues, revealing that our environment and lifestyle may play a far more significant role in determining health and lifespan than previously thought. While we've long understood that our choices influence our health, this study provides compelling scientific confirmation that we possess even greater control over our health than we might have imagined. And confirm how important what we do, and teach, in our day-to-day practice is! The researchers analyzed data from nearly half a million participants from the UK Biobank, a large, ongoing study following middle-aged adults across the United Kingdom, capturing extensive genetic, lifestyle, and health information. They carried out an exposome-wide association study (EWAS), examining 164 environmental and lifestyle factors—including diet, socioeconomic status, living conditions, and early-life experiences—and assessed their impacts on: All-cause mortality over roughly 12.5 years Biological age, as measured by a proteomic aging clock, a sophisticated biomarker reflecting biological rather than chronological age Incidence of 25 age-related diseases, including heart disease, diabetes, cancer, and dementia, along with biomarkers like cholesterol and blood pressure levels To quantify genetic influence, the researchers computed polygenic risk scores (PRS) for 22 major diseases, allowing them to estimate how much genetic factors contribute to health outcomes compared to environmental and lifestyle influences. Remarkably, the study concluded that lifestyle and environmental factors (collectively termed the "exposome") dramatically outweigh genetics in influencing aging and early mortality risk. Specifically, environmental factors accounted for approximately 17% of the variation in mortality risk, whereas genetic factors explained less than 2% beyond age and sex. This clearly demonstrates that our daily habits, environment, and socio-economic conditions profoundly shape our longevity and quality of life. The researchers identified 25 significant environmental and lifestyle factors consistently linked to higher mortality risk and accelerated biological aging. Prominent among these were smoking, physical inactivity, socioeconomic disadvantages, poor living conditions, dietary choices, and even early-life exposures, such as maternal smoking during pregnancy and childhood body weight. Smoking alone was associated with increased risk for 21 different diseases, while socioeconomic factors impacted 19 conditions. Contenuto dell’articolo Contribution of different factors of the exposome to mortality. The X axis indicates hazard ratios, negative values indicate a protective effect while positive values indicate a detrimental effect. The Y axis indicates the strength of the associations and the higher the value the stronger the association. Figure extracted from Argentieri et al. 2025 The relative influence of genes and environment varied by disease type. The contribution of genetic predispositions was stronger than the exposome contribution to particular diseases, such as neurodegenerative disorders (dementia) and some cancers (breast, prostate, colorectal), accounting for about 10-26% of disease incidence variance. Conversely, lifestyle and environmental factors were dominant in determining risk for major diseases like heart, lung, and liver conditions, explaining up to 49% of disease risk, far surpassing genetic influences. Contenuto dell’articolo Contribution of Age and sex (purple), the exposome (green) and genetics (yellow) to particular disorders. Figure extracted from Argentieri et al. 2025 A particularly striking finding was the enduring impact of early-life exposures. Conditions experienced during childhood or even in the womb, like maternal smoking or childhood obesity, had measurable effects on biological aging and mortality risk decades later. This underscores the critical importance of preventive health measures starting early in life. These findings carry profound implications for public health policy and individual health choices: given that modifiable environmental and lifestyle factors play a dominant role, there's a tremendous opportunity to improve public health dramatically. Initiatives aimed at reducing smoking rates, enhancing nutrition, encouraging regular physical activity, and addressing socioeconomic inequalities and environmental pollution can significantly extend healthy lifespans across entire populations. Importantly, this study emphasizes that we are not merely prisoners of our genetic makeup. Even individuals with a high genetic predisposition to certain diseases can substantially reduce their risk through healthy lifestyle choices and better environmental conditions. The power to shape our health destiny lies largely in our own hands. The research also underscores the importance of a life-course approach to health, emphasizing interventions from as early as prenatal development through childhood. Early life measures such as nutritional support, health education, and preventive care could have profound long-term health benefits, improving outcomes decades into the future. The study has several limitations that should be acknowledged. First, association does not imply causation; observing a correlation between a factor and an outcome does not prove that the factor is responsible for the outcome. Causation can only be established when confounding variables are carefully controlled, as seen in randomized controlled trials. Second, some findings appear paradoxical. For example, Black and Asian participants had lower mortality rates than White participants despite having lower socioeconomic status. However, the authors did not explore this discrepancy further. Third, the genetic analysis did not include rare polymorphisms strongly linked to morbidity and mortality, such as BRCA1/2, due to their underrepresentation in the study population. In conclusion, I'd like to highlight three key pillars central to our philosophy—nutrition, movement, and wellbeing—by summarizing the most impactful findings from this recent study: 1. Movement: A Powerful Ally in Longevity Physical activity emerged as one of the most critical factors in slowing biological aging and reducing mortality risk. Participants with high levels of physical activity showed an impressive 18-32% lower risk of mortality compared to sedentary individuals. Even moderate daily movement, such as walking 7,000-10,000 steps, provided substantial protective effects. Regular exercise reduced biological age by 3-7 years and significantly lowered the risk of several chronic diseases: type 2 diabetes (-42%), cardiovascular diseases (-35%), Alzheimer's (-30%), and certain cancers (-25%). Sedentary lifestyles, conversely, accelerated aging with effects comparable to smoking 15 cigarettes daily. 2. Nutrition: Essential for a Long, Healthy Life Diet proved crucial for longevity, particularly diets rich in fruits, vegetables, fish, plant-based proteins, and healthy fats, reducing mortality risk by 20-28%. Regular intake of oily fish like salmon and mackerel decreased cardiovascular mortality risk by 30%. Mediterranean and Nordic diets offered robust protection for heart and brain health. Mild caloric restriction and intermittent fasting (such as 16:8 or 5:2 patterns) positively influenced metabolism and aging, although not more than a balanced, nutrient-rich diet. Conversely, diets high in refined sugars and ultra-processed foods accelerated biological aging by 4-6 years and significantly increased risks of diabetes (+27%) and cardiovascular diseases (+18%). Interestingly, regular consumption of aged cheeses appeared to slightly boost longevity, possibly due to beneficial effects on gut microbiota. 3. Wellbeing: The Hidden Factor in Longevity Mental health profoundly impacts longevity, with chronic anxiety, depression, and social isolation accelerating biological aging. Individuals with depression had biological ages 2-4 years older than their chronological ages, linked to increased inflammatory markers. Social isolation raised mortality risk by 26%, dementia risk by 29%, and cardiovascular disease risk by 19%. Practices such as meditation, mindfulness, and stress management significantly reduced heart disease risk by 18% and protected cells from aging. Moreover, regular, quality sleep (7-8 hours per night) markedly lowered oxidative stress and inflammation, reducing mortality risk by 22% compared to insufficient sleep. Ultimately, these results confirm that the fountain of youth might just be hiding in plain sight—in our sneakers, our salad bowls, and a good night's sleep. So let's lace up, eat smart, sleep well, and enjoy the exciting adventure of aging gracefully and joyfully! For those interested in exploring the details further, the full study is available in Nature Medicine. The "Unlock Longevity" newsletter is my personal contribution to exploring, but most importantly simplifying and making accessible, the themes, techniques, and strategies related to longevity. If you believe these insights could benefit your network, feel free to share this article! This article reflects my personal views and is not intended to replace professional medical advice. Commenti

Today, we have a super interesting but quite complex topic: we will discuss metabolomics and lipidomics through a special interview with Julijana Ivanisevic. This conversation is designed primarily for professionals and enthusiasts deeply engaged in the field, but as always, allow me to offer you a brief and straightforward introduction to these fascinating concepts. Metabolomics and lipidomics are advanced scientific techniques that enable us to measure and analyze thousands of small molecules known as metabolites and lipids within our bodies. Metabolites can be seen as chemical messengers or building blocks, offering a snapshot of what's truly happening at the cellular level. Imagine the metabolome as a personal chemical fingerprint—it reflects our unique lifestyle choices, dietary habits, environmental exposures, and even genetic makeup. Metabolomics broadly examines a wide variety of these small molecules, providing comprehensive insights into the metabolic activities and overall health status of an individual. Lipidomics, on the other hand, is a specialized branch within metabolomics focusing specifically on lipids such as cholesterol, triglycerides, and fatty acids. These lipids play crucial roles in cell structure, energy storage, and signaling processes, and changes in lipid profiles can significantly impact our health. By using metabolomics and lipidomics, researchers and clinicians can better understand individual health conditions, detect early signs of diseases like diabetes, cardiovascular disorders, and metabolic syndrome, and develop more personalized approaches to treatment, nutrition, and lifestyle management. Enjoy the interview! What exactly is metabolomics, and how would you describe it to someone with no scientific background? Metabolomics is a technological approach used to characterize and measure small molecules or metabolites, including lipids. A great example of metabolites routinely measured in clinics are glucose and cholesterol, markers of diabetes and dyslipidaemia, respectively. Far beyond glucose and cholesterol, today, with metabolomics, we can measure thousands of metabolites along with lipids, in a wide variety of biological samples, including all different biofluids (blood plasma, serum, whole blood, urine, cerebrospinal fluid, tears, saliva, sweat, seminal fluid, breast milk, etc.), tissue and cell extracts. Importantly, today, due to significant advancements in technology, metabolomics allows us not only to measure the highly abundant nutrients implicated in “energy flow” (energy production and storage) but also the low abundant messenger metabolites responsible for “information flow” through chemical signaling. The acquired comprehensive metabolic profiles reflect our chemical individuality (because of polymorphisms in our DNA sequence and lifestyle exposures unique to each individual). Can you explain what metabolites are and why they are important for understanding the human body? Metabolites are known as building blocks of structural components of cells (e.g., macromolecules, cell membranes), or fuels for cellular energetics (amino acids and other organic acids, sugars, lipids, energy currency metabolites, etc.). They are often qualified as downstream products of gene and protein activity, and therefore, the biomarkers of the functional status of an organism. Besides these well-known roles described in biochemistry books, recent findings have shed the light on metabolite activity showing that metabolites are likely “body’s most important signaling molecules” (David Wishart, Physiological reviews, 2019). Indeed, metabolites play the paramount role in the regulation of gene expression and protein activity, and modulate cell differentiation, growth, activation, proliferation and death. Thereby, they actively regulate and drive multiple biological processes including DNA repair, epigenetic modifications, autophagy, nutrient sensing, maintenance of mitochondrial function and microbiome balance, immune response and inflammation (https://www.nature.com/articles/s41580-019-0108-4, https://www.nature.com/articles/s41580-022-00572-w). How does metabolomics help us understand what’s happening in the body at a cellular level? Through the measurement of metabolite levels and/or tracing the fate of stable isotope-labelled substrates/nutrients (i.e., isotopic profiling), metabolomics provides us the readout of cellular activity. This readout helps us understand which pathways are more/less active in which cells and/or physiological conditions. The activity or utilization of specific pathways (glycolysis, oxidative phosphorylation, de novo lipid synthesis, lipolysis, fatty acid oxidation, etc.) provides the information about the cellular status and function. What makes metabolomics different from studying genes (genomics) or proteins (proteomics)? We often like to say that the information in genes is inherited, and the genotype describes the potential of the system or “what may happen”, the proteins “what makes it happen” while the metabolites tell us “what has indeed happened”, describing the current functional (physiological or developmental) status of the studied system. Therefore, metabolomics complements the information provided by genomics and proteomics by increasing the functional understanding of the studied system (a cell, an organ, or an organism). Importantly, our metabolome (e.g., circulatory metabolite levels) is not only genetically determined but also strongly influenced by different environmental stimuli such as our diet, physically active or sedentary lifestyle, drug therapy, pollutants, toxicants or climate we are exposed to, our internal microbiome, etc. These environmental stimuli include the social interactions we are involved in or exposed to. Why is metabolomics often referred to as the "closest layer to the phenotype"? What does this mean in practical terms? Metabolome can be defined as a phenotype at the molecular level or endophenotype. As such, the information stored in metabolite levels represents an intermediary phenotype which can be used to explain the biology behind the associations revealed between the genes (i.e., gene variants) and complex, endpoint clinical phenotypes (i.e., different cardiometabolic or neurodegenerative diseases, as well as different cancer types). Importantly, the so-called metabotype (in analogy to genotype) is genetically less complex (compared to clinical outcomes) but equally heritable. How are metabolites measured? What kind of technologies or tools do you use in metabolomics research? Metabolites can be measured using multiple technologies, approaches and methodologies. The most widely used technologies for ‘omics-scale metabolite measurement are mass spectrometry (MS) and nuclear magnetic resonance (NMR) spectroscopy. While NMR is endowed with high measurement reproducibility (essentially because there is of direct interaction between the sample and the instrument), it lacks the sensitivity. It is well suited for the analysis of “dirty” samples such as urine and plasma in the context of large-scale population studies. Mass spectrometry, either through direct injection analysis (DIA) or coupled to separation techniques such as gas or liquid chromatography (GC or LC), offers a significantly wider metabolome coverage, due to enhanced measurement sensitivity and specificity. We use mainly LC-MS which is recognized as the most versatile technology for metabolite measurement. With LC-MS, today, we can measure thousands of metabolites (including lipids) with more sensitivity and specificity than ever before. What are some challenges in collecting and analyzing metabolites from biological samples like blood or urine? Main challenges are related to sampling time and compliance, sample handling and storage. The plasma samples, for example, should be collected in the same physiological state, ideally, in a postabsorptive or fasting state, or alternatively, within the same time delay following a meal (i.e., postprandial state). This is important to avoid introducing bias due to diurnal variation in metabolite levels and the feeding regimen. For sample handling and storage, one should pay attention to how long after sample collection samples can be stored. Ideally, the sample aliquots should be snap frozen and stored at –80°C as soon as possible to avoid the residual enzymatic activity and metabolite degradation (or other chemical modifications such as oxidation, for example). It is known that some metabolites are not stable and prone to spontaneous chemical oxidation, however, this has not been systematically evaluated for the entire set of polar and lipid metabolites. The accurate quantification of chemically unstable metabolites is challenging due to presence of artefacts, and thus, they are not good biomarker candidates. In addition, one should pay attention to the collection tubes, all the samples should be collected in the same tubes, coated with same anticoagulants, to avoid differences in matrix effects which can bias the measurement. Finally, the freeze-thaw cycles should be avoided because they can induce metabolite degradation and/or other chemical modifications, as highlighted above. For clinical applications, the metabolite analysis should be performed using validated quantitative approaches, ideally with authentic internal standards. This was nicely demonstrated in the latest interlaboratory study to which we have also participated: https://www.nature.com/articles/s41467-024-52087-x. Is metabolomics a snapshot of a person’s current health, or can it also reveal long-term patterns? Metabolite levels can be readily altered as a response to short-term stimuli in the external (e.g., exposure to specific toxicants or drugs, cold stress, fasting) or internal environment (e.g., acute infection or inflammation, changes in microbiome, hypoxia while holding breath), but metabolites also get depleted or accumulated over longer periods of time, with aging and/or chronic exposure to specific lifestyle factors (e.g., dietary patterns such as the excessive calory supply via high fat or high sugar intake, sedentary lifestyle and related low-grade inflammation, pollutants). Therefore, metabolomic signatures can provide both the person’s current health status (nutritional status, metabolic imbalance such as diabetes or dyslipidemia, toxic exposure) but they can also reveal the long-term health patterns; this depends on the experimental design. To reveal the long-term trends, the longitudinal data, or repeated measurements over time, are necessary. Although, cross-sectional case-control studies can also be used to identify the individuals at risk. There are multiple metabolite markers, such as ceramides or branch chain amino acids, which have been identified as diabetogenic and atherogenic when they accumulate over longer periods of time or chronically. Changes in ceramide levels, for example, can be detected much earlier, before the manifestation of traditional clinical symptoms (i.e., high cholesterol). This is why metabolomics (along with lipidomics) represents a powerful phenotyping tool for personalized health monitoring. What is lipidomics, and how does it fit within the broader field of metabolomics? Lipidomics is a branch of metabolomics, which focuses on lipid analysis. Lipids are classified as small molecule metabolites, mainly < 1700 Da in molecular weight. As nicely specified on Lipid Maps website, lipids are “a broad group of naturally occurring molecules which includes fatty acids, waxes, eicosanoids, monoglycerides, diglycerides, triglycerides, phospholipids, sphingolipids, sterols, terpenes, prenols, fat-soluble vitamins (such as vitamins A, D, E and K) and others” (https://www.lipidmaps.org/resources/education/classification). While the principle of analysis is very similar to polar metabolites, we must apply more non-polar solvents for lipid extraction (compared to polar metabolites) and adjust the analytical conditions for lipid analysis (i.e., solvents, chromatographic gradients, etc.). The optimization of extraction and analysis conditions is a current practice in the analytical chemistry field, depending on the targeted class of metabolites. Why are lipids (fats) so critical for understanding diseases like diabetes or cardiovascular conditions? Ever since the Framingham Heart Study revealed the tight association between the circulatory cholesterol and the risk of heart disease, lipid measurement has become the mainstay of cardiometabolic risk assessment. Lipid metabolism, with respect to lipid functional roles in energy production and storage, membrane integrity and as messenger molecules in the inflammation process, immune response or insulin signaling, is obviously tightly associated with our cardiometabolic health. Therefore, depending on their biological roles, representatives of specific lipid classes can have a beneficial or deleterious effect on our cardiometabolic health. Importantly, this effect is not only lipid class, but lipid species dependent; and structurally closely related species, even stereoisomers, can have distinct biological roles and be associated with distinct metabolic consequences. Further mechanistic understanding of the roles that lipids play in the onset, development and progression of cardiometabolic diseases (such as obesity, diabetes and cardiovascular disorders) but also neurodegenerative diseases, and cancer, will be useful to improve the disease risk prediction, diagnostics, prognostics as well as the presumed therapeutic strategies. What are ceramides, and why are they considered harmful in the context of cardiometabolic health? Ten years ago, using a global sphingolipid profiling, specific species of ceramides were revealed to be strongly positively associated with the risk of cardiovascular death in coronary artery disease (CAD) patients (independently of traditional risk factors). The prognostic value using ratios of four distinct ceramides was found to be superior to the currently used standard LDL-C measurement. Following this discovery, a high-throughput analytical assay for ceramides was optimized, Coronary Event Risk Test 1 (CERT1) was established by Zora Biosciences and the results were cross-validated in several independent prospective CAD cohorts. Furthermore, the relative risk estimates were finely tuned for different risk categories in an independent large-scale population study. Distinct ceramide species were confirmed to be significantly associated with the incidence of major adverse cardiovascular events in apparently healthy individuals. In parallel, in 2016, Mayo clinic was licensed and introduced the CERT1 score to the clinical routine. However, and despite of the fact that ceramide scores have already been introduced to some private clinics, we still don’t know enough about the ceramide mode of action, and further intervention and fundamental studies are necessary to gather more data, and mechanistic insights, at least before ceramides become new cholesterol. What we do know is that ceramides mediate atherosclerosis via promotion of low-density lipoprotein (LDL) aggregation and their uptake into macrophages which drive foam cell formation and vascular inflammation. They are also implicated in endothelial dysfunction, by the enhancement of superoxide production and by reducing the bioavailability of nitric oxide. Finally, they were also found to promote insulin resistance, mitochondrial function impairment and cell “suicide” or apoptosis. Importantly, ceramides are present in human plasma at low micromolar levels and therefore, the sensitive MS-based technique is necessary for their quantification (compared to enzymatic assays used to measure cholesterol and other bulk components of plasma lipidome). How does the body produce and regulate lipids, and what happens when this regulation goes wrong? Lipid production (or synthesis), dietary intake, storage and utilization (or catabolism) are coordinated through a complex interplay of metabolic pathways (i.e., lipogenesis, lipolysis) and transport (via lipoproteins), involving primarily liver, adipose tissue and cardiovascular system (blood circulation). Master regulators of lipogenesis, lipolysis and lipid transport are hormones, enzymes, and complex feedback mechanisms. Lipid production or de novo lipogenesis occurs mainly in the liver and adipose tissue, where excess carbohydrates are converted into fatty acids. The key enzyme involved is fatty acid synthase (FAS), which catalyzes the synthesis of palmitate (C16:0) from acetyl-CoA and malonyl-CoA. Fatty acids (synthesized or taken from diet) must get further activated (by forming fatty acyl-CoA) for their assembly into triglycerides or esterification, by the attachment to the glycerol (specifically glycerol-3-phoshate) backbone (a product of glycolysis). In adipose tissue, triglycerides are stored as fat droplets and, in the liver, they are packed into very-low-density lipoproteins (VLDL) to enable their transport in the blood. The lipogenesis is promoted by insulin (after meals) and inhibited by glucagon and epinephrine which promote the breakdown of triglycerides during fasting or exercise. The key enzymes involved in lipid catabolism include the hormone-sensitive lipase (HSL) which catalyzes the breakdown of stored triglycerides in adipose tissue; and lipoprotein lipase (LPL) which hydrolyzes triglycerides in lipoproteins, thus facilitating the uptake of fatty acids by tissues. To resume, lipid synthesis, storage and utilization (or catabolism) are regulated by hormones, essentially insulin, which promotes lipid synthesis and storage while glucagon and epinephrine stimulate lipolysis, the breakdown of triglycerides into free fatty acids and glycerol. Other hormones, such as cortisol and growth hormone, also influence lipid metabolism. Cortisol can either promote the breakdown of triglycerides or their storage, depending on the stress duration and intensity (i.e., cortisol levels). Another two hormones secreted by adipose tissue, adiponectin and leptin, play key roles in the regulation of lipid metabolism. Adiponectin or “fat-burning” hormone promotes breakdown of triglycerides and fatty acid oxidation (in liver and muscle). Leptin regulates satiety, food intake and promotes lipolysis (when the energy levels are sufficient). Beyond hormones and enzymes, feedback mechanisms are also employed to maintain lipid homeostasis. For example, high levels of circulatory fatty acids can inhibit further lipogenesis and stimulate oxidation. The aim of lipid regulation is to ensure the steady supply of lipids for energy while simultaneously preventing excessive accumulation that could lead to specific cardiometabolic pathologies such as obesity, diabetes and cardiovascular disorders. Deregulated lipid metabolism over longer periods of time leads to obesity (excessive lipid storage or accumulation due to increased lipogenesis or decreased lipolysis), to dyslipidemia (abnormal levels of lipids in the blood, such as high triglycerides or low HDL cholesterol, resulting from genetic factors or poor diet/lifestyle), to atherosclerosis or the formation of plaques in blood vessels, increasing the risk of heart attacks and strokes. Excessive accumulation of fat in the liver can induce a Non-Alcoholic Fatty Liver Disease (NAFLD) often leading to inflammation, insulin resistance and metabolic syndrome. Chronic obesity and inflammation can lead to a metabolic syndrome, a cluster of conditions, including hypertension, high blood sugar, excess body fat around the waist, and abnormal cholesterol levels, which increases the risk of heart disease, stroke, and diabetes. In the context of our research projects, we continue to decipher the molecular mechanisms underlying lipid (de)regulation and the presumed therapeutic strategies. How can metabolomics help diagnose diseases earlier than traditional medical tests? Metabolomics allows us to measure metabolites with more specificity and sensitivity than ever before. This means that with the latest mass spectrometry technology, we can detect subtle changes in early metabolite biomarkers (in blood or urine, for example), which are physiologically relevant and will allow us to diagnose the disease onset or early disease stages far before conventional diagnostic assays (which are much less sensitive and specific). For example, ceramides, powerful biomarkers of cardiometabolic risk, are present in the blood at concentrations thousands of times lower than cholesterol. Their accumulation in blood precedes the changes in cholesterol levels and have been proven to identify individuals at risk before cholesterol levels change and before clinical symptoms appear. This can boost the people’s awareness and induce earlier intervention (when changes are reversible and easier to operate) with lifestyle changes or drug treatment (like statins or ceramide-targeting therapies). Can metabolomics be used to track the effectiveness of lifestyle changes or medical treatments in real-time? Yes, metabolomic profiling is ideally situated as a powerful phenotyping tool for monitoring the health status, including the response to lifestyle changes or medical treatments. The set of identified/selected biomarker metabolites (e.g., amino acids, lipids, microbiome-derived metabolites) can be easily measured over time to track the changes in their levels which can inform us about the effectiveness of specific dietary regimen, physical activity, etc. Even more, the dose and duration of treatment can be adjusted as a function of individual’s response. This type of dynamic monitoring allows for the design of personalized interventions, based on patient's unique metabolic response. What role does metabolomics play in understanding chronic diseases like obesity, diabetes, and heart disease? The capacity to record the biochemical readout of cellular activity makes metabolomics a powerful tool for early diagnosis, disease progression tracking, and personalized treatment. Beyond the biomarker-based health and disease monitoring, this biochemical readout of metabolite levels also provides insights into coordinated changes in biochemical pathways (involving measured intermediates as substrates and products of specific chemical reactions) associated with the phenotype under investigation. The up- or down-regulation of specific pathways (deduced from changes in metabolite levels, stable-isotope enrichment assays or multi-omics data integration) can help us to elucidate the molecular mechanisms that underlie the disease onset and progression. This is how the ceramide metabolism, branched-chain amino acid metabolism, short-chain fatty acid metabolism, circulating lactate, ketone bodies, oxidized lipids, etc. were positively or negatively associated with specific metabolic processes and disease states. This metabolomics data-derived information helps us to understand the metabolic consequences (i.e., deleterious or beneficial effects) of specific metabolite(s) accumulation or depletion and associated pathway activity/utilization in different physiological conditions. How does metabolomics help in identifying biomarkers for diseases? Could these biomarkers eventually guide personalized treatments? As highlighted above, metabolomics allows for simultaneous measurement of a wide range of polar and lipid metabolites in biologically relevant samples such as urine, blood, other biofluids and tissue lysates (e.g., muscle or adipose tissue biopsies). As such, the acquired metabolic signatures capture the dynamic variations in metabolite levels which can be due to disease onset or environmental exposures, or both. The metabolites whose levels change significantly in response to an exposure (e.g., drug treatment) or confirmed disease (compared to apparently healthy control group) can be used as biomarkers, indicative of specific disease state or metabolic response to exposure. The correlation, and ideally, the causality, between the biomarker change and the outcome must be demonstrated with the appropriately designed and statistically powerful studies. In brief, metabolomics provides a comprehensive and dynamic view on metabolic changes which can be associated with specific physiological states that precede the disease onset, facilitating the identification of biomarkers that can improve risk prediction, diagnostic accuracy and treatment. The observed metabolic changes are unique to each individual and thus, the metabolic signatures are ideally suited to support the design of tailored or personalized intervention strategies and prognosis. For example, metabolic signatures can be used to predict the response to treatment or stratify the population to responders or non-responders (to specific treatment), or fast or slow metabolizers (depending on the genetically determined enzymatic activity), etc. Specific metabolite deficiency or accumulation can inform us about individual’s metabolic needs and help to design the dietary regimens or recommend interventions through nutrition and/or physical activity. Metabolic profiling using metabolomics can also help to determine the most adequate or personalized drug dosage. Does metabolomics provide insights into how people age differently? Could it help us slow down or reverse aging? Along with sex and hormonal status, the age is considered as the main determinant of our circulatory metabolic profiles. The levels of multiple polar and lipid metabolites have been shown to either accumulate (e.g., ceramides, oxidized lipids, branched-chain amino acids, acylcarnitines) or get depleted (e.g., NAD+, taurine, spermidine) with aging. This is one of the reasons why it’s usually very challenging to disentangle the age effect from the disease effect. Studies on centenarians have demonstrated that they have unique circulatory signatures, often enriched in protective lipids (e.g., plasmalogens) and antioxidants. Metabolic signatures are highly individualized and can help us to deduce how different individuals might age differently based on their lifestyle choices, such as dietary regimen or physically active vs. sedentary lifestyle. By identifying the metabolites with “protective” or deleterious effect, metabolomics can guide the design of interventions to promote healthy aging. These interventions comprise the specific dietary strategies (e.g., mediterranean diet, intermittent fasting or caloric restriction), supplementation with metabolites which decline with aging (and have been positively associated with cell renewal, autophagy, mitochondrial function, microbiome diversity, etc.), physical activity therapies, sleep optimization, etc. Can lipid profiles reveal individual risks for diseases like heart attacks or strokes, and how can we act on this information? Lipidomic profiles at the molecular species level are indicative of cardiovascular risk, and can predict, with high accuracy, the incidence of cardiovascular events. As described above, multiple lipid species, such as ceramides, specific phosphatidylcholines, triacylglycerols and pro-inflammatory oxidized phospholipids, have been identified as diabetogenic and atherogenic, i.e., strongly positively associated with insulin resistance, atherosclerosis and plaque instability, increasing heart attack and stroke risk. Importantly, these lipidomic signatures can predict the cardiometabolic risk in apparently healthy population, and the risk of cardiovascular events in coronary artery disease patients, with more sensitivity and accuracy compared to traditional lipid assays (based on bulk lipid measures). Finally, lipidomic data can be integrated with other clinical parameters (e.g., blood pressure, glucose levels, genetic factors) to further improve the risk assessment. This multi-faceted approach enhances further the accuracy of cardiovascular risk prediction. Lifestyle changes, such as dietary strategies to increase the intake of unsaturated fats and lower the intake of processed foods (with high-sugar and saturated lipid content), regular physical activity and intermittent fasting, as well as medical interventions (e.g., statins, PCSK9 inhibitors) can help to reduce the established risk. Regular lipidomic assessments can help monitor the effectiveness of these interventions in reducing cardiovascular risk. How do diet, exercise, and lifestyle choices influence metabolomic profiles, especially lipid levels? Diet, exercise, and lifestyle choices significantly influence metabolomic along with lipidomic profiles, through various metabolic pathways and processes. For example, the type of consumed lipids (saturated vs. unsaturated) can alter circulatory lipid profiles. The diet rich in refined sugars can lead to accumulation of triacylglycerols. On contrary, certain vitamins (e.g., vitamin E) and phytochemicals (e.g., polyphenols from fruits and vegetables) have antioxidant properties that protect against lipid peroxidation. Regular exercise can also improve the lipid profiles by reducing the “bad” fat such as specific ceramides. For example, high-intensity interval training (HIIT) has been shown to effectively reduce triacylglycerols and increase HDL levels. Smoking was also proven to be associated with lower HDL levels and higher LDL levels, while moderate alcohol consumption may increase HDL levels. Stress hormones like cortisol can promote fat accumulation and alter lipid profiles. The interplay between diet, exercise, and other lifestyle choices strongly influences metabolomic profiles, particularly lipid levels. Personalized approaches considering these factors can help in managing and preventing metabolic disorders. Could metabolomics eventually lead to "metabolic coaching," where individuals get tailored advice based on their unique metabolite profiles? Metabolomics is a promising phenotyping tool for "metabolic coaching" where individuals receive tailored advice based on their unique gene and lifestyle determinants and therefore, unique metabolite profiles. Metabolomic and particularly lipidomic signatures are highly individualized, compared to transcriptomic and proteomic profiles. As specified above, by analyzing the individual’s metabolomic/lipidomic profiles, including the identified biomarkers (of specific disease states), nutritionists, sports and internal medicine physicians, and other healthcare providers will be able to tailor interventions that align with the individual's needs to improve metabolic health. The metabolomic profiles will help to design specific dietary regimens (e.g., low carbohydrate), and optimize training programs for weight loss, muscle gain, or overall health improvement. The integration of metabolomics with self-sampling and wearable devices will facilitate real-time monitoring of metabolic changes. This data can be used to adjust dietary, and exercise plans dynamically, providing ongoing support and motivation for individuals. Metabolic coaching could play a significant role in preventive health strategies, by identifying risk factors early, enhancing individual’s awareness and boosting patient’s adherence to amenable lifestyle changes before the onset of metabolic diseases. For metabolic coaching to become mainstream, the clinical utility based on the relationship between metabolite profiles and health outcomes, must be proven across multiple large-scale, longitudinal population studies, including individuals with different ethnic and clinical backgrounds. The integration of metabolomics into clinical practice is highly relevant and will lead to enhanced quality of life or healthy lifespan. Two key messages can be extracted from this interview. First, the importance of metabolomics in tracking health, since they can be used to understand both the person’s current health status and their long-term health trajectory. The second key message is that metabolites are highly modifiable through diet, exercise, and lifestyle choices, emphasizing their dynamism. This malleability has significant implications for preventive health strategies, and it could eventually lead to the emergence of a new longevity field of application : metabolic coaching. The "Unlock Longevity" newsletter is my personal contribution to exploring, but most importantly simplifying and making accessible, the themes, techniques, and strategies related to longevity. If you believe these insights could benefit your network, feel free to share this article! This article reflects my personal views and is not intended to replace professional medical advice. Commenti

Dear Readers, Following the last edition, which delved deeply into the science of aging, I’d like to shift the focus to something less technical but equally fascinating—something that has always intrigued me in my personal and professional journey. Throughout my life, I have met many individuals who have reached old age in exceptional health, full of energy and vitality. What has always struck me is that, beyond genetics and lifestyle, they all seem to share a specific mental attitude. Similarly, some of the most successful entrepreneurs, elite athletes, and high-performing individuals I have encountered exhibit common psychological traits that appear to contribute to their resilience and longevity. While it is challenging to scientifically prove every aspect of what I am about to share, my personal experience—alongside a growing body of research—suggests that a longevity mindset plays a crucial role in how we age. This is a topic I will continue to explore in future editions, but for now, let’s dive into four key traits that seem to define those who live longer, healthier lives. 1. Curiosity: The Desire to Keep Learning and Growing One of the most consistent traits I’ve noticed in long-lived individuals is an insatiable curiosity. They are deeply interested in life, eager to learn new things, and open to new experiences. This isn’t just anecdotal—science supports the idea that curiosity is linked to longevity. Studies have shown that people who remain curious tend to live longer. A five-year study found that those who scored higher on curiosity had a significantly higher survival rate compared to their less curious counterparts. Even after adjusting for other health factors, individuals with a strong interest in learning and exploration were more likely to be alive at the end of the study period. Curiosity also brings cognitive benefits. Research suggests that older adults who stay mentally engaged and continue to seek out new knowledge tend to have better memory, greater emotional well-being, and a more resilient brain. An active, inquisitive mind doesn’t just make life more interesting—it also appears to support brain health and longevity. Contenuto dell’articolo 2. Positivity: The Power of an Optimistic Outlook Another defining trait of those who age well is a positive mindset. The most energetic and fulfilled older individuals I’ve met tend to approach life with optimism and a sense of possibility. Science backs this up: optimism has been consistently linked to a longer lifespan. Large-scale studies have found that optimistic individuals live 11–15% longer on average and have significantly higher chances of reaching 85 or beyond. What’s even more remarkable is that this holds true regardless of health conditions, depression, or lifestyle factors like diet and exercise. In one study of over 150,000 U.S. women aged 50–79, the most optimistic participants had a 5.4% longer lifespan and were 10% more likely to live past 90 than those in the least optimistic group. These findings suggest that focusing on positive psychological traits—rather than just physical health markers—may be an overlooked but powerful strategy for healthy aging. Ultimately, optimism appears to buffer against stress, improve overall well-being, and contribute to better health outcomes. It’s not just about seeing the glass half full—it’s about fostering a mindset that supports longevity on a biological level. 3. A Strong Sense of Purpose: Knowing Your "Why" Many of the individuals I’ve seen thriving in old age have one thing in common: they have a clear sense of purpose. Even in their later years, they remain engaged in activities that give them meaning, whether through work, creative projects, community involvement, or personal passions. Research has shown that individuals with a clear sense of direction in life tend to live significantly longer. A study of 7,000 middle-aged and older adults in the U.S. found that those with the lowest sense of purpose had more than double the risk of dying compared to those with a strong sense of purpose. Similarly, a five-year study of 1,200 elderly participants showed that individuals with a strong life purpose had a 40% lower mortality risk, even after controlling for factors like health conditions and income. Having a purpose isn’t just a motivational concept—it has tangible physiological benefits. It reduces stress, promotes healthier behaviors, and improves overall biological function, all of which contribute to a longer, more fulfilling life. Contenuto dell’articolo 4. Adaptability: Embracing Change with Resilience Finally, one of the most striking characteristics I’ve observed in long-lived individuals is their adaptability. As we age, we naturally tend to become more rigid—not only physically (which is why I always recommend yoga!) but also in our thinking, habits, and willingness to embrace change. However, those who continue to challenge themselves, travel, engage in meaningful work, and stay open to new experiences seem to have a greater capacity for longevity. Adaptability is closely linked to resilience, the ability to adjust to life’s challenges and transitions. Studies of centenarians (people aged 100+) have found that a common trait among them is a "go-with-the-flow" attitude. They tend to approach difficulties with a problem-solving mindset rather than resistance, allowing them to navigate change with less stress. Research has also linked low neuroticism (the tendency to remain calm and emotionally stable) with a longer lifespan. In my experience and observations, curiosity, positivity, purpose, and adaptability consistently emerge as common traits among individuals who live long, vibrant lives ….While we often focus on physical health and lifestyle choices in longevity maybe the mind plays an equally crucial role? In future newsletters, I will continue to explore the longevity mindset, diving deeper into the psychological and emotional factors that influence how we age. I'll also examine traits that limit our potential for longevity, such as inconsistency, disorganization, and procrastination—habits that drain our energy and negatively impact our health. Until then, I encourage you to reflect on these traits in your own life—where do you see curiosity, optimism, purpose, and adaptability playing a role? And how can you nurture them further? The path to longevity isn’t just about living longer—it’s about living better. What do we live FOR? The "Unlock Longevity" newsletter is my personal contribution to exploring, but most importantly simplifying and making accessible, the themes, techniques, and strategies related to longevity. If you believe these insights could benefit your network, feel free to share this article! This article reflects my personal views and is not intended to replace professional medical advice. Commenti

At Clinique La Prairie, we believe that the journey to better health starts long before treatment begins—and continues well after it ends. To dive deeper into what this really means, I sat down with Henri Magistretti, our Longevity Patient Experience Lead. He’s at the heart of shaping how our clients experience care, and in this conversation, he shares how rethinking the traditional patient journey can lead to more personalized, proactive, and ultimately transformative health outcomes. Simone: Henry, thanks for joining me today. Let's dive straight in. In traditional healthcare, we often hear about the "patient journey." Can you explain exactly what that entails? Henry: Of course. The patient journey in traditional healthcare refers to all the steps a patient experiences—from first realizing there's a medical issue, through the treatment itself, to the follow-up care afterward. It's about the full spectrum of interactions, like initial consultations, booking treatments, and even billing. The goal is to ensure patients feel guided and supported throughout the process. Simone: Why is mapping out this journey considered so essential? Henry: There are two main reasons. Firstly, operational efficiency. Understanding the patient journey allows healthcare providers to optimize resources, plan effectively, and streamline procedures. Secondly, it provides crucial insights for improving patient care quality. Identifying any gaps or challenges enables providers to enhance the overall patient experience. Simone: Can you describe a typical patient journey in traditional healthcare? Henry: Certainly. It typically starts with the patient recognizing a health issue and contacting a healthcare provider—this is the initial contact. Next, the provider schedules an appointment, ideally including a preliminary consultation. When the patient arrives, there's usually a welcoming stage, followed by a detailed explanation of the treatment plan. After the treatment, there's an evaluation phase where feedback is collected, and follow-up guidance is provided. Regular communication often continues to support ongoing patient care. Simone: How does a patient-focused approach enhance this journey? Henry: A patient-focused approach ensures each step is centered around the patient's needs, improving outcomes significantly. When patients clearly understand their conditions and treatments, they're more likely to adhere to medical guidance and engage proactively with preventive measures. Simone: You mentioned feedback earlier. How important is patient feedback, and how is it typically collected? Henry: Patient feedback is extremely valuable. Healthcare providers often use satisfaction surveys, online reviews, and direct patient interactions to gather feedback. This information helps identify specific areas needing improvement and informs how services are adapted and delivered. Simone: Communication seems to play a crucial role in healthcare outcomes. Could you elaborate? Henry: Clear communication is fundamental. As mentionned previously, I would like to reiterate the concept of when patients truly grasp their conditions and treatment options, they become active partners in their own health, leading to better outcome. Effective communication ensures patients follow treatments accurately and helps providers deliver better-coordinated, higher-quality, patient-centric integrative care. Simone: How do healthcare providers maintain continuity of care throughout the patient journey? Henry: Continuity relies on effective collaboration among all parties involved—doctors, nurses, care coordinators, and administrative staff. Clear and consistent information sharing, along with standardized processes and protocols, helps ensure smooth transitions between treatment stages. Care coordinators often serve as central points of contact, helping patients navigate the healthcare system seamlessly. Simone: Emerging technologies are reshaping healthcare. How do they impact the patient journey? Henry: Technology is revolutionizing the patient journey - making care smarter, faster and more personalized than ever before. New tech innovations can support preventive care through advanced diagnostic and AI-driven tools in order to reduce misdiagnosis rates for example. It allows healthcare providers to deliver more personalized treatments and maintain proactive patient engagement. Simone: Looking ahead, let's discuss how the patient journey might evolve, particularly in the context of longevity-focused care. How do you see this developing? Henry: I envision the patient journey in longevity care becoming much more proactive, personalized, and preventive. Longevity-focused healthcare shifts the emphasis from merely treating illnesses to actively maintaining health over the long term. Providers will integrate advanced diagnostics, personalized health assessments, and predictive analytics to identify potential health risks early. This allows healthcare professionals to craft highly individualized treatment plans that encompass lifestyle changes, nutritional guidance, targeted supplements, and exercise regimens. To sum up, longevity-focused care is about empowering individuals to take charge of their health like never before. With the right strategies and innovations, we're not just extending life - we're redefing what healthy aging looks like. The "Unlock Longevity" newsletter is my personal contribution to exploring, but most importantly simplifying and making accessible, the themes, techniques, and strategies related to longevity. If you believe these insights could benefit your network, feel free to share this article! This article reflects my personal views and is not intended to replace professional medical advice. Commenti

Imagine if each bite you take could literally add or subtract minutes from your healthy lifespan. This intriguing idea is at the heart of a groundbreaking study led by Dr. Katerina Stylianou at the University of Michigan, published in Nature Food (2021). I've read extensively about this research in recent years, and I'd love to share what makes it both fascinating and practically significant. The study analyzed over 5,800 foods commonly consumed in the U.S., measuring their impacts on health—in terms of healthy life minutes gained or lost—and their environmental footprint. Unlike previous research, this study uniquely combines health and sustainability into one clear, intuitive metric. Researchers developed the Health Nutritional Index (HENI), which quantifies how specific foods can either extend or shorten periods of disease-free living. The results were striking: eating one hot dog could potentially cost you 36 minutes of healthy life, while conversely, a 30g serving of nuts or seeds might add about 25-26 minutes. Overall, the effects ranged dramatically from +80 minutes to -74 minutes per portion. Importantly, the findings emphasize patterns and consistent choices rather than isolated indulgences—highlighting how even minor adjustments compound significantly over time. To simplify these insights, the researchers created a straightforward "traffic-light" labeling system for food choices, clearly categorizing foods based on their combined health and environmental impact. Foods that fall into the "Green Zone," such as fresh fruits like apples and berries, field-grown vegetables, legumes, whole grains, nuts, seeds, and sustainably sourced small fish like sardines and anchovies, offer dual benefits for both health and the planet. These "win-win" foods enhance our longevity while minimizing environmental harm. Foods in the "Yellow Zone," including poultry, eggs, dairy products, farmed fish, certain greenhouse-grown vegetables, and plant-based processed foods, have a more nuanced profile. They can still play a valuable role in a healthy diet, but their overall impact depends heavily on context, quantity, and production practices. Conversely, the "Red Zone" foods—processed meats such as hot dogs and bacon, red meats including beef and lamb, pork, farmed shrimp, sugar-sweetened beverages, and energy-intensive greenhouse-grown vegetables—are identified as particularly harmful both to our health and to environmental sustainability. These items should ideally be limited or enjoyed only occasionally. Encouragingly, the study suggests even small dietary shifts—such as replacing just 10% of daily calories from red meat with plant-based alternatives—could add about 48 minutes of healthy life daily and reduce dietary carbon footprints by a third. Over decades, these tiny adjustments could cumulatively add an entire extra year of vibrant health. As study co-author Prof. Olivier Jolliet states, “Small, targeted changes offer a powerful and practical path to better health and a better planet.” While the study offers inspiring practical advice, experts caution that some methodological limitations should temper how we interpret the results. Firstly, the research uses population-level averages to predict individual outcomes, an approach critics call overly simplistic. While useful for general guidance, these averages can't capture individual variability influenced by genetics, lifestyle, and personal dietary habits. Additionally, there’s considerable uncertainty inherent in combining complex nutritional and environmental models, leading critics to suggest the precise minute-by-minute calculations (e.g., losing 36 minutes per hot dog) could be misleadingly exact. Further critiques highlight gaps in risk factor selection. For example, ultra-processed foods and added sugars weren’t fully accounted for, meaning some unhealthy items might inaccurately appear neutral or harmless. Nutrition scientists also emphasize the importance of overall dietary patterns rather than isolated food items. While single-food swaps illustrate the potential benefits clearly, long-term dietary habits matter more significantly. Experts also noted that HENI doesn’t fully capture the nutritional complexities of foods—such as essential vitamins, minerals, and protein quality. This oversight led to counterintuitive results, like sugary snacks appearing neutral, or peanut butter and jelly sandwiches scoring better than certain healthy proteins. Additionally, the simplistic categorization of red and processed meats ignores nuanced differences between lean, unprocessed meats and highly processed variants, potentially oversimplifying health risks. The study’s vivid "minutes-of-life" framing successfully grabbed attention but inadvertently encouraged literal interpretations—leading to sensational media headlines and public misconceptions. Experts and fact-checkers have since clarified that these numbers represent statistical averages rather than immediate personal consequences. The "traffic-light" system, while intuitive, also risks oversimplifying complex nutritional and environmental trade-offs, potentially misguiding consumers. Despite critiques, many acknowledge the study’s valuable contribution in sparking broader discussions about diet, health, and sustainability. Nutritionists and public health experts emphasize focusing on balanced, overall dietary patterns rather than becoming fixated on specific foods. Dr. Stylianou’s research presents a compelling new framework for understanding the health and environmental impacts of our food choices. While not perfect, it offers actionable insights: making modest dietary adjustments toward plant-based foods can significantly enhance our healthspan and sustainability. Recognizing the study's limitations allows us to appreciate its core message without losing sight of practical and balanced eating habits, encouraging us to thoughtfully approach each meal as an opportunity for positive change. The "Unlock Longevity" newsletter is my personal contribution to exploring, but most importantly simplifying and making accessible, the themes, techniques, and strategies related to longevity. If you believe these insights could benefit your network, feel free to share this article! This article reflects my personal views and is not intended to replace professional medical advice. Commenti

The idea of longevity is no longer a futuristic vision reserved for science labs and think tanks. It is becoming one of the defining economic forces of our century. And yet, its growth is not loud or theatrical—it’s quiet, steady, and profoundly transformative. It reshapes how we think about value creation, how governments shape public health policy, how businesses design services, and how individuals envision their future. In 2023, the global wellness economy reached $6.3 trillion. But what’s striking isn’t just the magnitude—it’s the distribution. Over 90% of this value is concentrated in North America, Europe, and Asia-Pacific. North America leads in absolute numbers, with the United States alone accounting for over $2 trillion. Americans now spend more than $6,000 per year, per person, on wellness. The consumer wellness market, as McKinsey outlines, stands at $480 billion with annual growth rates between 5% and 10%. And this figure reflects only a fraction of the broader longevity economy, which also includes biotech therapies, regenerative clinics, wellness travel, and precision nutrition. In Europe, the story is different—but equally revealing. While the continent accounts for approximately $1.65 trillion—about 26% of the global wellness economy—it stands out for its cultural authority and institutional infrastructure. Countries like Switzerland, Germany, France, and Italy are home to some of the world’s most iconic medical spas and longevity clinics. The rebound after the pandemic has been not only strong but also qualitative: the European wellness market reached 125% of its 2019 levels, driven by a renewed emphasis on integrative medicine, natural supplements, anti-aging skincare, and high-end wellness retreats. Supplement consumption alone in Europe exceeded $40 billion in 2023, while herbal and botanical products grew steadily at 5–7% per year. But if we are to understand the future, we must look to Asia-Pacific. With a market valued at $1.88 trillion in 2023—already matching and poised to overtake Europe—this region is on a fast-track trajectory. The reasons are both demographic and economic. By 2050, one in four people in Asia will be over 60. In China alone, the over-60 population surpassed 321 million in 2024. And that figure is just the beginning. Estimates suggest that by 2040, over 200 million Chinese consumers aged 50+ will enter the market with dramatically increased health awareness and spending capacity. The country’s silver economy, valued at over $900 billion in 2023, is forecast to grow beyond $4 trillion by 2035. Add to that a cultural openness to innovation, state-backed investment in biotech and AI, and rapid adoption of genomic testing, and the picture is clear: Asia-Pacific is becoming the epicenter of the global longevity economy. Of course, other regions are not standing still. The Middle East, Latin America, and Africa, though representing a smaller share of the pie—roughly $600 billion collectively—are showing high-growth potential. The Gulf states are rapidly positioning themselves as hubs for luxury wellness and preventive medicine, with post-pandemic recovery reaching 130% of 2019 levels. Brazil and Mexico are leading the Latin American market, driven by a growing middle class and rising demand for supplements, fitness, and cosmetic procedures. These regions, though less mature, benefit from one powerful advantage: exponential momentum. It’s important to note that these figures represent an aggregated estimate covering a wide array of sectors—not solely focused on clinical longevity. They include everything from beauty and skincare to fitness, gym memberships, spas, nutritional supplements, and mental wellness services. While longevity is becoming a central theme within this broader wellness economy, the boundaries are still fluid, and definitions vary significantly across reports and institutions. These numbers should therefore be read as directional rather than absolute. For sure, traditional healthcare systems are not designed to meet this emerging demand. That’s why the private sector—from startups to multinationals—is stepping in to offer longevity solutions that combine medicine, technology, and lifestyle. And it's why the boundaries between biotech, wellness, and consumer health are blurring. The result? A new global economy where health is not just a service but an investment class, not just a personal priority but a geopolitical lever. As investors scan the horizon for resilient, purpose-driven industries, the data is unambiguous. The longevity economy is one of the few sectors poised to grow across all continents, all age groups, and all income levels. It addresses the needs of aging populations, the aspirations of the health-conscious young, and the systemic pressures facing our healthcare systems. And unlike many other industries, it is not dependent on hype or sentiment—it is grounded in measurable demand, long-term trends, and fundamental human needs. Yet it’s important to recognize a key truth: despite the sector’s size and growth potential, the number of clients truly ready to invest significantly in a structured and serious longevity journey remains limited. High-end, personalized longevity care is still a niche, not a mass-market phenomenon. Similarly, the number of business models that have demonstrated genuine economic sustainability in this field is still small. Longevity is not a “sell it and scale it” model—it’s complex, highly personalized, and requires long-term engagement and trust. This is why vision and courage are no longer enough. The future of longevity demands seriousness and professionalism. It calls for leaders who can balance innovation with evidence, aspiration with operational discipline, storytelling with scientific rigor. As the market matures, the real opportunity lies in building models that are not only inspiring, but also enduring. What does this mean for decision-makers, entrepreneurs, and thought leaders? That now is the time to engage—not just as observers, but as contributors. The transformation is already underway, not in theory, but in transactions, habits, clinical protocols, and regulatory shifts. We can all be part of this mission to create a better life. Sources: Global Wellness Institute – Global Wellness Economy Monitor 2024; McKinsey & Company – The Future of Wellness Survey 2024; European Spa Magazine – Global Wellness Market Insights 2023–2024; Grand View Research – Anti-Aging Products Market Size & Trends, 2023; Brookings Institution – China’s Emerging Silver Economy and Aging Population Forecast; GII Research – Therapeutic Longevity Treatments Global Market 2023; Technavio – Global Health & Wellness Market Growth Forecast 2024–2028; Asian Development Bank – Aging Asia: Demographic Trends and Economic Impact Report 2023; Statista – Wellness Tourism and Medical Spa Market Growth Projections 2023–2030. The "Unlock Longevity" newsletter is my personal contribution to exploring, but most importantly simplifying and making accessible, the themes, techniques, and strategies related to longevity. If you believe these insights could benefit your network, feel free to share this article! This article reflects my personal views and is not intended to replace professional medical advice. Commenti

Imagine standing nearly naked in a chamber cooled to around -130°C. Icy vapor swirls around your body, and within seconds your skin prickles as if caught in a winter storm. Your first instinct is to gasp – the cold is breathtaking, literally – yet you feel oddly exhilarated. This is whole-body cryotherapy: a brief, intense exposure to extreme cold that lasts just two or three minutes. As the countdown begins, your body’s ancient survival mechanisms kick in, turning this frosty ordeal into a cascade of remarkable biological reactions. At these ultra-low temperatures, the body thinks it’s in serious danger of freezing. Sensors in your skin send alarm signals that trigger the fight-or-flight response – an automatic survival reflex. In an effort to protect your core, blood vessels in your limbs constrict, shunting warm blood toward vital organs in your chest and abdomen . Your heart rate may quicken and you release a surge of adrenaline and noradrenaline, sharpening your alertness. This hormonal rush also prompts the release of endorphins – the body’s natural painkillers and mood elevators . In the moment, you hardly notice these invisible changes; you’re focused on enduring the cold by hopping lightly in place as lively music in the chamber distracts you from the chill. Yet inside, your body is orchestrating a powerful defense: constricting blood flow, ramping up metabolism, and preparing to heal. After what feels like an eternity (but is in reality only a few minutes), the session ends. You step out and warm air floods over your skin, which has cooled by only a few degrees despite the Arctic conditions. As your body senses safety, the blood vessels rapidly reopen, and blood flow returns to your hands and feet. Flush with freshly oxygenated, nutrient-rich blood, your muscles and tissues are rejuvenated . Many people describe an almost euphoric rebound feeling at this point – a rush of energy and calm happiness that can last for hours after the session. In fact, participants in one study often reported elevated mood and vigor immediately after cryotherapy, a kind of “runner’s high” achieved through cold instead of exercise . This isn’t just imagination: the biochemical cocktail released during extreme cold exposure (adrenaline, endorphins, and other neurotransmitters) truly can leave you feeling invigorated and clear-headed once you re-emerge into warmth Contenuto dell’articolo For an elite athlete nursing tired muscles or an older adult seeking relief from arthritis, this immediate payoff is a big part of cryotherapy’s appeal. The extreme cold acts like an accelerated ice pack for the entire body, numbing nerve endings and reducing swelling. Cryotherapy as a healing practice actually dates back decades: it was first developed in 1978 by Dr. Toshima Yamaguchi in Japan as a way to help patients with rheumatoid arthritis . By briefly exposing patients to subzero temperatures, he found he could significantly reduce joint pain and inflammation. Today’s whole-body cryotherapy builds on that idea, enclosing the person in a chamber chilled by liquid nitrogen or electricity for a short burst. The treatment has swept into the mainstream of sports medicine – from NBA locker rooms to Olympic training centers – because it’s been shown to speed up muscle recovery and ease soreness after intense exercise. In fact, studies confirm that a quick freeze session can act as a potent anti-inflammatory and pain-relieving therapy, helping the body bounce back faster from muscle trauma and overuse . By taming the microscopic tears and inflammation that follow hard workouts, cryotherapy not only aids recovery but can also prevent some of the usual next-day muscle ache if used shortly after exercise . No wonder so many pro athletes and fitness enthusiasts have made it a routine part of their regimen. When used regularly, cryotherapy seems to nudge the body into a state of lower overall inflammation – a biological change that could have profound implications for long-term health and longevity. Numerous studies have found that whole-body cryotherapy can dial down key markers of chronic inflammation in the blood. For example, sessions of extreme cold have been shown to significantly reduce levels of C-reactive protein (CRP) and inflammatory cytokines like interleukin-6 (IL-6) – substances that, when elevated, contribute to systemic inflammation and many age-related diseases . One pilot study in healthy adults noted that after repeated cryotherapy sessions, participants had measurably lower CRP, suggesting their bodies were maintaining a calmer inflammatory state over time . Patients with severe arthritis not only report feeling better, but blood tests show fewer inflammatory signals after regular cryo sessions . By effectively putting out these “invisible fires” in the body, cryotherapy is tackling what scientists sometimes call inflammaging (weh ave seen it in previous Newsletter) – the chronic, low-grade inflammation that accompanies aging and degenerative diseases. Beyond quelling inflammation, stepping into the cold may spark a beneficial adaptation at the cellular level – one that mirrors the effects of other longevity-boosting practices like exercise or fasting. The extreme stimulus of cold is a form of hormetic stress: a short, tolerable shock that triggers the body to grow stronger in response. Just as lifting weights causes muscles to adapt by growing, repeated cryotherapy seems to push our cells to bolster their own defense mechanisms. Researchers have observed, for example, that after a series of cryotherapy sessions, the body ramps up its production of antioxidants. Enzymes such as superoxide dismutase and glutathione peroxidase – our cells’ front-line defenders against harmful free radicals – become more active, especially in individuals who undergo cryotherapy regularly . In essence, a few minutes shivering in the chamber may be nudging your cells into an anti-aging mode – clearing out damaged molecules, boosting resilience, and enhancing repair processes. Over time, this could translate into better overall vitality: less oxidative damage accumulating in your tissues and a body that bounces back more quickly from daily stresses. Contenuto dell’articolo The metabolic effects of cryotherapy are another piece of this longevity puzzle. When you expose the body to intense cold, it has to work harder to maintain its core temperature. This thermogenic demand means you’re burning extra calories during and after the session – a fact not lost on those looking to manage weight. But more interestingly, cold exposure can activate brown adipose tissue, commonly known as brown fat . Unlike the energy-storing white fat that many of us struggle with, brown fat’s job is to burn energy to produce heat. It’s packed with mitochondria (the power plants of cells), and when switched on, it draws fuel (sugars and fats) from the blood to incinerate calories and warm the body. Whole-body cryotherapy essentially bio-hacks this system: studies indicate that cold is one of the most effective ways to stimulate brown fat activity and increase this fuel consumption . In fact, the physiological stress of cold looks a lot like exercise in some ways – one review noted that cryotherapy can mimic exercise by triggering the release of certain molecules (like myokines from muscles) and could be harnessed to complement workouts in combating obesity and metabolic disease . While cryotherapy alone is not a magic weight-loss cure, this activation of brown fat and metabolic pathways adds to the therapy’s whole-body benefits. It’s important to remember that, like any intervention, cryotherapy is not a panacea. It works best as one component of a holistic approach to health – alongside smart nutrition, exercise, and medical care where needed. However, cryotherapy is not without risks. Mild side effects, such as transient skin redness or numbness, are common, yet manageable. Serious complications, although rare, can occur—particularly if protocols are neglected or unsuitable candidates undergo treatment. Cardiovascular responses, respiratory risks from nitrogen-cooled chambers, and skin reactions like frostbite or cold urticaria highlight the necessity of careful screening and supervision. In conclusion, while cryotherapy is generally safe for healthy individuals when proper protocols are followed, it is not without risk. Most side effects are mild and manageable, but serious complications can occur if precautions are neglected or inappropriate candidates are treated. Until stronger clinical validation emerges, WBC should be considered a complementary wellness intervention, applied under professional supervision and with full awareness of its limitations and potential hazards. The lack of formal medical regulation means that the quality and safety of centers can vary widely. Institutions like the FDA have cautioned that, while preliminary results are promising, definitive evidence is still limited, and adverse effects—although rare—must be taken seriously. Their warnings highlight the need for continued research, through larger, rigorously controlled clinical trials, to better define therapeutic indications, optimal protocols, and biological mechanisms. The "Unlock Longevity" newsletter is my personal contribution to exploring, but most importantly simplifying and making accessible, the themes, techniques, and strategies related to longevity. If you believe these insights could benefit your network, feel free to share this article! This article reflects my personal views and is not intended to replace professional medical advice. Commenti

In this edition of my Unlock Longevity newsletter, I’m proud to feature a thought-provoking conversation with Prof. Patrizia D’Amelio, a leading expert in gerontology, member of Clinique La Prairie’s Scientific Committee, and practicing clinician at CHUV. With a deep understanding of aging from both a clinical and molecular perspective, Prof. D’Amelio offers a compelling look into the evolving science of healthy aging. 1. What does "Healthy Aging" mean, and what are its main components? Healthy aging refers to the process of maintaining physical, mental, and social well-being as individuals grow older. Its main components include: Physical health: Maintaining mobility, strength, and a low burden of chronic diseases. Cognitive health: Preserving memory, decision-making, and mental resilience. Social engagement: Staying connected to family, friends, and the community. Psychological well-being: Managing stress, ensuring emotional stability, and maintaining a sense of purpose. 2. The World Health Organization introduced the concept of "Intrinsic Capacity." Can you explain what it is and how it applies in clinical practice? Intrinsic capacity is the composite of an individual’s physical and mental capacities, reflecting their functional abilities. It encompasses domains such as cognition, mobility, vitality, sensory function, and psychological well-being. In clinical practice: It guides comprehensive assessments of older adults. Promotes interventions targeting reversible declines (e.g., nutritional support or physical therapy). Helps in designing personalized care plans to optimize aging outcomes. 3. Can you illustrate the "Evolutionary Theory of Healthy Aging" and how it differs from the "Biological Theory of Aging"? Evolutionary Theory: Suggests that the way we age is influenced by our intrauterine and perinatal life, stating that the availability of nutrients and the perinatal environment can deeply influence the pathway to aging through epigenetic modifications. Biological Theory: Focuses on cellular and molecular mechanisms such as DNA damage, telomere shortening, and mitochondrial dysfunction as causes of aging. 4. Mitochondria are often referred to as the "powerhouses" of cells. Can you explain their role and why they are fundamental to cellular health? Mitochondria generate ATP through oxidative phosphorylation, providing energy for cellular functions. They also: Produce reactive oxygen species (ROS), signaling molecules but also potential sources of damage. Participate in calcium homeostasis and metabolic integration. 5. Is there a mitochondrial-based theory of aging? How does this theory unify different observations about aging? Yes, the Mitochondrial Theory of Aging posits that mitochondrial DNA damage and altered membrane permeability leads to dysfunction, decreased energy production, and increased ROS, accelerating cellular aging. It unifies aging theories by explaining energy deficits in tissues like muscles and brain, linking increased oxidative stress to DNA damage and integrates with theories of immunosenescence and chronic inflammation/"inflammaging". 6. Are we currently able to measure biological age? How reliable are the biomarkers available? We can measure several markers, both at the biological and clinical levels, that are associated with biological age, such as: • Epigenetic clocks (e.g., Horvath clock): Based on DNA methylation patterns. • Telomere length: An indicator of cellular aging. • Mitochondrial function: ATP production efficiency. While promising, these biomarkers vary in reliability and require further validation for routine clinical use. • Hand grip strength • Four-meter walking test However, today we cannot definitively measure biological age in an effective way, but only some indicators of this variable. 7. How would you define old age, and what does the term "frail aging" mean? Old age: Traditionally referred to as individuals aged 65+, however, in recent years several societies have proposed shifting this threshold towards 75 years due to the general aging of society. Moreover, it is important to underline that functional age varies widely. Frail aging: A state of increased vulnerability due to reduced physiological reserves, characterized by weight loss, fatigue, weakness, slow walking speed, and low activity. This can be associated with, or without, cognitive impairment. 8. What are T-cells, and what is their role in the immune system? T-cells are lymphocytes critical for adaptive immunity. Their roles include: Recognizing and destroying infected or cancerous cells (cytotoxic T-cells). Regulating immune responses (helper T-cells). Maintaining immune tolerance (regulatory T-cells). 9. Can you explain the concept of immunosenescence and how it affects immune function in older adults? As we get older, our immune system gradually becomes less effective—a process known as immunosenescence. This means we produce fewer fresh T-cells to fight new infections, and many of the T-cells we do have become "worn out" and less useful. As a result, our bodies don’t respond as well to vaccines and are more vulnerable to infections. On top of that, aging immune cells start releasing more inflammatory substances, which can contribute to chronic health problems. 10. Is there a correlation between immunosenescence and T-cells? How does this relationship impact the aging process? Yes, immunosenescence heavily impacts T-cells: Thymic involution reduces naïve T-cell output. Senescent T-cells contribute to chronic inflammation (inflammaging). This weakens the immune defense and promotes age-related diseases. Moreover senescent and pro-inflammatory T cells can be responsible for chronic diseases associated to unhealthy aging as osteoporosis 11. Do you believe that mitochondrial dysfunction is connected to immunosenescence and the aging process? Absolutely. Mitochondrial dysfunction leads to: Energy deficits in immune cells. ROS accumulation, exacerbating inflammation. Impaired T-cell activation and proliferation. This tight connection accelerates both immunosenescence and aging. 12. Is it possible to improve mitochondrial function? If so, what strategies are currently considered effective? Yes, strategies include: Exercise: Promotes mitochondrial biogenesis. Dietary interventions: With dietary supplements of whole proteins or branched-chain amino acids, with or without cholecalciferol. Supplements: CoQ10, NAD+ precursors (e.g., NR or NMN), and antioxidants. 13. Can you tell us more about branched-chain amino acids (BCAAs) and their impact on mitochondrial health? BCAAs (leucine, isoleucine, and valine) support mitochondrial biogenesis by activating the mTOR pathway, thus improving energy metabolism and reducing muscle wasting. We have recently demonstrated that supplementation with BCAAs is effective in increasing muscle strength and performance, ameliorating general health and cognition in older malnourished patients, as compared with sole dietary intervention. 14. Are the data on the efficacy of urolithin in humans conclusive? What are the future prospects for this compound? Current data show promising results for urolithin A, particularly in improving mitochondrial health and muscle endurance. However, to propose this supplement for humans, future research is needed to clarify its long-term benefits, optimal doses, and broader applications, especially in older adults. 15. How do you respond to critics who argue that dietary supplements are ineffective in improving mitochondrial function? Evidence supports the use of targeted supplements (e.g., BCAAs, NAD+ precursors, CoQ10) in specific contexts. However, it must be emphasized that supplements are meant to complement, not replace, lifestyle changes. Additionally, their efficacy varies depending on individual biology and dosage.. 16. How can nutrition positively influence mitochondrial function? Are there specific nutrients or diets that support mitochondrial health? Nutritional strategies sustaining longevity and influence mitochondrial function are Mediterranean diet: Rich in antioxidants and anti-inflammatory compounds found in foods such as olive oil, tomatoes, leafy greens, nuts, legumes, and fatty fish. This diet helps protect mitochondria from oxidative stress and supports overall metabolic health. Omega-3 fatty acids: Improve mitochondrial membrane integrity and function. Excellent sources include salmon, sardines, chia seeds, flaxseeds, and walnuts. Polyphenols: Plant compounds that enhance mitochondrial biogenesis and protect against cellular damage. Found in dark berries (like blueberries and blackberries), green tea, dark chocolate, and red wine (in moderation). Branched-Chain Amino Acids (BCAAs): Improve mitochondrial biogenesis by activating the mTOR pathway, thus enhancing energy metabolism. BCAAs are found in dairy products, eggs, chicken, beef, and protein supplements. 17. Is there a connection between mitochondrial function and dementia? What scientific evidence supports this relationship? Yes, there is a mitochondrial theory explaining the development of Alzheimer’s disease. Mitochondrial dysfunction is implicated in dementia through several pathways. Energy deficits impair neuronal function, while the accumulation of reactive oxygen species (ROS) damages neuronal structures, exacerbating neurodegeneration and increasing neuroinflammation. Some studies have demonstrated reduced mitochondrial efficiency in mouse models and in patients with Alzheimer’s disease. The "Unlock Longevity" newsletter is my personal contribution to exploring, but most importantly simplifying and making accessible, the themes, techniques, and strategies related to longevity. If you believe these insights could benefit your network, feel free to share this article! This article reflects my personal views and is not intended to replace professional medical advice. Commenti

I entered the Longevity field because I believe in the possibility of a healthier, longer life—for everyone. But the more I immerse myself in this field, the more I see just how uneven the playing field still is. Advancing longevity isn’t just about scientific breakthroughs—it’s also about confronting inequities that continue to define populations. As professionals in this space, we can’t afford to turn a blind eye to the stark disparities in life expectancy across the globe. This article is about those imbalances—particularly the nutritional challenges faced by different populations, societies, and regions. It’s meant to challenge assumptions, raise uncomfortable questions, and push us toward a more inclusive vision of what it means to live not only longer—but better. I hope it sparks reflection, action, and meaningful dialogue toward a future where longevity is a possibility for all, not just a privilege for the few. Imagine two children born on the same day. One is in Japan, a country where average life expectancy tops 84 years – one of the highest in the world. The other is in Lesotho, where life expectancy is barely over 50. This staggering 33-year gap in lifespan is not a quirk of genetics or fate. It is the result of stark global inequalities. According to a World Health Organization (WHO) report, people in the country with the highest life expectancy (Japan) live on average 33 years longer than those in the country with the lowest (Lesotho) . Such a gulf, while narrower than in 2008, remains an alarming reminder that where you are born can determine how long you live. In this edition of Unlock Longevity, we explore how environmental and nutritional inequalities are driving this divide – and what can be done to bridge it. The difference between Japan and Lesotho is the extreme tip of a broader trend: wealthier nations generally enjoy far longer lifespans than poorer ones. WHO’s latest report on health equity warns that progress in closing this gap has been far too slow. Children born in low-income countries remain 15 times more likely to die before their fifth birthday than those born in high-income countries. Eliminating such inequalities could save the lives of an estimated 1.8 million children under five each year. Furthermore, the WHO notes that health disparities are not only international but also intranational – they exist within countries, between rich and poor communities. In the United Kingdom, for example, men in the most deprived areas live almost 10 years fewer on average than men in the wealthiest areas (women about 8 years fewer). In the United States, the richest 1% outlive the poorest 1% by over 14 years for men (and 10 years for women). But what lies at the heart of these inequities? Two major pieces of the puzzle are our environment and our nutrition. Contenuto dell’articolo One key driver of the life expectancy gap is the environmental conditions in which people live. Clean air, safe drinking water, and a non-toxic habitat are fundamental to a long, healthy life – yet these basics are starkly lacking in many parts of the world. Air pollution alone is now responsible for an astonishing number of premature deaths. A recent Lancet study found that pollution (from air, water, soil, and workplaces) causes about 9 million deaths per year worldwide, or one in six total deaths. The burden falls heaviest on low- and middle-income countries undergoing rapid industrialization. South Asia, for instance, faces some of the worst air quality in the world. Water and soil tell a similar story. Access to clean water and sanitation is a dividing line between long life and early death. Diseases like cholera, dysentery, and typhoid fever – practically unheard of in wealthy nations – still thrive where water is contaminated. Some 1 million people die each year from diarrheal illnesses due to unsafe water, sanitation, and hygiene. Then there is the overarching environmental threat of our era: climate change. Climate change is not a distant speculation – it is hitting vulnerable populations now, through heatwaves, crop failures, and extreme weather. The WHO projects that between 2030 and 2050, climate change will cause an additional 250,000 deaths per year globally, through impacts like malnutrition, malaria, diarrhea, and heat stress. Climate change is a risk multiplier that exacerbates all other environmental challenges: it worsens air pollution (through wildfires and dust), undermines water and food security, and can spark conflicts over resources. The cruel irony is that the populations who contribute the least to global greenhouse gas emissions – for example, rural villagers in Somalia or Bangladesh – are among those suffering the most from climate-related losses. As WHO Director-General Tedros Adhanom Ghebreyesus has emphasized, achieving health equity now requires tackling this climate emergency alongside traditional health measures. We cannot truly unlock longevity for all without healing the environments in which people live. Just as critical as the air we breathe is the food we eat. Nutrition is the fuel for life, and its absence (or poor quality) is a major reason why some lives are cut short. Paradoxically, the world today faces a double nutrition challenge: undernutrition in poorer regions and overnutrition (obesity) in wealthier ones – sometimes even within the same country or community. Both extremes take years off people’s lives. In low-income countries, hunger and undernutrition remain deadly scourges. Children are the most vulnerable: nearly half of all deaths in children under 5 worldwide can be attributed to undernutrition, which weakens their immune systems and makes common infections lethal. Globally, about 149 million children are stunted (chronically undernourished) – a sobering indicator of persistent deprivation. Undernutrition in childhood raises the risk of health problems like diabetes and hypertension in adulthood, compounding the cycle of ill health. At the other end of the spectrum, obesity and diet-related diseases have surged, becoming leading killers in middle- and high-income populations. Poor diets – high in sugar, unhealthy fats, and salt, and low in fruits, vegetables, and whole grains – are now a top risk factor for death globally. In fact, one landmark study in The Lancet found that 11 million deaths worldwide in 2017 were attributable to poor diets, accounting for one in five deaths overall. These deaths largely stem from cardiovascular diseases, diabetes, and cancers that are linked to obesity and dietary habits. We often associate obesity with wealthy countries like the United States (where over 40% of adults are obese) or the United Kingdom (around 28% obese), and indeed these countries have seen life expectancy gains stall or reverse partly because of lifestyle-related conditions. For instance, the U.S. – despite its wealth – has a lower life expectancy than many peer nations, due in part to a high burden of heart disease, diabetes, and even “deaths of despair” (such as drug overdoses) that often accompany social inequalities and unhealthy living. However, the nutrition transition is a global phenomenon: many developing countries now face a “double burden” of malnutrition. It is not uncommon to find communities where some families struggle with undernutrition while others face rising obesity as cheap processed foods become available. South Asia for example grapples with high child stunting alongside an epidemic of adult diabetes. The common thread is a shift away from traditional, wholesome diets toward ultra-processed, high-calorie, low-nutrient foods – often because these are the most affordable or aggressively marketed options for poorer communities. The result is shorter lives: an overweight teenager today may develop type 2 diabetes by their 30s and heart disease by their 50s, potentially living a shorter life than their parents did despite living in a richer world. As the Global Nutrition Report has pointed out, no country is currently on track to meet all global nutrition targets; in fact, every country now experiences some form of malnutrition, be it hunger, micronutrient deficiency, or obesity. Nutrition is a cornerstone of longevity: you cannot live a long life if, for extended periods, your body doesn’t get the nutrients it needs or if it’s inundated with harmful foods. As one Lancet Commission starkly noted, we are in the midst of a “Global Syndemic” of obesity, undernutrition, and climate change – different forms of malnutrition and environmental stress that overlap and feed into each other. This syndemic is driven by systemic factors like agricultural policies, food industries, and urban planning. For example, globalized food systems have made cheap calories abundant at the expense of nutrition, even as they contribute to environmental damage. Thus, the worlds of environment and nutrition collide: climate change worsens hunger; industrial food systems worsen climate change and push unhealthy diets; poverty and inequality make both problems hardest to bear. It’s a vicious cycle. Closing a life expectancy gap of decades is no simple task – but it is one of the defining moral and practical challenges of our time. The good news is that we know many of the solutions. What’s needed is the collective will to implement them. The WHO Director-General has called for “a concerted effort to address the complex web of social, economic, environmental and political factors that impact health”. In practical terms, this means governments must prioritize the basics of well-being just as much as they prioritize economic growth or national security. Ensuring clean air and water isn’t a luxury; it’s as fundamental as defense. Policies to reduce air pollution could save millions of lives. Investing in water and sanitation infrastructure, from urban slums to remote villages, yields massive health dividends (and economic benefits too, by reducing healthcare costs and improving productivity). On the nutrition front, global and local leaders need to build food systems that deliver healthy diets for all. Education campaigns and policies to discourage sugary drinks and ultra-processed junk (for example, taxing soda or regulating marketing to children) have shown promise in countries like Mexico and Chile. Wellness leaders and the healthcare sector also have roles to play. Hospitals and clinics can screen patients for food insecurity or environmental exposures and connect at-risk families to assistance. Pioneering doctors and wellness practitioners are increasingly “social prescribers,” advocating not just medicine, but access to parks, exercise programs, and healthy cooking classes as part of treating patients. Organizations focused on longevity can leverage their expertise and influence to push for preventive care and holistic health approaches in the mainstream. As professionals in the field, but also as global citizens we must take the opportunity to share our voice on these essential topics. Whenever there is a chance to speak about nutrition, preventive medicine, movement, and healthy living, we have to take it. Even small contributions matter when the goal is as important as helping more people live longer, healthier lives. The "Unlock Longevity" newsletter is my personal contribution to exploring, but most importantly simplifying and making accessible, the themes, techniques, and strategies related to longevity. If you believe these insights could benefit your network, feel free to share this article! This article reflects my personal views and is not intended to replace professional medical advice. Commenti

Modern supermarkets are filled with foods that have been processed to some degree – from frozen vegetables to packaged ramen. In essence, a processed food is any food altered from its original form, whether by chopping, pasteurizing, freezing, or adding ingredients. Nearly all foods undergo some processing, and many processed foods are wholesome (for example, dried beans or plain yogurt). However, nutrition experts today warn that how a food is processed – and how much – makes a crucial difference. This is where the term “ultra-processed foods” comes in. The concept of ultra-processed foods was introduced by Brazilian scientist Carlos Monteiro to classify the most highly processed products in ourdiet. According to Monteiro’s NOVA classification, Group 1 foods are unprocessed or minimally processed (think fresh fruits, vegetables, eggs, milk, or pasta made simply from wheat); Group 2 are basic ingredients like sugar, oil, or salt; Group 3 are processed foods made by combining groups 1 and 2 (for example, cheese, breads, or canned beans) and are not automatically unhealthy. Group 4 – the ultra-processed foods (UPFs) – are industrial creations that go far beyond traditional cooking. A practical rule of thumb: if you couldn’t make it in your home kitchen from raw ingredients, it’s probably ultra-processed. For example, home-cooked pasta with olive oil and tomatoes would count as minimally processed, while a boxed instant pasta meal with powdered sauce and artificial additives is ultra-processed. Why does this distinction matter? Ultra-processed foods are designed to be convenient, affordable, and hyper-palatable, often combining lots of sugar, fat, salt and artificial flavorings to make them irresistibly tasty. As a result, they have come to dominate modern diets – in some high-income countries, over half of the average person’s calories now come from ultra-processed products. Understanding what ultra-processed foods are, and how they affect health, is a key step toward unlocking longevity in today’s food environment. After all, if a large portion of what we eat is ultra-processed, it’s crucial to know how these foods might be influencing our bodies and long-term well-being. Nutritional science is rapidly uncovering the profound effects that ultra-processed foods can have on our metabolism, gut, and risk for chronic disease. While processed food manufacturers long focused on individual nutrients (like reducing fat or sugar content), researchers are now learning that the processing itself matters greatly. Here’s what recent science tells us about ultra-processed diets and health: • Overeating & weight gain – In an NIH ward study, volunteers on ultra-processed menus unconsciously ate about 500 extra calories a day and put on weight, yet the same people slimmed down when fed fresh meals with identical fat, salt and sugar. Processing itself, not nutrients, drove the extra bites. As a fun fact, this study was led by Kevin D Hall, the scientific mind behind the US TV show “The biggest loser”. Contenuto dell’articolo Graphical abstract from the study of Hall et al. Cell; 2019; published with a creative commons license. • Hyper-palatable & hard to stop – UPFs pack huge energy into tiny bites and marry sugar, fat and salt in ways nature rarely does; a slice of cheesecake keeps you nibbling long after a handful of grapes would satisfy, which is why a whole bag of chips can vanish without you noticing. • Metabolic ripple-effects – The same trial showed UPFs spike blood-glucose and insulin and dial down fullness hormones, nudging the body to stash more fat even when calorie totals look the same on paper. • Gut trouble & inflammation – Low-fibre, additive-rich UPFs leave friendly microbes hungry; one species (B. theta) starts chewing the gut’s own mucus lining when fibre runs short, while sweeteners like sucralose further scramble the microbiome—fuel for chronic inflammation. • Chronic disease ripple – Heavy UPF eaters aren’t just heavier; studies link the habit to higher odds of depression and colon cancer in men, hinting that these foods quietly touch everything from mood to tumour biology. In summary, science is building the case that ultra-processed foods – with their engineered appeal, rapid digestibility, and additive-laden formulas – can disrupt normal metabolic signals, foster inflammation, and increase the long-term risk of many serious health conditions. This doesn’t mean that an occasional treat will doom anyone. But when ultra-processed products make up a large share of daily calories (as is true for many of us), they can create a perfect storm of metabolic stressors. The research is still ongoing (and we’ll discuss some debates in a moment), but a clear message is emerging: eating fewer ultra-processed foods and more whole or minimally processed foods is a smart strategy for protecting your health and longevity. If ultra-processed foods pose health risks, why do we eat so many of them? The answer lies not just in personal choice, but in the food environment that surrounds us – shaped by economics, marketing, and government policies. Ultra-processed foods rose to prominence because they offer powerful advantages: they’re cheap to produce, convenient to distribute, long-lasting on the shelf, and highly appealing to taste buds. What changed was the rise of packaged foods – more meals coming out of a factory package instead of a home kitchen. This pattern has played out worldwide. Public health experts describe it as a nutrition “epidemiological transition” driven by the food industry: as countries become wealthier, they transition from simple diets of fresh staple foods to diets dominated by branded snacks, fast foods, and soft drinks. As Professor Tim Lang put it, the industry is “hoist by their own petard. All the things they claimed as success are now flaws,” contributing to surges in obesity and diet-related diseases worldwide. Food marketing and accessibility are major forces shaping our choices. Ultra-processed products are often engineered for convenience – they’re ready to eat (or require just a microwave), saving us time in the kitchen. This is no small matter in a world where many people juggle busy schedules. One food researcher noted that preparing a full day’s worth of unprocessed, home-cooked meals can take three to four times longer than preparing a day’s worth of ultra-processed meal! And price is a factor: mass production and cheap ingredients make many ultra-processed items cost less per calorie than fresh, whole foods. All these factors – convenience, marketing, and affordability – create a powerful food environment that nudges people toward ultra-processed choices by default. Changing this environment is a social and policy challenge. Around the world, public health authorities are grappling with how to reduce ultra-processed food consumption and make healthier diets easier for people. Even the question of official dietary guidelines has become a battleground. Historically, national guidelines (like the U.S. Dietary Guidelines for Americans) have not explicitly warned against ultra-processed foods; they focus on nutrients (telling people to limit saturated fat, sodium, and added sugars, for instance). But as evidence mounts, some experts have urged that we update guidelines to advise limiting ultra-processed products as a category. The United States recently took a tentative step in this direction: after the aforementioned high-profile NIH study demonstrated the unique harms of ultra-processed diets, the U.S. government announced it would review the effects of UPFs as it prepares the next round of dietary guidelines Amid these challenges, there are hopeful signs of change. Public awareness of ultra-processed foods is growing quickly. Not long ago, few people outside academia knew the term “ultra-processed.” Now it’s entering common parlance. Fast-food chains and packaged food brands now at least acknowledge the demand for healthier, less processed options – even if progress is slow. Policymakers, too, are discussing measures beyond labeling, such as taxes on sugary drinks, restrictions on junk-food advertising to children, and programs to subsidize fruits and vegetables to make healthy food more affordable. All of these social and economic factors – from what’s on TV commercials to what’s in national food policy – influence our diet choices and thus our health. Understanding this context is empowering: it reminds us that if we want to eat better, we may need to reshape our food environment (at home and in our communities), not just rely on willpower alone. With all the attention on processed foods lately, some misconceptions and controversies have emerged. Nutrition is a complex science, and even experts don’t always agree on how to interpret the data on ultra-processed diets. Let’s unpack a few key debates and clarifications, so we can separate fact from spin: It’s important to realize that not all processing is harmful. Some people hear the term ultra-processed and assume everything processed must be avoided, but that’s an oversimplification. Food processing exists on a spectrum. Minimal processes like pasteurizing milk or canning vegetables preserve nutrients and prevent spoilage, which is clearly beneficial. In fact, processing has helped make the food supply safer and more accessible – it allows foods to last during transport and storage, and lets us enjoy a variety of foods year-round that our ancestors couldn’t. Ultra-processing, by contrast, often subtracts beneficial nutrients (like fiber and micronutrients lost in refining whole grains to white flour) and adds less healthy ingredients (like salt, sugar, unhealthy fats, and chemical additives) to create a final product that is convenient and craveable but nutritionally imbalanced. The takeaway: processing per se isn’t evil. What matters is the nature of the processing and the overall nutrition of the food. For decades, nutrition advice centered on nutrients – e.g. count your calories, cut saturated fat, watch your sugar. Ultra-processed foods challenge that approach, because they suggest that a food’s structure and processing level might matter as much as its nutrient profile. Without entering in more details, the consensus is that diets built around natural or minimally processed foods are healthiest – whether you arrive at that by thinking in terms of food groups or nutrient limits. For consumers, the key challenge is not to get lost in the details. For example, an energy bar might boast low sugar and added protein, ticking nutrient boxes, but still be a highly processed edible that doesn’t satisfy hunger like a handful of nuts and an apple would. Conversely, a food like olive oil is 100% fat (a nutrient some try to limit) but is minimally processed and considered a healthy staple in many longevity-promoting diets. Bottom line: Aim for nourishing foods in their natural form most often. The focus on ultra-processed foods is really a proxy for that larger goal. Big-food giants know the “ultra-processed” label threatens their business, so they muddy the waters. They insist the only villains are salt, sugar, and fat, then roll out “low-fat” cookies or “50 % less sugar” neon cereals and present them as healthy makeovers—never mentioning that the same industrial tricks, additives, and profit margins remain. The result is a health halo that hides behind buzzwords while the real issue – intensive processing designed to keep costs low and cravings high – stays untouched. Yet the UPF umbrella isn’t all or nothing. A dense, whole-grain loaf or a soy burger may be factory-made, but they still deliver fibre, protein, or fewer saturated fats than the foods they replace. Meanwhile, candy-coloured yogurts and processed meats carry little more than refined starches, additives, and cheap oils. The practical lesson: total avoidance of packages is unrealistic, but reading the ingredient list –and favouring the simplest, most recognisable one – lets you keep the convenience while trimming the hidden costs. Eventually, we can say that total abstinence from packets isn’t the goal: awareness is. The science shows that swapping even a handful of ultra-processed staples for real food can tip the scale toward better weight, calmer hunger signals and sharper energy in just a couple of weeks. Think oatmeal over frosted flakes, a quick veggie stir-fry over microwave lasagne—small edits, big return. So anchor your plate in foods that still look like foods; cook when you can; treat labels like truth-serum; and trade clever marketing for simple ingredients you recognise. Keep an eye out for the “health halo” (gluten-free candy is still candy) and remember every fresh choice – an apple, a handful of nuts – casts a vote for a saner food system. Longevity rarely rides on magic pills; it lives in the everyday menu. By nudging our diets toward the natural and reserving convenience foods for true convenience, we stack the odds for a longer, livelier life – one satisfying bite at a time. The "Unlock Longevity" newsletter is my personal contribution to exploring, but most importantly simplifying and making accessible, the themes, techniques, and strategies related to longevity. If you believe these insights could benefit your network, feel free to share this article! This article reflects my personal views and is not intended to replace professional medical advice. Commenti

Simone Gibertoni: This week’s Unlock Longevity takes you inside the world of longevity investing — where cutting-edge science meets visionary capital. As you know, longevity is more than just a concept for us at Clinique La Prairie. It’s our mission. And to accelerate that mission globally, we’ve launched the CLP Longevity Fund*: a private investment vehicle dedicated to identifying, funding, and scaling the most promising technologies that extend human healthspan.* The CLP Longevity Fund* is co-led by myself, Simone Gibertoni, CEO of Clinique La Prairie, and Professor Stefan Catsicas, a renowned neuroscientist, molecular biologist, former CTO of Nestlé, and now one of the most respected voices in biotech investment. Our goal is clear: bridge the gap between breakthrough science and real-world application and help shape the future of preventive and regenerative health. This isn’t a passive fund. We invest with purpose, we mentor, we connect science to business, and we accelerate the most credible, evidence-backed companies in the field of longevity. In this special interview, I sat down with Stefan to explore how we separate hype from science, what makes a startup truly investable in this space, and what we’ve learned in the last years of working together. Let’s dive in. Contenuto dell’articolo Simone Gibertoni: The longevity space is booming, but not everything is backed by solid science. Stefan, how do you separate genuine scientific breakthroughs from the buzz and hype that often surrounds longevity? Stefan Catsicas: It starts with a healthy scepticism and a demand for data. In longevity, there’s a tendency for exciting claims to race ahead of evidence. I’ve seen this both in academia and in industry – flashy marketing or sensational headlines claiming a new “anti-aging miracle” before peer-reviewed results are in. The first thing I ask is, what is the quality of the science? Are there robust studies, preferably in reputable journals or clinical trials run with major institutions, showing an intervention actually impacts aging markers or health outcomes? If the “breakthrough” is only supported by a couple of mouse experiments or, worse, just theoretical hype, we pump the brakes. Scientific rigor means reproducible results and well-designed studies. That said, some concepts that sounded like hype a decade ago are now gaining credible support. Take sound therapy as an example – it was once dismissed as new-age fluff, but now research shows it can improve heart rate variability and even help with tinnitus, as shown by Swiss start-up AudioVitality. In short, real breakthroughs come with real evidence, and my litmus test is always the people involved and their science. Hype might grab attention, but rigor is what ultimately earns my trust (and investment). Simone Gibertoni: From an investor’s standpoint, what makes a longevity innovation truly investable today? Many startups pitch anti-aging ideas – what must they have to catch your interest and funding? Stefan Catsicas: Excellent question. As an investor, I’m looking for a blend of strong science and clear business fundamentals. First, the science: the startup needs a compelling idea backed by solid evidence – something addressing aging in a novel way, but also grounded in biology we understand. For example, targeting a well-researched aging mechanism (like senescent cells, epigenetic changes, or stem cell exhaustion) with a new approach is intriguing if they have data to back it up. A mere hypothesis (“we think this molecule could extend lifespan”) isn’t enough. We often say to entrepreneurs: funding is out there if you bring strong science to the table. So show us your pilot studies, your mechanism of action, your best data. Second, a path to market is crucial. Longevity investors have learned to be both optimistic and practical. We aren’t interested in funding a science project that might pay off in 15 years – we need to see how this innovation becomes a product or therapy in a reasonable timeframe. In fact, at our fund we decided to avoid pitches that begin with “We have a molecule that could one day...”. If it requires a decade of R&D and hundreds of millions before the first human benefit, that’s outside our scope. We favor companies with a clear roadmap to deliver a product within, say, three to five years. That might mean starting with a shorter-term application or a digital component or focusing on healthspan improvements that can be measured in the near term. We also look at whether the company has a strategy for regulatory approval or clinical validation early on. The FDA is now reviewing dozens of anti-aging drug applications, which shows the field is maturing – but it also means startups must engage regulators and design proper trials. A venture that understands the regulatory pathway and has planful steps to get there is far more investable than one that hand-waves those details. Third, intellectual property and market fit matter. Does the startup have patents or other IP to protect their innovation? If it’s just another supplement anyone can make, that’s not compelling for investment. Longevity startups that secure strong IP, demonstrate a clear path to approval, and prove there’s real market demand stand out to top-tier investors. We also examine the team closely – do they have the right expertise (scientific and commercial) to execute? Ultimately, an investable longevity innovation is one that pairs groundbreaking yet credible science with a solid strategy to turn that science into a tangible product or service people will pay for. When those pieces align, you have our attention. Simone Gibertoni: The field of longevity is broad, covering biotechnology, AI, nutrition, and more. In your view, which longevity technologies or approaches are the most promising right now? What excites you in terms of actually extending healthy lifespan? Stefan Catsicas: We truly are seeing a renaissance in longevity science, with multiple fronts advancing. Let me highlight a few areas I find particularly promising: Epigenetic Reprogramming: This is arguably one of the hottest areas. The idea is to reset cells to a more youthful state by tweaking their gene expression patterns. It sounds like science fiction, but we have compelling evidence it can work – for instance, a landmark experiment at the Salk Institute showed that partially reprogrammed mice with a premature aging syndrome lived 30% longer. Since then, investors have poured over a billion dollars into reprogramming startups, and we might see the first human trials soon. The potential to reverse aging in cells – not just slow it – could be a game-changer if we can solve safety issues. I’m cautiously optimistic here. Senolytics and Cellular Clean-up: Another exciting avenue is targeting senescent cells – those “zombie” cells that accumulate with age and drive inflammation. The first generation of senolytic drugs had setbacks – one high-profile osteoarthritis trial failed to beat placebo. But that failure taught us a lot about choosing the right targets and outcomes. New senolytics and approaches to boost our natural cleanup processes (like autophagy) are in development. If we can safely clear senescent cells or renew our cells’ recycling systems, we could potentially prevent many age-related issues at the root. Advanced Regenerative Therapies: This includes stem cell therapies, tissue engineering, and even organoids. The regenerative medicine market is booming towards an expected $150 billion by 2030. We already see successes in narrow uses (for example, stem cell transplants for certain immune or blood conditions) . For longevity, the holy grail would be regenerating aged tissues – imagine restoring an 80-year-old’s heart or liver to how it functioned a few decades earlier. We’re not there yet, but incremental progress (like improving muscle strength or vision in older patients via gene therapy) is happening . These technologies hold enormous promise if they can be made safe and scalable. AI and Data-Driven Discovery: On a different front, we are excited by how artificial intelligence is boosting longevity research. AI-driven drug discovery is cutting down the time to find new geroprotective compounds by huge margins – some say by 70% or more. Similarly, AI is helping identify biomarkers of aging (biological age indicators) much faster and more precisely. This is crucial because to intervene in aging, we need ways to measure it. AI can sift massive health data to find patterns or targets that humans might miss. I see AI as an accelerant – it’s not an intervention by itself, but it’s making every other approach (from drug discovery to personalized nutrition) move faster and more effectively. Precision Nutrition and Microbiome: There’s growing evidence that dietary interventions and the gut microbiome have significant impacts on lifespan and healthspan. Companies using high-throughput data to tailor nutrition plans or develop compounds that mimic the effects of calorie restriction (so-called CR mimetics) are really interesting. For example, research on NAD+ boosters (like NR or NMN) shows mixed results, but those supplements have huge popularity. The key will be pairing them with science – maybe personalizing supplementation based on one’s genetics or microbiome. I’m optimistic that combining precision nutrition, gut health, and continuous monitoring can yield practical longevity gains for many people. See for example the US-startup, now mature, Prolon. The challenge will be to protect those inventions and drive compliance with users (or patients) with tangible changes in key aging biomarkers – even before any disease has strike. Those are a few areas, but the list could go on – from immunotherapies for aging to telomere biology. Importantly, I think the most promising strategy will ultimately be a stack of interventions. Aging is multifactorial. We might take senolytics periodically, undergo a gene therapy or reprogramming treatment once it’s safe, use AI-guided personalized diets, and monitor our biological age with smart devices. The future of longevity will likely be multi-modal, and that’s exciting because it means we have many opportunities. As an investor and scientist, I’m watching where the evidence grows strongest, but these areas I mentioned have me especially hopeful. Simone Gibertoni: We see both nimble startups and big established companies entering the longevity arena. In your experience, what advantages do startups have in this space that larger firms might lack? Where do you see agility coming into play? Stefan Catsicas: Great point – this is something I’ve experienced firsthand, having been in a large corporate and now working closely with startups. Startups bring agility and a willingness to take risks that big companies often can’t match. In a longevity startup, if new research points in a promising direction, the team can pivot quickly, try an unconventional experiment, or adopt the latest technology without layers of bureaucracy. That freedom to rapidly iterate is vital in an emerging field like longevity, where the playbook is still being written. Large companies, by contrast, are generally more conservative. They have established product lines and shareholders (and analysts) to satisfy, so they tend to focus on incremental improvements or proven markets. Many big pharmaceutical or nutrition companies have been hesitant to label anything as an “aging cure” because it sounds speculative. In fact, some major players avoid the word “longevity” entirely in their R&D, for fear of over-promising. This caution means truly radical anti-aging research often starts in academia or startups. A small company can form around a breakthrough discovery – say a new gene therapy for muscle rejuvenation – and dedicate itself 100% to that moonshot. They don’t have an existing billion-dollar product they might cannibalize; their success rides on making the new innovation work. The drawback, is that young companies may fail, and the majority do, while larger companies are here to stay. Another agility factor is talent and culture. Startups in longevity often attract mission-driven scientists and entrepreneurs who are okay wearing multiple hats. The team might consist of a professor, an AI expert, a clinician – all brainstorming together in one lab. That interdisciplinary, fast-paced culture can spark creative solutions. In a big corporation, departments are often siloed; the nutrition division might not talk to the AI analytics team, etc. Startups collapse those silos by necessity. This isn’t to say large companies have no role – they have resources and scale which are crucial for later stages. In fact, I foresee partnerships where big pharma or big tech acquires or funds the successful longevity startups to bring things to market globally. But early on, the disruptive ideas are coming from the little guys. One more thought: agility also means resilience through failure. In a startup, if an experiment fails, it’s painful but you learn and adapt by next week. In a large firm, a high-profile project failure can lead to budget cuts or years of delay. For longevity – a field with high scientific uncertainty – I’ll put my money on those who can fail fast, learn, and iterate. That’s one definition of real entrepreneurs. Simone Gibertoni: Thank you Stefan! This first half of our conversation highlights the importance of scientific rigor, strategic thinking, and market readiness in the world of longevity innovation. As the field rapidly evolves, separating hype from credible opportunity is essential — and it’s precisely this mindset that drives the CLP Longevity Fund*. In Part II, we’ll take the discussion further: from turning discoveries into real-world impact, to what makes a founder investable, and which bold bets may shape the future of human health. Stay tuned next week as we continue to unlock the next frontier of longevity. The "Unlock Longevity" newsletter is my personal contribution to exploring, but most importantly simplifying and making accessible, the themes, techniques, and strategies related to longevity. If you believe these insights could benefit your network, feel free to share this article! This article reflects my personal views and is not intended to replace professional medical advice. *Longevity Fund by Clinique la Prairie (the “Longevity Fund”) is a sub-fund of the EFG Alternative Investment SICAV-RAIF (“EFG”). EFG is an investment company with variable share capital (“société d’investissement à capital variable”) incorporated under the form of a corporate partnership limited by shares (“société en commandite par actions”) and organised as a Reserved Alternative Investment Fund (“RAIF”) under the Law of 23 July on RAIF (the “RAIF Law”) and registered on the official list of RAIFs held with the Luxembourg Companies and Trade Register and has reregistration number B220860. EFG qualifies as an AIF and its Authorised AIFM pursuant to the RAIF Law and the Law of 2013 is Funds Avenue S.A. Investments in EFG are available only to professional investors pursuant to Directive 2014/65/EU - MIFID. Longevity Fund and Clinique La Prairie do not provide investment advice, and make no representation or warranty, express or implied, regarding the completeness, accuracy, or reliability of the information contained herein. This is a marketing communication issued by the AIFM. Investing in the Longevity Fund involves significant risks including market risks, counterparty risk, liquidity & redemption risk, and operational risks. For detailed information about the risks associated with an investment in the Longevity Fund please review the “General Risks” and “SICAV/Sub-Funds Risks" of the Issuing Document. Commenti

Simone Gibertoni: Many longevity discoveries never leave the lab. How can we bridge the gap between cutting-edge science and real-world adoption so that people actually benefit from these innovations? Stefan Catsicas: This is a critical issue. It’s not enough to have a breakthrough in mice or a solid paper in Nature – we have to translate that into something practical for humans. I see a few key bridges we need to build: First, clinical validation. We need to move promising longevity interventions into well-designed clinical trials (meaning human participants. That implies defining measurable endpoints for “healthspan” or aging. It’s tricky – you can’t run a 50-year trial to see who lives longer, so you use proxies: improvements in immune function, slower cognitive decline, biological age markers, etc. The good news is there are over 1,500 aging-related trials ongoing worldwide right now, so the pipeline is filling. As these trials report results, they will separate which innovations actually work in humans. Getting real-world data is the bridge from theory to practice. Second, there’s education and credibility. Right now, longevity tech can sound like snake oil to the public – and sometimes it is, unfortunately. To gain adoption, companies must ground their products in science and be transparent. The best marketing for longevity is scientific credibility. Consumers and clinicians won’t embrace an anti-aging pill just because of hype. Third, accessibility and integration. To reach the real world, longevity solutions must fit into existing healthcare or wellness systems. That might mean a new therapy gets approved by regulators and prescribed by doctors as a preventative measure. Or a rejuvenation treatment is offered in clinics alongside traditional care. With scale and competition, costs come down and availability goes up. I’m encouraged by efforts to democratize longevity medicine, such as clinics focusing on preventive care that are rolling out around the world, aiming to make advanced therapies not just a luxury. When more people have access, we get more adoption, more data, and a virtuous cycle. Lastly, we need to bridge interdisciplinary gaps – bringing together biologists, clinicians, tech developers, and policymakers. Sometimes a great scientific idea fails to get adopted because, say, the user experience is awful or doctors don’t know how to fit it into practice. Collaboration between sectors can solve that. I’ve found that when life scientists sit at the table with, for example, digital health experts, they come up with practical solutions (like user-friendly apps that coach patients through longevity programs, or AI that helps doctors interpret aging biomarker data). Bridging science to real-world use is essentially the mission of our Longevity Fund: to fund companies that ground longevity in actionable, science-backed solutions. If we do this right, the incredible research happening in labs will translate into added healthy years in people’s lives – which is the ultimate goal. Simone Gibertoni: With so many new longevity startups appearing, credibility is a big concern. When you meet a startup, how do you assess if they’re the real deal? What are some red flags and green lights you look for, and can you give examples? Stefan Catsicas: This is near and dear to me, because the last thing we want is to invest in or promote something that has low probability to succeed and gives longevity a bad name. Here’s how we vet a company’s credibility: On the green light side, we look for founders with serious expertise and a track record. If the scientist or team behind the startup has published significant research on aging, or perhaps came out of a respected lab, that earns immediate points. For instance, companies like Retro Biosciences grabbed investors attention partly because their CEO, Joe Betts-LaCroix, is a known figure in aging research and they’ve assembled a top-notch scientific team. Credible startups often have well-known advisors or collaborators – people whose names on the masthead signal “we are doing real science here,” not just marketing. We also examine their data. Do they have peer-reviewed papers, and international conference presentations, demonstrating their technology works in some model? If a startup comes to us with a mouse study showing 30% improvement in some healthspan metric, we are intrigued (though we still expect more validation). Importantly, credible teams tend to be transparent about what they have and don’t have. If you ask them a tough question and they openly acknowledge limitations or what they’re still investigating, that honesty is a good sign. Now for the red flags: Number one is overblown claims without sufficient data. If a startup’s pitch sounds too good to be true (“we will definitively extend human lifespan by 20 years with this pill!”) and they can’t back it up with anything beyond cell culture data, that’s a huge warning. Science is complex and seldom so certain. We also get wary if a company is leaning more on marketing buzzwords than on explaining their science. Another red flag: no clear path to validation. If they don’t have plans for clinical trials or at least some kind of pilot with volunteers or real patients, it may suggest they’re not confident their product would hold up under scrutiny. And of course, lack of IP or a flimsy IP (like a patent that doesn’t really protect much) can be a sign they haven’t thought through how to sustain a real product. In summary, we assess credibility by digging into the people, the proof, and the plans. Green lights are strong team credentials, solid preliminary data, and transparency about the journey ahead. Red flags are grandiose promises, sketchy science, and an avoidance of external validation. Longevity is an exciting field, but it’s one where skepticism is healthy – we owe it to the public to fund and support only those innovations that stand on a foundation of evidence and integrity, and may generate important returns. Simone Gibertoni: Let’s talk big picture. How do you see longevity innovations disrupting traditional healthcare? Can these new approaches really upend the way we treat age-related diseases or deliver care? Stefan Catsicas: I do believe the rise of longevity science will be disruptive – in fact, it’s already starting. Traditionally, healthcare has been very reactive: wait for someone to get a disease, then treat that disease. The longevity approach flips this to a proactive, preventative model. That alone is a disruption to the business of healthcare. Think about it: if people can take interventions that delay or prevent diseases like diabetes, heart disease, or Alzheimer’s, that could reduce the massive burden on hospitals and chronic care systems. It shifts resources into early prevention. Over time, as actual longevity therapeutics (like senolytics or gene therapies) prove effective, you might treat aging itself as the ultimate preventive strategy for many diseases. For the pharmaceutical industry, this is disruptive because it challenges the paradigm of “one drug, one disease.” A longevity drug might simultaneously reduce the risk of multiple diseases by targeting a fundamental aging process. Pharma companies will need to adapt – possibly moving from acute treatments to chronic preventive treatments or combination therapies. There’s also a question of regulation: agencies like the FDA don’t currently recognize “aging” as an indication, but as data accumulates, we may see that change. Once an aging intervention is approved (say, a drug that convincingly extends healthspan), it opens floodgates for a whole new category of medicine. It’s reminiscent of how the concept of “wellness” was initially outside mainstream medicine and is now a huge industry; longevity might travel a similar path but even more scientifically grounded. Another area of disruption is in healthcare delivery and services. We’re already seeing longevity clinics and franchises pop up that promise advanced diagnostics and personalized longevity plans. These often exist outside the insurance system, catering to consumers directly. If they demonstrate better outcomes – for instance, keeping clients biologically “younger” and healthier – traditional healthcare providers will feel pressure to incorporate those practices or risk losing health-conscious patients. Imagine big hospital systems in 10–15 years having “Longevity Departments” focused on preventive regenerative treatments, or insurance companies giving discounts for participating in approved longevity programs (much like they do for gym memberships today). That’s a significant shift in the healthcare model from treating illness to actively maintaining wellness. We should also consider the economic disruption: longevity science is attracting new investment funds (as we know firsthand) and pulling talent from other industries into longevity biotech. It’s becoming an economic sector of its own. Traditional healthcare companies (from pharma to device makers) are investing or acquiring startups to not miss out. Those who stick strictly to old models might find themselves left behind if, say, a therapy emerges that replaces the need for one of their profitable chronic drugs. A successful anti-aging intervention that, for example, keeps joints healthy could disrupt the entire market for arthritis medications or joint replacements. Finally, longevity could disrupt public health policy. If governments see that investing in longevity (preventative health) saves on Medicare and pension costs in the long run, we might see public programs for mid-life interventions. This would alter how healthcare budgets are allocated. It’s often said that “the first person to live to 150 is already born” – if that’s true, our healthcare systems must transform to support not just longer life, but longer healthy life. In summary, longevity innovations are poised to transform healthcare from a sickness management system to a true health maintenance system. That’s as disruptive as it gets in medicine. Simone Gibertoni: Founders are crucial in this game. In your experience, what traits or backgrounds make for an ideal founder in a longevity startup? What kind of leader can actually drive these ambitious projects to success? Stefan Catsicas: I love this question because it zeroes in on the human element – and it’s often the make-or-break factor. The ideal longevity founder, in our view, is a bit of a hybrid talent. They need a combination of scientific depth and entrepreneurial grit, plus a clear vision. Here are some traits that stand out: Scientifically Grounded: Longevity isn’t a field where you can fake it till you make it. The science is complex. Great founders either come from a strong scientific background themselves (say, an MD/PhD who has studied aging biology) or they immerse themselves in the science and surround themselves with top-notch scientific advisors. This grounding is crucial to earn credibility and to steer the ship in the right direction technologically. If a founder doesn’t fundamentally grasp the biology, they may chase fads or misunderstand what’s actually feasible. Mission-Driven and Passionate: Almost every successful longevity entrepreneur I know has a personal motivation driving them – they genuinely care about extending healthy life, often due to some experience with aging in their family or themselves. This passion is important because the road is not easy; there will be skeptics, setbacks, maybe years before profit. A founder who’s in it just because “longevity is trendy” won’t last. The ideal founder keeps sight of the mission – helping people live healthier longer – as the north star through tough times. Visionary yet Practical: This is a balancing act. They must be visionary, able to see a future that doesn’t exist yet (say, a world where 80-year-olds run marathons regularly), and inspire investors, employees, and partners with that vision. But they also need a practical execution plan. I admire founders who can dream big but set realistic milestones. They might say, “Ultimately, we aim to add 20 years to human healthspan. Today, our goal is to reverse diabetes-related aging in the kidney within 2 years in trials.” The ideal leader can zoom in and out between the long-term vision and the next actionable step. Resilient and Coachable: Longevity startups will face scientific experiments that don’t work, regulatory hurdles, maybe public skepticism. The founder has to be resilient – not easily discouraged by failure. At the same time, they must be coachable and adaptive. If data tells them their hypothesis was wrong, they pivot rather than doubling down out of pride. I’ve seen, and paid the price for, some founders stubbornly stick to a hypothesis even when evidence contradicts it, and that usually spells doom. The best founders I know actively seek feedback from mentors, advisors, even critics. They’re lifelong learners, which is key in a field evolving as fast as longevity. Team Builders and Communicators: No one can tackle aging alone. The ideal founder knows how to attract a great team and create an environment where cross-disciplinary collaboration thrives. They can talk science with the PhDs and also translate that science into plain language for investors or the public. Communication is huge – whether it’s explaining your tech to a regulatory body or inspiring a recruit to join your cause. A founder who can clearly articulate the why and how of their company’s approach will rally the support needed. Simone Gibertoni: Can you share an example of a longevity startup that really surprised you – either by succeeding against the odds or failing unexpectedly? What did you take away from that story? Stefan Catsicas: Yes – one company that stands out is Volumina Medical, a Swiss medtech startup that has impressed us with its precision, vision, and execution. Both Clinique La Prairie and our investment fund have backed them. What surprised me is how they’ve combined deep scientific innovation with a clear, scalable clinical application in the field of regenerative aesthetics. Volumina’s core technology is a patented injectable biomaterial that mimics the extracellular matrix – the natural structural support of our tissues. Unlike traditional fillers that simply add volume, this material actively promotes soft tissue regeneration, stimulating the body’s own ability to rebuild fat and connective tissue. It’s a true regenerative solution, and that makes it very relevant to the longevity space. Now, here’s where it gets particularly interesting: while Volumina was originally focused on reconstructive and medical applications, and together with the management we brought forward the idea of applying this breakthrough in the world of beauty injectables. That insight led to a strategic evolution of their business model: entering the highly promising space of aesthetic longevity with a scientific foundation that few in the industry can match. What this example taught me is twofold. First, true longevity innovation can come from unexpected places – in this case, medtech and reconstructive surgery. Second, when visionary partnerships happen, they can unlock applications that even the inventors hadn’t initially prioritized. It’s a reminder that interdisciplinary thinking and cross-sector collaboration are often where the biggest breakthroughs occur. Simone Gibertoni: Final question – if you could make one bold bet on a single longevity technology or approach that you believe will have the biggest impact on extending healthy life, what would it be, and why? Stefan Catsicas: Ha, asking an investor to pick just one is cruel, but let me put on my visionary hat. If I must place a bold bet on one thing, I’d bet on partial cellular reprogramming – essentially the ability to rejuvenate cells in the body safely. This concept, using factors to reset the epigenetic clock of cells, strikes at the very heart of aging. We know by now that epigenetic changes (like DNA methylation patterns) are a primary marker of aging, and evidence is growing that they are not just markers but drivers of dysfunction. If we can periodically reset those marks, we might restore cells to a younger state without needing to replace them. Why reprogramming? Because it potentially addresses multiple aging hallmarks at once – gene expression, cell function, maybe even telomere lengths indirectly. The early animal studies are tantalizing: as we discussed, reprogramming extended life in sick mice and improved organ function in some experiments. Companies are racing here, and even though we have to solve issues (like preventing unwanted cell changes or cancer), the progress is steady. In fact, it’s plausible that in a decade or so, we’ll see the first reprogramming therapies in clinical trials for diseases like glaucoma or muscle degeneration – essentially using them to regenerate specific tissues. From there, it’s a hop to more systemic uses. I choose this also because it’s fundamentally rejuvenative, not just preventative. Many current approaches (exercise, diets, supplements, senolytics) are about slowing the clock or cleaning up damage. Reprogramming could turn back the clock. Imagine being able to take an aging organ and refresh it – that’s more sci-fi level impact. Now, I admit this is a bold bet because there’s a lot to prove. But I have a gut feeling that if we’re talking about something that could give, say, 20 or 30 extra healthy years to people in the latter half of this century, it’s this technology or something adjacent to it (like advanced gene therapy combined with cell regeneration). I’ll give a close second bet, just for completeness: AI-guided drug discovery of geroprotectors. This is a bit more abstract, but I suspect AI will unlock combinations of therapies (drug cocktails, if you will) that together have major longevity effects. It might not be one drug, but a protocol. And AI might be the only way to crunch the complexity of human aging and personalize those protocols. But that’s more like betting on a method to find many small interventions. So my one big bet: a true age-reversal intervention via cellular reprogramming. If it pans out, it could redefine medicine – we’d be treating aging at its root and not just putting patches on the diseases of old age. It’s bold, yes, but as an investor and a scientist, I believe in aiming high. If we can make that happen safely, the impact would be nothing short of revolutionary for human health. And frankly, someone is going to crack it – the momentum is there – so why not bet on the most transformative outcome? That’s the moonshot I’d choose. Simone Gibertoni: Thank you, Stefan. That was incredibly insightful – a masterclass in separating hype from reality and envisioning the future of longevity. It’s clear that a new generation of leaders, will bridge science and investment, and we are thrilled to have you onboard the CLP Longevity Fund*. To our readers: I hope this conversation has shed light on how to navigate the exciting yet complex world of longevity innovation. The "Unlock Longevity" newsletter is my personal contribution to exploring, but most importantly simplifying and making accessible, the themes, techniques, and strategies related to longevity. If you believe these insights could benefit your network, feel free to share this article! This article reflects my personal views and is not intended to replace professional medical advice. Longevity Fund by Clinique la Prairie (the “Longevity Fund”) is a sub-fund of the EFG Alternative Investment SICAV-RAIF (“EFG”). EFG is an investment company with variable share capital (“société d’investissement à capital variable”) incorporated under the form of a corporate partnership limited by shares (“société en commandite par actions”) and organised as a Reserved Alternative Investment Fund (“RAIF”) under the Law of 23 July on RAIF (the “RAIF Law”) and registered on the official list of RAIFs held with the Luxembourg Companies and Trade Register and has reregistration number B220860. EFG qualifies as an AIF and its Authorised AIFM pursuant to the RAIF Law and the Law of 2013 is Funds Avenue S.A. Investments in EFG are available only to professional investors pursuant to Directive 2014/65/EU - MIFID. Longevity Fund and Clinique La Prairie do not provide investment advice, and make no representation or warranty, express or implied, regarding the completeness, accuracy, or reliability of the information contained herein. This is a marketing communication issued by the AIFM. Investing in the Longevity Fund involves significant risks including market risks, counterparty risk, liquidity & redemption risk, and operational risks. For detailed information about the risks associated with an investment in the Longevity Fund please review the “General Risks” and “SICAV/Sub-Funds Risks" of the Issuing Document. Commenti

Longevity is no longer a distant dream; it’s a fast-moving research frontier. Few people are closer to that frontier than Peter Brabeck-Letmathe, Chairman Emeritus of Nestlé and current Chair of GESDA (Geneva Science and Diplomacy Anticipator). GESDA’s brand-new 2024 Science Breakthrough Radar maps the breakthroughs most likely to reshape our health in the next 5, 10 and 25 years—especially in Human Augmentation, the theme of Chapter 2 (here attached the full report). In this conversation I dig into the Radar’s most provocative ideas—cognitive upgrades, gene-editing “one-shot cures,” epigenetic age reversal, organoids-on-a-chip, AI-guided therapeutics—and ask Peter how they can translate into longer, healthier, more purposeful lives for all of us. His answers blend board-level pragmatism with visionary science, offering a rare 360-degree view of where wellbeing, technology, and responsible leadership converge. Read on to discover: Why Human Augmentation matters now—and the ethical guardrails it demands. What breakthroughs could erase frailty and compress late-life morbidity. How global collaboration can turn frontier science into a common good. Let’s unlock the future of health—together. Question 1: The Promise and Responsibility of Human Augmentation Simone Gibertoni: GESDA’s 2024 Science Breakthrough Radar highlights that researchers are finding ways to enhance our cognition, engineer our genome, extend our healthspans, and create novel disease-fighting solutions – but it also cautions that to realize the full potential of these innovations for human well-being, we must address the questions of how, why, and for whom they are deployed. As the Chairman of GESDA, how do you balance excitement about these longevity breakthroughs with the need to ensure they become a common good and benefit society responsibly? Peter Brabeck-Letmathe: Absolutely. The radar shows we are on the cusp of extraordinary scientific advances – from boosting our mental capabilities to editing genes for longer, healthier lives. It’s energizing to see how human augmentation could help people live better and longer. But as you noted, we can’t just chase innovation for its own sake. We have a responsibility to ask why we pursue these breakthroughs and who gets to benefit. In my view, technology should serve humanity as a whole, not create new divides. For example, if we develop a therapy to extend healthspan, I want to make sure it’s accessible and not just for a privileged few. My business experience taught me that scaling an innovation is as important as inventing it. So, we’re excited – but we’re also proactive about ethics, regulation, and equitable access right from the start. In practice, this means broad collaboration. We bring together scientists, policymakers, business leaders, and civil society to anticipate the impacts of these breakthroughs. Anticipation is key – it’s far better to guide the trajectory of innovation now than to react once it’s already transforming society. By openly addressing concerns like safety, privacy, or affordability early on, we build public trust. I often say our goal at GESDA is to ensure these scientific advances become a common good. If we get it right, human augmentation won’t just extend lifespans – it will improve the quality of those longer lives for everyone, in a fair and inclusive way. Question 2: Cognitive Enhancement – Upgrading the Brain and Mind Simone Gibertoni: One emerging area in the Radar’s Human Augmentation chapter is Cognitive Enhancement. The report suggests that in the next decade we could see brain–computer interfaces and neurotechnology allowing even healthy people to boost their cognition, aided by AI systems that decode and modulate our brain states. Looking further, by 25 years out, it even anticipates AI-informed gene editing and “digital twin” brain models that might fundamentally improve human memory and cognitive capacity. How do you envision these kinds of cognitive enhancements unfolding, and what implications might they have for our mental longevity and productivity? Peter Brabeck-Letmathe: The idea of upgrading the human brain is no longer science fiction – it’s happening in research labs today. In the near term, I see cognitive enhancement tools first aiding those who need them most (patients with injuries or neurological issues), and then gradually expanding to healthy individuals. For example, brain-computer interfaces could help stroke victims regain capabilities, and as the tech matures, similar interfaces or non-invasive neurostimulation might be used by healthy people to improve focus or memory. Initially, we’ll augment cognition in therapeutic settings – helping Alzheimer’s patients or those with learning disabilities – and that experience will pave the way for elective use in everyday life. As AI algorithms get better at interpreting neural signals, even consumer wearable neurotech might offer on-demand cognitive boosts or mood modulation. Looking 10 years ahead, it’s plausible we’ll have implants or headsets that integrate seamlessly with our own neural circuits. People might opt for “AI co-pilots” for the mind – devices that enhance our decision-making or creativity by providing real-time information and optimization of our brain states. We may also see non-invasive options like smart neurostimulation headbands that help us enter a state of peak concentration or relaxation as needed. The radar’s foresight about AI-driven tools decoding our brain activity is key: machine learning will personalize these cognitive enhancers, tuning them to each person’s neural profile for maximum effect. Further out, 20–25 years from now, it’s plausible we’ll integrate AI directly into our cognitive processes. We might use AI assistants literally plugged into our thoughts, expanding our memory or calculating solutions in real time. The radar’s 25-year forecast of AI-guided gene editing enhancing cognition is especially intriguing. If we could safely tweak gene expression in the brain, we might bolster learning capacity or resilience against neurodegenerative disease. However, I remain pragmatic – our brains are incredibly complex, and unintended effects are a serious risk. We must proceed carefully, with rigorous testing and ethical guardrails. The implications for productivity and society are profound. On one hand, enhanced cognition could usher in a new era of creativity and problem-solving – think of the innovations when more minds can operate at a higher capacity. On the other hand, it raises questions about fairness and identity. Would those without enhancements be left behind? How do we ensure cognitive upgrades don’t alter someone’s personality or autonomy? As a leader, I’m excited by the potential to prevent dementia and extend our cognitive healthspan, but I’m equally focused on establishing norms – perhaps even “neurorights” – so that our mental privacy and freedom are protected even as we embrace these new tools. Question 3: Rewriting Our Genetic Destiny Simone Gibertoni: Let’s talk about Human Applications of Genetic Engineering. According to the GESDA 2024 Radar, genome editing has already notched successes against certain cancers and rare diseases. The next frontier, it says, is moving from those rare genetic conditions into treating more common disorders and even “cracking the fundaments of ageing” itself. The report even speaks of an ultimate goal: a one-shot gene therapy – a single injection – that could cure disease for a lifetime. From your perspective, how realistic is this trajectory? And what would it mean for extending healthy lifespans if we can edit genes not just to fix illness but to prevent the diseases of aging? Peter Brabeck-Letmathe: The progress in gene editing over the last decade has been remarkable. We went from the first CRISPR experiments to actual therapies for certain inherited diseases and cancers in a very short time. The Radar rightly points out that so far we’ve tackled relatively uncommon, well-defined genetic illnesses – low-hanging fruit like specific mutations. The big opportunity now is to apply these tools to widespread diseases – think of common cancers, diabetes, or neurodegenerative disorders – and ultimately to the aging process itself. In principle, if aging is driven by accumulated cellular damage or genomic instability, advanced genetic engineering might help us repair that damage at the source. The vision of a “one-shot wonder drug” is inspiring. Imagine a single gene therapy that could permanently cure, say, a form of heart disease or even reverse aspects of aging. Is it realistic? Eventually, I believe yes – but it will take time and overcoming several challenges. Current gene therapies are often one-time treatments already, but they’re very targeted (for example, fixing one defective gene in blood cells). The idea of a broad-spectrum therapy that adds decades of healthy life by addressing multiple aging pathways is much more complex. We might need entirely new editing tools beyond CRISPR, given CRISPR’s limitations and off-target risks. There’s promising research into base editing, prime editing, and epigenetic edits that could be safer and more precise. I also think delivery is a major hurdle – getting gene editing tools into the right cells of an adult body efficiently. Viruses, nanoparticles, or even future stem-cell delivery methods are being tested to broaden what tissues we can target. And then there’s the cost and accessibility: today’s gene therapies are extremely expensive. A longevity treatment that only billionaires can buy would betray the whole idea. So alongside the science, we at GESDA emphasize innovation in delivery technologies and cost reduction – for example, using AI to find cheaper delivery vectors or improve precision. I remain optimistic that we will get there. Human ingenuity, especially aided by AI and global collaboration, is a powerful force. If and when we do achieve a true “age-cracking” gene therapy, it could revolutionize public health – imagine a world where we largely prevent the diseases of old age rather than treating them in hospitals. That would be a new chapter in human history. Question 4: Extending Healthspan – The End of “Getting Old”? Simone Gibertoni: GESDA’s Radar devotes a section to Healthspan Extension – essentially keeping people healthier longer, not just lengthening lifespan. It suggests we’re redefining what it means to get old. Research indicates the familiar markers of aging might not be inevitable – in fact, some physical changes of aging could be reversible – and new clinical trials are now poised to test therapies that may eradicate or roll back aspects of aging. There’s even talk of treating aging itself as a disease, with an endgame of eliminating frailty and long periods of ill health. How do you see this “longevity escape” evolving? Could we really reach a point where getting older no longer means getting sicker, and what steps are being taken now to move us in that direction? Peter Brabeck-Letmathe: We are indeed witnessing a paradigm shift in how science views aging. Traditionally, aging has been seen as natural and inevitable – “just part of life.” Now, as the Radar highlights, scientists increasingly view aging as a process we can understand and influence, perhaps like any other health condition. We know people age at different rates, and there are 80-year-olds who are biologically as fit as some 60-year-olds. The question is: why? What are the biological mechanisms that make one person age slower or stay healthier longer? Over the last few years, research has zeroed in on the hallmarks of aging – things like senescent (“zombie”) cells, DNA damage, loss of stem cell function, and changes in how our genes are expressed. The fact that we’ve identified several of these hallmarks and can even measure biological age tells me we’re on the right track. In practical terms, extending healthspan means compressing the period of decline. It’s not about living to 120 and spending the last 60 years in a hospital bed – quite the opposite. It’s about keeping people vital and independent until very late in life, and then having a relatively short period of decline at the end. I do believe it’s realistic that, within a generation, 80 could be the new 60 in terms of health. Early clinical trials are already testing drugs – like senolytics that clear senescent cells, or metabolic drugs that mimic calorie restriction – to see if they can slow aging in humans. GESDA’s radar notes that a new wave of trials is launching to test these bold ideas. This is a critical moment: if those trials show even modest success in safely reducing aging markers or extending healthy years, it will galvanize the field. Looking 20–25 years out, if we’ve truly cracked the code of aging, the implications are enormous. We could be talking about adding healthy years to everyone’s life, not by treating diseases one by one, but by slowing or reversing the underlying aging process. That said, I’m mindful of hurdles: delivering gene editors safely into the body, avoiding unintended mutations, and of course making such interventions affordable, as we said before. We may also need to rethink our healthcare and economic policies – if people are staying healthy longer, how do retirement ages, workforce dynamics, and preventive care models change? These are good problems to have, but society should start planning for them. The bottom line is I am optimistic – perhaps for the first time in history, a world where “getting older” no longer means a slide into poor health is within sight. It’s a future where added years are truly quality years. Question 5: The Future of Consciousness – Expanding the Mind’s Horizons Simone Gibertoni: Another fascinating theme is the Future of Consciousness. The Radar notes that new research – from electromagnetic brain stimulation to molecular psychedelics – suggests it’s possible to expand or alter human consciousness beyond normal limits of perception and cognition, even beyond what our senses typically allow. Such “consciousness augmentation” could improve learning, memory, and human connections, and also offer novel ways to treat severe disorders of consciousness. There’s even speculation about “beyond-human” consciousness, perhaps integrating our minds with AI or other entities. As someone looking at the frontier of human development, what do these possibilities mean to you? How might advancing our understanding of consciousness impact education, healthcare, or even our definition of being human? Peter Brabeck-Letmathe: The study of consciousness used to be almost taboo in science – it was considered too subjective or philosophical. That’s changing fast. We now have neuroscientific tools to observe how brain activity correlates with different conscious states. As the Radar indicates, we’re learning how to intentionally modulate those states. For example, controlled use of psychedelics like psilocybin or MDMA in clinical settings has shown great promise in treating PTSD, depression, and end-of-life anxiety by essentially “resetting” certain patterns in the brain. We’ve seen patients describe these guided psychedelic sessions as profoundly consciousness-expanding, helping them gain new perspectives on themselves and their lives. That’s a therapeutic benefit we can’t ignore – it’s very different from traditional drugs. In 5 years, I expect psychedelic-assisted therapy to become much more mainstream in psychiatry, which the Radar’s foresight also suggests (psychedelic drugs entering mainstream use). And beyond drugs, techniques like transcranial magnetic stimulation and direct brain stimulation are being tested to pull patients out of comas or improve cognitive function. We’re essentially learning the “dial settings” of consciousness. Now, the idea of augmenting consciousness for healthy people is both exciting and tricky. What does it mean to expand normal consciousness? It could mean enhancing cognitive aspects like focus or creativity (overlap with cognitive enhancement), or it could mean literally experiencing new qualia – new colors, new sensations – that humans normally can’t. Some researchers are even looking at whether we can extend consciousness beyond the individual, for instance through brain-to-brain communication networks or human-AI mind links. That sounds like science fiction, but early experiments with direct brain communication and the concept of neural “internet” are under way. If, one day, multiple minds could connect or we could interface our consciousness with AI, it raises profound possibilities: collective problem-solving, empathy at a distance, or entirely new forms of art and imagination. At the same time, this frontier raises deep questions. As we start altering consciousness, we’re touching the core of human identity and free will. There’s a reason we have strong ethical debates around things like military use of neuro-enhancers or coercive “mind hacking.” We will need guidelines – perhaps even international agreements – on what’s acceptable. Personally, I approach this with cautious optimism. Humans have always sought to expand their minds – through meditation, art, technology – it’s part of our nature. If done thoughtfully, consciousness augmentation could enrich human life in ways we can’t fully grasp yet. It might even enhance empathy and understanding, which society sorely needs. But I also recognize that maintaining our agency – the right to our own mind – is paramount. So any advances in this arena must come with ethical guardrails. We should enhance our minds, not infringe upon them. The "Unlock Longevity" newsletter is my personal contribution to exploring, but most importantly simplifying and making accessible, the themes, techniques, and strategies related to longevity. If you believe these insights could benefit your network, feel free to share this article! This article reflects my personal views and is not intended to replace professional medical advice. Commenti

In this second part of the interview, Peter and I explore one of the Radar’s most exciting frontiers: organoids—lab-grown mini organs that are transforming how we study aging and disease. From organoid banks to body-on-a-chip models, their potential to accelerate drug discovery and personalize treatments is enormous. We also dive into emerging therapeutics like AI-driven medicine, gene editing, and bioelectronic implants—alongside the ethical challenges they raise, from neurorights to mental privacy. The message is clear: the future of medicine can be predictive, personalized, and participatory—but only if we build it with intention, equity, and foresight. Question 6: Organoids – Lab-Grown Mini-Organs Transforming Research Simone Gibertoni: The Radar highlights Organoids – miniature lab-grown organs – as a breakthrough that could revolutionize biomedical research. These simplified versions of real organs can serve as more accurate models for human biology than traditional cell cultures or even animal testing, giving researchers a better proxy for studying diseases and treatments. We see forecasts of “organoid banks,” the ability to rapidly age brain organoids to study Alzheimer’s, and eventually a “whole human-on-a-chip” linking multiple organoids to test drugs on a complete system. How significant are organoids and related technologies for the future of longevity and medicine? Do you think they will accelerate the development of new therapeutics or personalized treatments? Peter Brabeck-Letmathe: Organoids are a game changer in many ways. In essence, an organoid is a tiny, self-organized cluster of cells grown from stem cells that mimics the 3D structure and function of an organ – be it a brain, liver, gut, lung, what have you. Twenty years ago, this was barely imaginable. Today, we can grow a mini-brain that shows brainwave-like activity or a mini-liver that metabolizes drugs. The radar’s emphasis on organoids underscores how far the tech has come and how fast it’s evolving. The immediate benefit is in research: organoids allow scientists to study human organ function (and dysfunction) in a dish, which is far more relevant to human health than, say, a mouse model. For longevity science, this is crucial because some aspects of aging and age-related diseases are very human-specific. For example, mice don’t get Alzheimer’s disease the way humans do. But now we can take human stem cells, push them to become brain organoids, and observe Alzheimer-like pathology emerging in that mini-brain. That helps us unravel what triggers the disease and test drugs in a human context. Organoids from patients’ cells can also be grown to see how a particular individual’s tissues respond to treatments – a step toward personalized medicine. Looking ahead, organoids could drastically speed up drug development and testing. The idea of an “organoid bank” – biobanks of standardized organoids – could mean that researchers worldwide have ready access to human tissue models for dozens of diseases. We might see pharmaceutical companies testing their new drugs on panels of organoids (heart, liver, brain, etc.) to predict efficacy and toxicity before ever going into a human trial. The Radar even talks about rapidly aging organoids: for instance, chemically or genetically accelerating the aging of a brain organoid to study Alzheimer’s in weeks instead of waiting months or years. That could compress research timelines dramatically. Organoids also hint at future therapeutic applications. There’s research on organoids-for-transplant – for example, growing a liver organoid and then implanting it or coaxing it to integrate with an existing organ to repair damage. It’s early, but some day we might grow replacement tissues or organs from a patient’s own cells, solving transplant shortages. I’m also intrigued by the “whole human-on-a-chip” concept: linking multiple organoids with microfluidic channels to simulate an entire body’s physiology. That would let us test a drug’s impact on, say, the heart, liver, and brain simultaneously in the lab. It sounds futuristic, but the building blocks are appearing now. There are challenges, of course. Scaling up organoids – they are tiny, after all – and ensuring they truly mimic the full organ’s behavior is ongoing work. We also have to be mindful of ethical questions, especially with brain organoids: if a brain organoid becomes too complex, could it develop some form of consciousness? It sounds far-fetched, but we’re already debating these things to set boundaries. Organoids let us fail faster in research – meaning we can eliminate ineffective or harmful drug candidates quickly – and also tailor approaches more closely to human biology. That acceleration and precision will definitely speed up the arrival of new therapeutics to extend healthy life. Question 7: Advanced Therapeutics – Next-Gen Medicine for Longevity Simone Gibertoni: The final theme in Human Augmentation is what GESDA calls Future Therapeutics (or Advanced Therapeutics). Over the past century, medicine has greatly extended average lifespans, yet as the Radar notes, we still lose many lives early to largely preventable conditions like cardiovascular and metabolic diseases. A range of new treatment modalities is coming into view – from bioelectronic implants and AI-guided diagnostics to cell therapies and immune-system engineering – all aimed at improving health maintenance, disease detection, and treatment outcomes. How do you see these emerging therapies changing the healthcare landscape in the next decade? And which do you believe hold the most promise for tackling the diseases that limit healthspan today? Peter Brabeck-Letmathe: We’re at the brink of a new era of medicine – one that’s far more proactive and personalized. In the next decade, I expect healthcare to shift from today’s largely reactive model (treating illnesses after they occur) to a predictive and preventative model. Imagine routine AI screening of your biomarkers that catches diseases like cancer or heart disease at Stage 0, when they’re fully curable. We’ll have multi-cancer early detection blood tests as a standard part of check-ups. We’ll wear smart devices that continuously monitor vital signs, blood sugar, maybe even circulating tumor cells, and alert us and our doctors to issues long before symptoms arise. This kind of always-on, data-driven vigilance will make it possible to maintain health rather than constantly play catch-up with disease. As for treatments, emerging therapies will dramatically broaden what we can do. Take bioelectronic medicine: tiny implants or stimulators that can modulate nerve signals to treat conditions – some are already in use for epilepsy or depression. In 10 years, I expect bioelectronic implants for common chronic illnesses (like devices tuning the vagus nerve to reduce inflammation in autoimmune disease, or pacemaker-like devices preventing migraines). We’re also seeing AI-guided diagnostics becoming routine – AI algorithms that analyze medical images, genetic data, even your voice or gait to diagnose conditions earlier and more accurately than any human could. That, combined with telemedicine and digital health platforms, means care will come to the patient (at home) much more. The Radar talks about cell therapies, gene therapies, and immune engineering – those are particularly promising for diseases that really limit healthspan today. CAR-T cell therapy (reprogramming one’s immune cells) has already cured certain leukemias; in a decade we might have T-cells engineered to attack senescent cells (an aging hallmark) or autoimmune diseases. Gene therapies might move from rare disorders to common killers – perhaps a one-time gene fix for cholesterol that could eliminate most heart attacks. And the idea of “hacking immunity” is powerful: our immune system is central to diseases from cancer to Alzheimer’s. Learning to boost it or fine-tune it (say, amplifying immune surveillance to clear out precancerous cells or protein aggregates in the brain) could tackle multiple aging-related diseases at once. Importantly, these advanced therapeutics won’t exist in isolation. They’ll converge with big data and AI. We might see something like digital twin models of patients – virtual replicas that predict how you’d respond to various treatments, so therapy can be ultra-tailored. And when intervention is needed, maybe you get a combo: say an AI finds an early tumor, a cell therapy is deployed to eradicate it, and a bioelectronic device monitors to ensure it doesn’t return. It’s a very different paradigm from the past. Of course, implementing this future will require changes in our systems. We’ll need to integrate a lot of data safely and ensure doctors are trained to use these new tools. Regulatory bodies will need to figure out how to evaluate AI diagnostics or gene-edited cell therapies efficiently without compromising safety. And cost is a consideration – many of these therapies are expensive now. I’m hopeful that as they scale and as we innovate in manufacturing, costs will come down (for example, automation in cell therapy production or AI making R&D cheaper). In summary, the healthcare landscape in a decade will likely be far more tech-integrated and proactive. I see a future where we intervene before someone becomes seriously ill, and if they do fall ill, we have highly precise tools to fix the underlying issue rather than just managing symptoms. That’s the essence of longevity medicine: maintaining wellness and quickly correcting problems at their source. It’s very much in line with the Radar’s vision of moving from reactive care to continuous, data-driven, personalized care that keeps people healthier longer. Question 8: Ethical and Governance Challenges in Human Augmentation Simone Gibertoni: With all these powerful technologies – from cognitive enhancers and neuro-modulators to gene editing and organoids – a big concern is ensuring they are used ethically. The Radar points out the need for new frameworks, like establishing “neurorights” and protections for cognitive privacy, and it warns that governance is urgently needed to manage unanticipated societal outcomes. In your view, what are the top ethical or governance issues we need to address as we unlock human augmentation and longevity technologies? How can we safeguard things like mental privacy and genetic equity, and prevent a longevity divide? Peter Brabeck-Letmathe: You’ve hit on perhaps the most important dimension: we need an ethical compass as strong as our technological drive. When I think of the challenges ahead, several key issues stand out. Equity is one – I often worry about a scenario where the wealthy can afford cognitive implants or life-extension gene therapies while others cannot. That could create a new class system of augmented vs. non-augmented humans, or dramatically extended lifespans for some while others face today’s limits. We must prevent that by proactively shaping access. This might mean public funding for proven longevity therapies, or international agreements to treat certain enhancements as public goods (much like essential medicines). Another crucial issue is privacy and autonomy, especially with neurotechnology. If devices can read or influence our brain states, we have to draw lines. GESDA’s community has indeed been discussing “neurorights” – essentially human rights for the mind. This would include the right to mental privacy (your thoughts and neural data should be yours alone unless you consent to share), the right to cognitive liberty (freedom to choose whether or not to augment your cognition), and protection from algorithmic bias or manipulation in neurotech. Imagine workplace brain-monitoring devices that ensure you’re attentive – some companies are already piloting that. Without guidelines, such practices could erode individual freedoms. We need to update our legal frameworks globally to keep pace with the neurotech and AI revolution. Safety and efficacy oversight is a more traditional concern but still very important. When we start gene editing in humans or giving people powerful neuropsychiatric tools, robust clinical testing and long-term monitoring are non-negotiable. Regulatory agencies will have to adapt – perhaps creating new pathways for enhancement technologies that are not strictly “treating a disease” in the classical sense. We might need international regulatory collaboration, because people could travel to less-regulated areas for enhancements (the way medical tourism happens). A global registry for human enhancement trials or a set of UN-endorsed principles might sound far-fetched, but I think it’s worth considering. There’s also the matter of ethical research practices. As we create organoids or AI that might have shades of consciousness, we face questions: Could an advanced brain organoid suffer? Do we owe anything to a synthetic yet human-derived consciousness? These are deep philosophical questions, but we should not wait for a crisis to ask them. GESDA’s approach has been to include ethicists, legal scholars, and citizen voices in our anticipation exercises. I believe in “built-in ethics” – ethics considered at the design phase of technology, not after the fact. Preventing a longevity divide is particularly dear to me. If we have the means to extend healthy life, it should not be only for rich countries or individuals. This is where diplomacy and global institutions come in. We may need something analogous to the COVAX initiative (for vaccine equity) but for longevity treatments. It sounds premature, but the earlier we plan, the better. Otherwise, we could see social unrest or ethical backlash that actually slows down progress for everyone. People need to see that augmentation technologies are adding value to society broadly, not just to a select few. In summary, I think we safeguard our future by establishing clear norms and policies now. We should encourage innovation – the potential benefits are immense – but within a framework that upholds human dignity, rights, and justice. If we do that, public trust in these technologies will grow, and they truly can become a common good. I often remind my colleagues: just because we can do something doesn’t always mean we should. Part of my job is to ask the tough questions and sometimes tap the brakes so that society can catch up to the science. Question 9: Global Collaboration and Anticipation – Making Breakthroughs a Common Good Simone Gibertoni: Many of these advances cross borders and will affect all of humanity. GESDA’s Radar is not just about science – it also explores opportunities for concerted action and how breakthroughs tie into global challenges and the UN’s Sustainable Development Goals. You’ve mentioned the importance of “anticipation” and bringing together different sectors. How critical is international collaboration in ensuring these longevity and augmentation breakthroughs benefit everyone? And what is GESDA doing – or what needs to be done – to foster a united approach in navigating the future it foresees? Peter Brabeck-Letmathe: International collaboration is absolutely critical. The challenges and opportunities we’re discussing are global in nature – aging populations, healthcare inequalities, disruptive technologies – no single country or sector can tackle these alone. I often say: science has become a global endeavor, but so must its governance and its benefits. If only a few nations develop and control, for example, age-extending therapies or AI neurotech, we not only risk inequity but also conflict or mistrust. On the other hand, if we collaborate, we can pool expertise, share risks and rewards, and set common standards so that everyone is playing by the same rules. GESDA was created with that spirit of multilateralism. We’re based in Geneva, a city known for diplomacy, because we see ourselves as a bridge between the scientific community and international policymakers. One concrete thing we do is our annual summit – we invite scientists to present these 5-, 10-, 25-year horizon insights to diplomats, UN agencies, industry leaders, and NGOs. I’ve seen eyes light up in those rooms – a minister realizes “this gene therapy could help my country’s demographic crisis,” or a UN official sees how consciousness research might inform education policy. By getting everyone anticipating together, we create a shared language about the future. It’s no longer science in one silo and policy in another – it becomes a joint effort to shape what’s coming. Policy-wise, I’d love to see the Sustainable Development Goals (SDGs) updated in the future to explicitly incorporate aging and transformative technologies. SDG3 (good health and well-being) already aligns with extending healthy life, but as we approach breakthroughs, setting global targets – like reducing the healthy life expectancy gap between countries, or ensuring a baseline of access to augmentation tech – could galvanize cooperation. GESDA’s Radar feeds into these discussions by highlighting what’s coming so policymakers can draft informed long-term strategies. For example, if we know a cure for type-1 diabetes might realistically emerge in 10 years, countries today can start strengthening their regulatory frameworks and health systems to integrate such a cure quickly when it arrives. I also believe in public engagement as part of collaboration. The global public should have a voice in these developments. Part of anticipation is outreach – making the science digestible and exciting to people, but also listening to their hopes and fears. Different cultures will have different viewpoints on human enhancement (due to religious, ethical perspectives). International dialogue helps us understand these perspectives and find common ground or at least respectful co-existence of views. In summary, collaboration turns these potential breakthroughs into a shared victory for humanity, rather than a source of new inequality or tension. At GESDA, we often invoke the idea of scientific advances as a “common good”. That’s a guiding principle. To make it real, we are pioneering this new kind of science diplomacy – one that doesn’t wait for crises to react, but proactively aligns stakeholders around the future we want. I’m encouraged by the response so far: we’re seeing more and more institutions reach out to join this effort. If we can keep that momentum, I’m confident we’ll navigate the coming wave of innovations in a way that everyone can benefit. Question 10: Looking Ahead – What Breakthrough Will Define the Future? Simone Gibertoni: Finally, looking to the horizon, the Radar paints an optimistic yet complex picture of 2040 and beyond – from one-time gene therapies curing diseases forever, to aging being treated at its root cause rather than symptom by symptom, to essentially living alongside intelligent machines with augmented consciousness. If you imagine an Unlock Longevity reader in the year 2040 reflecting on this interview, which breakthrough discussed do you believe will have made the biggest impact on their life? What do you hope will be the legacy of this era of scientific anticipation and innovation? Peter Brabeck-Letmathe: It’s a wonderful (and humbling) exercise to think about how the world might change by 2040. If I have to pick one breakthrough that I believe will define the coming decades, I would say treating aging itself will be a strong contender. By 2040, I expect we’ll look back and see that we transitioned from a paradigm of treating individual diseases to one of extending healthy human life as a whole. That fundamental shift – recognizing aging as modifiable and embracing “healthspan extension” as a public health goal – will, I hope, be seen as this era’s legacy. If a reader in 2040 enjoys 10 or 20 extra years of vibrant life, free from the chronic ailments that used to beset their grandparents, that will be the direct impact of breakthroughs happening right now. They might take a pill that clears senescent cells every few months, or have had a gene therapy at age 30 that guaranteed them no heart disease. They might even wear a device that continuously zaps early tumors or infections before they take hold. In short, medicine will feel less like medicine – it’ll be more like a built-in wellness maintenance program. On the flip side, the integration of AI and human consciousness could be just as impactful, albeit in a different way. By 2040, AI will be deeply embedded in daily life – perhaps even in some people’s minds via brain–machine interfaces. That could mean everyone has an ever-present cognitive aid or companion. The way we learn, make decisions, and even empathize might be expanded by that synergy. For our hypothetical reader, tasks that we struggle with today (managing vast information, learning new skills in mid-life, staying mentally sharp into old age) might come effortlessly with AI augmentation. Work and education could be transformed – possibly a world where 60-year-olds embark on entirely new careers because both their healthspan and their cognitive span are extended. What I hope the legacy of this era will be – beyond any single gadget or therapy – is the way we approached these breakthroughs. I’d like the future to say, they didn’t just innovate, they anticipated. We embraced a model of cooperation and foresight. We asked the tough ethical questions, we brought everyone to the table, and we guided technology toward enhancing human dignity and prosperity. If by 2040 the world has widely available longevity treatments, neuro-enhancements, etc., and we managed to avoid dystopian outcomes like a huge wealth gap in access or loss of personal freedoms, then we did our job right. Personally, I also hope the legacy includes a shift in mindset: a greater appreciation that science and humanity are not separate, that investing in long-term scientific thinking (the very ethos of GESDA) yields enormous societal returns. Perhaps by 2040, the idea of scanning the horizon 25 years ahead will be standard practice in governments and companies. We might see a global “Anticipation Council” or something that coordinates foresight on key technologies. So, to the future reader in 2040: I hope you are benefitting from these breakthroughs we’ve discussed – living a healthy, mentally enriched life – and I hope you feel we, back in 2025, made wise choices to set the stage for your present. If we maintain our vision and our values, I am confident the world of 2040 will be better, more vibrant, and more inclusive. That, more than any single innovation, would be the greatest legacy of this extraordinary period of scientific anticipation and innovation. The "Unlock Longevity" newsletter is my personal contribution to exploring, but most importantly simplifying and making accessible, the themes, techniques, and strategies related to longevity. If you believe these insights could benefit your network, feel free to share this article! This article reflects my personal views and is not intended to replace professional medical advice. Commenti

You may remember the inspiring interview we shared in a previous edition of Unlock Longevity, where I sat down with Dr. Justin Carrard – Sport and Exercise Physician and researcher at the University of Basel – to discuss how physical activity, especially high-intensity training, influences longevity. Dr. Carrard highlighted how regular movement, even in modest doses, has a profound impact on physical and mental health. He also introduced a concept that kept recurring throughout our conversation: VO₂max, the single most powerful marker of cardiorespiratory fitness – and one of the best predictors of how long and well we live. In this new edition of Unlock Longevity, we return to that crucial topic. What exactly is VO₂max? Why does it matter for healthy aging? How does it change over time? And most importantly, what can you do to improve it? Let’s dive into the science behind one of the most actionable, measurable, and transformative numbers in your longevity journey. Did you know there’s a single fitness number that can hint at how long and how well you might live? That metric is VO₂ max – the gold-standard measure of your body’s aerobic fitness. VO₂ max is essentially the maximum amount of oxygen your body can inhale, transport, and utilize during intense exercise. In practical terms, it’s how “fuel-efficient” your heart, lungs, and muscles are when you’re pushing your limits. The higher your VO₂ max, the more oxygen your body can use for energy, which translates to better endurance and overall cardiovascular performance. But VO₂ max isn’t just about sports or running faster – it turns out to be one of the strongest predictors of long-term health and longevity. In this deep dive, we’ll explore what VO₂ max means, why it’s so important for longevity, how it changes with age (and with training), and how you can measure and improve this crucial fitness metric. VO₂ max (short for maximal oxygen uptake) measures the body’s peak ability to take in and use oxygen during exercise. Scientists measure it in units of milliliters of O₂ per kilogram of body weight per minute (ml/kg/min). Think of it as the horsepower of your aerobic engine – it reflects the combined efficiency of your lungs (to inhale oxygen), your heart and blood vessels (to pump oxygen-rich blood), and your muscles (to extract and use oxygen for fuel). A simple way to understand VO₂ max is: the more oxygen you can utilize at maximum effort, the more work (and energy) your body can output. This is why VO₂ max is widely considered the best indicator of cardiovascular fitness and aerobic endurance. In exercise physiology labs, VO₂ max is measured with a graded exercise test: you might run on a treadmill or cycle on a stationary bike with a mask over your face that analyzes your breath. As the intensity ramps up toward all-out effort, the equipment determines the exact point where your oxygen usage peaks – that number is your VO₂ max. For example, if your VO₂ max is 40 ml/kg/min, it means at maximal exertion your body can utilize 40 milliliters of oxygen per kilogram of your body weight each minute. The higher the number, the fitter your aerobic system. Elite endurance athletes (like Olympic cross-country skiers or runners) often have astonishing VO₂ max values: in some cases above 70–80 ml/kg/min (even into the 90s for the very best). Meanwhile, an average young adult might be in the 30s or low 40s, and values tend to be lower for those who are older or out of shape. It’s important to note that VO₂ max varies by age and sex as well. For instance, a VO₂ max of around 40 ml/kg/min would be just “good” for a 30-year-old man, but the same 40 would be considered “excellent” for a 60-year-old man. In other words, a level of aerobic fitness that is average for a young adult can be outstanding in a senior. Now that we know what VO₂ max measures, let’s see why this number is so critical for long-term health. Staying fit isn’t only about looking or feeling good – it can literally be a life-saver. VO₂ max is not just a performance metric; it’s a powerful indicator of your health span and lifespan. Research has shown that a person’s VO₂ max (or overall cardiorespiratory fitness) has a strong inverse relationship with mortality risk. In fact, one meta-analysis called VO₂ max “the strongest predictor of cardiovascular and all-cause mortality”. In plain English: how high your VO₂ max is can tell a lot about your chances of living a longer life, free of chronic disease. How significant is the impact? Research shows that even moving from a very low fitness level to a slightly better one can lead to considerably better health outcomes. Improving further to an above-average level of aerobic fitness is associated with some of the most meaningful longevity benefits seen in preventive medicine. The gap between the least fit and the most aerobically fit individuals is among the most striking observed in lifestyle-related health indicators. Some studies even suggest that having very low cardiorespiratory fitness may carry risks for cardiovascular health comparable to other major lifestyle factors. That is a stunning comparison – being out of shape can be as harmful as smoking when it comes to heart health and longevity. Such evidence has made VO₂ max a focal point in preventive medicine. A 2018 scientific review even dubbed VO₂ max the strongest predictor of life expectancy, and the American Heart Association now recommends that clinicians consider VO₂ max in routine health evaluations because of its high predictive value for mortality and morbidity. Moreover, the benefits of improving VO₂ max appear to follow a dose-response – any improvement helps. According to one preventive cardiologist, for every single 1 ml/kg/min increase in your VO₂ max, your risk of all-cause mortality drops a percentage point! That means even modest fitness gains (like boosting your VO₂ max by 3–5 points) could translate into a lower risk of dying. Few medications or interventions can claim such a profound effect! Simply put, building your aerobic fitness is one of the most effective longevity strategies available. VO₂max is one of the most powerful predictors of cardiovascular health, performance, and longevity. Yet behind this single metric lies a complex biological triad: mitochondria, skeletal muscle, and oxygen delivery. Together, they form what we call the Mitochondria–Muscle–VO₂max axis — a dynamic system that determines our capacity to generate energy, resist fatigue, and age well. As we grow older, VO₂max declines steadily — by roughly 10% per decade after age 30. While some of this decline is attributable to changes in cardiac output or lung function, research shows that a large proportion stems from loss of skeletal muscle mass and mitochondrial efficiency. Starting as early as our 40s, we lose up to 1–2% of muscle mass each year. With this decline comes a direct reduction in mitochondrial density, respiratory enzyme activity, and oxygen-extracting capacity. Why does this matter? Because mitochondria in skeletal muscle are the primary consumers of oxygen during exertion. They convert the oxygen delivered by the blood into usable energy (ATP) via oxidative phosphorylation. When mitochondrial function deteriorates — as it naturally does with age — the muscles’ ability to utilize oxygen falters, directly suppressing VO₂max, regardless of how well the heart and lungs perform. Furthermore, aging mitochondria generate more reactive oxygen species (ROS), lose membrane potential, and impair the signaling needed for mitochondrial biogenesis. This not only weakens endurance but also slows recovery, impairs metabolic flexibility, and accelerates muscle atrophy — reinforcing a cycle of declining VO₂max and declining vitality. But this axis is not immutable. Through targeted interventions — including endurance and interval training, resistance exercise, hypoxic conditioning, and mitochondrial-supportive nutrients — we can stimulate mitochondrial regeneration, preserve muscle mass, and maintain oxygen utilization capacity. Exercise-induced activation of PGC-1α, AMPK, and mitochondrial fusion proteins helps rebuild mitochondrial networks even in advanced age. In essence, VO₂max is not just a number. It is a clinical window into the health of our mitochondria and the integrity of our muscles — and thus, into the sustainability of our physiological youth. The Mitochondria–Muscle–VO₂max axis stands as one of the most important levers in the practice of longevity medicine. It’s no secret that our bodies change as we age, and unfortunately VO₂ max is one of those things that typically declines with time. VO₂ max naturally declines as we get older, largely due to factors like a lower maximum heart rate, reduced cardiac output, and loss of muscle mass as decades pass. On average, studies show that after about age 25–30, VO₂ max drops by roughly 10% per decade (about 1% per year) if we do nothing to counteract it. To illustrate: a healthy but non-training 25-year-old man might have a VO₂ max near, say, 45 ml/kg/min. By 55, that same man might only test around 30–35 ml/kg/min if he’s become sedentary, just from aging effects. In fact, one chart of “natural” decline suggests that a 30-year-old capable of running at 10 mph could, by age 75, be reduced to barely managing a slow stair climb if no exercise intervention happens. A bit scary, right? The good news is exercise can dramatically slow (and partly reverse) this decline. Fitness level actually influences VO₂ max more than age alone in many cases. Sedentary individuals lose aerobic capacity about twice as fast as those who stay active over the years. By maintaining an active lifestyle and healthy body weight, you can roughly cut the typical decline rate in half. Instead of losing ~0.5 ml/kg/min per year, an active person might only lose ~0.2–0.25 ml/kg/min per year. Over decades, that makes a huge difference. It’s even possible for older adults to improve their VO₂ max with dedicated training. One study showed men around 63 years old increased their VO₂ max by 19% (from 2.35 to 2.8 L/min) and women around 64 boosted theirs by 22% after 9 months of endurance exercise training. In other words, a 65-year-old who starts exercising can gain back some oxygen capacity, effectively “turning back the clock” with fitness. It’s entirely possible for a fit 60-year-old to outperform a sedentary 30-year-old in VO₂ max. For example, a very active senior might clock a VO₂ max in the 40s, while an inactive young adult could be in the low 30s. Generally, VO₂ max values for the average person fall into these ranges (for non-athletes): about 30–40 ml/kg/min for young adult men, and 20–30 ml/kg/min for young adult women. If VO₂ max is so important, it’s worth knowing your own number. The most accurate way to measure VO₂ max is via a graded exercise test in a laboratory or clinical setting. This typically involves wearing a mask or mouthpiece hooked up to a machine that analyzes your breath by measuring oxygen and carbon dioxide exchange. You’ll perform a treadmill run, stationary bike ride, or similar cardio exercise where the intensity gradually ramps up to your maximum effort. The test usually lasts around 10–15 minutes until you hit exhaustion. At that point, the testers determine the highest rate of oxygen your body was able to utilize (VO₂ max) along with other data like your peak heart rate. This kind of VO₂ max test is often referred to as a “metabolic exercise test” or “cardiopulmonary exercise test,” and it’s considered the gold-standard assessment of cardiorespiratory fitness. Some universities, sports medicine centers, or longevity clinics offer VO₂ max testing to the public. Besides satisfying curiosity, it can be motivational and help tailor your training zones (since it also measures your heart rate at VO₂ max and other thresholds). Of course, not everyone has access to a lab test, so many people rely on indirect VO₂ max estimates. Fitness wearables and smartwatches these days often provide a VO₂ max reading based on your heart rate and pace during runs or other activities. These estimates can be useful for tracking trends, but take them with a pinch of salt. Research shows that many wearable devices can mis-estimate VO₂ max by around 10% (either too high or too low). So if your watch says your VO₂ max is 50, the true value might be mid-40s or mid-50s. The error isn’t usually huge, but it’s enough that you shouldn’t solely rely on it for an exact number. The trends over time (is your VO₂ max going up or down?) are often more meaningful than the absolute number. For those who want the most precise measurement without guesswork, a lab test is the way to go. Knowing your VO₂ max can thus be a great first step in a longevity-focused fitness plan. Here’s the encouraging part: no matter where you start, you can improve your VO₂ max with training. VO₂ max isn’t a fixed number; it responds to exercise habits. Improving it essentially boils down to making your heart stronger, your circulation more efficient, and your muscles better at using oxygen. How do we achieve that? By consistently challenging our cardiovascular system. Here are some proven strategies to boost VO₂ max (and maintain it as you age): Mix Up Your Cardio Intensity: A combination of steady endurance training and high-intensity workouts is ideal. Lower-intensity aerobic exercise (often called “Zone 2” training) – where you can carry on a conversation – helps build the foundation by increasing the density of capillaries in your muscles and the number of mitochondria in your cells. These adaptations improve how efficiently your body delivers and uses oxygen. On the other end, high-intensity interval training (HIIT) or vigorous efforts close to your current max capacity will push that capacity higher over time. Intense intervals stimulate your body to increase heart stroke volume and even enlarge your mitochondria (so they can process more oxygen). In short, do most of your cardio at a comfortable pace, but sprinkle in interval workouts or fast pushes that leave you out of breath – those are the ones that nudge your VO₂ max upward. Get Enough Aerobic Exercise Each Week: Consistency is key. Experts recommend at least 150 to 300 minutes of moderate aerobic exercise per week, or half that duration if doing vigorous exercise. For longevity and VO₂ max boosting, a good approach is to make sure you’re active almost every day – for example, 30-60 minutes most days doing something that gets your heart rate up. Within that, include a couple of tougher sessions a week (like a speed workout, a spin class, or a hill/sprint routine). Over time, your heart and lungs will adapt to handle more. If you prefer exact numbers: working out at ~70-80% of your max heart rate for prolonged periods will raise your aerobic base, and hitting 90%+ in short bursts will expand your VO₂ max ceiling. Choose activities you enjoy – cycling, running, swimming, rowing, even fast hiking – any cardio that you’ll stick with is great. The main point is to challenge your circulation and breathing regularly. Incorporate Strength Training: Surprised? While classic VO₂ max gains come mostly from aerobic exercise, resistance training plays a supporting role. Strength workouts help you maintain lean muscle and reduce body fat, which indirectly boosts VO₂ max because it’s measured per kg bodyweight (less excess weight = higher relative VO₂) and because more muscle means more metabolic tissue to use oxygen. Additionally, having stronger muscles can improve your exercise economy and power, allowing you to push harder in cardio sessions. Aim for at least 2 days a week of strength training targeting major muscle groups (using weights, resistance bands, or bodyweight exercises). This helps prevent the age-related muscle loss (sarcopenia) that would otherwise drag your VO₂ max down over the years. Stay Active Lifelong – Use It or Lose It: The ultimate secret to preserving VO₂ max is never becoming sedentary. It sounds simple, but it’s true – consistency over decades beats short spurts of intense training followed by long breaks. You don’t have to be an endurance athlete, but do keep moving regularly. Studies show that people who remain physically active can slow their VO₂ max decline to a crawl. Even starting later in life has major benefits. As noted, seniors have boosted their VO₂ max by ~20% with dedicated training in under a year! It’s never too late to gain fitness. On the flip side, detraining (stopping exercise) will cause VO₂ max to fall fairly quickly. There’s a popular saying in the fitness community: “We don’t stop exercising because we get old; we get old because we stop exercising.” In the context of VO₂ max and longevity, this couldn’t be more true. Staying active keeps your body young at heart. Finally, remember that improving VO₂ max is a gradual process. You might only see a few points of increase over a couple of months, but those small gains are very meaningful for your health. Track your progress – maybe repeat a VO₂ max estimation every few months to see if your new routine is working. And celebrate non-number benefits too: as you train your aerobic system, you’ll likely notice you can climb stairs or run with less huffing and puffing, recover faster, and just feel more energetic. Those are real quality-of-life improvements. In summary: VO₂ max is a key to unlocking longevity. Know it, improve it, and protect it by living an active lifestyle. Your heart, your cells – and your future self – will thank you for it. The "Unlock Longevity" newsletter is my personal contribution to exploring, but most importantly simplifying and making accessible, the themes, techniques, and strategies related to longevity. If you believe these insights could benefit your network, feel free to share this article! This article reflects my personal views and is not intended to replace professional medical advice. Commenti

At Clinique La Prairie, we believe that understanding the biological mechanisms of aging is key to unlocking the potential for a longer, healthier life. In this edition of Unlock Longevity, I am honored to speak with Fabrizio d'Adda di Fagagna, a leading researcher whose groundbreaking work explores the cellular and molecular foundations of aging. As one of the foremost experts on the DNA damage response (DDR), telomere biology, and cellular senescence, Fabrizio has made remarkable contributions to the field of longevity science. His research sheds light on how aging at the cellular level influences overall health and the development of age-related diseases. More importantly, it opens doors to potential interventions that could one day revolutionize how we approach aging itself.

At 58, Halle Berry – once a cardio devotee – now swears by lifting heavy weights. The Oscar-winning actress admitted, “I used to do a lot of cardio... Now I just do... heavier weights than I’ve ever lifted, and I do it probably two days a week at least”. Like many women of her generation, Berry spent years avoiding the weight room for fear of looking “muscly.” But times have changed. “I never wanted to get muscly... Now I’m lifting heavy weights and I’m still not getting muscly. I’m just... holding on to the muscle that I have, and that’s important at this age,” Berry says[IG1] during an interview on the Tamsen Show Podcast.

Cardiovascular exercise, simply known as “cardio,” encompasses any movement that gets your heart pumping and your body energized. Think brisk walking, jogging, cycling through beautiful scenery, swimming leisurely laps, or dancing freely—activities that raise your heart rate and breathing rhythm. Alongside strength and flexibility, cardio completes the trilogy of fitness pillars, nourishing both your body and mind. Health experts widely recommend adults engage regularly in moderate to vigorous aerobic activities, and science continually confirms the value of incorporating even more movement into our daily lives. Let’s explore why cardio is such a powerful tool for your health journey.

When it comes to fitness and longevity, people often focus on cardio for heart health and strength training for muscles and bones. But there’s a third pillar in this triad of movement that is just as crucial: flexibility. Being able to bend, stretch, and move freely isn’t just for gymnasts or yogis – it’s a key component of staying youthful and active as the years go by. You may think of stretching as something only athletes do, yet we all need to stretch to protect our mobility and independence. Flexibility training is essentially an investment in your future self, helping ensure that you can continue to do the things you love (and need to do) well into old age. So, why is flexibility often overlooked? Part of the reason may be that the benefits of stretching are less immediately obvious than lifting weights or running miles. You don’t see big biceps or a calorie burn readout from touching your toes. But behind the scenes, keeping your muscles and joints supple pays off over time. It maintains your range of motion, prevents stiffness, and reduces wear-and-tear on your body during everyday activities. In fact, flexibility might be the secret sauce that makes all other exercise safer and more effective. A flexible body moves with ease; an inflexible one is prone to strains and pain. As one Harvard health publication put it, “It’s not enough to build muscle and achieve aerobic fitness. You need to think about flexibility, too.” Stretching regularly keeps your muscles flexible and healthy, so they don’t become tight and short – a problem that can set you up for joint pain or injuries when you do try to move. In short, flexibility is the glue that holds your fitness together and helps unlock longevity by enabling an active, pain-free life. It might surprise you to learn that your flexibility level could be linked to how long you live. In a recent long-term study, researchers tested the joint flexibility of over 3,100 middle-aged adults (measuring range of motion in shoulders, hips, ankles, and more) and then followed them for 13 years. The results were striking: those with the least flexibility had almost twice the risk of dying prematurely during the study period compared to those who were more flexible. In other words, the stiffest people were the most likely to experience an earlier death. Meanwhile, participants who maintained greater flexibility tended to live longer lives on average. While this study only shows an association (not proof of causation), it highlights an intriguing point: staying limber may help you stay alive longer. Scientists suspect one reason is that flexible older adults can move more and stay active with less pain – and an active lifestyle is a well-known contributor to longevity. When your joints and muscles allow you to keep up with exercise, hobbies, and daily tasks, you’re far more likely to remain healthy and independent into your later years. Flexibility might even reflect the health of your body on a deeper level. Fascinating research suggests a connection between how flexible your muscles are and the stiffness of your arteries. One meta-analysis found that people with poor trunk flexibility (for example, those who struggle to reach their toes) tend to have stiffer arteries and poorer cardiovascular health. In that analysis of multiple studies, lower flexibility was linked to higher arterial stiffness, especially in older adults. Why does this matter? Well, stiffer arteries can raise blood pressure and increase the risk of heart disease, a leading cause of death. The theory is that flexibility exercises might improve the elastic quality of muscles and connective tissue, which in turn could translate to more elastic (and healthier) blood vessels. In fact, other studies have shown that a simple stretching routine can significantly reduce arterial stiffness in just a few weeks. It appears that when you stretch your limbs, you’re also giving your arteries a beneficial stretch. This emerging science implies that maintaining flexibility could protect not only your mobility but also your heart – a two-for-one boost for longevity. Musculoskeletal fitness as a whole is a strong predictor of healthy aging. Consider the everyday act of sitting down on the floor and standing back up. It sounds trivial, but it’s actually a quick test of flexibility, balance, and strength all working together. In one study, middle-aged and older adults who could sit and rise from the floor without using their hands or knees for support were found to have significantly better survival rates than those who struggled to do so. This sitting-rising test is essentially measuring functional flexibility and mobility. The findings underscore an important message: mobility is longevity. If you can easily bend and move your body through various positions, you’re likely to stay healthier and live longer. In places known for exceptional longevity, like Okinawa in Japan, older adults often sit on the floor and stand up dozens of times per day as part of their traditional lifestyle. Even people in their 90s and 100s continue this habit, which keeps their bodies naturally flexible and strong. Experts believe this constant gentle motion is one secret to their long lives. The takeaway for the rest of us? Use it or lose it. By regularly challenging your body to move freely – whether through stretching routines, yoga, or simply getting down on the floor – you maintain the physical freedom that helps add years to your life. One of the most tangible benefits of flexibility is preserving your mobility for daily life. As we age, many of us notice tasks that were once easy – bending to tie shoes, reaching overhead to a high shelf, twisting to look behind – gradually become more difficult. This isn’t inevitable, though. Often, the culprit is not age itself but inactivity leading to muscle tightness and joint stiffness. When you don’t regularly move a joint through its full range, the surrounding muscles shorten and the joint’s movement becomes limited. For example, if you spend hours each day sitting, your hamstrings (the muscles in the back of your thighs) can become chronically tight. Later, when you stand up or try to walk, those shortened hamstrings make it harder to straighten your legs, altering your gait and posture. Over time, this can turn something as simple as climbing stairs or taking a brisk walk into a challenge. The good news is that regular stretching can counteract this stiffness, essentially turning back the clock on your joints. Flexibility exercises increase the length and elasticity of muscles and tendons, allowing your joints to move more freely. In studies of older adults, even simple stretching programs have proven effective at increasing range of motion in various joints. Hips, shoulders, knees, ankles – all can benefit. And when your joints move better, your whole body moves better. Think of flexibility as lubricating the hinges of your body. With well-oiled hinges, you can squat down to garden, kneel to play with a grandchild, or twist to back the car out of the driveway without strain. In fact, some research shows that seniors who commit to stretching exercises can improve their performance on daily functional tasks – one trial found that a group doing flexibility training significantly improved their Timed Up-and-Go test scores (a measure of basic mobility) and could stand up from a chair faster and more easily. Those are real-world measures of independence: being able to get out of a chair, walk around, and maintain balance confidently. Maintaining flexibility is also crucial for posture and alignment. Over time, muscle imbalances and tightness can literally pull your body out of alignment – think of rounded, hunched shoulders from tight chest muscles or an exaggerated lower back curve from tight hip flexors. Stretching helps correct these imbalances by lengthening chronically tight areas. For example, stretching the chest and shoulder muscles can help you stand up straighter, relieving pressure on your spine. Loosening tight hip flexors and hamstrings can alleviate the tug on your lower back that contributes to back pain. According to physical therapists, a well-designed flexibility routine can reduce common aches and pains that might otherwise limit your activity. Even people with arthritis, who often wake up with stiff, painful joints, find relief through gentle range-of-motion stretches. Exercises that put joints through their full range of motion help ease arthritis stiffness and pain, allowing those joints to move more freely. It’s a simple formula: less stiffness equals more freedom. By staying limber, you preserve the ability to take care of yourself and continue the activities that give your life meaning, from hobbies to travel to playing with the kids in your life. In essence, flexibility preserves independence – and there are few things more important than that as we grow older. If you’ve ever tried to sprint off the couch or lift a heavy box without warming up, you know how unforgiving tight muscles can be. Lack of flexibility sets the stage for injuries and chronic aches by making your muscles and tendons less resilient. Imagine a dry, brittle rubber band – stretch it suddenly and it might snap. Now imagine a supple, elastic band – it can handle the pull. Regular stretching ensures your muscles and connective tissues stay more like the supple band. Flexible muscles are less likely to tear or become strained during sudden movements or exertion. For instance, an inflexible calf or hamstring is a common cause of strains in middle-aged “weekend warriors” who play sports occasionally. By improving your flexibility, you give your body a buffer against such injuries. That’s why coaches often incorporate dynamic stretching routines for athletes – warmed-up, flexible muscles can handle jumps, lunges, and quick changes of direction with a lower risk of pulls. It’s not just athletic injuries we’re concerned with. Everyday life can injure you if you’re stiff. Reaching awkwardly for a heavy object, twisting to get out of a car, or simply stumbling on an uneven sidewalk can lead to a muscle or ligament injury if your body isn’t prepared to move in that way. Flexibility training prepares your body by expanding what is a “safe” range of motion for your joints. Your joints become comfortable moving through positions that might otherwise be perilous. For example, improving the flexibility of your ankles, hips, and knees can help you recover your balance when you trip, potentially preventing a fall. In older adults, falls are a major cause of serious injury and can even be life-threatening. Here, flexibility plays a supporting role alongside strength and balance: supple joints and muscles allow you to make the quick, wide motions that can keep you upright when balance is lost. One reason activities like yoga and tai chi are so strongly recommended for seniors is that they enhance flexibility, balance, and proprioception together – leading to fewer falls and injuries. Chronic pain is another enemy that flexibility training can combat. Many common pain issues – lower back aches, neck and shoulder tension, knee pain – have roots in muscle tightness and poor range of motion. Take lower back pain: tight hamstrings and hip flexors can tilt the pelvis and put stress on the lumbar spine, while weak, tight back muscles themselves become easily fatigued and sore. Stretching these areas regularly helps relieve tension and can dramatically reduce back pain episodes, as countless individuals have discovered through yoga or prescribed physical therapy stretches. Similarly, stretching the neck and upper back muscles (trapezius, neck extensors) can ease the stiffness of “tech neck” caused by hours at the computer. The Arthritis Foundation and physical therapists routinely recommend stretching as part of pain management for conditions like osteoarthritis or fibromyalgia, because it increases blood flow and reduces joint stiffness. It’s not a cure-all, but as flexibility improves, pain often diminishes. In essence, staying flexible keeps the aches and pains of aging at bay, letting you continue moving comfortably. And if you do combine stretching with strength and proper movement technique, you create a robust defense against both acute injuries and chronic musculoskeletal problems. Your body becomes more resilient, able to withstand the surprises life throws at it – whether that’s an unexpected slip on ice or simply a long day of walking and standing. Flexibility isn’t just a physical asset; it also brings mental and emotional benefits that contribute to longevity. If you’ve ever finished a stretching session or a yoga class and felt a blissful, relaxed sensation, that isn’t your imagination. Stretching triggers your parasympathetic nervous system – the “rest and digest” mode – which helps reduce stress hormones and promotes a sense of calm. In fact, scientific studies have shown that engaging in a regular stretching or gentle movement practice can lower levels of the stress hormone cortisol in your body. One year-long clinical trial compared a group doing low-impact stretching exercises to a group doing restorative yoga, and the stretchers ended up with significantly decreased cortisol levels and reported feeling less stressed than the yoga group. The act of slowly stretching muscles and focusing on your breath seems to unlock a relaxation response in the body. Over time, lower chronic stress can translate to numerous health benefits – better sleep, improved immune function, and happier mood. All of these factors indirectly support longevity, since chronic stress is known to accelerate aging and contribute to diseases. There’s also a mindful, almost meditative aspect to flexibility training. Activities like yoga, Pilates, or simple stretching at home force us to slow down and pay attention to our bodies. This mind-body connection can improve mental well-being. Many people report that stretching helps relieve anxiety and even mild depression. Part of this may be due to biochemical changes (like endorphin release or improved circulation to the brain), and part of it is the empowering feeling of caring for your body. Not to mention, when your body feels loose and free of kinks, it naturally puts you in a better mood. Stiffness often contributes to that irritable, restless feeling – think of how cranky you feel after hours cramped on a long flight. Now imagine the relief of stretching out afterwards; it’s a literal sigh of relief for your muscles and your mind. By incorporating flexibility exercises, you’re also carving out a bit of me-time for self-care, which can reduce emotional burnout. Some research even suggests that stretching in the evening can help improve sleep quality by signaling your body to wind down, leading to a more restorative night’s rest (a crucial factor in long-term health). Furthermore, flexibility routines often come with a social or mindful dimension that benefits emotional health. Joining a yoga class or a tai chi group, for example, provides social interaction and a sense of community – both known to be great for longevity. Or if you prefer stretching quietly at home, it can become a form of mindfulness practice, similar to meditation. You learn to breathe deeply, clear your head, and be present in the moment as you hold each pose. In high-end wellness retreats like Clinique La Prairie, flexibility and mindfulness are combined through activities such as guided stretching sessions, yoga, and even innovative technologies that make stretching fun and engaging. The goal is not just a flexible body, but also a balanced mind. After all, true longevity is a harmonious balance between mind and body – staying limber in both spirit and form. By reducing stress and enhancing mental resilience, flexibility training indirectly protects your brain health and emotional well-being as you age. A calm mind, better sleep, and lower stress hormones can each add a figurative “deposit” into your longevity bank account. The human body is amazingly adaptable – at any age, you can improve your flexibility with consistent practice. The key word here is consistent. Just as you wouldn’t expect to build strength from lifting weights once a month, you can’t become flexible with sporadic stretching. Experts recommend making flexibility training a regular part of your week. In practical terms, aim to stretch most days if you can. Even stretching 2-3 times a week can yield noticeable improvements in mobility, but a little bit each day is ideal. You don’t need marathon stretching sessions; even 10–15 minutes of gentle stretching per day can make a big difference if done routinely. The best time to stretch is often after some light activity, when your muscles are warmed up. Muscles stretch more easily (and safely) when warm – think of taffy that softens with heat. So you might take a brief walk, do a quick dance in your living room, or simply do stretches after your workout when your blood is already flowing. Never force a cold muscle to stretch too far – this can cause injury. Instead, ease into each stretch gradually, and listen to your body’s signals. When planning a flexibility routine, focus on the major muscle groups and joints that tend to tighten with age or inactivity. According to fitness experts, the most critical areas for mobility are often the lower body: calves, hamstrings, hip flexors, and quadriceps. These affect your ability to walk upright, climb stairs, and maintain balance. Don’t neglect your upper body though – stretches for the shoulders, neck, and lower back can relieve tension and improve posture. Aim to gently work each target area through its comfortable range of motion. Here are some tips for a safe and effective flexibility practice: Start Small: If you’re new to stretching, begin with small movements and dynamic stretches (moving through a range, like arm circles or leg swings) to warm up. Then move to static stretches (holding a position) for deeper lengthening. Hold, Breathe, and Don’t Bounce: When holding a static stretch, breathe deeply and relax into it. Hold each stretch for about 20–30 seconds (up to 60 seconds for older adults on tight areas). Avoid bouncing, as this can trigger a muscle reflex that actually tightens the muscle and increases injury risk. Feel Mild Discomfort, Not Pain: You should feel a gentle pull or mild discomfort in the muscle – never sharp pain. Pain is your body’s way of saying you’re pushing too far. Ease up and maintain a pain-free stretch. Over time, that “edge” of discomfort will gradually move further as your flexibility improves. Be Consistent and Balanced: Consistency beats intensity. It’s better to stretch a little every day than to do a one-hour session once a month. Also, keep your routine balanced: stretch the front and back of your body, and both left and right sides evenly, to avoid creating imbalances. Incorporate Movement: Activities like yoga, Pilates, tai chi, or dance can be fantastic ways to build flexibility while also improving balance and strength. They make stretching feel more engaging and can teach you new stretches you might not do on your own. Plus, they add the benefits of mindfulness and coordination. Listen to Your Body: Flexibility is highly individual. Don’t compare yourself to the person in a pretzel pose on Instagram. Some people are naturally more flexible; others have tighter structure. What matters is gradually improving from your starting point. Celebrate small gains – maybe this week you can reach a little closer to your toes than last week. That’s progress! Remember that the goal of flexibility training is not to perform circus tricks; it’s to enhance your functional mobility and well-being. If you stay diligent, you’ll likely notice everyday movements becoming easier within weeks. You might wake up with less stiffness, notice your stride lengthening, or find it easier to turn and check your blind spot while driving. These little victories indicate that your efforts are working to keep your body youthful. Many health organizations also suggest integrating stretching into other routines – for example, finishing a cardio or weight training session with stretches to cool down and improve muscle recovery. This can reduce soreness and improve how your muscles adapt to exercise. If you’re ever unsure how to start, consider consulting a physical therapist or certified trainer; they can design a personalized stretching program that takes into account any limitations or goals you have. Longevity isn’t achieved through any single magic bullet – it’s a combination of factors, and physical fitness is a big piece of the puzzle. Within that, think of flexibility, strength, and cardio as three legs of a sturdy stool. All three support you in different but complementary ways. Flexibility training often doesn’t get the spotlight, but it quietly enables the other forms of exercise to happen. In a holistic longevity program – such as the approach taken by Clinique La Prairie’s famed Longevity Method – all these elements are combined to maximize healthspan. Their experts recognize that preserving joint and muscle function through flexibility and mobility work is just as important as aerobic endurance or muscle strength in the quest for a long, healthy life. In the journey of healthy aging, staying flexible means staying youthful. It’s never too late (or too early) to start, and every little stretch brings you one step closer to a long, active, and vibrant life. The "Unlock Longevity" newsletter is my personal contribution to exploring, but most importantly simplifying and making accessible, the themes, techniques, and strategies related to longevity. If you believe these insights could benefit your network, feel free to share this article! This article reflects my personal views and is not intended to replace professional medical advice. Commenti

Plastics are nearly inescapable in modern life – from water bottles and food packaging to cosmetics and clothing. Yet emerging science reveals that these convenient materials carry a stealthy health toll. Experts now warn of a global “plastics crisis” that is undermining human health from infancy to old age. Far from inert, plastics can leach chemicals and shed microscopic particles that infiltrate our bodies. In this Unlock Longevity newsletter, we explore how chronic exposure to plastics may be impacting our hormones, driving inflammation and disease, and even accelerating cellular aging. We’ll also highlight recent scientific findings (including a 2024 Lancet report and a University of Maryland study) and offer practical tips to reduce everyday exposure. One of the most well-documented dangers of plastic-derived chemicals is endocrine disruption – interference with the body’s hormone systems. Many plastics contain additives like bisphenol A (BPA) and phthalates that can mimic or block natural hormones. BPA, used in polycarbonate plastics and can linings, is known to bind estrogen receptors, essentially pretending to be estrogen in the body. Phthalates, used to soften plastics and found in everything from vinyl tubing to personal care products, can lower testosterone and alter other hormone signaling. Research has linked exposure to these chemicals with a host of hormonal and developmental problems. For example, BPA is an estrogen-mimicking compound associated with fertility issues, reproductive disorders, and developmental defects, as well as hormone-related cancers like breast and prostate cancer. Likewise, phthalates are implicated in decreased fertility, childhood development issues, obesity, and asthma – consistent with their endocrine-disrupting effects. Scientific evidence is mounting on just how significant these effects can be. A recent University of Maryland-led study in PNAS highlighted BPA as a widespread endocrine disruptor “associated with cardiovascular diseases, diabetes and reproductive disorders” in the population. Another analysis reviewed dozens of studies and confirmed that both bisphenols (like BPA) and phthalates “can interfere with hormonal systems; for example, BPA can change how the body responds to estrogen”. These disruptions in hormone signaling can have lifelong consequences, especially when exposures occur during critical windows like prenatal and early childhood periods. Indeed, experts stress that infants in the womb and young children are especially vulnerable to plastic chemicals’ effects on development. Prenatal exposure to endocrine disruptors has been linked to higher risks of birth defects, neurodevelopmental delays, and future health problems. For instance, the recent Lancet review reported that fetal and early-life exposure to plastic chemicals was associated with increased risks of miscarriage, prematurity, birth defects, and even childhood cancers. In short, plastic-related toxins are not just a theoretical concern – they are measurably perturbing the delicate hormonal choreography that underpins human growth, metabolism, and reproduction. Beyond hormone havoc, plastic exposures are fueling subtle inflammation and metabolic disturbances that can snowball into chronic disease. Microplastics – tiny plastic fragments often less than a millimeter wide – have emerged as a new frontier in toxic exposure. These particles flake off larger plastics or form as plastics degrade, and we now know they are finding their way into the human body via food, water, and even the air. Disturbingly, microplastics have been detected in human blood, lungs, placentas, breast milk and other tissues such as the brain and the liver, and their accumulation seems to have increased in recent years. A post-mortem study published in Nature Medicine showed that the amount of microplastics in the liver and brain of people who died in 2024 was greater than those found in those who died in 2016, independent of their age, gender, or race. This means that in only 8 years we have detected an increase in the accumulation of microplastics in the body, making it crucial to understand the potential health consequences of these substances. What happens once microplastics are inside us? One concerning finding is that such particles may trigger inflammation. In a recent study of people with atherosclerosis, researchers discovered microplastics embedded in the plaque of major arteries; individuals with plastic particles in their arteries had elevated inflammatory markers and were more likely to suffer a heart attack, stroke, or death in subsequent years compared to those without plastics present. While this doesn’t prove causation, it strongly suggests that microplastics lodged in our tissues could provoke chronic inflammation that contributes to cardiovascular disease (for example, by making arterial plaques more unstable). In fact, the Lancet health analysis cautioned that microplastic particles in the body have been linked to heart disease and strokes, advocating a precautionary approach given their ubiquity. Plastics may also be insidious promoters of metabolic disorders. A growing body of epidemiological research links exposure to chemicals like BPA and phthalates with conditions such as obesity, insulin resistance, and type 2 diabetes. In humans, one large analysis found that people with higher phthalate metabolite levels had increased risks of diabetes and abdominal obesity, suggesting these chemicals might be contributing to our epidemics of metabolic disease. The mechanisms are still being untangled, but chronic low-grade inflammation may be a common thread. The bottom line: our everyday contact with plastics could be silently raising our risks for heart attacks, strokes, and metabolic illnesses that undermine longevity. Does plastic exposure contribute to cancer or accelerate aging at the cellular level? Emerging evidence suggests it very well might. Some plastic additives are known carcinogens or tumor promoters. Epidemiological studies have linked prenatal or early-life BPA exposure to greater susceptibility to breast and prostate cancers later in life. Infants and young children have immature detoxification systems, which could explain their heightened vulnerability. At the other end of the spectrum, older adults often show a decline in liver clearance capacity due to the combined effects of aging and chronic disease. As a result, while middle-aged healthy adults typically metabolize and excrete BPA effectively, both the very young and the elderly face greater challenges. Even aside from hormone-driven cancers, plastic chemicals may contribute to cancer development through indirect means such as chronic inflammation (which can spur cell DNA damage) and impaired immune surveillance. Toxins that derail our immune balance could potentially lower the body’s defenses against emerging cancer cells. On an even more fundamental level, plastic-derived toxins can interfere with the basic cellular mechanisms of aging. One key pathway is oxidative stress – an excess of cell-damaging free radicals. Microplastics have been shown to cause lipid peroxidation, DNA damage, and activation of stress signaling pathways inside cells. They can lodge in cells’ lysosomes and mitochondria, leading to mitochondrial dysfunction and even triggering cell death (apoptosis) in laboratory studies. All of these effects – DNA damage, loss of mitochondrial efficiency, and chronic inflammation – are known accelerators of biological aging. In essence, the wear-and-tear that microplastics inflict on cells may add up over time to premature aging of tissues. There is evidence that other plastic chemicals have similar effects. BPA, for instance, can cross into our cells and has been found to suppress telomerase (the enzyme that maintains chromosome ends) and shorten telomeres – the protective caps on our DNA that shorten as we age. In one human cell study, chronic low-dose BPA exposure led to significantly shortened telomeres and reduced mitochondrial DNA copy number in T-lymphocytes, indicating accelerated cellular aging and less robust function. Additionally, scientists are discovering that plastic additives can alter our epigenetic markers – the chemical tags on DNA and proteins that control gene expression. Studies have shown BPA exposure can induce changes in DNA methylation and histone modification (epigenetic mechanisms) that can disrupt normal gene regulation. Such epigenetic changes might silence tumor-suppressor genes or activate inflammation-related genes, thereby linking environmental exposure to long-term disease risks. It’s sobering to consider that the plastics around us may be tweaking the biochemical switches that influence how fast our cells age and how likely we are to develop age-related diseases like cancer. Given the myriad ways plastics can affect our biology, what practical steps can we take to protect ourselves? The good news is that you can meaningfully reduce your exposure to the worst offenders with some conscious changes in daily habits: Mind Your Food and Drink: Avoid heating food in plastic containers – heat can cause plastics to leach chemicals like BPA into your food. Use glass, ceramic, or stainless steel for cooking and microwaving. Try to minimize canned foods (many cans are lined with BPA-based resins) or seek out “BPA-free” labeled cans. For drinking, consider switching from bottled water to filtered tap water in a reusable metal or glass bottle. Not only do plastic water bottles contain microplastics and potentially leach chemicals over time, they also contribute to environmental pollution. Using a home water filter (such as a carbon block or reverse osmosis system) can help remove microplastic particles and other contaminants from your drinking water. Choose Fresh, Less-Packaged Foods: Some of the highest dietary exposures to phthalates and other plastic chemicals come from processed and packaged foods. For example, opt for fresh or frozen vegetables instead of those wrapped in plastic or microwavable steam bags. Prefer glass jars over plastic bottles for pantry staples. Eating fresh not only boosts nutrition but cuts down on the “stealth” ingredients leaching from plastics into processed foods. Be Wary of Fragrances and Personal Care Products: Many cosmetics, lotions, and scented products contain phthalates (used as solvents and fragrance carriers). These can be absorbed through the skin. Favor products labeled phthalate-free and try to choose unscented or naturally scented items (or those that use essential oils instead of synthetic fragrance). Also, avoid aerosol sprays and air fresheners that can disperse chemicals into your indoor air. Baby Steps for Babies and Kids: Children are more vulnerable to plastic toxins, so take extra care with items they eat from, drink from, or play with. Use glass baby bottles or BPA-free bottles (and never heat plastic bottles of milk/formula in the microwave). Supportive Habits: Some research suggests certain dietary choices might mitigate toxin effects – for instance, a diet high in antioxidants (from fruits, vegetables, green tea, etc.) could help combat oxidative stress from any ingested microplastics. While more research is needed, maintaining a nutrient-rich, antioxidant-heavy diet is a good practice for overall health and may offer a buffer against environmental stressors like pollutants. No one can completely avoid plastics in 2025, but we can choose safer alternatives in many cases and create a healthier home environment. Over time, these individual choices also drive market demand for non-toxic products and food packaging, pushing companies to innovate away from harmful plastics. Finally, it’s worth noting that the movement to curb plastic health risks is not only at the individual level – it’s becoming a global policy priority. Spurred by accumulating scientific evidence, many governments have started banning or restricting the most dangerous plastic chemicals. Dozens of countries have outlawed BPA in baby bottles and children’s products. The European Union has gone further by banning several phthalates (like DEHP, DBP, BBP, and DIBP) in toys and restricting them in other consumer goods. Just recently, the EU’s food safety authority drastically lowered the tolerable daily intake of BPA to near-zero based on new data about immune and endocrine effects, reflecting a much more cautious stance. Other policies target plastic pollution at large – for example, the U.S. and many countries have banned plastic microbeads in cosmetics that wash into waterways, and single-use plastic bag bans are increasingly common. The most ambitious effort is happening on the international stage: the United Nations is negotiating a Global Plastics Treaty. In 2022, 175 nations agreed to draft a legally binding treaty to end plastic pollution, with a target of finalizing it by the end of 2024 (unfortunately not achieved). As of 2025, negotiations are in full swing, with health experts demanding that the treaty address not just waste management but also chemical safety and human health impacts. The health costs of inaction are simply too high – an estimated $1.5 trillion per year in health damages from just a few common plastic chemicals, a. By some calculations, curbing toxic plastics could save hundreds of thousands of lives and millions of disease cases worldwide. By unlocking longevity through tackling this hidden toxin, we take a step toward a healthier future where convenience doesn’t come at such a high cost to our well-being. The "Unlock Longevity" newsletter is my personal contribution to exploring, but most importantly simplifying and making accessible, the themes, techniques, and strategies related to longevity. If you believe these insights could benefit your network, feel free to share this article! This article reflects my personal views and is not intended to replace professional medical advice. Commenti

Alzheimer’s disease is one of the biggest challenges to longevity. It’s a condition that doesn’t just take memories – it shortens healthspan and independence for millions of older adults. Despite billions poured into research, treatments so far only manage to delay the decline, not prevent or reverse it, for the over 7 million Americans living with Alzheimer’s. As the CEO of Clinique La Prairie, dedicated to longevity science, I’m deeply interested in any breakthrough that might change this. Recently, a Nature paper published in August 2025 caught my attention. It suggests a surprising culprit and ally in Alzheimer’s: lithium. Yes, the simple metal lithium – known as a psychiatric drug – might play a key role in brain aging. Today I’ve invited Dr. Isabel Garcia, our senior researcher in neuroscience and psychology, to discuss this study and its implications. Simone Gibertoni: Isabel, thank you for joining me. Let’s start with the basics. What exactly is lithium, and why has it been used in psychiatry? Isabel Garcia: Great question. Lithium is a chemical element – a soft, silvery metal – that exists in trace amounts in nature and even in our bodies. In fact, it’s considered a trace nutrient for humans. It enters in our bodies through the food chain and water in tiny doses. Historically, people noticed that mineral-rich waters (which often contained lithium) had mood-calming effects. In modern medicine, lithium has been used for decades as a mood stabilizer, especially to treat bipolar disorder. Psychiatrists found in the mid-20th century that lithium could drastically reduce mania and prevent mood swings, although we still don’t know how it does so. It’s one of the oldest and most effective psychiatric medications. What’s fascinating is that while we know it helps stabilize mood and even reduce suicide risk, we’re still uncovering how it supports brain cells and brain function. It appears to protect neurons and promote neural health in various ways – which is why researchers have speculated it might also help with neurodegenerative diseases. So, lithium is both an essential micronutrient in tiny amounts and a powerful drug at higher doses, bridging nutrition and psychiatry. Simone Gibertoni: That’s really interesting – a single element being both a nutrient and a medication. Now, regarding the new Nature study by Aron et al., what did the researchers find in the brains of people with Alzheimer’s disease? Isabel Garcia: The researchers made a striking discovery. They examined postmortem brain tissue from people who had Alzheimer’s disease (as well as those with mild cognitive impairment, which is often an early stage of Alzheimer’s) and compared them to healthy brains[4]. They measured about 30 different metals and minerals in these brain samples. Lithium stood out dramatically: lithium levels were significantly lower in the brains of individuals with Alzheimer’s and even mild impairment, compared to healthy controls. Interestingly, lithium levels in the blood of those patients were normal – it was the brain that was deficient. This suggests that something in Alzheimer’s was depleting lithium specifically from the brain. The team found a clue when they looked at the hallmark Alzheimer’s pathology, the beta-amyloid plaques. They discovered that lithium was getting trapped in these amyloid plaques. In other words, the sticky protein clumps accumulating in Alzheimer’s brains were soaking up lithium ions. The more severe a person’s Alzheimer’s was, the more lithium was sequestered into the plaques, leaving correspondingly less lithium available to the rest of the brain. This was a eureka moment – it indicated that Alzheimer’s disease pathology itself might be causing a lithium deficiency in the brain by locking it away in plaques. Simone Gibertoni: So the plaques were basically stealing lithium from the brain? How does lithium interact with beta-amyloid plaques – why would it get stuck there? Isabel Garcia: It appears that as beta-amyloid proteins misfold and aggregate into plaques, they have chemical sites that bind metals – and lithium is one of them. The study showed that amyloid-beta has an affinity for lithium and can bind to it as plaques form, effectively hoarding the lithium. Imagine amyloid plaques as sponges soaking up lithium. Normally, lithium (at natural low levels) might be doing supportive things for brain cells – but when plaques form, they capture the lithium and prevent it from doing its job. This binding means the available lithium in brain tissue falls. In early Alzheimer’s (even mild cognitive impairment), they saw lithium dropping, suggesting this starts happening at the very onset of plaque formation[8]. Essentially, the disease process (amyloid accumulation) directly creates a lithium deficiency state in the brain. This is a new insight: Alzheimer’s isn’t just a disease of excess (excess amyloid, excess tau tangles) but also a disease of nutrient depletion, lithium being the key nutrient lost. It’s a vicious cycle – plaques cause lithium loss, and as we’ll discuss, low lithium in turn might make the disease worse. Simone Gibertoni: That brings me to the next point. We know correlation isn’t causation – just finding low lithium in patients doesn’t prove it caused anything. Did the researchers investigate what happens if the brain is low on lithium? For example, what did they find when they created lithium deficiency in animals? Isabel Garcia: Yes, they addressed that directly with animal experiments. They used mice (including a transgenic mouse model prone to Alzheimer-like pathology) and essentially put them on a lithium-deficient diet to lower their brain lithium levels. The consequences were pretty dramatic. The lithium-deficient mice showed several Alzheimer-like changes: · More amyloid and tau accumulation: Mice kept on a lithium-deficient diet developed significantly more beta-amyloid plaques in their brains, and similarly higher levels of phospho-tau (the toxic tangles inside neurons) compared to mice on a normal diet. In other words, lacking lithium accelerated the very protein deposits that define Alzheimer’s disease. · Neural damage and inflammation: The brains of lithium-deficient mice showed signs of stress – increased inflammation and loss of important connections. The study noted things like activated microglia (brain immune cells) that weren’t effectively clearing debris, and even thinner myelin coating on neurons, indicating impaired brain cell health. Essentially the aging process in the brain sped up. · Memory and cognitive decline: Perhaps most striking, the mice low on lithium developed learning and memory problems. In a water maze test (a standard test of memory in rodents), lithium-deficient mice took much longer to learn and remember the platform location, indicating impaired spatial memory[11]. This mirrors the memory loss seen in Alzheimer’s. All these changes suggest that having enough lithium in the brain helps keep it resilient, whereas a lithium deficiency makes the brain more vulnerable to Alzheimer-like degeneration. In fact, the researchers concluded that lithium deficiency was not only a result of Alzheimer’s pathology but can also be a contributing cause of that pathology. It’s like a two-way street: Alzheimer’s plaques deplete lithium, and low lithium levels, in turn, exacerbate Alzheimer’s features – a feedback loop. Simone Gibertoni: That’s compelling – and a bit concerning – because it raises the question of intervention. The study didn’t stop there, right? They also explored possible solutions. What did they test in terms of lithium treatment, and what makes lithium orotate different from the standard lithium used in medicine? Isabel Garcia: Exactly, the researchers wanted to see if adding lithium back could help, and if so, in what form. They compared two forms of lithium in the Alzheimer-prone mice: lithium carbonate versus lithium orotate. Lithium carbonate (Li₂CO₃) is the classic pharmaceutical form – used in psychiatry – and lithium orotate is a form of lithium bound to orotic acid, often available as a low-dose nutritional supplement. They gave these to the mice in drinking water and observed the outcomes. Both forms did raise lithium levels in the brain, but there was a key difference. The standard lithium carbonate largely got trapped in the amyloid plaques, just like the natural lithium in the brain had been. Because of that, the free lithium available to brain cells didn’t increase much with lithium carbonate. In contrast, lithium orotate was far less sequestered by the plaques. It managed to evade the amyloid “traps” and significantly boosted the free lithium in the brain. The results in the mice were dramatic. The mice treated with lithium orotate had about a 70% reduction in amyloid plaque burden, greatly lowered tau levels, and their brains were much healthier. Under the microscope, neurons in lithium orotate–treated mice were better preserved, and markers of brain cell health like active microglia and intact myelin were maintained. Behaviorally, these mice had protected cognition – even older mice with advanced disease showed memory improvement when given lithium orotate. On the other hand, mice given standard lithium carbonate did not show these benefits – their plaque levels and memory were almost as bad as untreated mice. Another huge point is dosing and safety: Lithium orotate achieved these benefits at an extremely low dose. The researchers noted it was effective at about one-thousandth the typical lithium dose used in bipolar treatment, essentially just enough to mimic the natural trace levels. At that low dose, the mice had no toxicity issues over their lifespan. This is important because high-dose lithium (like what’s given to bipolar patients) can be toxic, affecting the kidneys or thyroid over time. So, lithium orotate seems to be a form that can get lithium to where it needs to go in the brain, without having to use high, toxic doses. It’s more bioavailable in the presence of amyloid. That makes it quite different from standard lithium and potentially a game-changer in approach. Simone Gibertoni: These results make lithium orotate sound almost too good – preventing plaques, preserving memory in mice. Why do experts think this study could change how we approach Alzheimer’s prevention? Isabel Garcia: This study is causing excitement because it challenges the conventional thinking on Alzheimer’s. For decades, we’ve targeted the “bad guys” of Alzheimer’s – amyloid plaques and tau tangles – with drugs or antibodies to remove them, with only modest success. What this paper suggests is a more fundamental, preventative strategy: ensure the brain isn’t running low on an essential element like lithium in the first place. It positions Alzheimer’s, at least partly, as a disease of lithium deficiency, which is a radical shift. If low lithium contributes to the onset of Alzheimer’s, then maintaining healthy lithium levels in the brain could help prevent the disease or slow it way down. That could mean monitoring people’s lithium levels as they age – something we’ve never done routinely – to catch if they’re low. It also means that instead of waiting for plaques to form and then trying to treat them, we might start earlier with a nutritional or prophylactic approach (like giving a low-dose lithium supplement to at-risk individuals) to keep the brain environment healthy. Another reason this could change the game is the broad action of lithium. Unlike drugs that target amyloid or tau specifically, lithium seems to support multiple aspects of brain health simultaneously – plaques, tangles, inflammation, neural connectivity, you name it[22]. One of the researchers, Dr. Bruce Yankner, said he’s never seen anything that touches so many facets of Alzheimer’s pathology at once. And another expert, Dr. Ashley Bush, called the findings “groundbreaking” because lithium targets all major disease pathways at once. This means a lithium-based approach might do what single-target drugs haven’t: address the whole spectrum of Alzheimer’s degeneration. In practical terms, this could inspire new preventive trials – for example, giving a safe, low-dose lithium orotate to people in middle age or with mild cognitive symptoms to see if it lowers their risk of progressing to Alzheimer’s. It also suggests we could use lithium level in the brain as a biomarker – perhaps using advanced imaging or other indirect measures – to identify early Alzheimer’s risk. Of course, we have to be cautious; these findings, while powerful, are mostly from mice and observational human tissue data. The real proof will come from human clinical trials. But if those trials confirm even a fraction of these benefits, it could inaugurate a new era where preventing Alzheimer’s might be as simple as correcting a mineral deficiency. Simone Gibertoni: It’s amazing to think an old element like lithium could become part of preventive medicine for Alzheimer’s. Given this excitement, many of our readers might be asking: Should people consider lithium supplementation now for brain health or Alzheimer’s prevention? Isabel Garcia: I’m glad you asked, because this is where we need to translate science into practical advice carefully. The short answer is: not yet, at least not on your own. While the study is very promising, we cannot automatically assume that what worked in mice will work in humans the same way. Alzheimer’s is a complex disease, and human trials are needed to see if low-dose lithium can truly prevent cognitive decline. That said, we do have some encouraging human data. Epidemiological studies have long noted that areas with higher natural lithium in drinking water have lower rates of dementia. And there have been small-scale clinical trials where patients with mild cognitive impairment were given micro-doses of lithium (far below psychiatric levels); some of those showed slower cognitive decline or biomarkers improvement. So, the concept isn’t coming out of nowhere – it’s gaining traction. If someone is considering lithium for brain health, the key is dose and medical guidance. High-dose lithium (like the prescription levels for bipolar disorder) can be toxic and is absolutely not something to start without a doctor – it can damage kidneys or thyroid over time. However, the kind of doses we’re talking about for nutritional or preventive purposes are tiny : these low doses tend to be well-tolerated, but we still want a physician’s oversight, especially for older adults or those with health issues. At this point, most conservative experts would not recommend everyone start taking lithium pills for Alzheimer’s prevention until more evidence is in. What you can do now is ensure you get some lithium through a healthy diet and environment. Lithium is present in many foods and water naturally. For instance, certain foods like potatoes, tomatoes, grains, and cabbage are good sources of trace lithium. Some mineral waters also contain lithium. Focusing on a nutrient-rich diet (which has many benefits anyway) will give you a baseline intake of lithium. In summary: stay tuned (clinical trials in humans are likely on the horizon), and in the meantime, it’s reasonable to eat lithium-rich foods and perhaps discuss low-dose supplementation with your doctor if you’re at high risk. Just remember that more is not better with lithium – it’s about finding the right, tiny amount that the brain needs. Simone Gibertoni: This has been a fascinating discussion. From a longevity perspective, I’m struck by how a discovery like this exemplifies the mission we have at Clinique La Prairie. Our goal is to extend healthy lifespan – and that means preventing diseases of aging, not just treating them after the fact. Alzheimer’s has long been a formidable barrier to living longer and better. What we’ve discussed today is essentially a potential way to unlock longevity of the brain: by addressing a simple nutritional deficiency, if indeed that’s a key factor. It’s a beautiful example of how cutting-edge science can illuminate simple, actionable insights. Who would have thought that an ancient element like lithium, used since antiquity, could be part of the future of Alzheimer’s prevention? It reminds us that sometimes longevity science isn’t about high-tech interventions alone, but also about understanding the fundamental needs of our biology. At CLP, we believe in a holistic approach to longevity – nutrition, environment, and early preventive therapies are as crucial as gene therapies or high-tech solutions. The "Unlock Longevity" newsletter is my personal contribution to exploring, but most importantly simplifying and making accessible, the themes, techniques, and strategies related to longevity. If you believe these insights could benefit your network, feel free to share this article! This article reflects my personal views and is not intended to replace professional medical advice. Commenti