How to Exercise to Live Longer | Lifespan with Dr. David Sinclair - S2, Ep. 5

0:00 Many people actually take caffeine containing beverages before they start exercising. The data here is really interesting. One thing that's been making headlines lately is that some of the weight loss by people on GLP-1 agonist is muscle mass, not just fat. People with higher grip strength tend to live substantially longer and healthier lives. For sedentary individuals, those that sat around more, they concluded that walking for just an hour adds an additional 6.3 hours to life expectancy. A lot of the marketing targeted to women is confusing. Exercising for longevity differs from exercising, say, for pleasure, general health, or for a specific sport. Welcome to Lifespan, a show where we discuss the cuttingedge science of aging and

0:45 how to live healthier at any stage of life. I'm David Sinclair, a scientist and professor working on understanding why we age and discovering new ways to slow and even reverse the aging process. On this show, I share an insidider look at the latest from my lab, the field, and what's just around the corner. Hey everyone, this show is about physical activity, a topic that always generates so many questions and controversies. Questions like, "How much do I need to do?" "Is there a substitute?" "Yeah, I wish." "What supplements should I take? Do I need to eat meat? What should

1:33 men do? What should women do?" The list goes on. I brought out some props to show why a strong handshake is actually one of the best indicators of your biological age. And I also showed that it's possible to be super fit even at 80. I'm so excited to share that our health and education platform at lifespan.com is now live. The mission of the site is simple, is to help you and your loved ones live your longest, healthiest life. When you join us at lifespan.com, you'll get early access to lifespan episodes, a newsletter from me, and updates about the clinical trials, comprehensive show notes, and what I'm particularly excited about is that you'll receive Lifespan magazine, the world's first longevity magazine written by scientists. We also have

2:20 Ask Me Anything Sessions, a book miniseries and movie club, behindthe-scenes content, and much, much more that's coming. I couldn't be more excited. Lifespan connects you directly with the longevity scientists doing the research so you can understand the science and apply it to your life. We're making the best evidence-based health insights accessible to everyone and building the world's largest longevity community. Lifespan is proud to support the Lifespan Foundation, a nonprofit whose mission is to fund the careers of young researchers and to support the most exciting longevity research. So do join us at lifespan.com and let's live longer together. Okay, let's go. So we all know that we should be exercising to live longer. Of course,

3:07 we all try to do as much as we can with our busy lives. But there are some real subtleties and debates about what the science actually says. For instance, how much and how often should we be exercising? Which medicines and even supplements can prevent us from receiving the benefits of exercise? and how the heck do I skip breakfast if I need to work out in the morning? I'll also talk about supplements that enhance exercise and even can mimic aspects of the benefits of exercise for those people like me who have really not a lot of time to get to the gym. So, there's no doubt that physical activity is one of the most powerful and indispensable tools that we have at our disposal in our broader longevity toolkit. While most people understand and appreciate the relationship between exercise and health, few people know how to optimally exercise to maximize

3:57 their chances of living a very long, healthy, and vibrant life. By the end of this episode, you're going to leave with an understanding that exercising for longevity differs from exercising, say, for pleasure, general health, or for a specific sport. So, let's talk about physical activity as a powerful prolongevity intervention. No existing drug on the planet compares to what exercise can do for our health and aging. I once thought that the time gained in lifespan would be equal or even less than the time spent in the gym. So I use this as an excuse to slack off. But actually that's not true. In 2025, for example, there was a fascinating paper published in the British Journal of Sports Medicine that totally refuted this. Using data from individuals in the US aged 40 or more, the authors concluded that being as active as the top 25% of

4:47 the population could yield an extra 5.3 years of life on average. For sedentary individuals, those that sat around more, they concluded that walking for just an hour adds an additional 6.3 hours to life expectancy. That's crazy if true. This is a remarkable conclusion as it suggests a 6:1 ratio benefit for life gain versus time spent exercising and makes it essentially impossible to argue that exercising is not a good use of your time and you'll also feel better too. These findings very much corroborate research published more than a decade earlier in 2011. In a seminal paper published in the medical journal the Lancet, people that didn't exercise at all were compared to people that minimally exercised. People that worked out on average for 15 minutes a day had

5:37 life expectancy that was 3 years longer. That's approximately 7 minutes of life gained per minute spent exercising. Here's another interesting fact. Studies have consistently shown that people with higher grip strength tend to live substantially longer and healthier lives. Grip strength itself isn't going to make you live longer, of course. So, you don't need to go out and buy a grip strength trainer, though I do use them often when I'm just sitting around. It's always good to have better grip strength, but it's used as a proxy for overall muscle tone and especially upper body strength because it's a a direct reflection of how much strength training a person has done. Grip strength can be measured directly using a device known as a dynamometer, which outputs a value either in kilograms or pounds. Another good test of grip strength is how long you can

6:25 hang from a pull-up bar. In your 20s, 45 to 90 seconds is common and often over a minute without training. In your 30s and 40s, 30 to 75 seconds is very achievable if you stay active. In your 50s, like me, 20 to 45 seconds is solid. In your 60s, 15 to 30 seconds is already good. Then in your 70s and beyond, hanging at all is a strong sign of healthy aging. There's a particular graph, Andrew, can you pull it up that's worth talking about? Those of you who are listening, I'll explain. This is a graph from the paper. And what it's got on the x-axis is your age and on the y- axis grip strength in kilograms. And you can see multiple inverted U-shaped curves. The different symbols and colors represent different populations. And the lines indicate the 10th, 25th, 50th, and 75th,

7:16 and even 90th percentiles. Notice how grip strength peaks around age 30 and then gradually continues to fall. I've seen many graphs like this and one thing that strikes me every time is that grip strength in very old age starts to resemble the grip strength of little kids. Grip strength is one of the most robust low tech aging biomarkers and a clear example of a metric that is strongly associated with both health span and lifespan. Now I want to take a look at a different graph which is from a 2015 paper published in the Lancet again. All right, so let's call it up Andrew. This one's really interesting. The different colors indicate how high or low someone's grip strength is with blue being the lowest third, red the middle third, and green the highest third. The

8:02 case fatality rate percentage, in other words, the chance you can die, is on the left hand side y-axis, and different diseases and incidents are on the lower horizontal x-axis. These diseases and incidents include falls or fractures, being admitted to the hospital, having cancer, or having cardiovascular disease. People with a higher grip strength have a lower case fatality rate and are also less likely to develop dementia and other age- related chronic diseases. For all these reasons, it's becoming more common for doctors and people at home to include grip strength as a routine measurement and use this as a guide for their rate of aging. Well, of course, having a grip strength that's stronger doesn't mean you're going to live longer, but it's a good proxy. That

8:49 said, I always leave one of these things in front of my TV or next to my couch so that I can do this even at work. It's great to have one around. For those of you who are listening only, I've got one of these grip strength trainers here. This one's plastic. It's got a spring. They're pretty common. You can dial up the strength. This one's on maximum. Or a rubber ring. In this case, it looks like a donut, but it's actually very hard to squeeze. And I take these things with me when I travel, and they're very good for just doing a bit of exercise. You can do this while you're on the plane, sitting even. My doctor in New York often tests my grip strength when I visit. My grip strength is over 50 kg, and it's probably from carrying Serena suitcases around the airport, and of course, having these grip strength trainers lying around the house and also around the office,

9:35 which I highly recommend. Not surprisingly, we see the same incredibly compelling data for people with higher cardiorespiratory fitness. In a really interesting study published in JAMAMA network open, the journal in 2018, mortality rates were analyzed for people with different levels of fitness as assessed by how they could run on a treadmill. Compared to people with elite levels of fitness, the lowest performing group had an all cause mortality hazard ratio of 5.04. This means that that group was 404% more likely to die of any cause during the tracking period than the elite group. So just like grip strength, the persuasive data supporting cardiorespiratory fitness has inspired a large number of people to routinely measure their V2 max, which is a measure

10:23 of how much oxygen you consume while doing maximum exercise. One of the easiest ways to measure your V2, perhaps not the most accurate, is to use a biotetracking device. These days, some of them actually output this number. Usually, it takes about a week's worth of data measuring your heart rate and how fast you move. The most accurate way, however, is to actually go to a clinic or a sports lab or even some longevity labs these days have these tests. You exercise on a treadmill or on a bike while wearing a mask that can measure your oxygen intake and your carbon dioxide output, and the intensity ramps up until you reach your max effort. It only takes about 10 minutes of real work and it gives you a precise number. Given what I've said so far, I'm guessing you wouldn't be

11:08 surprised if I tell you that people with superior balance are also more likely to live longer and healthier lives. Unfortunately, as we get older, balance tends to deteriorate starting around your mid-50s. Several systems age at once, but one important piece is the neuromuscular junction or the NMJ. This is the connection between your nerves and your muscles. With aging, those connections become less precise, so muscles fire a bit later and a bit less cleanly. Later in the season, I'm going to talk about my lab's work on regrowing the NMJs in old animals. I might even bring Kelly Rich, the doctor who's working on that, into the studio to talk about it. Other things actually happen that make things worse. We're losing fast motor units in our muscle. Our

11:54 propriception, which is the body's ability to know where it is in space, like our GPS, that declines from the ankles and hips, and gets noisier. And the brain gets slightly slower at integrating the balance signals. One thing that's important to me is that Lifespan only partners with companies that I genuinely believe in. They must be grounded in science and willing to support medical research that will ultimately change how we treat aging and diseases. Their support also helps keep this podcast free for millions of listeners around the world. One of those companies that I'd like to mention is Ketone IQ. I've known the founder, Mike, for over 5 years, and I'm a huge fan of what he's doing. I've been studying the benefits of fasting for over 25 years now. And one of the most important molecules is beta hydroxybutyrate or BHB, the primary ketone

12:43 that our bodies make during fasting. That's an important metabolic fuel for your brain and your muscles. More recently, science has shown that BHB is also an epigenetic regulator of your immune tea cells. These are cells that protect against viral infections. Ketone IQ is a little shot that contains R13 butin dial, a naturally occurring molecule that your liver converts into BHB and it happens in minutes instead of the day or two it normally takes through fasting. One of the studies on BHB that caught my attention recently was by Steven Krenine and colleagues. Their work in 2016 showed that while the aging brain loses its ability to use glucose efficiently, its ability to use ketones remains largely intact. That finding has helped spark an exciting new area of

13:31 research on brain metabolism. And more recently, Quinonius and Lemon published a randomized trial in 2022 in the journal Nutrients showing that ketones help preserve reaction accuracy during prolonged mentally demanding exercise. And another study in that same year found that patients with severe CO 19 had impaired ketogenesis, the ability to make ketones. In their experiments, adding BHB improved both the CD4 and CD8 T- cell functions, suggesting that ketone bodies may help restore antiviral immune responses under those conditions. Personally, I use ketone IQ quite often when I have a long day, when I'm recording podcasts, I'm writing, or I'm feeling a little down, or maybe getting a virus. I'd love you to try Ketone IQ, too. I asked the guys at the company

14:18 to offer a 30% off discount for your first monthly order, which they kindly agreed to. You can visit ketone.com/lifespan or at the checkout, just use the code lifespan. Balance isn't about strength, of course, it's about timing. The good news, though, is that this is a highly trainable aspect of our physiology. According to a 2022 study that was in the British Journal of Sports Medicine, people aged between 51 and 75 years that couldn't pass just a 10-second one-legged stance test were a whopping 84% more likely to die than those that could do it. In the United States, approximately 40% of adults aged over 65 even struggle to climb stairs or walk a quarter of a mile without

15:05 assistance. As one might expect, this not only makes their life harder, but far less enjoyable. While there's a great saying that the best kind of exercise is the kind that you enjoy and will do routinely, it's also true that exercising for longevity requires important considerations. If we want to proactively confront these challenges headon and do our best to protect against them, we need to take a multi-pronged approach to exercise. This means that an ideal exercise regimen is one that includes cardiovascular exercise, strength training, and work to maintain balance. According to the US physical activity guidelines, it's recommended that we get at least 75 minutes of vigorous aerobic exercise or double that, 150 minutes of moderate aerobic exercise each week,

15:51 ideally spread out over multiple days. If you're wondering what differentiates moderate from vigorous activity, moderate activity is something that makes you breathe harder, increases your heart rate, and causes you to break a sweat. It doesn't, however, prevent you from talking, meaning that it's something that you can do while you're holding a conversation with somebody. Examples of this include brisk walking or riding a bike on ground level at a sustainable pace. Vigorous activity on the other hand is something where your heart rate and breathing rate are relatively higher and it includes activities that are difficult for you to do while holding a conversation. Examples include intense forms of exercise such as running, swimming, laps, or playing singles tennis. Now, let's talk about strength training. The American College of Sports

16:36 Medicine recommends targeting all major muscle groups at least two times a week. And the science on this is very clear that that's much better than doing it just once a week. The upper bound in terms of sets or groups of repetitions per week is thought to be quite high. For example, one systematic review concluded that 12 to 20 weekly sets per muscle group is an optimal range for increasing muscle hypertrophy or muscle growth in young trained men with diminishing returns beyond that. Unlike weekly aerobic activity and strength training, the guidelines aren't as established for incorporating weekly balance work. While some recommendations do exist, they're largely for older adults. For example, the physical activity guidelines for Americans from the US Department of Health and Human Services recommends that older adults incorporate balance activity into their

17:25 weekly physical activity regimen. Beyond old age, even throughout our whole life, we should be doing balance work. It'll not just make daily life better, but it'll protect you against falls, sprains, and as you get older, it could even save your life. While it's difficult to say just how much is ideal, given the current data, it's certainly safe to conclude that this is something that should be part of a regular fitness routine for sure. Luckily, many forms of fun and effective exercises incorporate balance work as well, such as yoga, martial arts, dance, Zumba, and Pilates. Many of these can also be social, which is advantageous since we know that social support and satisfaction are important for healthy aging as well. These are also multicomponent exercises that can overlap with cardiovascular and strength training. For example, venyasa yoga is absolutely

18:15 going to get your heart pumping. While other moves like arm balances and inversions can be seen as a type of calisthenic strength training, there are some pretty remarkably fit and strong people out there that only do yoga for exercise, which is a testament to how effective this type of exercise can be. There's actually some really good evidence that yoga can improve cellular aging hallmarks. For example, in 2017, a paper showed that just 12 weeks of yoga combined with some meditation significantly improved levels of 8 og, which is a marker of DNA damage, and lowered cortisol and IL6, an inflammatory cytoine. In addition, tomeorase levels went up, which is what we want to see, as well as increased betaendorphine, so people would feel better, increased BDNF, which

19:02 is going to help new neurons grow and help with memory. and cert one the gene that we work on were also significantly increased by this regimen. Some people assume that because two hours of vigorous exercise a week is good then 20 hours must be better. That's actually not true. Our bodies need to rest and repair. Hormesis what doesn't kill you makes you stronger. It really does need time to work. You need some rest. A major study published in the journal called Circulation in 2022 tracked more than 100,000 adults in the US over a 30-year follow-up period. It showed the near maximum benefit for exercise and mortality was 2.5 to 5 hours of vigorous activity per week or 5 to 10 hours of moderate physical activity or an equivalent combination of the two. Let's look at

19:50 figure one from that paper. Andrew, can you pull that up for us? There it is. On the y-axis on the left, you can see the relationship between risk of death from any cause compared to on the x-axis along the bottom, the amount of physical activity performed each week. The dark line represents vigorous activity while the gray line represents moderate activity. It's interesting to see that vigorous activity quickly reaches a plateau while moderate activity continues to offer benefits for quite a while. Similar findings are seen for cardiovascular mortality and non-cardiovascular mortality. Now that we've reviewed existing guidelines and have an idea about what the upper bound is for weekly physical activity, let's start to think about what an ideal weekly routine looks like for you. Obviously, it's something that's going to incorporate cardiovascular exercise,

20:38 strength training, and balance. As we've discussed, at a minimum, the goal should be to hit all three of these pillars on a weekly basis. If your goal is to max out what can be done, then an ideal routine is going to look a bit like this. Doing strength training for every muscle group at least twice a week. Doing at least 75 minutes of vigorous activity, aerobic activity or 150 minutes of moderate aerobic activity per week. Making sure that you do balance exercise as well, at least once per week. We'll list this in the show notes, of course, which you can find at lifespan.com. Here's an example of a a good strength training regimen that you could do four times a week. One day would be a push day involving triceps, chest, and front shoulders. Another day would be a pull day involving your back, biceps, and rear shoulders. And the third

21:27 day would be a leg day. Then the fourth day would be a chance to hit every other major muscle group a second time. A nonstrength training day could be devoted to balance heavy exercise like yoga. And yet another day could be an intensive aerobic activity day, which could look like a longer hike, a run, or a bike ride. The remaining day of the week could be a rest day or incorporate some light walking. Or if you're more interested in cardio, you could flip this around and consolidate all of the strength training into two different days a week and make more time for hiking, cycling, running, the stair master, or whatever aerobic exercise you like. If this sounds way too intimidating or infeasible given your busy schedule, the main thing to keep in mind here is that an ideal routine is one that blends these three pillars of exercise into a weekly

22:17 regimen that you do consistently. There are also many sneaky ways to engage in physical activity that contribute to your total weekly number. One of the best strategies is to do mini exercises, which some people call exercise snacks. These are quick bursts of physical activity that happen throughout the day. I don't particularly like the term snacks because I tell people all the time not to snack. This could look like taking the stairs instead of the elevator, like in my building, it's nine floors up, or parking your car further away from the store or your workplace, or walking short distances instead of driving. These are all great ways to get in some extra movement. So, for example, in my case, I spend a lot of time traveling, so I'm going to carry my hand luggage instead of rolling it. I avoid those moving walkways. And when I'm at home, I'm fixing up

23:03 my own house and planting my own trees. Going on walks while talking, getting a treadmill desk or a standing desk, which is what I have, or taking a stroll during your lunch break. These are also really great ways to rack up your weekly exercise minutes. Some people take this even further and do push-ups, sit-ups, or squats in between meetings. I usually stand up and pace around my office during chats. I very rarely sit down during the day. And my father, for example, he incorporates exercise into things he really loves doing. Going on bushw walks for hours, and twice a week, he actually walks six miles to go get coffee with a friend. These are enjoyable activities, and they're really not considered exercise. They're more just a social event for him. There's no right or wrong way to do this, of course. It's really about your schedule and what you can fit

23:50 in. Although standing doesn't technically count as moderate or vigorous exercise, it is better than sitting in terms of metabolic expenditure. And for this reason, getting a standing desk can also be really advantageous. Okay, let's briefly summarize what we've covered so far. And we've covered a lot. So, in this section, we've covered how aerobic exercise, strength training, and balance work are the three major pillars supporting an ideal weekly regimen geared towards optimizing your healthy aging. One common question that people have is whether or not too much exercise is dangerous or harmful. This is actually pretty tricky to answer because the science isn't clear. There's some evidence that really intense exercise can promote some types of cancer, for instance, but there's other evidence that people who exercise their whole lives intensely live

24:35 longer and have less other diseases. So, let's break that down. Let's see what the science says. As an example, Olympic athletes in the US were documented to live 5.1 years longer than their counterparts in the general population. Of course, these are people that exercise a great deal through a large part of their lives. These tracked Olympians also enjoyed lower risks of cancer and cardiovascular disease. That being said, however, there's some evidence that certain types of really intense and prolonged exercise might actually have uniquely negative effects, which I want to talk about. For instance, an abstract that was recently published in the Journal of Clinical Oncology linked long-distance running to a risk of precancerous tumors in the colon. Prior to

25:21 initiating a study to explore this relationship, the authors also observed that multiple people that presented to a cancer center with advanced colon cancer were all ultramarathoners. The authors therefore chose to look at people who had completed at least two ultramarathons that were at least 50 kilometers in length or five marathons which are about 26 mi each. Their findings suggest that intensive sustained long-distance running is a risk factor for colon tumors. Whether this is due to reduced blood flow to the intestines during prolonged runs or if it's a finding that holds true for larger subject sizes is still unknown. Ultimately, it isn't necessary to do exercise this extreme to get the maximal or near maximal benefits in terms of longevity. Another question

26:07 that people sometimes ask is, are there tests you can take to know how much exercise you actually need? Because we're all different, of course. People often ask if there's a test that tells you whether you should exercise more or exercise less. Well, while there there isn't actually a single test to say how much you need, there are very good signals that tell you how well your body is handling training. So, let's talk about those. One thing I've learned after decades of studying aging is that you simply can't consistently improve anything that you don't measure. A few months ago, after a lot of travel and speaking engagements and probably too many dinners out, I realized I'd put on a few extra pounds. And I could see the graph on my wthing scale and I needed to shed a few. My goal, however, was not to simply lose weight. I wanted to get back to my usual body composition.

26:56 Had I lost muscle? Was my visceral fat creeping up? What did I need to focus on? That's why I like the Wings body scan scale. It tells me much more than my weight. It measures body fat, muscle mass, visceral fat, and even includes an FDA cleared ECG. As I made a few changes to my diet and got back into my normal routine, I could actually watch my body fat come down while preserving my muscle, and that's far more useful than watching a single number on a scale. I've actually been using Wings products for well over 10 years. And lately, I've become a big fan of their watches as well. They continuously track heart rate, sleep, activity, temperature trends, and even blood oxygen. I wear the Wings silver scan watch Nova, which looks a lot like an expensive diving watch.

27:44 And my partner Serena wears one of the slim gold models. She loves that it looks like an elegant watch first and a health tracker second. Wings also makes one of my favorite blood pressure monitors for home use. Also, a sleep analyzer that can help identify sleep issues. To me, that's what longevity is all about. Measuring what matters, making small improvements, and letting those improvements compound over the years. Wings makes it easy to build your own health home lab. So whether you're tracking your body composition, blood pressure, sleep, heart health, or activity, you'll have the data you need to understand whether the choices you're making are actually improving your health or even harming them. If you'd like to build your own health home lab like I have, visit wings.com/lifespan and use the code lifespan to receive 10% off. Fitness tests like V2

28:35 max and lactate threshold tell you how hard you can push your body, but they vary based on age, sex, and training levels. So, let's talk about that. In the general population, a V2 max above 51 is generally considered excellent for a man in his 20s. While excellent for a woman in her 20s is about 45 or above. These thresholds vary a bit depending on which classification system you use. But as we age, these benchmarks typically decline by about 10% per decade, especially in sedentary people. So that covers V2 max, one of the most accurate ways of measuring your physical fitness and even predicting how long you might live. The lactate threshold typically sits around 60 to 80% of V2 max depending on how well-trained you are. Training above that too often without adequate

29:22 recovery is where exercise can shift from being a helpful stimulus to an excessive stressor on the body. Wearables add another dimension. A resting daytime heart rate below the low 60s usually reflects a really good cardiovascular fitness and you can get those measurements from most wearables these days. Day-to-day drops in heart rate variability or HRV of more than 10 to 20% or poor sleep or a rising morning heart rate are often early signs that you're not recovering effectively even if you do feel fine. Blood tests matter, too. Inflammation markers like CRP, iron markers like feritin and hemoglobin, metabolic markers like glucose and insulin, and hormones like cortisol. They all shape how much stress your body can tolerate. Cortisol is one

30:09 of the hormones that helps you meet the demands of exercise. It mobilizes energy and it keeps you alert as intensity increases. That short-term rise is normal. It's part of a healthy stress response. Where it becomes relevant is when recovery starts to break down. Things like poor sleep, persistent fatigue, declining performance, or just feeling run down. Now, most people aren't measuring cortisol regularly. Some of you may never have checked it at all, even with your doctor. Maybe you check it occasionally, but it's not something that you're tracking every day. So instead of focusing on this single number, it's better to look at patterns in how you feel and how you perform. In a healthy rhythm, cortisol is high in the morning and it falls throughout the day. With excessive or prolonged stress, that rhythm gets disrupted. Some people can run chronically

30:59 high. Others show a blunted response. There isn't one single cortisol pattern for overtraining. If you're seeing signs of poor recovery and your training load hasn't changed at all, that's a good sign that you should start to pull back a bit. Even if you never measure cortisol at all, creatin kynise or CK, an enzyme that you find in muscle and heart, it's especially useful to measure that in blood because when it's elevated or at least it stays elevated, that tells you that your muscles are not recovering even if you feel fine. You might be wondering how your genetics can affect exercise and even which exercises are better for you. So let's run through those. So for example, there's a gene called actn3 and another one called ACE. And the variance of these genes bias you slightly either towards power or towards endurance. There's another gene called PG-1 alpha

31:50 which we've studied many times in my lab. That gene actually controls the mitochondria and how much energy you produce in your muscles. Then there's VEGF. VeF stands for vascular endothelial growth factor. The VEGF gene family which is present in all our cells modulates how your body grows new blood vessels to improve oxygen delivery. The amount of VEGF in your body declines with age and that's one of the reasons we are more out of breath and even develop vascular dementia as we get older unless we counteract that with healthy living such as exercising and a healthy diet. And then of course there's the inflammatory genes like IL6, TNF alpha. These genes actually can control how well you recover. And then finally, call 1 A1 and call 5A1. These relate

32:38 to how well your tendons can recover from injury. You can now get targeted or whole genome analyses from various companies, especially in the United States. It's also important to remember though that these genes don't act in isolation. They provide a blueprint of your potential, but your actual results still depend on how you live your life. There's, of course, the epiggenome, which we all now know about. There's also nutrition, recovery, and other lifestyle factors on top of that code that truly determine your long-term health and longevity. Many people also wonder if being a weekend warrior, just working out over the weekend is sufficient or if they really need to spread it out over the week. And while it's realistically hard to hit an ideal weekly regimen just over the weekend, the data here is pretty fascinating and may not be what you expect. A 2025

33:27 paper published in BMC public health looked at the physical activity patterns of 150,000 adults. They found that both regularly active people and the weekend warriors displayed substantially lower risks of all cause mortality compared to those engaging in no sports or exercise. Separate research involving about 52,000 US adults that had diabetes also found that both regular physical activity and weekend warrior patterns that met physical activity recommendations were associated with a significantly lower risk for all cause mortality. Still, there are benefits of spreading your exercise throughout the week. There's a 2025 study of 69 young adults that showed that daily movement might be better for your sleep than doing all of your exercise over the weekend. I know it's

34:14 tempting to do all your workouts over the weekend, and I tend to do a lot more on the weekend, but try to do some during the week, whether it's while you're watching TV or listening to music. Well, this of course is an area that could benefit from more research. These studies do suggest that the most important factor might be the weekly amount of exercise as opposed to exactly how it's spread out through the week. Once again though, getting multiple hours of different types of exercise over the weekend is a non-trivial task and most people are going to find it easier to stretch their exercise regimen across the week. What about the best time of day to exercise? I get asked that a lot and really there's no single answer that's best for everyone, but let's break it down. The question touches on the growing field of chrono exercise or aligning physical activity

35:01 with circadian rhythms. As you probably know, our bodies run on internal clocks which affect everything from sleep to energy use. Your liver has a different clock to the brain. And when you fly to a different country and you're in different time zone, actually the reason you feel kind of sick in part is because your different organs are on different time zones and might maybe even in a different time zone from each other. Did you know that exercise can act as a zeitge? A zitgyver is an external environmental cue such as light that synchronizes our internal biological clock, our circadian rhythms to the 24-hour day. Derived from the German word for time giver, these cues, including food and exercise as well, reset the body's master clock, dictating sleepwake cycles

35:48 and metabolic processes. Exercise tells your internal clocks, like the ones in your muscles, what time it is. If you're consistent with your exercise timing, say you go to the gym every day at 5:00 p.m. or go swimming at 7 a.m. every morning, there's scientific evidence that your muscles actually know that the time is coming and anticipate the stress. They seem to prime themselves to be stronger and more efficient at that specific hour. That's amazing. Some of you prefer morning workouts, I'm sure, if you feel more motivated or you want to knock it off your to-do list. And there are benefits to morning exercise. And many people do it just to feel great throughout the day. There is research showing that strength and overall athletic performance tends to peak in the afternoon though or even early evening. That's when your core body

36:35 temperature is higher and your muscles are more physically capable of greater force and power output. You're also more likely to experience better heart rate and blood pressure responses. In fact, peak performance is usually higher between 400 p.m. and 8:00 p.m. and lowest between 6:00 a.m. and 10:00 a.m. One study reported that cyclists had higher power output and oxygen uptake in the evening around 6:00 p.m. compared to 8:00 a.m. Even Olympic swimmers have been shown to record their fastest times late afternoon around 5:00 p.m. But timing really doesn't matter more than how you feel. All right, so now let's talk about chronoype. We all tick on slightly different clocks. Early birds tend to peak earlier in the day than night owls like myself who feel sluggish

37:22 in the morning and perform much better physically and mentally later on. So matching your training to your chronotype is a really smart way to work with your biology rather than against it. So now I want to talk to you about using exercise as a tool to support sleep. So how do we do that? Well, exercising very close to bedtime can disrupt your sleep. And it was really proven out in a large 2025 study using a Whoop wearable to track over 14,000 people across 4 million nights. And what they showed was that people who did strenuous exercise in the evening tended to fall asleep later and sleep less. And they also reported poorer sleep quality. But exercise ending at at least at least 4 hours before bedtime was not associated with sleep changes. Similarly, a 2021

38:10 study found that high-intensity workouts in the early evening around 2 to 4 hours before bedtime generally they don't seem to hurt your sleep. So my recommendation would be to wrap up your training sessions at least 4 hours before bed. You need that time for your core temperature to drop and your autonomic nervous system to shift towards a recovery state. moving away from the heightened arousal that comes with intense exercise. So, the summary is that you want consistency both in the time of day when you work out and keep doing that for years and even decades. That's the key. And I think the best time to exercise is whenever you can and whenever it feels good for you. I want to spend some time talking about the intersection of protein, exercise, and longevity. We'll dive deeper in future episodes, but today I want to clarify the debate around protein timing

38:59 and quality. We know that adequate protein intake is important for supporting hypertrophy or muscle growth and preventing muscle protein breakdown. I'll share my thoughts about total protein intake in a future episode. But depending on your age and physical activity levels, the optimal range for most people is around 1.2 to 2 g of protein per kilogram of body weight per day. It's even higher for older adults and for people who train a lot. For a long time, people talked about a narrow post-workout anabolic window. That's the time your muscles are primed for growth. So, the idea was to consume your protein within about 30 to 60 minutes after training. But we now know that the window is much broader. Your total daily protein intake

39:45 is likely to matter much more than timing. But protein timing is not completely irrelevant. Consuming it soon after training is still useful if your previous meal was many hours earlier or if you trained while you were fasting. Personally, I don't consume protein bars, protein shakes. I leave that to professionals whose livelihoods depend on another one or 2% muscle size. As you know, I'm a strong proponent of fasting for longevity and giving the body periods of metabolic and digestive rest. Even when fasting, you can still meet your protein needs effectively. The key is to distribute your protein across at least two meals rather than consuming most or all of it in one sitting. Spreading protein intake this way can help stimulate muscle protein synthesis more than a single large dose. That allows you to build more muscle during feeding windows while still

40:36 maintaining fasting periods that support cellular repair and boost longevity defenses. And remember, you have to vary your diet depending on how you're living. So on days you're not exercising or you're actually not doing a lot of workouts, maybe you're traveling, you can adjust your eating. You can eat once a day in those cases. That's what I do. I want to address a misconception that some people have about whether you have to eat animal products to really reap the benefits of exercise. Not all protein sources are created equal, but the differences are often overstated. Animal proteins like whey from milk are typically considered the gold standard largely because they're rich in essential amino acids and they're easy for the body to use. But for most people, especially if you're eating a varied diet, plant proteins can be just as effective. That's what

41:22 I focus on mainly. While there's no doubt that animal protein is complete and bioavailable, it's also true that plant-based protein can satisfy your needs on a vegetarian or a vegan diet. Indeed, there are many Olympians and world-class athletes that are vegetarian or vegan. And I know it's not trendy. It's about the science. And everything I say here is based on science, not trends. The existing data very much support this. So, for example, a recent 2025 meta analysis in sports medicine open compared omnivorous to plant-based diets and found that muscular strength is not compromised by plant-based diets. At the end of the day, it's more about adhering to certain dietary principles and hitting nutritional milestones than it is about one specific dietary

42:09 pattern over another. On a vegetarian and especially on a vegan diet, you want to make sure you're not deficient in certain vitamins and minerals. For instance, B vitamins and iron are particularly important. But the key here is total intake and variety. This becomes particularly important as we get older. With aging, many people develop what's called anabolic resistance. What this is is when the body doesn't respond to protein as efficiently as it did once. In that case, hitting a slightly higher daily protein target matters more than the specific source. Now, most plant proteins are lower in one or more essential amino acids. And that's also why variety matters. Foods like tofu, tempeh, edamame, quinoa, these are excellent staples. And combining

42:54 proteins across the day helps balance things out. Although if you're fasting, that's a different consideration. A good example of this is rice and beans. Each one complements the other, filling in the amino acids that the other lacks. If you're not thinking about combinations, you can take a simple approach and just eat a bit more to reach that leucine threshold that your muscles need if you're working out. For supplementation, whey protein is a solid option. But for those avoiding animal products like I do, pe protein isolate is one of the better studied plant-based alternatives. Now, this naturally brings us to a related topic that comes up all the time when we talk about protein, and that's mtor in simple animals like worms or more complex ones like mice. Inhibiting mTor either genetically or using chemicals like rapamy significantly extends their

43:45 lifespan, makes the animals healthier as well. Dudley Lamming, a professor who I used to train in my lab when he was a PhD student. What his lab has clearly shown is that isolucine actually extend lifespan when they are restricted, when they're limiting, not in excess. And they do this by turning off mTor signaling in the body and putting it into adversity mode. You might recall that mTor is the body's sensor of amino acids, in particular leucine, isolucine, and veene. And you can get those from meat or from protein shakes that turns on mTor and that's the signal to grow and divide and and grow more muscle for example. But actually what we found out is that lowering the activity of mTor is what extends lifespan. Protein intake and resistance exercise both activate mTor in skeletal

44:32 muscle. That's not a bad thing. It's actually essential for building, repairing, and maintaining muscle. At the same time, you'll often hear that suppressing or lowering mTor activity in the body through lowering say amino acids or fasting does extend lifespan in animals. So, it sounds like a contradiction, right? Well, actually it isn't. What matters is context, the tissue, the dose, and whether mtor is being activated in short bursts or left on all the time. in muscle. Short-term activation of mTor after exercise or on a protein- richch meal is normal. It's actually healthy. It's how the body repairs and builds muscle. Think of it as a pulse. It turns on, it does the job, it repairs, it grows muscle, and then what you want is for it to switch off again. Shouldn't

45:21 always be on. That would be the problem. We call that chronic activation. In animal studies, what we call preclinical studies, overeating keeps mTor elevated across the body that in the long run can interfere with processes like autophagy, the cell's cleanup system. This distinction becomes more important with aging. Given that we humans are really uniquely at risk for muscle wasting or sarcopenia as we get older, constant mtor suppression shouldn't be the goal and pulsatile on andoff activation is much more strategic. Some people looking to promote longevity similar to the mouse experiments have actually opted to take the drug that inhibits mTor rapamy. This is the drug you might remember that was discovered on Rapanui or Easter Island, hence the name. The dose

46:09 that people take it varies, but long-term we just don't know if lifespan will be extended. Everybody should of course acknowledge where they're at and exercise safely, but all of the evidence really suggests that it's never too late to make an improvement. As we've discussed, exercise and physical activity are essential for healthy aging. But to take it to the next level, you need an understanding of how your body responds to training. That information can help you make smarter decisions about when to push harder, when to recover, and how to support your long-term health. Which brings me to a science-based wearable that I'm particularly fond of. Partly because of its scientific foundation at Harvard, where I work, but also the founders's own research and scientific rigor. Of course, I'm talking about the Whoop band, the one that I rarely take off. As

46:56 a scientist, I like measuring things rather than guessing. And Whoop continuously tracks my sleep, my resting heart rate, my heart rate variability, respiratory rate, daily strain and recovery, and other aspects of my health, giving me objective data about how my body is responding to the changes that I make. On weekends, you'll usually find me on Cape Cod in my workshop or outside on the property, planting fruit trees, repairing the house, or hauling lumber in my old 1992 Ford F-150 pickup. Sometimes, however, I wake up eager to get outside, but my Whoop tells me a different story. My heart rate variability is lower than usual, my resting heart rate is elevated, and my recovery score is really poor. So, on those days, I still head out, but I pace myself. I found that

47:41 listening to those signals helps me recover better and work harder over the long term. I appreciate that Whoop is backed by great science. For example, in 2022, Miller and colleagues published a study in the journal Sensors comparing six leading wearable devices against clinical grade measurements of sleep, heart rate, and heart rate variability. Whoop was among the most accurate for measuring overnight heart rate and HRV. These are the two biomarkers that I pay close attention to because they provide valuable insights into recovery and physiological resilience. So, if you don't already use Whoop, I really encourage you to give them a try. So, visit join.woop.com/lifespan and you can use the code lifespan to receive your free Whoop and your first month of membership.

48:28 As an example of this, I want to highlight really phenomenal work spearheaded by Belinda Beck in my home country of Australia. In 2018, her group published the results of a randomized controlled clinical trial called Lyft More. In this trial, post-menopausal women with low bone mass were split into two groups. One group followed a home-based low-intensity exercise program for 8 months. That was the control. The other group did a supervised program twice a week, about 30 minutes each session, and focused on highintensity resistance and impact training. The average age was 65 and all participants had either osteopenia or osteoporosis, essentially bone loss and bone weakening. The higher intensity group wasn't doing anything exotic. They were doing compound movements like back squats, deadlifts, overhead presses along

49:18 with impact exercises. And the results were striking. The control group actually lost bone even more. In contrast, the highintensity group increased bone density both in the hip and the spine. They also improved balance, mobility, and leg strength as well as back extensor strength and even vertical jump height across the board. They outperformed the control group. And importantly, there were no fractures or major adverse events. They even gained a small amount of height likely due to improved posture and stronger back muscles. Well, I'm definitely going to remember that study. What this tells us is that the body remains highly adaptable even later in life. What this also shows is that consistency matters. You don't need to start heavy. Start where you are and then

50:04 progressively increase the load over time. More recently, a paper was published in the journal of cexia sarcopenia and muscle in 2025 that explored the effects of a 12week strength training program in centinarians people over 100. A total of 12 centinarians finished this study. Not only did the exercise group of the centinarians have enhanced physical capacity and performance, but their frailty status was dramatically reduced. These data suggest that even after age 100, it's still possible to reap benefits from physical activity. Personally, I find studies like this incredibly inspirational. It's remarkable that the body still has the ability to repair damage even at these exceptionally old ages. It may sound trit and cheesy, but the adage that it's never too

50:52 late to turn things around really is true here. I'm also often asked about joints. Did you know that about half of all adults in the US report joint pain in a given year? And it's not just arthritis. There's inflammatory joint pain, stiff hips and knees, back pain, and frozen shoulder. The instinct is to stop moving, but that's often what makes joints deteriorate even faster. What actually helps is very specific movement. For shoulders, daily pendulum swings, wall slides, and banded rows are important to keep the joint capsule moving without forcing it. Light external rotations with a band also protect the rotator cuff and restore control. For hips and knees, sit to stand from a chair and step ups and slow body weight squats maintain strength

51:40 that offloads the joint itself. add hamstring curls and glute bridges to stabilize the knees and the hips. A lot of people ask me if there are different considerations for men and women when it comes to training. And Serena sometimes says to me, you know, I'm not just a hairless man. And she has a good point. For decades, there's been a male female data gap in science, including exercise science. Yes, there are some gender differences in anatomy and physiology that influence things like injury risk, recovery, and athletic abilities. Some researchers argue that these biological differences are very meaningful. But after taking a close look at the science, my take is that some of those differences are really overstated. A lot of the marketing targeted to women is confusing, acting as a barrier to training and unnecessarily

52:26 complicating something that should be empowering to women. While there are sex differences in biology, similar cellular and molecular processes drive aging in all humans, regardless of gender. The overarching principles don't suddenly change based on sex, which means that longevity isn't a separate science for women. So, while personalization is essential, and we're going to talk about that, the foundations are broadly universal. For example, men and women generally gain strength and muscle at similar proportional rates, especially in those who are untrained. So when you look at relative improvements, the percentage gains from where they started, women arguably build muscle just as effectively as men do, the absolute numbers differ because on average, men tend to start with more muscle mass. And you can find the link to the study I'm

53:16 talking about in the show notes. It's important to know that men and women don't need to do completely different exercises. Everyone has the same muscles and bones that respond to the same stimuli. Of course, this doesn't mean that sex differences are irrelevant. They're very real, and we'll talk about some of those later. But these differences tend to show up in specific domains and priorities, not in the fundamental way you should train. For instance, women are particularly at risk of losing bone density and developing osteoporosis later in life because of the sharp drop in estrogen after menopause, unless of course they replace uh their hormones, a topic for another show. So strength training for both sexes throughout adulthood is important for building up a reserve of bone density. You might have heard that women need to exercise according

54:02 to the phase of their menstrual cycle. I'd say that if anyone, man or woman, is tired, in pain, or just not up for a tough session at the gym, you should always listen to your body. Hormonal fluctuations can affect things like perceived exertion, but the current science doesn't show a consistent advantage when women sync their workouts to different phases of their cycle. And for the vast majority of people, unless you're pregnant or managing other medical conditions, there aren't many hard dos and don'ts based on your sex or your hormonal phase. Now, I want to take a minute to talk about a common misconception about men. You might have heard that exercise, especially resistance training, increases testosterone. I definitely have heard this many times. And there is some truth to that, and I hear this from just about every trainer I talk to. It's

54:51 really important to separate the short-term acute effects from the long-term or chronic effects. A hard lifting session can cause a temporary rise in testosterone. We know that, especially after large compound movements. But that's not the same as raising resting testosterone long-term. That acute spike is transient and it doesn't necessarily translate into a sustained increase in your baseline testosterone. So if lifting doesn't stimulate more testosterone production long term, why do some men see improvements? I definitely do. Over time, the bigger story is metabolic health. In men, lower testosterone is often associated with higher visceral fat, which is the fat around your organs, and insulin resistance, which happens to all of us with age if we don't

55:41 watch out. And while most men do experience a gradual decline in testosterone as they age, it is often worsened by the loss of muscle and the gain of body fat, especially over time and around the the organs. As I mentioned, training improves body composition and insulin sensitivity. And it's that that leads to an increase in resting testosterone levels, especially in those who start off with poor metabolic health. But in men whose testosterone is already within the healthy range, long-term exercise training often has modest effects at best and in many studies, negligible effects on resting testosterone. So the real message isn't to lift weights to chase the testosterone spike. The more accurate message here is lift weights to improve muscle mass, strength,

56:29 and reduce your visceral fat. And that'll help with metabolic health, and that supports healthy hormonal regulation over time, especially when there's room for improvement. It's important you also know that there's a decrease in muscle cross-sectional area, even after a few days of disuse or immobilization, like when you go to hospital or you're bedridden. And that's even true in young healthy people. And while muscle loss might be less than what we see in older populations, it's still surprisingly significant. So for both men and women, it's really important to build up muscle reserve throughout your younger and middle adult years because there are likely going to be periods of inactivity. Muscle loss can begin within days of disuse, even in young,

57:15 healthy people. Sometime in your life, you're probably going to need surgery and be bedridden, and you're going to lose muscle mass. So, what you want to have is reserve in muscle because it will really help with your recovery. One of the hacks that I use that I don't even notice anymore to maintain my big muscles, especially in my leg and my back, is to have a standing desk at work. Every day I'm standing. I'm I'm stretching. If you're on a Zoom with me, you'll see I'm kind of like I'm in space. I'm not sitting still. And I don't even notice that I'm exercising. So, there's lots of things you can do like that. Here in this building, there are stairs and there's an elevator. I almost never use the elevator. So, try to use your legs, use your back, of course, lift carefully, but use your daily activities to work out. It makes it much simpler than just having to

58:01 go to the gym and do routine exercises, knowing how important it is to build up a reserve of muscle, even at a young age. At age 13, my son Ben started coming with me to the gym every weekend. This was recommended by my good friend Gil Blander and I think this was some of the best parenting advice I ever got and I highly recommend taking any of your kids to the gym before they leave the house and it's very good to bond with your kids as well. In fact, Ben and I are very close now and I think that's largely because we were going to the gym every weekend for many many years and even now we work out together when we can. One thing that's been making headlines lately is that some of the weight loss by people on GLP-1 agonists is muscle mass. It's not just fat. Of course, GLP-1 stands for glucagon like peptide 1. And GLP-1 drugs promote substantial weight loss by

58:51 suppressing appetite mainly. Some early studies suggested that lean mass, which includes muscle, water, and your organ weight, comprises 20 to 40% of the weight lost, and about half of that is muscle. But the extent of lean mass lost can also depend on the class of drug. For example, there's a recent preprint from a data analytics company which looked at muscle changes in people taking these drugs. They analyzed 1,800 people on Lily's drug tepatide which you may know as Mjaro or Zepbound and another 6,200 people on Novon Nordisk semiglutide which you probably know as WGO or ampic. The difference between these is that semlutide activates one hormone receptor

59:37 GLP-1 while tracepatite is what's called a dual agonist which mean it it works on activating both the GLP-1 receptor and another one called GIP or GIP gastric inhibitory polyeptide. They found that trespatide did result in more total weight loss but it also came with about 2% more lean mass loss over 12 months compared to semaglutide. They also reported that for both drugs, people who lost

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