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

25:20Dr. David Sinclair:Prior to 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 miles 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.

25:58Dr. David Sinclair:Ultimately, it isn't necessary to do exercise this extreme to get the maximal or near-maximal benefits in terms of longevity. Another question 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 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.

26:37Dr. David Sinclair: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 Withings 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. Had I lost muscle? Was my visceral fat creeping up? What did I need to focus on? That's why I like the Withings 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.

27:21Dr. David Sinclair:And that's far more useful than watching a single number on a scale. I've actually been using Withings 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 Withings Silver ScanWatch Nova, which looks a lot like an expensive diving watch. 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. Withings also makes one of my favorite blood pressure monitors for home use.

27:55Dr. David Sinclair: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. Withings 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 withings.com slash lifespan and use the code lifespan to receive 10 % off.

28:34Fitness tests like VO2 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 VO2 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 VO2 max, one of the most accurate ways of measuring your physical fitness and even predicting how long you might live.

29:13The lactate threshold typically sits around 60 to 80 % of VO2 max, depending on how well trained you are. Training above that too often without adequate recovery is where exercise can shift from being a helpful stimulus to an excessive stressor on the body.

29:29Dr. David Sinclair: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 percent 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 ferritin and hemoglobin, metabolic markers like glucose and insulin, and hormones like cortisol, they all shape how much stress your body can tolerate.

30:07Cortisol is one 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.

30:47In 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 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.

31:14Dr. David Sinclair:Creatine kinase, 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 variants of these genes bias you slightly either towards power or towards endurance. There's another gene called PGC1-alpha, which we've studied many times in my lab.

31:52Dr. David Sinclair:That gene actually controls the mitochondria and how much energy you produce in your muscles. And there's VEGF. VEGF 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 IL-6, TNF-alpha.

32:29Dr. David Sinclair:these genes actually can control how well you recover. And then finally, COL1A1 and COL5A1, these relate 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 epigenome, 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.

33:08Dr. David Sinclair: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 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 U.S.

33:49Dr. David Sinclair: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 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.

34:23Dr. David Sinclair:While 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 with circadian rhythms.

35:03As 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 a different time zone, actually the reason you feel kind of sick in part is because your different organs are on different time zones and maybe even a different time zone from each other. Did you know that exercise can act as a zeitgeiber? A zeitgeiber is an external environmental cue, such as light, that synchronizes our internal biological clock, are 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 sleep-wake cycles and metabolic processes.

35:50Exercise 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 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.

36:26There 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 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 4pm and 8pm and lowest between 6am and 10am. One study reported that cyclists had higher power output and oxygen uptake in the evening around 6pm compared to 8am. Even Olympic swimmers have been shown to record their fastest times late afternoon around 5pm.

37:08But timing really doesn't matter more than how you feel. Alright, so now let's talk about chronotype. We all tick on slightly different clocks. Early birds tend to peak earlier in the day than night owls, like myself, who feel sluggish 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.

37:51And 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 poor sleep quality. But exercise ending at least four hours before bedtime was not associated with sleep changes. Similarly, a 2021 study found that high-intensity workouts in the early evening, around two to four 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 four 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.

38:34So 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 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 grams of protein per kilogram of body weight per day.

39:23It'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 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.

40:02I leave that to professionals whose livelihoods depend on another 1 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 maintaining fasting periods that support cellular repair and boost longevity defenses.

40:41And 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.

40:53Dr. David Sinclair: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 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.

41:33Dr. David Sinclair: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 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.

42:16Dr. David Sinclair: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 proteins across the day helps balance things out.

42:57Although 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, pea 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.

43:35Dr. David Sinclair:In simple animals like worms or more complex ones like mice, inhibiting mTOR either genetically or using chemicals like rapamycin significantly extends their 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 isoleucine 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, isoleucine, and valine.

44:13Dr. David Sinclair: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 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 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?

44:52Well, 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-rich 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 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.

45:33That, in the long run, can interfere with processes like autophagy, the cell's cleanup system. This distinction becomes more important with aging.

45:41Dr. David Sinclair: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-and-off 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, rapamycin. This is the drug you might remember that was discovered on Rapa Nui, or Easter Island, hence the name. The dose 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.

46:23Dr. David Sinclair: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 founder's own research and scientific rigor. Of course, I'm talking about the Whoop band, the one that I rarely take off.

46:55Dr. David Sinclair:As 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.

47:37Dr. David Sinclair:So on those days, I still head out, but I pace myself. I found that 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.

48:12Dr. David Sinclair:So if you don't already use Whoop, I really encourage you to give them a try. So visit join.whoop.com slash lifespan, and you can use the code LIFESPAN to receive your free Whoop and your first month of membership. 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 Lift More. In this trial, postmenopausal women with low bone mass were split into two groups. One group followed a home-based low-intensity exercise program for eight months.

48:52That was the control. The other group did a supervised program twice a week, about 30 minutes each session, and focused on high-intensity 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 with impact exercises. And the results were striking. The control group actually lost bone even more. In contrast, the high intensity group increased bone density both in the hip and the spine.

49:30They 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 progressively increase the load over time.

50:06Dr. David Sinclair:More recently, a paper was published in the Journal of Cachexia, Sarcopenia and Muscle in 2025 that explored the effects of a 12-week strength training program in centenarians, people over 100. A total of 12 centenarians finished this study. Not only did the exercise group of the centenarians 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, and it's remarkable that the body still has the ability to repair damage even at these exceptionally old ages.

50:48Dr. David Sinclair:It may sound trite and cheesy, but the adage that it's never too 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.

51:26Dr. David Sinclair: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 bodyweight squats maintain strength 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.

52:10Some 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 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.

52:44So 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 in 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 talking about in the show notes. It's important to know that men and women don't need to do completely different exercises.

53:23Everyone 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 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.

53:59You might have heard that women need to exercise according 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 do's and don'ts based on your sex or your hormonal phase.

54:34Now 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 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.

55:19So 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 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 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.

56:06But 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, 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.

56:50And 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 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.

57:26One 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 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 go to the gym and do routine exercises.

58:03Knowing 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.

58:35Dr. David Sinclair:One thing that's been making headlines lately is that some of the weight loss by people on GLP-1 agonists is muscle mass, not just fat. Of course, GLP-1 stands for glucagon-like peptide 1. and GLP-1 drugs promote substantial weight loss by suppressing appetite mainly. Some early studies suggested that lean mass, which includes muscle, water, and your organ weight, comprises 20 to 40 percent 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.

59:17They analyzed 1 ,800 people on Lilly's drug trizepatide, which you may know as Monjaro or Zepbound, and another 6 ,200 people on Novo Nordisk semaglutide, which you probably know as Wagovi or Ozempic. The difference between these is that semaglutide activates one hormone receptor, GLP-1, while trizepatide is what's called a dual agonist, which mean it works on activating both the GLP-1 receptor and another one called GIP, or G-I-P, gastric inhibitory polypeptide. They found that trisepatide did result in more total weight loss, but it also came with about 2 % more lean mass loss over 12 months compared to semaglutide.

1:00:01They also reported that for both drugs, people who lost more lean mass were more likely to have reduced their exercise tolerance, and that link was a bit stronger with the trisepatide group. There's also a slightly increased risk of about twofold of nion, which is a blindness caused by a lack of blood flow in the eye. We'll talk about that more later and how we're working in my lab to treat that. While there's a lot of bad news about these drugs all the time, there's a lot of good news, so let's talk about that. There's a 2026 paper I want to mention that was about a 12-week pilot study published in Cell Reports Medicine.

1:00:36The authors found that looking at middle-aged men with diabetes and obesity, the GLP-1 drugs slightly reduced muscle mass, but they largely preserved strength. In the abstract, the authors write, quote, while absolute muscle mass and strength decrease, relative muscle mass and strength improve, resulting in better running performance. Patients with obesity on GLP-1 medicines improved their body composition without negatively affecting strength. So that's great news. So while GLP-1 drugs can promote substantial weight loss, we do know that if you exercise, you don't have to lose the muscle. But we do urgently need more research where actual muscle strength and performance is measured directly, not indirectly, which is how it's normally done.

1:01:28We need more data about the function and strength outcomes of the people on these medicines as they become more and more popular, and new drugs are coming out seemingly every few months. But for now, we just don't need to panic because according to these latest studies, there's no excessive reduction in skeletal muscle or strength, especially in people who are losing weight on these drugs while they exercise. So if you're taking one of these meds and you exercise and you eat enough protein, not only can you maintain your muscle mass, you can even increase it. These days, up to one in five people have either tried it or are currently trying these medicines.

1:02:07So this is very important to know and to share it with your family. Because there's so much misinformation out there about these medicines, I'm going to talk more about them later. But for now, let's talk about fasting.

1:02:18Dr. David Sinclair:As intermittent fasting has become more popular, it's also become common for people to wonder how to optimally fit exercise into an intermittent fasting regimen. As a reminder, intermittent fasting, which is also known as time-restricted feeding, typically involves only eating for a certain window of time in a given day. A more intense version of intermittent fasting involves fasting for 20 hours and only eating within a four-hour window of time. But regardless of the pattern, there are important considerations to keep in mind. In terms of timing, it likely makes sense to do more intense exercises during the eating window after having had some food.

1:02:57Dr. David Sinclair:If you choose to exercise during your fasting window, you may want to consider having it be lighter or sticking to a more moderate physical activity regimen. Since people that intimately fast typically skip at least one meal in the day, nutrition is absolutely critical. and someone that practices intermittent fasting needs to be much stricter about what they eat to make sure they're not missing major nutrient requirements. It's also important to make sure you're getting proper carbohydrate intake, which is essential for building up your glycogen stores. To help preserve or optimize body composition, protein intake should also be top of mind.

1:03:33During fasting, it's very important to stay hydrated. I'm always close to my water here. Even though fat burning or lipolysis does produce a molecule of water every time you break a fat to produce energy, it's not enough. Fasting does increase fluid loss, especially early in the fast. So keep those fluids coming.

1:03:55Dr. David Sinclair:I also want to talk about caffeine intake and exercise performance. Indeed, many people actually take caffeine-containing beverages before they start exercising. The data here is really interesting, and I want to point to a paper published in the British Journal of Sports Medicine in 2020. The paper itself had a fantastic title, which starts with, quote, Wake up and smell the coffee. In this work, the authors included 11 reviews and a total of 21 meta-analyses to explore the relationship between caffeine intake and exercise performance. Their conclusion was that caffeine improves exercise performance.

1:04:31Interestingly, the magnitude of the improvement was generally higher for aerobic activity compared to anaerobic or strength-focused exercises. I should note, though, that evidence for groups other than young men is weaker and more limited.

1:04:44Dr. David Sinclair:So based on this data, drinking coffee or a pre-workout drink could actually be advantageous in terms of overall performance. If you're someone that's really keen on getting revved up with caffeine before you exercise, I would encourage you to stay away from ultra-processed energy drinks for sure, especially those that have any sugar in them. While we're on the topic of caffeine, it's worth noting that both coffee and tea have been associated with reductions in all-cause mortality risk. So what are the really important takeaways from this episode? We of course started out by discussing just how powerful of an intervention exercise is when it comes to aging and longevity.

1:05:22Dr. David Sinclair:Exercise is strongly linked to life expectancy, and data show that every minute of exercise yields multiple minutes of extra life. We also talked about how some of the most useful aging biomarkers are based on physical activity measures like grip strength, VO2 max, and balance tests. We covered the three pillars of exercise for healthy aging, cardiovascular exercise, strength training, and balance. An ideal regimen for longevity blends all three of these pillars into a weekly routine. We talked about the typical changes that often happen with aging. that can compromise mobility, strength, and balance.

1:05:58Dr. David Sinclair:And finally, we covered the frequently asked questions when it comes to physical activity. So now I just want to reiterate that ultimately, the best kind of physical activity is the kind that you enjoy and can consistently do. When it comes to aging and longevity, there's a world of difference between being sedentary versus regular exercise. In our next episode, we'll be stepping away from the gym to go inside our bodies, and we're going to see why what my father and I do to stay healthy makes scientific sense. We're going to go beyond routines and reps to get into the deeper story of why we humans are built to move and what exercise is actually doing at the cellular level.

1:06:40Understanding how your body works will help motivate and help you optimize yourself. We're going to explore what I call survival circuits and talk about persistence hunting, Neanderthal genes, and even how exercise can literally thicken your skin. So if you want to understand the science of how we were built to outlast the competition and why physical activity is such an important lever in your longevity toolkit, I'll see you in part two.

1:07:07Dr. David Sinclair:It's been great to have you with us. This is a show where science and evidence come first. The team works hundreds of hours to bring you only the facts. To learn more and to join our community, visit lifespan.com and you'll get early access to future episodes to the Lifespan magazine and to detailed episode show notes. You also get transcripts and links to the papers that we talked about today. As a member, you'll actually be helping us support medical research to extend all of our healthy lives. If you found this episode valuable, do consider subscribing and also turn on your notifications so you don't miss new episodes.

1:07:45Dr. David Sinclair:It'll also help us make a better show for you. And feel free to share this episode with any family or friends who you think might enjoy it and learn from it. Finally, for the latest discoveries in longevity science, consider following us on Instagram at Lifespan and on X at Join Lifespan. From all of us at Lifespan, thank you for being part of this growing community. And remember, life's short, so let's change that together. Lifespan is produced by Andrew the Wonder Man Ying, Rajiv Geek Me Out Ramesh, Marissa Huzon First Vulgamoor, Kathleen TLDR Fitzgerald and our researchers Shivani Just One More Thing Sethi and Adiv Meet Me in the Year 3000 Johnson also I want to mention our new recruit Daniel Rocketman Salazar who's our new producer and of course Serena My Honeypun I also want to thank Inspiro Studio and Create Ape for making this show possible and finally thanks to our partners for helping us support longevity research we'll see you next time

1:08:57This show is for informational purposes only and is not medical advice. Please consult a qualified healthcare provider as individual results may vary. Views expressed are my own and not those of Harvard University or Harvard Medical School. Full disclaimer is in the show notes.