This Sugar Substitute May Extend Your Life | Lifespan with Dr. David Sinclair - S2, Ep. 10

27:25Dr. Jacob Marot and his team followed nearly 9 ,000 healthy adults for over 25 years, and they looked at how the amount of weekly sports activity related to longevity. What they found was a clear U-shaped relationship between exercise and mortality. So the people who did no sport, of course, has significantly higher risk of death. We expect that. This isn't surprising, but what caught my attention was the other end of the curve. Those doing very high volumes of sport, more than 10 hours a week, also had higher risk of death compared to people who exercised moderately. The lowest risk of dying from both cardio and all causes was seen in people who exercised about 2.5 to 4.5 hours per week.

28:10In other words, the sweet spot wasn't extreme training or endurance obsession. It was regular, moderate participation in sports. This pattern held up even after adjusting for age, sex, smoking, alcohol, body weight, blood pressure, cholesterol, and a bunch of other things. It also persisted when the first five years of follow-up were excluded, suggesting that the results weren't simply due to pre-existing illnesses. The takeaway here is super important. Exercise is definitely a powerful medicine, but like most medicines, dose matters. Pushing the body relentlessly may blunt some of the longevity benefits that we associate with physical activity.

28:49And this study supports the idea that for long-term health and for longevity, consistency beats extremes and recovery is just as important as movement. So how much exercise should you be getting every week? Well, the current guidelines are at least 150 minutes per week of moderate intensity aerobic activity or 75 minutes of vigorous activity or a combination of the two spread across the entire week. Hitting this minimum is associated with roughly a 14 % reduction in all-cause mortality. Importantly, the benefits begin well below that threshold. Just 75 minutes per week of moderate activity, which is only about 11 minutes per day, is associated with a meaningful reduction in the risk of premature death and cardiovascular disease.

29:40So moving from nothing to just something delivers a large return on investment. And again, these large cohort studies consistently show a dose-response relationship. More activity generally confers more benefit, but only up to a point. The largest gains are between 5 and 10 hours per week of moderate activity. So that's mortality risk, but what about aging? Well, analyses of national data sets with millions of people show that those who accumulate around three hours of activity per week, not a lot, they have the lowest risk of accelerated biological aging, but with diminishing returns beyond that range.

30:19There is no single optimal schedule though. But remember this, adherence beats optimization. So let's talk about sitting. It's a serious matter because most of us for our jobs have to sit for some of the day. And the problem is exercise does not fully offset prolonged sitting. Regular movement throughout the day, standing up, walking, any brief activity breaks, adds independent benefits beyond these structured workouts when you go to the gym or play a sport. So get a standing desk, one that you can lift up and down during the day. That's what I have in my office. And at home, you can get a small treadmill.

30:57I have one in my living room and I open it up and even preparing for this podcast, I

31:02Dr. David Sinclair:was walking while reading. 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 withing 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.

31:38Dr. David Sinclair: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 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.

32:21Dr. David Sinclair: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. Also a sleep analyzer that can help identify sleep issues. And they have a smart thermometer as well. 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.

32:59Dr. David Sinclair: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. For children and adolescents, the bar is higher though. At least one hour per day of moderate to vigorous activity supports musculoskeletal development, metabolic health, and long-term habits. For older adults, it's also never too late to start. Even people in their 80s and beyond that show improvements in aerobic capacity and strength, even after short training interventions. Biology responds to stimulus at any age. The central message here is really simple.

33:39Do enough to matter and just keep doing it. Longevity is built through accumulation. Start where you are, progress gradually, stay consistent. Your body will reward you. So now let's talk about cardiorespiratory fitness, the strongest predictor of longevity. If I had to pick one physical attribute that best predicts longevity, it would be cardiorespiratory fitness. Not body weight, not cholesterol, not blood pressure. Epigenetic clocks that incorporate fitness metrics show younger biological age in individuals with greater fitness. Cardiorespiratory fitness reflects how well your heart, your lungs, blood vessels, and muscles work together to deliver and use oxygen during sustained effort.

34:23It integrates multiple systems into a single functional outcome. The gold standard metric for cardiorespiratory fitness is the VO2 max, the maximum amount of oxygen your body can use during intense exercise. It's a direct window into whole body physiological capacity. V stands for volume, O2 is for oxygen, and max means maximum. VO2 max is grounded in the Fick principle, cardiac output multiplied by the arteriovenous oxygen difference. In plain terms, it reflects how much blood your heart can pump and how efficiently your muscles extract oxygen from it. This is why elite endurance athletes sit at the top of the VO2 max distribution.

35:06Their hearts pump large volumes of blood, their hemoglobin carries a lot of oxygen, and their capillary networks are dense. Their mitochondria are also highly trained. Without regular training, though, VO2 max declines roughly 10 % per decade starting in early adulthood. And by age 70, the decline even accelerates. This loss reflects reductions in the maximum heart rate, stroke volume, and peripheral oxygen extraction. With consistent training, though, that decline can be cut roughly in half. Fitness does not eliminate aging, of course, but it can meaningfully slow this functional decline. This matters because low cardiorespiratory fitness is one of the strongest predictors of all-cause mortality that we have.

35:52Across multiple large studies of people, those in the lowest fitness percentiles have four to five-fold higher risk of death compared to those in the highest percentiles. A very large study published in 2018 in the Journal of the American Medical Association involved over 120 ,000 people, and they looked at their cardiorespiratory fitness using treadmill tests, which is essentially a proxy for VO2 max. What they found was that the fitter you are, the lower your risk of death, with actually no upper limit for where the benefit disappeared. When compared side by side, low fitness predicted mortality more strongly than smoking, diabetes, hypertension.

36:33Importantly, improvements do not require elite performance. Just moving from low to moderate fitness produces the largest survival gains. And fitness also predicts outcomes late in life. In adults over 80, those with preserved aerobic capacity have dramatically lower mortality risk than their less fit peers. It's worth remembering that fitness is not a snapshot of what you did last week. It's an accumulated record of how consistently you've challenged your physiology over years, VO2max is earned. You might wonder how VO2max is actually measured if you haven't done it before. Typically, you need a face mask or a mouthpiece, and that's required to directly measure oxygen consumption using indirect calorimetry, and this tracks how much oxygen you inhale and how much carbon dioxide you exhale breath by breath.

37:23Laboratory VO2max tests typically cost a few hundred dollars and are not appropriate for everyone, especially those with underlying cardiovascular disease unless medically supervised. Wearables can estimate VO2 max using heart rate, pace, age, sex, and body weight. These estimates can be useful for tracking trends over time, but of course they're not precise measures of the true maximal oxygen uptake. There are also protocols like the six-minute walk, the 12-minute Cooper movement test, step tests, which estimate aerobic capacity without requiring maximal exertion. These methods trade precision for accessibility.

38:01So the Cooper test is how far you can run or walk in 12 minutes. Very simple. And its inventor, Kenneth Cooper, is one of those people who quietly changed how the world thinks about health. He was the one that literally coined the term aerobics in the 1960s. His book, Aerobics, helped move exercise from something just athletes did to something medicine can prescribe. I had the distinct pleasure of meeting Mr. Cooper a few years ago, and it was really striking to meet someone whose ideas have influenced millions of people. And now he's 94, so obviously something's working. So if you don't want to use a device, prediction equations based on age, resting heart rate, body composition, and activity habits can still provide a reasonable approximation.

38:45What matters most is not the exact number, but the trend. Improving fitness over time, even modestly, is strongly associated with better health outcomes. Fitness also interacts with strength? And people often ask, which matters more? The answer actually is both. Studies comparing grip strength and cardiorespiratory fitness show consistently that higher aerobic fitness lowers mortality risk across all strength categories. Strength matters, but fitness often carries more weight. That said, strength independently predicts survival and functional independence. The greatest protection comes from combining aerobic fitness and muscular strength.

39:26So now let's talk about heart-based metrics. Beyond VO2max, several simple heart-based measures can reveal a great deal about health and aging. They're easy to track, inexpensive, and strongly predictive. Resting heart rate is the number of beats per minute when you're fully at rest. For most adults, it's between 60 to 80 beats a minute. But physically fit individuals often sit lower, sometimes in the 40s or the 50s. My awake average is 67 and it goes down to 57 at night. A lower resting heart rate generally reflects higher stroke volume of the heart, better capillary health, and better autonomic balance, your body's ability to shift smoothly between stress mode and recovery mode.

40:14A higher resting heart rate is independently associated with higher risk of all-cause mortality. For every 10 beat per minute increase, It's associated with roughly a 15 to 20 % increase in risk. Your resting heart rate is influenced by many factors, your genetics, fitness, how much sleep you've had the night before, your stress level, even your hydration, and of course illness, medications, caffeine, and even the ambient temperature can matter. But what matters most is the trend over time, not your day-to-day noise. So you might be wondering, what if I naturally have a low resting heart rate, even without exercise?

40:53And the answer there is intriguing. It turns out that those who don't even exercise and have a low resting heart rate tend to live longer. There is just some people with a naturally slow resting heart rate. They're born with a high vagal tone. They're the lucky ones. But for most of us, we have to work a little harder. And sometimes people say, well, do we just get a certain number of heartbeats in our lifetime? And is exercise going to affect that, reducing how long I live? And that's actually not true. the number of heartbeats doesn't determine how long you live. And in fact, if you compare a rat and a bat that have roughly the same kind of heartbeat, a rat lives about three to four years and a bat can live 30.

41:31So that really doesn't hold. But in general, species that have slower heart rates do live longer, but not because of the heartbeats. It's because that's just their general physiology. But importantly, despite transient increases during your workouts where your heart rate goes up, Habitual exercise lowers your average heart rate. Fit individuals accumulate fewer total heartbeats per day than sedentary people. This is a sign of greater cardiovascular efficiency. Another variable is heart rate recovery, which measures how quickly your heart rate drops after exercise. It reflects parasympathetic reactivation, the body's ability to shift from stress back to recovery.

42:11A drop of 20 beats per minute or more in the first minute after exercise is generally considered healthy. Slower recovery is associated with higher risk of cardiovascular events and mortality. Heart rate recovery actually gets worse with overtraining as well as illness or chronic stress. It functions as both a fitness metric and an early warning signal. So now for heart rate variability, one of my favorites. HRV is one of the better measures of cardiovascular fitness.

42:42Dr. David Sinclair:Most people assume a healthy heart beats like a perfect metronome. It doesn't. In fact, a healthy heart actually shows quite a lot of variation, and that's a healthy thing. That's what heart rate variability, or HRV, measures. The small differences in the time between each heartbeat. When your HRV drops below your normal baseline, your heart starts to behave more like a metronome. That usually means your fight or flight system is taking over. In other words, your body is under stress and it has less capacity to adapt. That can show up for a number of reasons. Psychological stress, poor sleep, illness, fatigue, even a heavy training load.

43:21Dr. David Sinclair:So HRV can be useful as a check engine light for your recovery. You can measure it with most wearables these days. It's not a perfect measure, but it's really informative. It's one of the things I look at most during the day. What matters most here is the trend though. If you see a sustained drop of around 10 to 20 % below your baseline, especially alongside a rising resting heart rate and worsening sleep, that's a signal that your body may need more recovery. In adults, normal HRV varies widely depending on age, sex, genetics, and how it's measured. There are two main ways to measure HRV. One is the RMSSD, and the other is SDNN.

44:03So if you want to know, RMSSD is the root mean square of successive differences, and then the other one is the standard deviation of normal to normal intervals.

44:14Dr. David Sinclair:These are just two different ways of measuring HRV. The one that's used by WHOOP, one of Lifespan's partners, is the RMSSD. RMSSD is the gold standard marker of parasympathetic recovery. Understanding the biology behind exercise is of course important, but having real-time data about how your own body responds to exercise is essential for putting that science into practice every day. 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.

44:53Dr. 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.

45:35Dr. 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.

46:11Dr. 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. Typical adult values are between 20 and 50 milliseconds. For optimal health and longevity, higher HRV relative to your own baseline is what matters most. So in general, people who are physically fit, sleep well, manage stress, and recover properly tend to sit above average for their age, between 40 and 70 milliseconds or higher, though there's no single magic number. Low HRV is associated with increased risk of cardiovascular disease, metabolic dysfunction, even cognitive decline, and of course mortality.

47:00HRV tends to decline with age, but you can modify it. In fact, by exercising, sleeping well and managing stress, you can raise your HIV. It's very sensitive. You can go the other way as well. Some alcohol. And if you don't sleep well, you're ill or you have stress. Even overtraining can reduce your HIV. And as with resting heart rate, trends matter more than isolated readings. We've talked about aerobic fitness. So now let's talk about muscle. Muscle is not just for movement. It's a metabolic endocrine and longevity tissue. Resistance training matters independently of aerobic fitness, so we need to focus on that too.

47:40Just one to two strength training sessions per week are associated with much lower mortality risk. Going far beyond that does not appear to add substantial longevity benefits, at the population level at least. So what do I mean by strength training? I mean squats or sit-to-stands, deadlifts, hip hinges, push-ups or bench presses, rows or pull-downs, these kind of things that build muscle. But what matters is progressive resistance, working the muscles against the load, done consistently. Just 30 to 60 minutes per session, even once or twice a week, is enough to preserve muscle, bone, insulin sensitivity and independence, which likely explains the longevity benefit.

48:23Muscle mass and strength decline with age, a process known as sarcopenia. This loss accelerates after midlife and contributes to frailty, loss of independence, metabolic dysfunction, and increased mortality. One of the simplest ways to assess your muscular health is grip strength. It's an imperfect proxy, but remarkably predictive. Lower grip strength is consistently associated with higher risk of death, cardiovascular disease, disability, and even cognitive decline. One of the measures of longevity and age reversal in my lab is grip strength. We do it with the mice, they have to hang on to a little mesh, and we see how hard and how long they can hold on for.

49:02It's very predictive of not just how healthy they are and strong they are right now, but how long they're going to live ultimately. Grip strength typically peaks in early adulthood and declines steadily thereafter. The rate of decline accelerates after about age 70, particularly in the absence of resistance training. Yet every additional kilogram of grip strength is associated with a meaningful reduction in mortality risk, probably because the hand is a bellwether, like a canary in the coal mine representing your overall fitness. So why do we get weaker? We take it for granted. But there are a lot of reasons for it.

49:36Not just muscle shrinkage, but even the nerves. They fire less and they make less contact with the muscles. These motor neurons that contact the muscle retract. and this is actually something we're trying to reverse in my lab. There's also hormonal changes, growth hormone declines, and testosterone, both of which are important to maintain muscle mass. But strength alone, of course, is not the whole story. Muscle power, the ability to generate force quickly, declines earlier and faster than strength, and this loss strongly predicts falls, fractures, and loss of functional independence. Starting around age 40, we lose about 0.5 to 1 % of muscle mass and strength per year.

50:18And that's why you've probably heard that doing resistance training and eating enough protein, even well into your later years, is important. But here on this graph that we're showing, we can see that after 40, we lose around 2 to 4 % of muscle power per year. That's due to motor neuron loss and denervation, as I mentioned, the retraction of nerves out of the muscle. It's also due to a preferential atrophy of what are called fast twitch or type 2 fibers in the muscle. Catching yourself when you trip or standing up from the floor, reacting to a sudden loss of balance, these are tasks that depend much more on power than on maximal strength.

50:56Studies suggest that muscle power may be a stronger predictor of mortality than muscle strength alone. Preserving power is therefore central to healthy aging. One of my colleagues at Harvard once said, the secret to longevity is hanging onto the handrail. And what he meant by that is falling is so damaging to older people, especially in their 80s and 90s. One fall and a broken bone can send you into the operating theater. You can lose oxygen to the brain. And most people over 90 never fully recover. The good news is that muscle responds to training at any age. So just as a reminder, power is the ability of a muscle to generate force quickly.

51:37In physics terms, power is force times velocity. So power can be gained safely by doing a variety of things, sit to stands, step ups, and even medicine bowl throws. So if you only train for strength and ignore power, you're missing a major piece of the healthy aging puzzle. Another important reason for exercising is because muscle is an endocrine organ. Contracting muscle releases myokines that influence metabolism, inflammation, brain health, and immune function. But a common misconception is that there is a narrow window early in life when physical activity matters, and that once it closes, the benefits are largely lost.

52:20That's absolutely not true. The evidence doesn't support this view. Muscle loss during aging is not inevitable. In many cases, it's simply disuse. Muscle stays young if it is used. Remember that. Regular movement early in life does build capacity and establishes habits that carry forward. But starting later, even at 90 and 100, is known to produce meaningful gains. Biology remains responsive to stimuli well into advanced ages. Researchers who have studied sedentary octogenarians, so people who are in their 80s, have found large improvements in aerobic capacity and workload tolerance, even after only a few weeks of training.

53:02And while these gains in older people generally fade faster than in younger individuals if they stop training, this simply reinforces the central rule, consistency matters more than intensity. Exercise also improves resilience during illness and recovery. Older adults who remain active recover faster from hospitalization, surgery, and acute illnesses than their sedentary peers. One of my favorite studies comes from Aging Cell, led by Abel Plaza Florido, with collaborators across UC Irvine, Copenhagen University Hospital, and Lund University, published in 2025. The researchers studied people aged 100 to 104, and they asked a simple question.

53:45does movement still matter that late in life? The answer was a resounding yes. After just a brief bout of physical activity, centenarians showed a measurable drop in inflammatory proteins and the activation of protective immune and stress response pathways that were largely silent at rest. What's remarkable is that these were not lifelong athletes, yet their cells still woke up when they moved. It's a powerful reminder that even at extreme ages, the body retains the machinery to respond to exercise. Movement doesn't just maintain health, it actively flips protective molecular switches right up into advanced ages.

54:26The takeaway is straightforward. There is no expiration date on adaptation, and the body does not need perfection, it needs stimulus. So start Start where you are, progress gradually, and repeat. So we've covered what happens at the physiological level, so now let's look at the molecular to see what's really happening. Exercise influences nearly every hallmark of aging through a coordinated set of molecular and cellular responses. Mitochondria are central to this process. Regular movement and exercise increases mitochondrial number and efficiency. Pathways involving AMP kinase, PGC1-alpha, and SIRT1, the gene we study in my lab, become activated, improving energy production and metabolic flexibility.

55:10Exercise also promotes autophagy. As you know, the cellular recycling system that clears damaged proteins, single bouts of resistance exercise, weight training, transiently suppress autophagy to prioritize muscle growth, but repeated training actually increases the baseline autophagic capacity over time. Endurance exercise appears to activate autophagy across multiple tissues, though long-term human data are still really emerging. Exercise also mobilizes stem cells, and it improves proteostasis, which is the maintenance of proteins, and it enhances stress response pathways that maintain tissue and function as we get older.

55:49At the epigenetic level, physical activity reshapes DNA methylation, as well as histone modifications and non-coding RNA profiles, in a direction opposite to that of age-related drift, the process that we study in my lab. So trained tissues consistently show a more youthful molecular signature. These effects are observed across muscle and blood and brain, liver, and even adipose tissue or fat. So exercise doesn't just target one organ. It coordinates the whole system, slowing and even reversing aspects of aging. So while we're on the topic of epigenetics, let's talk about epigenetic clocks. As you probably know, they can estimate biological age by measuring DNA methylation patterns that change predictably with age.

56:36Multiple independent clocks now exist, each one trained on different outcomes, such as mortality, disease risk, or physiological decline. At the epigenetic level, the level where we're talking about gene regulation, exercise doesn't just slow aging, it actively pushes biology in the opposite direction. Across large population studies, higher physical activity and higher cardiorespiratory fitness are both associated with younger epigenetic ages. This relationship holds across multiple clocks, including ones called Grimmage, PhenoAge, and the Dunedin-Poam clock.

57:13Dr. David Sinclair:For example, a 2023 scientific paper in the journal Aging Cell that studied over 3 ,500 adults in Germany, showed that higher physical activity, including more steps and greater energy expenditure, is associated with lower grim age and pheno age rates of change. This might occur partly by lowering cardiovascular risk, but also by counteracting something called immunosenescence, a term referring to how our immune system ages and gradually becomes slower, less responsive, and also more prone to chronic inflammation. Importantly, the association between movement and clocks is dose-dependent, moderate to vigorous activity shows stronger links to slower epigenetic aging than light activity alone.

57:57In this case, your effort matters. My good friend Steve Horvath

58:01Dr. David Sinclair:has co-authored several studies showing that higher physical fitness is associated with younger biological age. Based on specialized aging indicators like DNA mFIT age, which incorporates metrics like VO2 max, walking speed, and grip strength, highly active individuals can be between one and a half and two years biologically younger than their sedentary peers, even though other lifestyle factors like smoking and diet can play a role. In longitudinal studies, individuals who remain active over years show slower biological age acceleration than those who become sedentary. Even recent activity matters.

58:41The system responds dynamically. And data from elite athletes show that long-term physical activity is also linked to slower

58:48Dr. David Sinclair:biological aging. For instance, a 2024 study of over 400 Hungarian athletes found that athletes had lower rates of biological aging. This aligns with data from U.S. Olympians who live about 5.1 years longer than the general population. It's important, of course, to note that Olympians differ from the general population in many ways beyond just exercise. So the longevity gap can't be attributed only to physical activity. Still, when researchers looked at Hungarian Olympic champions, they found that they had slower epigenetic aging rates compared to non-champions, which is really interesting. And when scientists look directly at human muscle itself, they see the same thing.

59:29Dr. David Sinclair:A 2023 meta-analysis looking at over 3 ,000 human skeletal muscle samples, they reported that higher aerobic fitness was linked to younger epigenetic and gene regulation profiles. Essentially, exercise training shifts the muscle towards a more youthful molecular state, while muscle disuse actually ages the cells. And since gene regulation is one of the cell's biomarkers of aging, this suggests that staying fit helps your muscles preserve their youth. These clocks are not perfect, of course. They're statistical models, but when independent clocks all point in the same direction, we can increase our confidence.

1:00:07So aging pulls the epigenome towards disorder, as we've shown in my lab, but movement, exercise, training, these all reliably pull them back. They restore the epigenome to a more youthful state, and the net effect is preserved function and less chance of disease in later years. So how about the effects on immune function and inflammation. Meta-analyses, the so-called study of other studies, these have shown a consistent anti-inflammatory adaptation with regular training. Acute exercise actually increases inflammatory signals, and sometimes we see that with spikes in cortisol, for example. But chronic training lowers baseline inflammation and reduces age-related inflammation, which is important for longevity.

1:00:52Acute exercise has been shown in many studies to mobilize immune cells, particularly natural killer cells and cytotoxic T cells, which are required to keep cancer cells at bay. And a new study of older adults from 2025 showed that long-term endurance training led to an increase in natural killer cell activity. The key nuance is dose. Moderate, consistent training improves immune readiness. while excessive training without adequate recovery can at least transiently impair certain immune parameters which is one reason periodization and recovery are really important. Physical activity is one of the most powerful interventions we have for the brain as well.

1:01:36Its effects extend from mood and cognition all the way to long-term protection against neurodegenerative diseases like Alzheimer's. Regular movement improves attention in the short run as well as your processing speed and executive function. And these benefits appear across your lifespan and are observed both in observational studies and controlled intervention studies. Exercise increases the level of RAIN-derived neurotrophic factor, or BDNF. This growth factor supports synaptic plasticity, neuronal survival, and learning. Higher BDNF is consistently associated with better cognitive performance.

1:02:14And in rodents, exercise robustly stimulates what's called hippocampal neurogenesis or the growth of new nerve cells in the hippocampus. Hippocampus is the part of the brain where we store and process memories. And in humans, direct measurement is much more difficult, but structural and functional imaging studies support improved hippocampal integrity with regular aerobic activities. As we get older, we tend to lose blood flow, not just in our muscles, but also in our brains. And the good news is that physical activity is known to improve cerebral blood flow, enhancing the delivery of oxygen and nutrients to brain tissue.

1:02:52This vascular contribution likely underpins at least part of exercise's protective effect against cognitive decline as we get older. Mental health benefits are substantial with exercise. It reduces symptoms of depression and anxiety and it's comparable to first-line therapeutics for mild to moderate depression, and that's been shown in many, many studies. These effects are not just limited to intense training. Even moderate exercise and consistent activity is sufficient to produce meaningful improvements in mood. What science is showing is that exercise, even late in life, can slow neurodegeneration, either by reducing inflammation, improving blood flow in the brain, and activating neurotrophic pathways that stimulate new nerve growth.

1:03:40A large prospective cohort study published in 2019 followed older adults for over a decade, and they found that higher levels of physical activity were associated with a significantly lower risk of dementia, even after accounting for genetics and vascular risk. This work aligns with more mechanistic studies, showing that exercise is associated with lower circulating neurodegeneration markers, including neurofilament light chain. The take-home message is optimistic. Starting earlier appears to confer the greatest protection, but the brain does remain plastic even in older ages. As we all know, exercise is also good for sleep.

1:04:18So regular movement improves not just your sleep quality, but your circadian regulation, which in turn supports memory consolidation and even emotional regulation. So now let's talk about metabolic health. Metabolic dysfunction sits at the center of many age-related diseases, and physical activity is one of the most effective ways to preserve metabolic health across our lifespans. Exercise improves insulin sensitivity by increasing glucose uptake into muscle through insulin-dependent and insulin-independent pathways. GLUT4 is a transporter that goes to the outside of cells to suck the glucose out of the bloodstream, and contracting muscle acts as a powerful glucose sink.

1:05:00A single bout of exercise improves glucose control for hours. And repeated bouts produce durable improvements in insulin sensitivity, which is what we need for long-term health, and also glycemic regulation. And importantly, physical activity also reduces the amount of visceral fat, the kind of very dangerous fat that lines your organs that you can't really see on the outside. Lipid metabolism improves as well with regular movement. Exercise can raise HDL cholesterol, the good type, lower triglycerides, and even improve lipid particle size and function, contributing to reduced atherosclerotic risk.

1:05:36Exercise also reduces the risk of metabolic-associated fatty liver disease, and it improves hepatic insulin sensitivity. Importantly, many metabolic benefits arise independent of weight change. So fitness modifies risk even when body weight remains stable. So we've talked a lot about how exercise can make your brain and your body healthier for longer. But what about your skin? It turns out that movement affects tissues that we don't typically associate with exercise. In a randomized clinical trial published in 2023 in Scientific Reports, a study of middle-aged, sedentary women compared aerobic training and resistance training over 16 weeks and they found improvements in skin elasticity and upper dermal structure in both groups.

1:06:22Resistance training uniquely increased dermal thickness and it was also linked to increased dermal bi-glycan which is involved in maintaining skin structure. Regular exercise is associated with increased cutaneous blood flow too. So it's not just the brain and the muscle, your skin gets more blood as well. Connective tissues also respond to exercise. Tendons and ligaments strengthen. This supports joint integrity and reduces injury risk. Disuse has the opposite effect, reduced collagen turnover, greater stiffness, and higher risk of strain. I was surprised to learn that about 30 % of adults after the age of 40 have some form of rotator cuff tear, and this can rise much higher with increasing age.

1:07:09In my experience, almost half the men that I talk to have shoulder problems. So you've got to keep moving and maintain the strength of your shoulders. So the principle here is really simple. Structure follows function. Tissues that are used are maintained. Use them or lose them. We've covered a lot. In this episode, we've looked at the evolution, the physiology, the molecular biology, and even population data. And the central message is super simple. Humans evolve to move. Our biology expects it. When movement disappears, systems drift out of calibration. We age more rapidly. But when movement returns, many of those systems realign.

1:07:56Physical activity is not a single intervention, of course. It's a systems level signal. It engages the cardiovascular system, skeletal muscle, immune function, metabolism, brain health, skin, and connective tissue. It's difficult to find another behavior that we can do that touches as many longevity pathways at once. Exercise slows functional decline. It preserves capacity and compresses morbidity. More years of life spent capable, independent, and engaged, and maybe even better looking. The evidence is strongest for cardiorespiratory fitness and muscular strength and power. These are not abstract metrics.

1:08:34They translate directly in how we live day to day. The benefits are not reserved for athletes. The largest gains occur when people move from inactivity to modest, consistent movement. It's also never too late. Adaptation persists into advanced age. The biology does not close its doors. The takeaway is this. Movement and exercise are not optional for healthy aging and longevity. They're foundational. And unlike most interventions, they remain available to nearly everybody, every day.

1:09:08Dr. 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'll 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.

1:09:46Dr. 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, who's on First Vulgamoor, Kathleen, TLDR Fitzgerald, and our researchers, Shivani, Just One More Thing Sethi, and Adiv, Meet Me in the Year 3000 Johnson.

1:10:29Dr. David Sinclair:Also, I want to mention our new recruit, Daniel Rocketman Salazar, who's our new producer. And of course, Serena, my honeypoo. 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.

1:10:58Dr. David Sinclair:this show is for informational purposes only and is not medical advice please consult a qualified health care 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