Fasting as a Path to Longevity: The Facts | Lifespan with Dr. David Sinclair - Season 2, Episode 2

24:45And this guy and his colleagues claimed in a very flawed study that eating five meals a day was better for you and actually produced less obesity than eating three or fewer meals a day. And, of course, after 1964, it really became the darling of the media, especially the advertising media, to say, hey, you should eat more. Eat all the time. Eat snacks. This Czech study was really flawed, and it should not have been the basis for nutritionists and certainly advertising over the last 50 years.

25:23Dr. David Sinclair:But instead, this study, which was not randomized, it didn't control for physical activity or socioeconomic status or even total calorie counts. It became the darling of nutrition educators and public health agencies, especially in the West. and from the 1970s onwards we've been told by most nutritionists that eating starting in the morning and small meals throughout the day is the best thing to prevent obesity. Unfortunately a lot of nutrition studies over the years have been sponsored by food companies and some nutritionists, not all of course, some have really repeated the mantra of the advertising campaigns.

26:01Dr. David Sinclair:For example breakfast cereal is essential for children's learning and fruit snacks and juice boxes are healthy options. The funding of science by the food industry can blur the lines between independent advice and marketing, and it's very hard to know what's true and what isn't. Before we get into the science, there's something I want to talk about that really bugs me. It's how our children are being trained to eat in a way that actually speeds up their aging and will almost certainly reduce their lifespan ultimately. I'm talking about the rise of the snack culture. Now, I was born in 1969, right?

26:38That was a long time ago. But in the 1970s and up until about the mid-1980s, it was pretty normal for kids to go play outside without supervision and really not eat anything after school, at least until dinner. And that was really quite normal. We stayed thin, we exercised, we were out there. But then came the 1980s and 1990s culture, which I saw in my 20s and 30s and then certainly for my kids in the 2000s, there was this idea that parents shouldn't let their kids feel hungry. The helicopter parenting wasn't just do your homework, it was here have a snack, don't feel hungry. To fuel that was the rise of certain brands, of course, Go-Gurts, Snack Packs, Lunchables.

27:21These were must-haves for growing kids and for their concentration to do work at school and at home. What did we get? we got childhood obesity going through the roof. And unfortunately, we're still trying to reverse that today. So what does the science say? What is the healthiest way to eat?

27:39Dr. David Sinclair:Is it five meals, three meals plus snacks, three meals, two meals, one meal? Well, we poured through the data, the scientific literature, and the results are mixed. Some studies say that it really makes very little difference how many meals you eat, as long as the same number of calories go into your body each day. The exception being if you eat late at night and sleep with a full stomach, that's probably not the best. But there's also confusion about how hungry you feel. Some studies say that if you eat six meals a day, you're less hungry than if you eat three. There's another one that says the converse of that.

28:14Dr. David Sinclair:So even though you may not gain extra weight by eating small meals throughout the day, what we do know is that time-restricted eating is healthier for your metabolism and your long-term health. Why? It increases your insulin sensitivity, which helps your body take the sugar out of your blood. And also, it increases your fat oxidation, so burning fat, and even can help prevent feeling hungry. Now let's talk about calorie or caloric restriction, abbreviated as CR. This is the diet that has been extending the lifespan of animals for nearly 100 years. Is it good for us? Is it even possible to do this?

28:52Dr. David Sinclair:We're going to dive in. But first let's talk about what is a calorie. The term calorie was first coined in 1824 by a scientist Nicolas Clement in Paris. And he said that a calorie with a little c is the amount of energy you need to raise the temperature of a gram of water by one degree Celsius. The reason that's important is that today we use capital C, which really represents a thousand of those little calories. A calorie with a capital C is the amount of energy that's needed to raise the temperature of a kilogram of water by one degree Celsius. Just be careful because a kilocalorie and calories are sometimes mixed up on labels and when people talk about it.

29:34Dr. David Sinclair:In the United States, often you see a large C, which represents a thousand calories, a kilocalorie. Even though people have been fasting or calorie restricting for thousands of years, the formal scientific study of these diets really didn't begin until the early 20th century. The first study that used fasting to treat a disease is in 1915. We have a study from physicians, Frederick Allen and his associate Elliot Joslin, who gave his name to the Joslin Diabetes Center here in Boston. These two physicians came up with what became known as the starvation diet. It doesn't sound very good, but it worked.

30:12Dr. David Sinclair:They were treating diabetics, and they were the first to show that by limiting food and exercising patients, they could literally cure them of their disease. This approach was abandoned by about 1922 when insulin was discovered. A couple of years later, Osborne and Mendel are known for doing some of the early studies of diet and lifespan. and they were using rats and they showed that female rats that were eating less or given fewer amino acids, they developed slower, so they were smaller, but they had longer lifespans. The first real formal studies of the effect of caloric restriction on longevity in rats was done in 1935 by Clive McKay and colleagues at Cornell University.

30:55Dr. David Sinclair:And they're really regarded as the founders of this field of caloric restriction. I actually have a book by Clive McKay and his memoirs between him and his friends and his wife. I have it down here. This book is near and dear to me. It normally sits on my bookshelf at home. So it's Clive McKay, Nutrition Pioneer, his memoirs. And there's some real nuggets about what it was like doing this research in the 1930s. Can you imagine not knowing whether diet had any impact on lifespan? And so I'll just read you a little bit. the animal work involves much art as well as science each animal should be carefully studied and minor adjustments made to suit the needs of the animal always handle animals with great gentleness and try to make pets of them now that's pretty funny because in my lab we study mice and the golden rule is don't make pets of them well clive mckay's wife must have really loved him because she was the one that pulled this book together based on their love letters.

31:57Dr. David Sinclair:Andrew, you've got a picture of Clive McKay. There he is. This is in the 1930s. He's weighing out probably some food for the animals. What Clive and his colleagues showed in those rats was that restricting the amount of calories that they were eating every day by about 30 to 40 percent, which is a lot, of course. They're probably quite hungry at that point. That led to an average lifespan extension, a mean lifespan extension, are between 33 to a whopping 50 percent. And that remains pretty close to the world record for a lifespan extension for a mammal. What this actually at the time meant was that by doing something very simple, just by restricting the amount of food an animal would get, you could dramatically increase their lifespan.

32:44Dr. David Sinclair:Of course, they didn't know how it was working. It took a number of decades later, and we're going to get into that. That's some of the work that I did when I was at MIT and then in my lab at Harvard. But this was an important paradigm shift in longevity research at a time when really nobody else was studying longevity. This study transformed calorie restriction and fasting from a curiosity in science to a whole field that's been studied ever since. Which brings us to the modern era. In the 1980s and 1990s, Richard Weindruck and Roy Walford were doing experiments in mice on caloric restriction.

33:18Dr. David Sinclair:And what they showed was that just like the rats, calorically restricting those mice extended their lifespan 20 to 30 percent and made them much, much healthier. There's another thing that's worth mentioning. Roy Walford, who was an avid calorie restriction advocate, went into a greenhouse called Biosphere 2 to see if they could recapitulate the Earth within a closed environment. So they were locked up for, I believe, close to a year. and here's a picture of them in their Star Trek suits. There's Roy right down the middle with the handlebar mustache. Unfortunately, they couldn't grow enough food and inadvertently, they all had to undergo caloric restriction.

33:58Dr. David Sinclair:And this was one of the first informal studies of the effect of that diet on the human body. And what they actually showed was that some of the biochemical changes that they underwent were very similar to what was seen in the rats. Which brings us to modern times, the 2000s, when the CALERIE restriction study was started. Now, CALERIE is an acronym. It stands for Comprehensive Assessment of Long-Term Effects of Reducing Intake of Energy, CALERIE for short. And it was at three sites, at Tufts University, Louisiana State, and Washington University. I went down to Louisiana to visit Eric Ravison, my friend, and one of the big complaints was that people were not sticking to the diet.

34:38Dr. David Sinclair:The goal was for two years to eat 25 % less than what they would normally be eating, but it was very difficult and on average people only reduced their calorie intake by 12%, which was a reduction of about 280 calories. Let's talk about the benefits of calorie restriction per the calorie study. One of the landmark papers that came out of the calorie study was by Waziri et al. in 2023 in Nature Aging. First of all, they looked at the pace of aging, and the clock that they used is called the Dunedin pace clock, which was developed out of New Zealand in a town called Dunedin. And what they found was that the calorie-restricted group that were eating 12 % fewer calories than the controls had a decreased pace of aging of 2 % to 3%, which could correspond to a whopping 10 % to 15 % decrease in all-cause mortality risk.

35:29That's a big deal. Makes me want to try it, actually. Another study that's worth talking about, also by Belsky et al, was done a few years earlier in 2018. And what they looked at was what's called the KD years. This is another measure of aging. And they could use those KD years to say how many years were these people aging per year. Anyway, if you look at the controls versus the calories restricted group, the people that were eating a normal diet were aging at 0.71 KD years per year, which is still pretty healthy but the calorie restricted group was aging at only 0.11 kd years

36:06Dr. David Sinclair:per year which is 0.6 fewer biological years per chronological year. That's astounding. As we talked about in this episode most of us won't die from infections or accidents. What we're going to die from are diseases caused by aging. So that's why it's really important that we all track our own health closely over time. And that's how we can know if we're progressing and what we're actually doing is working. Wearables make that super easy. You don't need to watch these numbers all the time. You can look at them once a week or even once a month. But it's really important that you check how you're doing, which brings me to a wearable that I'm particularly fond of, partly because of its scientific foundation at Harvard, where I work, and also the founder's own research and scientific rigor.

36:54Dr. David Sinclair:The company's only a couple of blocks up the street here from the studio, and I visit them occasionally and see what an active, caring company they are. I'm talking about the Whoop Band. This wearable is a health and fitness coach that gives me insights into my sleep, my recovery, and my body strain. The researchers have studied how accurate these devices are, and in a 2022 study, they compared six wearable devices, including Whoop, against clinical-grade ECG and sleep recording devices. WHOOP showed strong accuracy for heart rate and heart rate variability measurements, during sleep especially.

37:31Dr. David Sinclair:Using the WHOOP band, I can see how my daily behaviors are impacting my health wearing the WHOOP over the last two months. I've seen dramatic improvements in my personal biomarkers, indicating that the changes that I'm making to my lifestyle, including a much healthier diet and more exercise, is definitely having a positive effect on my body. For example, my resting heart rate has gone down to 45, which is great, and my heart rate variability, which you want to be higher, that number has shot up to 90, putting me in the top few percent or so for my age. It's not only interesting and useful, but it's also important to build up a record about your body that you can aim for when you're older.

38:11Dr. David Sinclair:When you're 90, you can go back and aim to be what you were in your 40s or 50s. If you're a regular listener to this show, you'll know that we only partner with companies like Whoop who we really believe in. These are products that I use daily, the team uses daily, and these companies align with our values, our mission of supporting medical research and supporting young scientists. If you want to try it and get a free Whoop 5.0 smart band and a month off membership, go to join.whoop.com slash lifespan or use the code lifespan. So even though we don't yet know whether calorie restriction or even fasting truly extends lifespan, we do know that they have remarkable health benefits.

38:57Dr. David Sinclair:So let's first talk about those. In the calorie restricted group, of course they lost weight, but it wasn't that dramatic. They didn't become emaciated. They lost a bit of weight, on average about 16 pounds, which is roughly 7 kilograms. You know, and there are a lot of people who wouldn't mind losing that amount of weight. And what happens is you reach a new set point where you don't keep losing weight on 12 % calorie restriction. And there were some other really interesting health benefits. First of all, there was a great improvement in lipids. There was decreased LDL or bad cholesterol by about 10 milligrams per deciliter, lower triglycerides of 24 milligrams per deciliter, and an increase in good cholesterol, HDL, of four milligrams per deciliter.

39:39Dr. David Sinclair:These are real improvements just based on restricting the amount of calories by 12%. Other benefits included lower blood pressure and overall improved physical endurance. Surprisingly, there was better cognition, more sex drive, again surprising, and better sleep. These are all really quite remarkable benefits that you get from restricting calories by about 12%. One interesting thing about the calorie study was that the calorie restricted group received coaching and education on nutrition. And that allowed them to, at least 90 % of them, maintain adequate amounts of pretty much all of their nutrients, including omega-3s, vitamin B, C, E, K, calcium, and a whole range of others.

40:24Dr. David Sinclair:But the ad libidum group did not receive coaching, their diet actually did not improve. So what I think this is telling us is that if you practice calorie restriction, you do need to maintain an adequate diet and measure yourself to make sure that you're not deficient in any nutrients. So far, we've talked about just the calorie study with 12 % calorie restriction, but there are dozens of other studies in the literature, some with 15 % calorie restriction, some up to 47%. And these largely concur with the findings of the calorie study where people tend to be healthier. And there are indications based on molecular clocks, on epigenetic clocks, that there's a slower rate of aging as well.

41:06Dr. David Sinclair:Besides these clinical studies, is there other evidence around the world that calorie restriction is good for you? Well, one of the best places to study calorie restriction is on the island of Okinawa off the coast of Japan. These individuals, for over a century, have been eating less than the mainland. One thing that Okinawans do well is they eat less than most of us. They have this saying, which is harahachibunmei, which means eat until you're 80 % full, which means on average they're eating less than most of us would. And actually that's a very good practice. And they also eat a highly nutritious diet, mostly of plants and not a lot of meat.

41:45And if it's meat, it's fish. They also do other things like exercise a lot. They work in the fields. They have a great social life. And on average, Okinawans live longer than the mainland of Japan and definitely longer than the U.S. population. In the 1990s and 2000s, a lot of the research was performed by a couple of friends of mine, Brad Wilcox and Craig Wilcox, based in Hawaii. And what they did that was really interesting was that they could compare the health and the longevity of Okinawans that moved to Hawaii.

42:17Dr. David Sinclair:And it was very clear that if you left Okinawa and started adopting an American lifestyle, that longevity benefit went away. They wrote a book called The Okinawa Diet in the early 2000s. And I loved the book. And I was so convinced by their data that I actually adopted for a few years that diet that consisted mainly of fish and some green leafy vegetables and not a lot else. But I did it for three years and it became super healthy. I had the best cholesterol levels and I was super lean. Did a lot of exercise like the Okinawans do. I wasn't pulling rice out of the fields, but I did go to the gym and I felt really great.

42:54Dr. David Sinclair:I actually stopped, if you're wondering, because I had kids. But if I'd continued it, I'm sure that I would have, you know, probably been even more biologically young than I am now. I highly recommend these type of diets of highly nutritious foods, plant-based, and a lot of exercise to seemingly slow down the aging process. As the calorie studies showed, nutrition is very important if you're practicing calorie restriction. In fact, there's a term for it. It's called calorie restriction with optimal nutrition or C-R-O-N, Cron, which brings us to the next topic I want to talk about, which is the cronies or cronies, actually.

43:35Dr. David Sinclair:These are people that have been practicing calorie restriction for many years. In fact, I know some of them. There's, for instance, Paul and Meredith McLaughlin. So Andrew's going to call up a picture of when Paul and Meredith visited the lab. And if you're watching this show, you can see it was a number of years ago. This is the 2000s. There I am. And on the right, Paul and Meredith, they at the time were calorie restricting for about a decade and they still practice it. And on the left is Brian Delaney, who at the time was the president of their society, the Calorie Restriction Society International.

44:10Dr. David Sinclair:Compared to them, I look kind of obese. What's interesting about them is, first of Well, they loved life. They were not tired. They were energetic. Paul, at the time, was the New York State chess champion. So obviously, it doesn't affect your brain. And they were loving life. In fact, there was a 60 Minutes episode on Paul and Meredith. And I remember him talking something a little bit too much information about his sex life. But apparently, it was fine. What really is interesting, though, as a scientist, is that their blood work was analyzed. I do have a lot of their blood work that I'm not going to share with you.

44:43Dr. David Sinclair:but what was published was that typically their blood work looked a lot like calorie restricted primates. They had better blood work, low inflammation, low risk of atherosclerosis as well and at the time this was some of the first data that we had on calorie restriction before the more formal placebo-controlled randomized study known as CALERY. And while we know a lot about the health effects in humans partly from the cronies but also Okinawans and especially the real studies like the calorie study. In animals, we know a lot more, of course. And there's one particular fascinating outcome of calorie restriction in animals that I want to tell you about.

45:24It's lifespan extension, of course. Since Clive McKay's work on rats, we've seen CR improve the health and extend the lifespan of many different organisms, from worms to flies, spiders, little water fleas called Daphnia, dogs, of course rodents, and even monkeys, which we'll get to. In my lab, we studied yeast calorie restriction for many years, and I can tell you the yeast that were eating less glucose lived a lot longer and looked a lot healthier under the microscope. And the effects, at least in mammals, on diseases and lifespan are really promising, though there are some caveats which we'll get to.

46:00Now I want to talk about one particular study that was really well designed that came out in 2019 in Cell Metabolism. It was led by my good friend and colleague, Rafael DeCabo, down at the NIH in Bethesda, Maryland. They compared three groups. They had mice that ate freely, or what we call ad libitum. That was the control group. Then they had a group of mice on 30 % calorie restriction. And the third group, the mice were fed just one meal a day. But interestingly, they ate roughly the same amount of calories as the ad libitum group. So we could ask, is it timing or is it calories that makes a difference?

46:38Dr. David Sinclair:What they found was that the calorie restricted group lived about 28 % longer, which fits with what's known about rodents. But even the once daily feeding group saw a lifespan bump, about 11%. That's a big deal. What it showed, and I remember reading this at the time, it showed that not only is it important how much we eat, but also when we eat that matters. Now I want to move up the evolutionary ladder. We'll talk about non-human primates. There's a small and very cute primate called the grey mouse lemur. Researchers based in France looked at the effects of 30 % calorie restriction on the health indices and lifespan.

47:19And what they found was that the mortality rate from age-related diseases dropped by a whopping 60%. And the average, well actually the mean survival times were 6.4 years in the regular animals eating a normal diet and a massive 9.6 years in the calorie restriction group. But the crown jewel of calorie restriction studies in animals is the decades-long work in rhesus monkeys, our closest relatives that have ever been studied under calorie restriction. The National Institute on Aging, again where Rafa de Cabo works, and he was involved in this study. And then another site, the University of Wisconsin, separately ran decades-long studies on calorie restriction in these rhesus monkeys.

48:05The NIA study was launched in 1987, and that's probably before some of you were born. And the University of Wisconsin study started in 1989, shortly thereafter. Rafa runs the monkey study with his colleagues, And Rosalind Anderson, an ex-postdoc from my lab, now runs the Wisconsin study. So I've had a front row seat and a backstage pass. Both of these studies were aiming for roughly 30 % calorie restriction. And both showed impressive improvements in health, including decreases in diabetes, in cancer, and heart disease. And in 2009, and I will never forget the day I opened up this paper, the group at Wisconsin, which had initially enrolled 76 monkeys for the study, reported in the journal Science that 80 % of the CR monkeys were still alive compared to just 50 % of the controls at the same time point.

49:01Andrew Collop, that paper, it was a landmark paper at the time. It's worth looking at. So here we see the title, Caloric Restriction Delays Disease Onset and Mortality in Rhesus Monkeys. This is what we'd been waiting for for a couple of decades. And it was run by Richard Weindruck, a good friend of Roy Walford, who we talked about earlier in the Biosphere 2. Andrew, scroll down. Let's have a look at these monkeys. I believe they're both roughly 27 years old at this point. And there's a massive difference. If you look at the one on the left, there's pretty shoddy hair and there's inflammation on the skin.

49:35And the one on the right that's on the calorie-restricted diet, even though he looks kind of frustrated in the picture of his face, such a big difference in the coat, the hair. And actually, if you scroll a little bit down further, Andrew, you can see the mortality is massively different, right? So figure B, age-related mortality and overall mortality, big differences at this point. though it even got more significant later and further down this is really important i wanted to show you this this is showing how much disease these animals have cancer cardiovascular disease and essentially glucose metabolism and the blue is the control so there's an eating ad libitum and the red is the cr and if you look at the number of cancer cases in the cr group there's only four cases and there's a lot more in the controls.

50:27But if you summarize all of this in that graph on the far lower right, you could see very clearly that the percentage of animals that have age-related diseases is much greater in the controls versus the ones that are eating the calorie-restricted diet. So this was the first really good evidence that calorie restriction slows down aging, age-related diseases, and probably extends lifespan of primates as well. Remember, these are some of our closest cousins. So this was a real landmark, but things got a little bit more complicated very shortly thereafter. There was an NIA study that was published a few years later in Nature that reported no significant impact of calorie restriction on survival in these monkeys.

51:10Dr. David Sinclair:That's confusing, right? Both sites had seemingly similar study designs. Both aimed for about 30 % CR, but they found different things when it came to lifespan extension. They all agreed that it made the monkeys healthier, but they disagreed on whether it extends lifespan in primates. So, these two groups, thankfully Rafa and Roz are very good people, very friendly, cooperative, collaborative, those two groups did something very cool and very rare in science. They teamed up. They analyzed data gathered over many years from almost 200 monkeys from both studies and published their joint findings in a Nature Communications paper in 2017.

51:54And that data confirmed that calorie restriction does indeed delay aging in non-human primates, though they disagree as to the extent of the lifespan extension. That difference in lifespan in those monkeys was still confusing. And so what Roz and Rafa did was they did a study in mice and varied the diet in ways that might mimic the variations between the two sites. They gave one group of mice the equivalent of the monkey diet from Wisconsin and another group the equivalent of the NIA monkey diet. And what they found was it didn't really matter what was in the diet, it mattered much more when and how many calories they ate.

52:36There's a story I want to tell you about at the NIA study that Rafa shared with me and it was that the monkeys were gaining weight and they couldn't figure out why, the ones on calorie restriction. And it turns out there was a technician who felt sorry for the monkeys that were a little bit skinny. So she was feeding them extra snacks on the side. Of course, she was promptly fired. And hopefully it didn't affect the study too much. So now we know from these studies, at least in mice and primates and many other species, that calorie restriction, eating less without malnutrition, can extend lifespan.

53:09But the question is, it's a really big question, how and why does it actually work? What's happening inside the cells, behind the scenes, that turns fewer calories into more years?

53:20Dr. David Sinclair:I want to address one thing up front, and that is that the benefits of calorie restriction, despite what you might think, are not just because you lose weight. Losing weight is not sufficient to extend lifespan in animals. And it doesn't explain why yeast and spiders and water fleas also live longer. Back in 2005, my lab published a paper where I wrote,

53:56Dr. David Sinclair:I called it the hormesis hypothesis of calorie restriction. In other words, calorie restriction flips a molecular switch, activating survival circuits that have been with us for millions and possibly billions of years. So it's not about being thin, it's more about being resilient. So in other words, what doesn't kill you makes you live longer. And if this hypothesis is right, calorie restriction is working in our bodies by tipping the balance between two competing forces in the body, growth signaling and maintenance. So when nutrients are abundant, your cells get the green light to grow and build.

54:41Dr. David Sinclair:But when calories or other essential nutrients like aminos are limiting, your body shifts gears. It quiets the growth signals and it activates the survival mode. Things like repair and cleaning up misfolded proteins and stress resistance, these things get turned on and protect us against diseases and against the aging process. I can tell you that calorie restriction puts you in survival mode, but what's really happening at the molecular level? You'll recall there are three main longevity pathways. There's mTOR, which senses amino acids, AMP kinase, the target of metformin, the drug, and sirtuins, which we work on in my lab, and they are activated by NAD.

55:24When you calorie restrict, All of these three pathways get adjusted in ways that turn on repair pathways for DNA, turning down inflammation, and other things that preserve health, prevent disease, and ultimately, we hope, extends your lifespan. How do we actually know it's not just lowering metabolic rate? Well, it all started in model organisms. And one of the model organisms that we worked on in the early 2000s, as I mentioned earlier, is yeast. and what we could show was that by putting in more of the SIR2 and genes they lived longer but then you also want to do the opposite. You want to ask is the gene necessary for calorie restriction and we found that it was.

56:04So if you delete the SIR2 gene you don't get lifespan

56:07Dr. David Sinclair:extension by calorie restriction in yeast. What this showed really for the first time was that the benefits of lowering calorie intake acted through a genetic pathway not just by slowing down metabolism. It might seem obvious today that sirtuins and genes are involved in the effects of calorie restriction, but in those days it wasn't. Most people thought that it was due to slowing of metabolism, fewer free radicals, less DNA damage. But here we were finding that a gene was responsible for defending the cells against adversity. Since then, we've actually found that sirtuins are controlling calorie restriction, not just in yeast, but in mice and even in our own cells.

56:51Another thing we haven't yet covered is that calorie restriction also dials down insulin and IGF-1, or also known as insulin-like growth factor 1, which regulate mTOR. Cynthia Kenyon, one of my colleagues, had a landmark paper which showed for the first time in worms that deleting a single gene could double the worm's lifespan. At the time, a lot of people didn't believe this could be relevant to us. But now we know that DAF2 has an equivalent in our bodies. It controls the human insulin and IGF-1 receptor pathway. And that's why when I see I have low IGF-1 levels in my blood tests, I'm happy about that.

57:32Now let's talk about some of the effects of calorie restriction in humans. It improves DNA repair. You have less inflammation, oxidative stress drops, autophagy increases, autophagy being the recycling of old proteins. Expression patterns of genes become more youthful, turning back the epigenetic clock, in other words. Mitochondria, the power packs of cells that generate cell components, they multiply, they regenerate, and the gut microbiome, which is very important for inflammation and the absorption of nutrients gets more diverse.

58:06Dr. David Sinclair:Now there's something new and exciting I want to tell you about. But before I do, if you've listened to this show before, you've probably heard me say that you cannot optimize what you don't measure. That's what we do as scientists. And it's true also when it comes to body metrics. Many people only measure their total body weight, if anything, but this only tells a small part of the story. So how can you measure these other aspects? Withings, one of Lifespan's partners supporting medical research, makes some of the coolest devices that you can measure yourself with. They have watches, a sleep monitor pad, and advanced bathroom scales, one of which I use every morning.

58:44Dr. David Sinclair:I've actually been using Withings devices for over 13 years since they first came out with their first scale. And today the Withings vision clocked me at 59 beats per minute heart rate, which I'm very happy with. It's actually pretty healthy, and at night it drops down to about 49, as I previously mentioned. Another metric that impacts lifespan is body composition, and it's impossible to know this unless you measure it. We've already talked about visceral fat, the evil fat that sits around your organs, and it's associated with risk of cardiovascular disease, diabetes, and even death. So getting rid of visceral fat, or at least minimizing it can have a strong impact on your long-term health and longevity.

59:25Dr. David Sinclair:I've got all the valuable data on my scale in my bathroom here and also on my phone. The Withings Body Scan scale can help estimate your muscle mass, your fat mass, and importantly, your visceral fat percentage, among other things. I stand on this scale almost every morning. Here's the digital twin on my phone spinning around. So the numbers speak for themselves. I've got 11.3 % fat on my arms, 14 % torso, and visceral fat, which we mentioned is the evil fat at 2.7. All of these numbers I'm very happy with. And you can also look at muscle and other different things here. And in the past couple of months, by changing my diet and improving my exercise regimens, I've lost over 12 pounds for spring.

1:00:09Dr. David Sinclair:And importantly, I was able to ensure that I didn't lose any of my muscle mass. This is a common problem when you're eating less. And especially if you take a GLP-1 receptor agonist like a Zempick, a withing scale can really help ensure that you lose only the fat, not muscle. It's the only smart scale that also comes with an FDA-cleared ECG that can analyze your heart rhythm and even detect atrial fibrillation, which is a heart condition that can cause strokes and even heart failure. We here at Lifespan are partnering with Withings because we share a common commitment to preventative health and also we want to support medical research and young students.

1:00:49Dr. David Sinclair:So as a Lifespan listener, we invite you to join us. You can learn more about Withings or get a scale or just one of their other really cool smart devices at withings.com slash lifespan or for a 10 % off discount use the code lifespan. What's really relevant is something that we did in 2003. My lab discovered that there are molecules in plants that activate sirtuins. One of them is called resveratrol from red wine. You've probably heard about that. And over the years we've figured out how resveratrol and other what we call STAX, activate SIRT1. STAX stands for sirtuin activating compounds. Now it was controversial for many years because it's quite unusual to find molecules activating enzymes.

1:01:34Dr. David Sinclair:Usually they inhibit them. But what we found was that resveratrol binds to SIRT1 and makes one of the arms of the protein come in and activate it. But what this led me to propose was that maybe there's a molecule that's not from plants, but made in the human body that activates sirtuins, a molecule that would be made during adversity, say, when we're calorie restricted. Now, we looked for many years for this endogenous molecule, and we came up short. We found NAD, but that really wasn't what we were looking for. Which brings us to the 2024 Nature Study, which found that lithocolic acid, or LCA, which is a bile acid in the gut, could mimic the anti-aging effects of calorie restriction.

1:02:17Dr. David Sinclair:Bile, you might remember from high school biology, is a digestive fluid produced by the liver that helps in the digestion and absorption of fats in the small intestine. LCA isn't something you get directly from food. It's made by the bacteria in your gut. The liver produces a precursor molecule and certain species of bacteria break it down into LCA. LCA enters the bloodstream that was already known. But these authors showed something else that really is quite remarkable. that LCA finds cells, goes inside and activates SIRT1, this SIRT2N that we originally showed back in 2003, 2002, is involved in caloric restriction.

1:02:58Dr. David Sinclair:But what they showed were two really important things in addition to that. Firstly, that LCA activates the enzyme in exactly the same way as resveratrol by bringing in one of the arms of the enzyme to activate it. And they also showed that LCA alone, when given to mice, could mimic caloric restriction. What I think this paper shows is that LCA is the endogenous activator that gives some of the benefits of caloric restriction in mammals, including our own bodies. Things like muscle regeneration, improved grip strength, endurance, how our bodies handle glucose, potentially underlying some of those age-defying benefits of calorie restriction that we've been talking about.

1:03:40Dr. David Sinclair:And then finally, what this discovery says that's extremely exciting is that it's involving the microbiome in the benefits of caloric restriction and in fact those authors did something quite remarkable. They changed the microbiome of the mice and calorie restriction didn't work anymore. If this paper is true for us it means that our gut microbiome plays a role in how calorie restriction or even fasting benefits us. We know that there are microbes that produce things like short-chain fatty acids that are good for us. This paper shows that bile acids may also be involved in those health benefits when we don't eat as many calories.

1:04:20So while it's tempting to think about immediately trying to boost your LCA levels, going out to buy some bile acids and eat them,

1:04:28Dr. David Sinclair:be careful because these researchers themselves emphasized caution. High levels of LCA are thought to potentially cause liver toxicity and even increase the risk of cancer in animal models, especially when combined with DNA damaging agents. What we need now are carefully designed human clinical trials to understand how LCA and other bile acids, first of all, whether they're safe to consume and also whether they do mimic the benefits of caloric restriction in our own bodies. There's a related compound I also want to talk about called TUDCA, T-U-D-C-A. TUDCA is also a type of bile acid made by the liver.

1:05:06and what we know about it is it's been used in traditional Chinese medicine for centuries, particularly bear bile, which contains a lot of it.

1:05:15Dr. David Sinclair:So while it might not directly activate the SIRT1 enzyme in the same way that LCA does, Tudka has extensively been studied for its own impressive protective effects on cells throughout the body. And here's what makes Tudka particularly interesting. Tudka is known as a chemical chaperone because it helps cells deal with stress, particularly in a part of the cell called the endoplasmic reticulum. This cellular support is crucial for healthy cell function and can help prevent cell death which is a factor in many age-related diseases. It also appears to reduce inflammation and oxidative stress both of which are key drivers of aging and various chronic illnesses.

1:05:55Dr. David Sinclair:Research largely in animal models not humans suggests that TADCA can improve insulin sensitivity and help regulate glucose metabolism, which is really beneficial for diseases like type 2 diabetes that often become more prevalent with aging. In animal models, Tudka shows promise in neuroprotection, protecting against Alzheimer's and even Parkinson's disease. It's important, just like in the LCA study, to remember that much of this is still in its infancy. And if you do decide to explore Tudka as a supplement, read about it on PubMed and consult your doctor if you're interested. After we reach about age 30 most of us gain a few pounds per year.

1:06:35If you add it up year after year it's really significant. It's not just about how you look or carrying some extra weight. That steady gain is linked to faster aging and to shorter lifespans. So we really want to do something about it and one of the best ways to counteract that is to calorie restrict or to use the more simpler version what I do fasting. Both of these approaches can help slow down that weight creep and potentially extend the years that we live in good health. But first, I also want to be clear. My goal here isn't to push you into calorie restriction.

1:07:09Dr. David Sinclair:I'm not trying to make you go into a fasting protocol. My goal is to explain the science so you can make your own informed decision. And while we've already looked at the upsides of fasting and CR, let's talk a little bit about the downsides. Some researchers argue that calorie restriction doesn't truly slow aging. And while it may work in many animals, including mice, they argue that really it's just reducing the effects of obesity. And it's true that in many studies, the control animals are overfed. Adlibetim, as the diet's called, basically is giving animals as much as they want to eat. And they do overeat sometimes.

1:07:51Dr. David Sinclair:So of course, the calorie restricted groups are going to come out looking healthier. But that doesn't explain everything. Let's take the NIA monkey study for example. In that case, even the control monkeys ate modestly. They were thin. But still, the restricted animals fed better and were much healthier. Another concern is muscle. There's a lot of people worried about muscle. Some say you can't preserve it or even build muscle on a calorie-restricted diet. And that matters because as we get older, we lose muscle, of course. Sarcopenia, as it's called. and muscle loss is strongly tied to poorer longevity outcomes.

1:08:30Dr. David Sinclair:So what does the science say? Well, actually, in the calorie study that we talked about, the first large randomized trial of calorie restriction in humans, the participants did lose a little lean mass, but their muscle quality actually improved. And beyond this calorie study, other human studies are also showing that calorie restriction can improve other aspects of skeletal muscle metabolism, like mitochondrial function, oxidative stress, and insulin sensitivity, all which bode well for a longer life. But just like with weight loss drugs, you can't sit on the couch and expect to maintain strength.

1:09:06Dr. David Sinclair:You still have to move, and of course you need to lift weights as well. Now, does calorie restriction always work in animals? Of course not. You sometimes hear scientists saying it works on every species it's ever been tested on. That's fundamentally not true. For example, in one study in houseflies, CR actually shortened lifespan. And my friend Rafa DiCabo at NIH showed that while CR improves the health across many strains of mice in both sexes, it didn't always extend lifespan. And then there's a fascinating study from my colleague Steve Ostad, who, by the way, was originally trained as a lion tamer before becoming a longevity scientist.

1:09:46If you ever meet him, you've got to ask him about his previous career. Steve's study was interesting because he studied genetically diverse mice, mice descended from wild ancestors, with far more genetic variation than typical inbred lab mice like I use in my lab.

1:10:03Dr. David Sinclair:Compared to humans, and I just called this up here, humans have a variation of about 0.1%, and these mice were pretty close, about 0.3%. A typical mouse in my lab is virtually 0%, so this is more like humans than what we study in my lab. And in those mice, while calorie restriction lowered cancer risk, which is important, it didn't extend lifespan. And in 2009, my colleague Jim Nelson ran a really interesting study looking at more than 40 strains of inbred mice. Andrew can call up a picture from that study. What you'll see is that some strains live dramatically longer under CR, hundreds of extra days, which is huge in mouse years.

1:10:46Dr. David Sinclair:but others lived shorter lives under the same calorie restriction protocol, which was totally surprising at the time. We used to think that CR worked on every strain in a positive way. What this shows is that genetic background matters a lot. And if that's true for lab mice, it's almost certainly true for us as well, with our mixed set of genes across the planet and with different lifestyles, diets, and microbiomes. So where does that leave us? Even with these caveats, calorie restriction is still one of the most powerful tools we have to lengthen our health span and possibly our lifespan. But I found it very difficult to do.

1:11:27Dr. David Sinclair:So this raises the question, can we get similar longevity benefits without having to live on a calorie-restricted diet? The answer is yes, but the how is what we're tackling in the next episode. If there's one thing to remember from today, it is this. Your body was built for a struggle. On the African plains where we evolved, food was far less available than today, of course. Meals were less frequent, and our genome evolved to cope with that reality. But now, many of us live with snacks available everywhere, and late night eating is very common. I count myself as one of those people. In this episode, we also explored how modern habits around breakfast, snacking, and constant grazing have become normal, even when the science behind some of those ideas was very shaky and a lot of it was just marketing.

1:12:15Dr. David Sinclair:What we've seen is that eating less and less often is not just about weight loss. It switches on ancient repair and survival pathways that slow aging and help the body stay healthier for longer. But understanding the history, the science and the why of calorie restriction and fasting is only half the story. A big question, the one I get asked everywhere I go is, how do I reduce my food intake without it actually becoming a big deal in my life? So in part two, we're going to get practical. I'm going to walk you through the roadmap for implementing these diet strategies safely and intelligently without a lot of effort.

1:12:55Dr. David Sinclair:It's really not that hard if you know what to expect and what the little tricks are. We're going to bust some of the myths and look at what the evidence really says about things people worry about most, such as will you lose your muscle if you fast? What happens to your hormones, your sex drive, and your mood when you're fasting? We're moving from the why to the how. 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.

1:13:35Dr. David Sinclair: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. 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.

1:14:12Dr. David Sinclair: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, Volgamore, 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 honeypoon. 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.

1:14:55Dr. David Sinclair:We'll see you next time.

1:15:06Dr. David Sinclair:This 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.