TOP Harvard Scientist: These 5 Habits Are Aging You Faster | David Sinclair | FO562 Raj Shamani

30:21and I could say between friends possibly because every patient is their own experiment you measure their eyesight before treatment during and actually for another five years so if it works even though it's a small number of patients it's only 18 people we might see if it's working this year wow i i hope it works out for everyone because this is gonna be this is this is gonna be one of the biggest this is gonna make one of the biggest impacts in human life like all around the world because we could treat diseases we could just make people more healthy like they don't have to suffer through all these things all the things while they're even alive forget like coming back from 90 to being 50 again but at 90 can this at least feel and live like a 40 year old that is going to be incredible right yeah it's it's really worth pondering because we have to throw away our our misconceptions the first misconception is that we're treating aging and that we're just trying to make frail people look better or feel better this if it works could be a treatment for almost every disease known to humans.

31:44We can improve in my lab, multiple sclerosis, wound healing, brain aging, so memory loss, the kidney, the heart, the muscles, liver. There's no part of the body that could not theoretically be improved, treated, healed, repaired, rejuvenated, restored by this technology. it's not just aging it's all diseases even young children if they hurt themselves and they need to rejuvenate and and fix something that the body doesn't normally heal yes lizards can regrow parts of their body and salamanders can regrow a whole arm maybe we can do that for ourselves one day too but but explain while you're explaining i've written like few words and i want to go in that okay the most most basic thing is is that this is there in every human being right and if you cut these yellow part that's like damaging and we are damaging uh we are damaging on an everyday basis we're damaging 20 things maybe 20 000 things on an everyday basis in our life right uh every day you will get at least 20 trillion of those breaks in your body so these the DNA is breaking in my body oh yes right and that is causing the aging why is it breaking oh well so DNA why am I getting older and why yeah you versus me let's say there are two different people right in your body this this breakdown is happening probably let's say in a different way and then mine is happening faster or slower or I don't know why why is yeah we all are born same right?

33:29Well, partly it depends on our parents. If our parents had good genes to repair DNA and stop breaking, then we have an advantage. People that live a long time have less broken DNA and have a much more stable epigenome, so less epigenetic noise. And whales that live the longest of all mammals, they have low DNA damage and their epigenome, those structures stay stable. um but between you and me let's say um let's say i'm aging faster than you okay let's let's say we're twins right okay and i i obviously don't look as young as you so what what what's wrong with my body well what one thing that might be different is that the the enzymes that mop up free radicals um so i'm drinking coffee right it's it's got free radicals there's coffee has quite a lot of hydrogen peroxide in it and you're drinking let's say you're drinking coffee i think that's water but maybe i don't repair my broken dna faster as fast as you do and that means that these these proteins that hold the dna in place uh they don't get distracted as quickly um the other thing might happen is that these these proteins that go away in your body maybe they find their way back better than in my body for whatever reason there's a better signal to come back but why why mine are probably better and yours are not well there's lots of different reasons uh one is that um there are signals that tell proteins where to go in the cell i'll give you an example okay this is a tennis ball but let's imagine it's a protein proteins get modified they don't just get folded okay here's a folded amino acid sequence all of our proteins get modified uh and i've got this little thing this represents what we call acetylation it's uh it gets attached to typically an amino acid called lysine and now that this has been acetylated it will behave differently it will be active and will help repair the dna and it will go and fold up the DNA better because it's got this attached.

35:46And maybe your body puts these on more frequently than my body does to make this protein more active. That's a difference between people. But yeah, go ahead. You were saying something. Well, there's another big difference that is not genetic. It's actually as important as the genetic parent component. And this is the good news. The way you live your life impacts the pace of aging and how much DNA damage there is, right? So if you don't get a lot of x-rays, you don't fly a lot and get hit by cosmic rays, you don't get CT scans. Okay. That's one thing that would give you no advantage. If you eat a lot of colored plants, I call this xenohormesis, but basically Serena says, eat colored food, eat the rainbow.

36:35Colored food has chemicals that help repair DNA, that help proteins bind up the epigenome. And these chemicals we get from our food supply. Now, if we eat a regular lettuce from California that's not, or I don't know, in India they grow terrible food, but if it's just grown mass market and it's not colorful, like what we call iceberg lettuce. That's not going to have a lot of these, what we call polyphenol chemicals. But if you eat, gee, it would be the best. So green tea matcha is full with it. There's a bit in red wine, but we don't like alcohol anymore. Another good one would be dark green leafy vegetables, spinach.

37:22Anything that's got a lot of color will have chemicals that - Like bell peppers and stuff. Bell peppers are great. The other thing that helps plants become colorful is adversity, stress. So if you eat a great healthy plant-based diet, you don't get it from meat, by the way. So my diet and Serena's is plant-focused. For that reason, it's healthier. And these chemicals come from plants, not from animals. That's an advantage that we can all have. And then there's the usual things, running, moving, fasting, these also boost the activity of these proteins that help repair DNA and help bind up the epigenome and stabilize it.

38:05So this is some of the things my lab has done over the last 25 years is to connect what we live, how we live, what we eat, how we move to this process of aging. I'll come to activities later, but before we go to colored plants, what is there in colored plants like why specific why specific very dark colored plants are better not the normal colored plants okay so when i look at two plants they look same to me like a lettuce look lettuce or a spinach will look like a spinach yeah the darker spinach will be better for me that's what you're trying to say yes yes and and why why so this comes to my theory called xenohormesis okay It's not just my theory.

38:53I came up with a colleague of mine who I want to mention, Conrad Howitz. So in 2006, we published this theory. And the idea came from the observation that we couldn't explain this observation with current theory at the time. In the pharmaceutical world, almost all drugs are based on plant molecules. Aspirin, for example, a lot of the cancer drugs. These are plant, originally plant molecules, even metformin, which is for diabetes, very popular in India. It comes from a plant, which is goat rue, it's called in Europe. So why are these plant molecules so good for us? It makes no sense. The plants don't care about us, do they?

39:38I don't think so. Xenohormesis hypothesis says that when plants need to survive, too much shade or not enough water in the case of grapes where they dry out right they try to survive the plants make these chemicals many of which are colored they have color not all of them but many of them colored and they make them to survive these are plant stress survival molecules polyphenols a polyphenol if you're wondering a phenol is a chemical ring do can you make it to you yeah sure anything yeah there's a bit of chemistry lesson yeah please uh so phenolic a phenolic ring looks like this okay okay and the all stands for like an an oh and alcohol on there well just an

40:38polyphenol okay so this is a what's called a phenolic ring and you can make chemicals out of this structure. Plants make a lot of things out of it. There's one in, easiest one to draw is in grapes called resveratrol. And it looks like this.

41:00These are, if you haven't done chemistry, what's at these joins here are carbons. Okay. And they all have a little hydrogen on there. But basically, this is two phenols connected by a bridge. And this is resveratrol. Plants make this molecule, a polyphenol, phenol, two phenols, when they want to survive, when they get stressed. If there's not enough light, not enough water, or even infection by a fungus, they make a lot of this, especially grapes. But most plants make this. and when you drink red wine, you're getting a lot of this. If there just wasn't so much alcohol, it'd be even healthier. But you can buy resveratrol.

41:45I've been taking resveratrol powder every morning for the last probably 20 years because I truly believe that resveratrol is one of the polyphenols that can slow down aging. Why? Because one of the proteins that controls the epigenome, which we study called SIRT1, gets activated by this molecule. So when I'm eating resveratrol in the morning my body gets filled with it i eat about a gram so it's a lot it floats through the body gets inside the cell and it makes my epigenetic regulator more active so i'm not going to age so quickly is the theory that's why but you can eat stressed plants which make these molecules stressed plants are good for you colored ones yeah so because they're stressed they're trying to survive and that the stuff that they're making a little thing inside them which helps them make which helps them survive for longer that is the stuff that we need so it helps us survive as well it does and why is that is a good question why would they make us survive better my theory is it's because we get a signal when our food supply is going to run out our bodies will hunger down and try to survive and be stronger.

42:58So these chemicals signal human adversity in the future. And by eating resveratrol every morning, I'm tricking my body into thinking that food supply might run out. Big famine is coming. Exactly. Famine is coming. Exactly. Yeah.

43:18This is, I never knew that science is going to be this interesting for me. okay so so that's why you want to eat colored plants and that's why it's make it's making us better so that was the first part the second is what's happening inside my body as i sit here right now okay i'm on this chair right now and this is making me older right as i'm just sitting here yes why like what's happening inside my body what's happening inside each of my cells which is making me older. Well, there's a few things that are happening. There are at least 12 major causes of aging. I just happen to think that what we're talking about here with the epigenome is one of the primary major ones.

44:04But some of the things that are happening are the ends of your chromosomes, the DNA. If this is the end of a chromosome, it's getting chewed away slowly. Every time the cell divides, it gets shorter. So these are like fuses that get shorter. That happens, particularly in cells that divide a lot, like your blood cells in your liver. That's one thing. Your stem cells are getting older. The one thing though that you can't stop is this DNA breakage. This is happening even if I put you in a lead box at the bottom of the ocean with no x-rays, no cosmic rays, DNA still breaks. Why? Because during the copying process, remember how I said DNA copies by unzipping this down the middle, cut it down the middle.

44:51Now you get two strands. As you do that to the six foot long piece, inevitably it's going to break once or twice every time. It's weak. You can't stop it. So the process of being alive is causing DNA breaks. So you cannot stop that. But can I slow that down? Yes. By eating the right foods, by exercising, by fasting, by doing all those good things will slow down that process okay you said slowing down comes with let's say eating colorful plants that's one one way of doing it what's there in meat why because meat has a lot of protein meat has a lot of good things a lot of people will argue that you should start eating liver and whatever yeah but that's not going to give you longevity it's going to give you you know some some strength and you're going to build muscle a bit bit faster not a lot faster but a bit but that's not longevity Here's one way to think of it.

45:51There's adversity mode, right? So the body thinks that it's stressed. There's this, and then there's abundance mode. Lots of meat, just killed a mammoth. Lots of food, energy, fat, protein. This abundance mode accelerates aging. And adversity mode, as we've talked about, slows this down, protects the body. So if you want to be in abundance mode and grow big and be Mr. Universe, live this lifestyle. If you want to live a long time, be in adversity fast, eat plants, run. That signals of adversity to the body to preserve the body. Preservation, growth. Or what you can do, what I think is probably the best, especially for someone young like you, do both.

46:42a few days a week eat protein workout be abundant but have some adversity too sauna running fasting that's also good so this applies in every every aspect of life if i am making myself and my body stressed and trying to signal that i'm in adversity then it's going to live longer? Yes. Now, we haven't done a human trial. So yes is the answer to all of the evidence in animals points to it being true in humans as well. But if you take a mouse and you feed it resveratrol or you feed it other polyphenols, yes, it will live longer and be healthier in general. It can be resistant to obesity even. In 2006, we published resveratrol, given to fat mice makes them as healthy and long-lived as thin mice, lean mice.

47:39So yes, you can eat these molecules and get the benefits of adversity without actually having to be hungry. But you might say, well, then why do I have to fast if just eating plants is good enough? I don't think it's good enough. What we found in my lab looking at these animals is if you do both, if you don't eat three meals a day or if you're a mouse, you don't constantly eat and you take these molecules as well in the diet, you get double the effect. So that's why in my lifestyle, I focus on plants, I exercise, I try to do hot, cold as much as I can, and I'm taking polyphenols every day. That's my belief.

48:25It's not proven yet but all the science points to doing all of these things together they're additive give me specifics the way you give me specific of how colorful plants will make you better what kind of other protocols will make me better will it help me age slower you said running you said so how much running you said sauna or cold like how much of that like it's so many things right now so this is why i restarted my podcast and this is a shameless plug for my podcast okay It's called Lifespan because I get these questions every day. What are the details? How much should I fast? What should I eat?

49:03If I'm a woman, is it different than being a man? Yeah. So my podcast has a lot of that. Okay. So if you have a little bit of time, I know you've watched some of it, so I appreciate that. But we can cover some of it today, but it really takes many days of listening to know all the details. But there are some general rules. Let's start with fasting. Is that okay? Yep. Okay, so fasting. if you're not a young child, let's say in your 20s, three main meals a day is too much. How many meals a day do you eat? Three. Three? Do you think you could get away with two? Easily. Because you can eat the same calories, just reduce the window of eating.

49:49That's been shown in many clinical trials, even in humans, to have vast health benefits. I read that you need to eat small, six small meals in order to, I mean, grow and get better. Yeah, who told you that? So much of like internet chatter just gave me. It's wrong. That's old school nutritional advice that didn't understand longevity, science. The idea was don't stress your pancreas, have a little bit of food, snack. Actually, a lot of that, I hate to admit it. When you do the research, it's marketing food companies. Breakfast is not the most important meal of the day. That's a cereal company marketing breakfast cereal.

50:33No way. It is. All my life I've believed breakfast is, in fact, I've made certain changes in the last four or five years to make sure that I eat breakfast no matter what, because breakfast is going to help me do so many things. Well, if you love breakfast, that's fine. but you should have almost no dinner in that case. What you want to do is have a period of fasting, so no food. So you can sleep. You're not eating when you're sleeping. Yeah. But if you're eating first thing in the morning, then you'll want to finish eating in the early afternoon so that you get that big stretch of no food. Why?

51:12Because it's going to do this. It's going to turn on our anti-aging natural defenses against DNA damage and this epigenetic change. If you're always fed, if your body always has sugar and protein, it's going to be in abundance mode, not adversity mode. And we know what abundance mode does. It speeds it up. What's the most important meal then? Well, it depends on the person. We have different chronotypes. Some of us like to eat in the morning. Some like to exercise. I'm not a morning person. I don't like or need food in the morning. So for me, I've been skipping breakfast most of my life. and my father, who's now 87 in perfect health, same.

51:51That's the Sinclairs. But you might love breakfast. You wake up, you're hungry, you want to eat, you want to exercise. But you may not feel hungry at night. So you can choose. But I do want everyone to consider that this old idea of eating constantly through the day and snacking is actually a marketing ploy. You know, you've just, you've just ruined my belief right now, which is I, I eat very heavy breakfast and I eat very heavy dinner lunch probably I'll skip or maybe have like small thing that's it but he's Raj we're gonna have to measure your biological age now I'm worried like the two things that you told me these are the two things which I'm doing very man you might be 35 for all we know don't don't tell me we can fix you it here's a good point that I want to make for everybody if you're nervous and I can tell yeah I just hit a nerve Yeah.

52:46It's never too late. We have really good protocols now to slow down aging and soon to be reversing it, I believe. So don't worry. It's never too late. And you're very young, so you'll be fine. I do want to stress, though, something that a lot of people don't think about is we mentioned that we're getting DNA damage all the time. Now, there are other things that can accelerate aging as well besides DNA damage. Since we published our work in 2023, we and others have shown that any major damage to a cell can accelerate its age, not just DNA damage. For example, if you pinch the nerves like we did for the eye, those nerves got old very quickly by years.

53:31Within days, they went years old. And that's in a mouse. So that's like 20, 30 years in a human. I think that every time we go to a rock concert and we're blasting our ears, we go home with older ears than when we went to the concert. It makes sense, right? Because now when you get to 60, you're losing your hearing. Why? Because your ears have gotten older faster than someone that lives in the countryside. What I think is happening is every time we stress a cell beyond what it's capable of handling, these proteins that control the epigenome the the genetic readers they move around to help repair the problem and they don't all go back to where they came from and so if you could make sure that this structure here stays stable and not unravels anytime you could live hundreds of years in fact and that's why whales live hundreds of years we think is they stabilize this structure Whereas we humans, we're damaging ourselves and they fly away.

54:32Some animals only live a couple of years and some only for a few days. And so in a mouse, if you damage the DNA, these structures just fall apart. They're not very strong. It's easy to actually damage a mouse cell. And if anyone has seen me at a rock concert, I've got earplugs in. If I'm walking down the street and a loud noise, I now have my fingers in my ears. I know I look stupid. Like, why is this guy? It's just an ambulance but I truly believe that these loud noises do age you particularly your ears and you know what you get if you drink a lot of alcohol or smoke you get you get cancer and other issues I don't smoke or I don't drink so that's I'm safe there I love that well then I've never tried all of that then you're probably younger than than your actual chronological age we call it so that's good you're doing all those right things now now we just need to reduce your number of meals down to two and you'll be good.

55:27Okay, let's go back to fasting. Actually, we deviated. Yeah, you were telling me about fasting. Yeah. Yeah. So what I talk about on my podcast is how to practice fasting and it not be a real problem. What most people do is they say, I'm going to stop eating for a day and see what happens. Then they say, this is too hard. I'm hungry. I can't think. I've got brain fog. That's the wrong way to do it. The way you would do it is, let's say you love dinner, but you want to stop eating dinner or just eat early. Don't stop eating immediately. Just have a smaller meal each day or eat something that's filling a lot of vegetables and fill your stomach up with tea instead.

56:08If it's at night, not caffeinated, but perhaps some hot water. Serena and I are always with water, hot water. We just got off a plane from Tokyo. We were always saying we need hot water. We want hot water because it's not just healthy to drink and cleanse out your blood, but also it fills you up. You don't feel hungry. So that's one hack for fasting is to fill yourself up with liquids. Another hack is to do it slowly. And then another hack actually is just get over it. You might feel a little bit hungry, but so what? It's not going to kill you. I've been able to fast for, I went without a meal really for two and a half weeks.

56:53Fairly recently, last month I did that. And yeah, there were times where I thought, yeah, I should just go to the cupboard and eat everything that's in there. I wanted to. but your mind is very strong. Everybody has that power to resist going into the fridge. It's not easy. We all want to do it, but you have to think, do I really want to achieve this or am I going to give in to my animal instincts? That's one of the keys to fasting is don't give into that quick fix. It's worth it. And if you fast actually for over three days, then you start to get into this new phase called chaperone-mediated autophagy.

57:32Have you ever heard of that? Never. All right. So autophagy is autophagy, self-eating. And our cells are always eating themselves. When there's a damaged protein, let's say this thing unfolds or gets too many of these attached in the wrong place, the cell can detect it and send it to be destroyed and recycled. Proteins will get turned into amino acids, amino acids rebuilt into protein. That's autophagy. It happens all the time, but it happens much more when we're hungry. And it happens even deeper cleansing after three days of not eating. And that will get rid of the really old crappy proteins.

58:13So these days, I try to do a three or a five day fast, probably once every few months, partly for autophagy, partly because it helps me - Drink water. Stay the same weight and live life well. And drink water. So for three days, you drink only water. I'm definitely drinking all the time. If it's a strict fast, I won't eat anything. If I'm going for a few weeks, I will eat some vegetables, small amounts like a carrot, some celery. But not a lot. Not a lot. Just enough food to fill my little tummy up. But I feel great. Actually, once you get past three days, you don't feel hungry anymore. What happens is remarkable.

58:57Have you ever fasted? No. It's really amazing. And I can tell you, I'm not good at fasting. And in fact, I don't have a lot of willpower. If I can do it, most people can do it. I decided to try it. I was actually doing it before a podcast. So I could say on the podcast, I did it. After the third day, something remarkable happened. And I went from feeling a little bit hungry, a little bit tired to, wow, my brain turned on. My body was making what are called ketones and the brain loves them. They fuel the brain. So I was super awake. It was like taking a few shots of caffeine. I was also more energetic.

59:41I wasn't tired at all. I woke up every morning. I was feeling great. And so I love that feeling. So when I fast, I'm actually looking forward to getting into that state again. But most people don't get there. After the second day, they're like, oh, I can't do this anymore. Or, you know, I'm going out to dinner. I have to eat with my friends. That's also the hardest problem with fasting is we're social animals. I do find that. And when I'm with Serena traveling, she's a trained chef, actually. And so we do like to eat really well. Every time we go to a new city, we eat at one of the top restaurants.

1:00:15but when I come home that's my recovery fasting period and the clean out autophagy process you know in India in a lot of in India a lot of small communities and cultures they have a practice around fasting and a deep rooted religion it's so wise they knew it was healthy you know the problem that I've seen perhaps not in India but in the Middle East because there's so much food, they eat late at night after the daily fast, but they eat so much. They eat probably twice as much as normal. So that counteracts probably any good that they get. But if you fast and you don't overeat, I think the health benefits are really huge.

1:01:04And there have been studies of caloric restriction and fasting in humans. And I think actually the The best way to rejuvenate yourself and feel better and even get younger is to fast. Yeah. Once a month. I would say at least once a month. I would say every day you could skip a meal. And fast for how long? What should be the break between? There's a few different versions. And again, on the podcast, I get into it. There's one that is very popular in Australia called the 5-2, which is you fast for two days and eat five. It depends what you can do. In terms of a daily window, you try to fast for 14.

1:01:51If you can do 16 hours, it's great. I try to go for 18. But it's not that hard. If you sleep for eight of those hours or seven, then it's really just skipping a meal and having a late lunch, skipping breakfast, late lunch, or having a late lunch and not eating till breakfast. that's that is the way that i think is the healthiest is to do it every day not just once a month and would you consider a morning smoothie or a morning protein or morning whatever a breakfast as well yeah but i'm not as strict as most people well so i i've measured myself over the years this is all scientific right so i'm not just making stuff up um like some people do i've found that having small amounts of food, particularly if it's not carbohydrates, it doesn't break my fast.

1:02:42So I've been having, with resveratrol, mixing it with a bit of yogurt, vegan yogurt now. I used to have Greek yogurt. That doesn't break my fast. If it's a little bit, it's okay. A little bit of olive oil, that's okay. But a real smoothie, that's loads of calories. That could be 600 calories right there if you put a banana in there. So that's a meal there. I'm vegetarian so I think I'm not very concerned about my meals because I eat vegetables all the time that's all only once once in a day I would eat like bread or rice and other meals it's just the vegetables or protein yeah good now I'm going to get a lot of people hating on me because people love the carnivore diet I just want to say carnivore diet can work great it has seemingly improved health of a lot of people, lost weight.

1:03:33What I'm saying though is long-term, by the time you're 90, I think that it's not as beneficial as a vegetarian or a vegan diet. If you're going to do something, you don't need to do it every day or every hour. Do it for a couple of days, then have a rest, do it again. And that way you can get the benefits of exercise and protein, but also this adversity, hunkering down, survival mode. I think that actually probably works the best because your body gets the chance not just to hunker down and slow down, but gets some time to heal as well and grow fast and fix things. Got it. Have you heard about water fasting?

1:04:15Yes. Like seven-day water fasting actually repairs a lot of stuff, stuff like that. Yeah, there's a lot of good evidence. I believe in it, yeah. What does a seven-day water fasting would do? What would it do? What would it do? Well, it activates this chaperone-mediated autophagy CMA. It'll also activate these repair systems, probably rebuild your epigenome. It also raises the level of a molecule called NAD, which the proteins that we study called sirtuins, they need NAD. So by being hungry, you raise your NAD levels and these now become super active. So it's another hack is to get your NAD levels higher.

1:04:57What is NAD? I'm glad you asked. NAD is one of the most important molecules for life. There are two molecules that we cannot survive without for 10 seconds. And we're full of these two chemicals. One is called ATP, which is chemical energy. If you take cyanide, you stop making ATP and you're dead. Okay. You need ATP. The other one, which is more of a machinery reaction, chemical reaction mediator, is called NAD. NAD, the full name, if listeners want to know it, nicotinamide, which is vitamin B3, fused to adenine, actually part of DNA, dinucleotide, anyway, NAD. You don't need to remember the full name, but NAD is in our bodies.

1:05:49And when we exercise or if we're fasting, we do get more of it. So for the last 10 years, I've been working with teams to test if boosting NAD levels in humans gives health benefits. As a theory would predict, it should use these proteins to repair DNA and do other cool stuff. And the answer is yes. We've published. well my colleagues have published and i've been fortunate to be part of that group number of harvard studies people could check them out they're online raising nad levels reduces blood pressure lipids cholesterol um and what was the latest um oh it's not published yet but there are some benefits to cognition as well but this molecule NAD is being tested around the world in different studies, Alzheimer's, kidney disease, heart failure.

1:06:44And those studies are just finishing up this year. So that's another reason why I'm optimistic that something big is going to happen this year. So what I've said just to summarize is we've got ER100 to reverse aging, but we've also got this other molecule, which we call MIB626, which boosts NAD, which can slow aging. And slowing aging is important until we get the age reversal worked out. And this is the supplement or this is the thing that you were telling me that you take after the long flight? Exactly. So we don't take NAD because NAD is a big molecule. You know, I told you all the components.

1:07:24If you eat it, it's not going to get absorbed easily. so we take a piece of nad called nmn okay so this nmn which is nicotinamide mononucleotide not dinucleotide one mononucleotide it can be swallowed it's absorbed we know that it raises blood levels of nad by twofold in most people um and that is what i've been doing for at least 13 years in the hopes in the science that we would see a slower aging because of that what see we're talking about aging we're talking about damage but i was reading that a child's repair system is much better than an adult's for sure yeah so what's what happens why a kid is able to actually repair themselves with all these damages, all the things.

1:08:24Let's say if a kid doesn't fast or the kid doesn't run or kid doesn't do anything, still he's been or she's been able to actually repair all these damages. But I'm not. Or like as we age, we are not. That's such a good question. And the best questions are the obvious ones, you know, but we don't talk about them. Why is a child so good at repairing? Yeah. Why doesn't a child get Alzheimer's disease? Why don't they get heart disease? Yeah. You know why? Yeah, even kids have lower rates of cancer as well. Like, why? Like, these are the same things which happens to all of us. Okay, here's what I believe to be the truth.

1:09:05Their epigenome, which controls the genes, is optimal. Every cell knows what it is, what it should do, and can do it. But starting even before birth, this process of aging starts to happen, and cells eventually forget how to be optimal. And that's what we see as aging. It's what we see as diseases of aging. But we start out optimal. And ER100, the drug that we're testing, is designed to get us to go back to that optimal point where we can heal pretty much anything so as i'm getting older these things in my body are forgetting and they because they're too many so they don't know where to go what was the original place to go is that yes they your cells are forgetting which which piano keys to play which genes to turn on because these these are the these are the piano players yeah they're getting lost and they're not hitting the right keys anymore and the beautiful music of our youth becomes a terrible noise a cacophony of terrible music but then the question is can you play it again beautifully and heal like a baby again see and this is there in every organ right so every organ is like now operating in a different system can i find out which organ or which specific place where they are damaging more in your body yeah yeah we can read it we can see like specifically you can find out whether my heart is older or my brain is older or my immune system i don't know yeah what all is possible and what all is not possible for sure we could do what we do to the mice to you but it would just require a sample if you give me a tissue sample i can tell you how old your tissue is now that's easy i can take your skin from your mouth i can take your blood taking your heart tissue is a little harder but from a cheek swab we've actually found and it's been published that using a test that we developed partially in my lab the signature of the cells in your cheek also have a signature of how well your heart is aging or not it's crazy right?

1:11:25Yeah I don't Why? We don't know but there is that signature of different organs in the mouth and it might be because there's a memory of how you've been living, right? If you've been fasting your whole life, which you haven't, your cheek cells would tell you, we have a memory of that. If you've been smoking, you haven't, thank God. There is a memory of smoking in every one of these cells that we measure. And actually my friend, Steve Horvath, who invented this clock, he said that the clock is much more accurate than people's memory of smoking. I think most people are in denial, but anyway that's that's that's an aside we can there are surrogates for different tissues in the mouth so what i think will happen in the future is you'll give a sample of your cheek or your blood to your doctor and you get back a a picture of yourself saying this part of your body is old this part is young we need to target this part interesting wow pretty fascinating and And if I get to know that my heart is old, okay, and it has aged.

1:12:37Yeah. Is it because of some disease, which is why it's aging? Or is it because it's aging, that's why I'm getting a lot of diseases? It's mostly the second one, that because you're aging, you get diseases. And if we can reverse the age of that diseased tissue, the disease goes away. We know this from studies in my lab and others. if you give a mouse Alzheimer's disease, dementia, and you make the brain young, the disease goes away. The body can cure Alzheimer's if it's young. That's why young people don't get Alzheimer's. We have to think about that, right? But yes, the answer would be, we think that the reason that organs get diseases is because they get old.

1:13:22But you are right also that diseases can accelerate aging. If you genetically have a problem with your heart, it can age faster. And some people have diseases that accelerate aging in all tissues. Have you heard of progeria? No. There are progeria diseases which accelerate aging in essentially the whole body of the child. And a teenage kid can look 80 years old. And we actually, we made the same mice in the lab. We have mice that look old rapidly, like the ones that we cut the DNA. But they're the same mutation in the mouse as in the human patient. And now what we're testing is, can we reverse the age of those mice to make them young again?

1:14:08And if that works, then there's hope for these children. Can one organ, which is getting older in my body, can make my entire body older? Or can make all the other organs in the body old? That's so fascinating. all well i wouldn't say all but most of the tissues and organs are talking to each other and one old tissue can accelerate aging in other tissues i'll give you a couple of examples one is if you implant old fat into a mouse or maybe a rat a rodent okay it will make the rest of the body old. The age spreads from this one old part of the body in fat. And all of us, my age in 50s, we have old fat.

1:14:58We can actually stain it. There's a color we can stain it. Your fat is probably light blue. I don't know. Let's imagine a light blue. No, that's more like my fat. A 90-year-old would be super dark blue like this Velcro, almost black. So we can measure that. Anyway, those cells are secreting inflammation molecules called inflammatory cytokines, and they age the rest of the body. The second example I want to give you is if you accelerate aging of part of the brain called the hypothalamus, which is at the base here, that's a part of the brain that communicates to the body with lots of different molecules, hormones.

1:15:42If you accelerate the aging of that tissue, the body gets older but here's the cool thing if you keep it young it makes the whole mouse young and the mouse lives longer and how do i keep them young adversity well yeah like i said don't eat as much exercise all that i think that polyphenols are a very good way to keep your brain young the other thing that i do which i don't talk about a lot so let's talk about it now okay between friends no one's no one else is listening right the blood flow by the time you get to my age there's always a loss of blood vessels of course you know i've got an aorta that's still flowing well or i'd be dead and i measure it all the time here i get it not all the time but every few years i measure this with an ultrasound my carotid but what we forget is that all the tissues are filled with microscopic capillaries or capillaries, as we say in Australia, those become less numerous as we get older.

1:16:44So you can think when we're young, blood's flowing easily, but when we're older, it's pushing it hard through. There's not a lot of gaps. It's one of the reasons we're not fit when we're older. The blood just can't get through. And if you are obese, one of the things that I do, besides try to exercise aerobically, which I should do a lot more of, but I'm on plane a lot of the time. The other thing that I do is I take a small dose of a erectile dysfunction drug. I won't say the name, but you know what I'm talking about, right? ED. I'm not taking it because I have problems with erectile, with erections.

1:17:24I don't have any dysfunction, but it does open up blood vessels. Certainly it makes them more flexible and you get better blood flow it's the reason that it works down there but it doesn't just work there blood vessels yeah and allowing my tissues to be filled with more oxygen and the reason i mentioned that is that a lot of the problems in the brain especially are caused by a lack of blood flow do you think tracking blood flow can actually be helpful for anybody yes the brain blood flow well if you can track it. It's not easy. But yes, I think I've had it done with an MRI. You can measure that.

1:18:04I think if it was available, it would be worth doing. It's very important to maintain healthy blood flow. And one of the things that I attribute my father's health, mental health, is that he's done everything he can to maintain a healthy cardiovascular system. Yeah. Interesting. So the friend I was talking, you're talking about the entrepreneur friend, in india who's trying to solve this yeah right i ended up meeting him and he's he's he's built this device called temple which is now they're trying to actually measure the brain blood flow that would be very useful i would love to try that and we could even see if fasting helps and polyphenols help ed drugs should help yes but all of that's that's great and uh we could see using this temple device yeah if if we're brain aging faster or not because it's it's a good indicator that's the whole bet right you know and you know it's fascinating like every time i do these exercises which you were telling me right now on the device on the app i can see my brain blood flow going up so every time i'm in sauna or every time i'm doing the i'm running like like crazily that it just grows really it just goes up and then when i'm laying down i'm doing my breath work i'm lying i'm doing nothing and it just like it's you can see all the things that you were talking about you can see your brain blood flow actually increasing amazing now that that'd be very helpful because like i said right now it's expensive mri not most people can't do that or afford it but if there was a cheap way to measure it i'd walk around with it all the time we were when we were talking about this you were also telling me about entropy Yes.

1:19:47What is entropy? Like, tell me, and why is it becoming such an important conversation all around the world? Well, there's different types of entropy. What is entropy? Well, people even disagree on what entropy is. Okay. At its fundamental level, it's information. But what most people teach it in college is that it is disorder and order. And the more entropy, the more disorder. Though if real professionals disagree with that description, it gets the fundamental, it's information and informational noise. But the reason that's important in my field, in many fields, including AI, but in my field, this is ordered.

1:20:34A young cell is ordered and has pristine information, right? All the information is there. Now we're doing some aging, right? Now we're 57 years old, unfortunately. This is loss of information. It doesn't remember how to be like it was when it was young. This is increased entropy, is disorder, a loss of information. But the question that I had in 2014 was, is there a backup copy of this information? Is it possible to reverse entropy? of course, it requires energy. You don't just circumvent the second law of thermodynamics for free, but we can eat, we can get energy, and maybe there's a system, a memory of how the cell was put together, the DNA wrapped up from 30, 40, or in my case, 50 years ago.

1:21:32And that was Won Cheng's PhD thesis. Can he find a way to get this to go back? Is there a memory of that? and I think we found it, that it exists. There's a backup copy of the original state of the cell. Where? Now that's the question that we're trying to answer in my lab right now. Where is that information stored? But every piece of information from 30, 40, 50 years is stored. It's somewhere there. We believe so. It's new biology. We're looking at it, we think we've found evidence that there's new structures on this original molecule that tells the cell this gene should be wrapped up tightly and this other one should be opened up, like when we were young.

1:22:19And that's sitting in every old person. So now when I see an old person who's frail, can't cross the street, well, I don't see an old person. I just see someone that needs to be reset. Someone just who's forgotten how to be young again. Yes, but inside is a young person, just needs to be switched on again. Can you do that? Can you switch it on? We do it in my lab every day. And if someone's been switched on for a long time, is it bad for them then? We don't think so. That's why the FDA gave us permission. We did a lot of safety studies in the monkeys and in the mice. For years, we looked at this.

1:22:55We haven't seen any negative issues so far. Cross your fingers. We have to be very careful because we are playing with very strong technology, powerful technology. But we wouldn't have started the clinical trial if we thought there was any risk to the patient. I'll give you an example. We've published that if you turn on those three genes in the eye at high levels, not just for two weeks, three weeks, we did it for six weeks. If you leave it on for a year, even up to 21 months, there's no negative effects. In fact, the longer you leave it on in the eye, the better the effect, the vision gets better and better and better.

1:23:41And here's the thing that I love in that paper that we published on glaucoma. If you turn it off, and we have ability to turn it on and off, right? We actually just give the patient a pill, it turns it on. They stop taking the pill, turns it off. It's the world's first regulatable gene therapy, by the way. But we did this in mice. We turn it on, cured, or at least improved vision, turn it off. Okay, what happens? The disease comes back, or aging happens. They lose their vision now for the second time. Now we do a cool experiment. We turn on the genes again. What do you think happened? You saw positive results?

1:24:22We can do it multiple times. Now, I would have wanted to turn it on three, four, five times, but the mice got old and they died. But they died with very good eyesight. So what this tells me is that this can be turned on many times. So imagine a future where we have these genes in our body that we can turn on with a pill. We just take a pill for a few weeks, every few years, and we just go back in time. That would be so cool. That would be so amazing. But essentially you're telling me that most of the old people are not old. They've just forgotten that they are a young person inside and you just need to switch on that thing.

1:25:05Does that mean for every part? Like even for, let's say you said spine, right? Spine is very difficult to do that. do you do because spine degeneration is one of the biggest problems in the world right now because we all are sitting like i have it oh you do oh no it's like my my l4 l5 s1 is just it's gone there was a recent study that came um out of china actually but and it was done very well they injected these three yamanaka age restoration genes into a joint of an animal um it was a mouse that had osteoarthritis okay all right i think it was the leg it wasn't the spine but still yeah it's a good model the uh cartilage regrew so i'm excited about testing this in human patients back injury sports injury or just old age wearing out wouldn't that be good instead of putting stem cells in there to try and fix a little bit yeah we just give you a young new joint it grows again true but with your thing yeah can those pills can that switch it on my degeneration and stop that as well well i i would be optimistic given this study that we've just talked about we'd have to test it so the way we would do it theoretically we'd need fda approval but we could take er 100 and put it into your spine um and then we would give you the the pill and we would do an mri and see if your spine regroup i mean that's what we're doing with the eye right now yeah if it works in the eye it's gonna start we should talk absolutely you tell me when i think okay another thing is about immune system yeah people who have a weak immune system they age faster and what's there is it because i'm doing all the bad things that's why my immunity is weak or my immunity is weak and that's why i'm like what's the correlation There are a few possibilities.

1:27:25It's not fully agreed upon by scientists, but one is the immune system can be overactive and secrete inflammation factors. And having a lot of inflammation, like IL-6, IL-1 beta, these can accelerate aging because the inflammation is just bad overall. We know that. The other thing that can happen is if your immune system is not very active, it's the opposite. It can actually not destroy old cells. So some old cells, like the blue ones in my fat, they're called senescent cells. Okay. Have you heard of senescent cells? These are, some people call them zombie cells. Okay. The reason they're called zombie cells is when cells divide, they're young, they're healthy.

1:28:12But when they get really old, either because their epigenome is unraveled and they're confused or the ends of their DNA gets too short, they run out, then the cell has a signal, stop dividing. Then they just become a useless zombie cell. Actually, they're worse than useless. They start putting out inflammation factors. It's called SASP. Anyway, it's well known. And we know that if you put senescent cells into the fat, like I was saying before, it makes you age faster. And your immune system is clearing out these senescent cells. And in fact, there are companies now working to give vaccines that will help the body kill them.

1:28:57But that might be another reason why if your body's not good at killing these senescent cells, then you would age faster. Coming back to the aging part, right? do you when you were explaining me about immune system and going these things yeah right i had this very basic question which is what's what determines whether in my future i'm gonna age faster or slower is it the pace of my aging is it my current scenario what is there in my body right now already or is it my psychological or physiological resistance that i'm fighting my whole body is fighting towards that aging and all these things what is the biggest like determiner or what is the biggest contributor the biggest contributor to your rate of aging is your environment and how you live your life um it's it's debated somewhere between 80 to 50 % of your future health and your rate of aging is how you live, how you live and how your body composition, right?

1:30:10If you're lean in good shape with lots of strength, you're going to age, probably age slower than someone who has let themselves gain weight and sit around. But some of it between 20 and 50 % is you're just born with that. There's not much you can do about that part. That's what you get from your parents. But the good news is at least half, maybe more, we can change that and we can slow it down by living the right life. Now, some changes take decades, right? Taking resveratrol, you're not going to suddenly get younger tomorrow, despite what some cosmetic companies say. So there's long-term things and you have to have some faith.

1:30:52But some things are quite quick. You see them quickly. So I switched to a vegan diet when I met Serena. It's about five years ago. I gave up wine. I gave up most meat and didn't eat as much calories. And I noticed really within days, I felt better. And then I did my blood work again. And after a month, my inflammation levels went way down and I was healthy already. There's an inflammation marker that everybody should get measured called CRP, C-reactive protein. Doctors usually measure it as a predictor of heart disease, but it's a good measure of overall inflammation. And my CRP levels went way down.

1:31:37The lower, the better, actually, with this molecule. And that was quite a quick effect. It didn't take decades to see the benefits. So we spoke about, in terms of benefits and changing your lifestyle, We spoke about fasting and we were speaking about exercise, but then we developed into other things. So in exercise, the running part is better or the strength training is better? Oh, gee. Well, I would say both, unfortunately. There isn't one that's better. They do different things. But I would say if I could only do one thing for health, it would be aerobic exercise. It would be losing my breath for 10 minutes, three times a week minimum.

1:32:20how much do you do very little let's just not go there yeah well I can sympathize because it is tough when you're as busy as you are it's hard to fit it in I do once a week for sure oh good you do lose your breath yeah I lose my breath at least once a week but I lift weights or at least do some of that for like two to three times in a week good well Well, lifting weights is important for other reasons. It's not going to massively change your blood flow, but it is going to help you with a few things. Strength, which is super important, even at your age for your back and limbs. Most people my age have a shoulder issue.

1:33:07And if you're older than me, let's say you're in your seventies or eighties, if you don't have muscle strength, you can fall, you can break bones, you can even die from falling so you do want muscles but at your age if you're in your 20s and 30s the biggest effect besides looking better is that you'll have better metabolism you'll be burning more energy so you can eat a little bit more enjoy life a little bit more but also it's very good for maintaining hormone levels you were when you were talking about improving brain blood flow and you were what the supplement which you would take, which will expand your vessels, right?

1:33:47Do you think L-arginine helps in that? I don't know if it does. A lot of people take L-arginine for improving the vascularity in the blood. Yeah, I don't off the top of my head know how that works. It's an amino acid. It may be involved in the production of nitric oxide, which is how the erectile dysfunction drugs work. Without this gas, it's interesting, it's a gas that's produced by what are called the endothelial cells that line the blood vessels. As you get older, you don't make as much nitric oxide gas and parts of your body fail because of that. It may be that L-arginine, as I would call it, the amino acid is helpful for the production of that gas.

1:34:36Though I'm not an expert, so I have to speculate um but there are other things you can do you can take nitric oxide boosters for instance beets have nitric nitric oxide you've heard about beets yeah now that i don't take that because typically it comes with a lot of sugar i regard sugar as like a poison um occasionally i'll eat some candy but i don't eat a lot of carbs and sugar i try to avoid it as much as possible why everybody's just like so anti-sugar i understand i understand what's going on and understand it's a poison and i absolutely the days when i'm not taking sugar those days are like tremendously better but just like demonizing everything around it i feel it's like we're doing so much injustice at least once a month is fine or like oh yeah once in 15 days is okay yeah everything in moderation it's just that the world especially the united states food I don't know.

1:35:33India is probably the same. Everything has sugar in it, even hidden sugar. Even the Chinese soups that I order, I realized, I thought, oh, healthy Chinese soups with vegetables, grams of sugar in there. The sauces, you have to be just really careful. It's the hidden sugars. Eating a candy once in a while is not going to hurt. It's every day taking in all this sugar. So why is sugar bad? There's a couple of main reasons. One is sugar attaches to proteins, right? We talked about this protein here. This protein and every protein in the body can have sugar stuck to it and that makes it old protein.

1:36:11Actually, just recently, a few days ago, a company announced that they found a way to remove the sugar off proteins, which is great. One day we can get rid of it. So glucose on the protein is called glycation. The problem is that a lot of proteins in the body cannot be easily recycled. the ones that make up part of the skin right that the collagen that's in the skin you don't recycle that easily so that when it gets sugar attached is almost permanently damaged so you don't want high levels of sugar so i try to keep and you should try to keep your sugar levels at a low level um because it's the high concentrations that are bad that's one thing the second is that you're you don't want to be susceptible to diabetes and diabetes is pretty prevalent in India and globally.

1:36:57So that's why. But you're right, it is demonized. But sometimes I say that it's a poison to make the point, because I'm trying to counteract the other group of people that are making billions of dollars off sugar. And fructose corn syrup is up there. In America, they use it in most foods, actually, especially the sauces. true it's you know diabetes is one of the biggest reasons why I started getting healthier in my life because my parents my dad has diabetes my grandmother has diabetes it's like it runs in my family and I remember when I was I think 16 or 15 probably I went to a clinic with my dad and I was eating a sandwich it's the doctor who was there who just looked at me and he's like you know what you should stop that or else you're gonna be diabetic and like before even you turn 25 because everyone in your family has it oh yeah and that just stuck with me so either you can call that doctor a devil or a blessing because since that day i was like okay my only challenge in life became that i want to beat diabetes by 25 like i don't want to have diabetes at the age of 25 yeah i just kept beating and then that's i measure my sugar levels to the t like yeah everything i do is just to defeat diabetes in my life what is your fasting blood sugar level right now yeah i don't remember but it's it's way below it's okay yeah it's it's much okay and there's b a1c is also good i was going to mention that yeah hba1c is good yeah all right everything is great like it's it's it's better than yeah like most of the people in the world I'm pleased.

1:38:42Obviously, if you're eating a vegetarian diet, that's going to help. For those of listeners and viewers who don't know what HbA1c is, it's worth speaking about it. HbA1c is when sugar gets attached to your hemoglobin in your blood. The red in your blood gets sugar attached and doctors can measure the percentage of your hemoglobin that has sugar on it, that's your HbA1c. And the more percent is covered in sugar means you've got more sugar over a period of a month in your blood. And if you're above seven, it's bad. Yeah, it's diabetic already. Yeah, I like mine to be around five, 5.2. That's a healthy level for someone my age.

1:39:31I have the same problem my family is diabetic if they don't watch out um my father my grandmother had a stroke in her 30s it's that bad uh so I have terrible genetics I've had to also be very careful same that that makes two of us so that's what that's so that's why I keep my blood markers like every three months I'm trying to test doing a lot of things yeah and just keeping everything in check and that's good news and you have to stay alive for or healthy for as long as possible because the breakthroughs are coming there are companies now that have figured out how to replace a pancreas to make insulin really yeah is it there already out there it's not on the market yet but they're able to do it and i i think they had success in the clinic now but my my intention and my goal is to not have it at first place ever yeah they just live such a healthy life that at least I can just delay it for as long as I can.

1:40:32Yeah. And there will be a time in your lifespan where you don't ever have to worry about getting cancer, diabetes, heart disease. We're already almost there. You can detect cancer very early. You can prevent diabetes pretty easily. I mean, just looking at the GLP-1 receptor drugs and And dementia is coming down rapidly. We are at a world, especially those who have the financial resources to spend on all of these tests where you don't have to die from these diseases anymore. True, true. Now it's getting better and it will keep getting better thanks to people like you. It will one day, there'll be a time in probably next decade where we won't worry about half of the diseases that we talk about today.

1:41:20Right. Right. And even in the past 12 months, there have been huge breakthroughs and about 15 new drugs on the US market and some breakthroughs in cancer. Pancreatic cancer is now treatable. It's incredible. The progress just happening now and AI is going to speed that up. it's also really exciting to think about what's happening in my lab remember we discovered this eye age reversal about nine ten years ago since then we've continued to innovate so we now have the ability to swallow a pill give a mouse a pill and reverse its age and rejuvenate it and we're working on getting it into humans to see if we can do this without an injection, just by swallowing something.

1:42:07How much of AI is going to help you? A lot. We've been using AI for a few years now. One way we use it is to use a camera to see whether an old cell has been rejuvenated. Using a camera, we can look at millions of cells and say those cells were 90 years old and now they're 20. That's AI. But the other thing that's even more impressive is we can start with a trillion molecules, theoretical molecules. It was like resveratrol, but trillions of them. And then instead of doing each experiment at the bench in the lab, which would take hundreds of years, even with robots, we can do it virtually. And AI can look at a target protein, and we actually know what the targets are that we want to reverse aging, and say, which of these trillion will reverse aging?

1:42:57And it's given us a few hundred to test, which we're testing right now. Interesting. And now, and what, give me in basic language, simple words that if you wouldn't be using AI, how many years it would have taken you to do exactly what you're doing right now? Well, I asked an AI model to estimate this and it did all the calculations and it said in my lab with, let's say there's 20 people working, it would have taken 160 years and over a billion dollars to do what we did for, it cost us about$20 ,000 and a few months before. Wow. And that was a few years ago. Now you don't even know. Now it's probably, you could do it on your phone.

1:43:49And it's going to get to the point where anybody can design a drug using their phone. We're almost there. The hard part, though, is taking the chemical that's been designed by the AI and put that into humans. And all of that's hundreds of millions of dollars, which is why, unfortunately, I think these claims that we're going to cure diseases in the next few years is wrong. Because finding the design of the molecule is the easy part. Remember, we've done this many times in my lab. it's making them work and testing them that's the slow part because that involves humans, the government regulation, money other mafias well we face a lot of competition so my company Life Biosciences which is leading some of the competitors are Jeff Bezos, Sam Altman and others they've put billions to try and catch up with us.

1:44:48But the good news is there's not just one winner. It's a whole big industry that will come. And there are lots of diseases that can be tackled. Do you think there's a pharma mafia? Oh, tell me a bit more what you're thinking. No, I'm asking you, what do you think when I say this? So I'll tell you what I don't believe. I don't believe that pharma companies, well, I hear this sometimes, pharma companies don't want me to be successful because it will put them out of business. Everybody that I know at pharma companies wants to help people. And if they see a new area of science, like what we're doing, they'll do it too.

1:45:26And in fact, a lot of large companies, pharma companies are working on age reversal now. So they're jumping on it. They're not trying to stop it. Are they banding together? I don't think so. I think that they are competitive. But I have seen really bad tactics against my lab, against my companies from certain pharmaceutical companies. Like what tactics? Doing poor science that was wrong to invalidate patents that we had filed. And these stories get into the newspapers and the journals. One of them is the resveratrol story. We published that resveratrol activates this enzyme, SIRT1, which is true.

1:46:14It's all been proven now. It's not disputed. But one company, I'm not going to mention because they're one of the most powerful companies in the world, put out a paper that said Sinclair's work is totally wrong. It invalidated. They tried to invalidate our patent. And it caused a lot of problems. I couldn't get any money in my lab for years. my lab dwindled down to just a few people hanging on for dear life. I almost was put out of business as a scientist because a large company and the newspapers and even the world's leading scientific journal believed that I was wrong. Even my university, I'm at Harvard, right?

1:46:56I had a group of people come into my office and quiz me and say, what's going on here? It was really bad. I stayed in bed for a week. I was so depressed. I thought of quitting. It was rough. And to this day, people still think that I was wrong, but we've been proven right since. But that was really bad tactics that they used. And they've still not either publicly apologized or said that they were wrong. And what kept you going then? because what I'm doing is bigger than me. What I'm trying to do is to give everybody a healthier life. And if I have to suffer as a consequence, I'm prepared to do that.

1:47:38I'm prepared to die for this cause. It's really that important to me. So having a little bit of trouble in my life, that's okay. I was a little bit depressed because I felt like the world was ungrateful, but I got out of bed, I went back to the lab and we just worked harder at trying to test the theory and see if we were right. We did turn out to be right. But what I learned from that episode, which was 2010, is believe in yourself, do great science and don't get discouraged. Just keep going. And that's a lesson that everybody in life should have. Because if you do something important, there will be critics.

1:48:20There will be people in the media They're telling you that you're not good. And you will face problems. It's not going to be easy. But you have to expect it and have a very thick skin and not take it personally. True. Yeah. I think it was Benjamin Franklin or one of the founding fathers that said that if you don't have enemies, you're probably not doing anything important. Yeah. How about you? Do you have critics? Of course. Really? Of course. Very, very few though. Yeah, good. because I'm in probably a good green zone. Well, you're also a very kind and honest person. But yeah, anyone who has fame will attract these critics.

1:49:02Absolutely, absolutely. There will be thousands of people who would not like, you know, just this part as well. Like there will be people who will be like, hey, why did you question about that thing? He was wrong and you just listened to him. And then they just bash me and call me that I was soft on you. And then there'll be people who would just call me and say, oh, you were clueless in front of him. And then there'll be people who will be like, if I do come very well prepared, do everything right, understand your scientific theories as well. And then I ask you on that, then people like, oh, if it was only about science, you would have done it in some journal.

1:49:37Why are you making podcasts about it? So it's like, no matter what you do, there'll be critics who will just, you make it at once, you make it curious, you make it dumb. In all three, you'll face critics. So it's okay. Yeah. and the lesson here is just keep doing your best be honest be authentic and you'll be okay yeah and but the work that you're doing i've i was i keep reading like almost every year it just appears some or the other place some quote like this where it says that anyone who is inventing anything new gets ridiculed by people of that generation oh yeah and only the next generation actually you know starts reaping the reward then they become grateful like people who were peers and colleagues of edison they ridiculed him right and now because of him we are doing all of these things and the desert so well i'm saying this is getting riddled then who are we right you have to expect it and people don't like change um they certainly don't like Were you experiencing this?

1:50:41Oh, yeah. It's been rough. The most vicious attacks are from my scientific colleagues. The public is generally very supportive. It's the scientists, but it's a scientist's job to criticize other scientists. That's how science progresses. There's nothing wrong with cordial, professional, gentlemanly, gentle person arguments. Fair. So all of these things, do you get stressed because of all of these things? I used to. Yeah, definitely when I was your age, because I hadn't made it yet. I hadn't reached my goal. I hadn't done everything I wanted to do. I'm now at a point in life where I've already achieved more than I thought I would in my lifetime.

1:51:31So everything else is a bonus. I have three wonderful kids. I have a wonderful partner. I have a great job. I get to have fun talking about my work. And I have really smart students who do the hard work. They're back at the lab today, working hard on a Sunday. I don't get stressed. And my heart rate is in the 40s, usually, at night for sure, during the day, maybe 50. And my heart rate variability, which I think you would know you want a high heart rate variability it's in the 90s which is like a you know a marathon runner yeah it's great and i think that's because of my practice which is to never get stressed nice see this is what we need to promote as well we need to get a lot of people to go india and then promote the indian wisdom like the indian ancient wisdom they figured it out Oh, they did.

1:52:29The food, the relaxation, the meditation. The routines. There's so many things which are yet to be discovered by the world. Well, it's the world's oldest religion as well. It's one of the oldest cultures. It's the oldest civilization. Yeah. So, of course, they figured it out early. Yeah. We're still catching up. And actually, some of the medicines, so Ayurvedic medicines, there's a lot of truth to that. And we're just finding the molecules that are working in those ancient medicines from the plant world, mostly. True. And you're a big, you promote plants a lot. So, of course, you would like that.

1:53:07You like a lot of Indian wisdom as well, I'm sure. Okay. Tell me, we were talking about stress. Is aging partly accumulated stress? um it is in the sense that when the cells the body gets overloaded with stress too much a little bit is good but if you go too far then these processes that drive aging happen faster but we have to be careful not to confuse psychological stress with biological stress explain both all right psychological stress we all know we're worried we have cortisol levels in our body, we're fight or flight mode, that is psychological stress. That will age you faster. We know that, mostly because the hormones that come out of your system are causing accelerated aging.

1:54:03That's psychological. That you can change within minutes. Right now, if we do breathing exercises, we can bring that down. That's easy to fix. That's step one. The other is biological stress. Now, a little bit of biological stress is good. Remember how I said fasting, exercise, sauna, cold plunge. These are going to activate your body's defenses against adversity. But if you do too much, if you, let's say, if you don't eat for so long that you start to chew up your muscles, that's too much stress. If you go to a rock concert, if you go out in the sun and get very sunburned, that's going to be too much for your cells.

1:54:55That's not mild stress. That's not adversity. That's serious damage. And that's going to help this process of unraveling. And we know the evidence of that. Anyone that spent their life in the sun will have experienced broken DNA from the light and that this process will accelerate. And you can even see there's a photo on the internet of a woman, I think it's a woman, anyway, a person who got sunburned on one side of the face because the sun was coming through the window of the car, the truck. And so one half is much older than the other side. And so we know that the sun can accelerate skin aging and it's the same for the rest of the body.

1:55:35Too much damage will accelerate aging. But shouldn't we be in the sun? A little bit, for sure, a little bit. Now, there's debate. Some doctors say no sun. No sun is good. In my life, I like to get a little bit of sun, but not enough to feel burnt. That's definitely too much. And I usually wear sunscreen and a hat. But yes, I like natural sun. But be aware that any sun is going to accelerate aging. And at what point this small damages becomes a permanent stress damage in my body? Yeah. All right. So that's a very good point. Let's go back to this, these balls here that I've got here. So what we, we want is this always to stay stable and in the structure and a little bit of damage, a little bit of adversity, a little bit of hunger or sauna is not going to change this.

1:56:35It's when it gets to a point where these proteins have to react and go away and fix. That's too much. So rock concert or x-rays will cause this. So a little bit is okay. And then this is too much because then these don't always come back to where they come from, for where they started. That's what we've seen. And so actually, if you if you just give a little bit of DNA damage, a tiny bit, it doesn't cause this problem. The cells can deal with it. But if there's a broken chromosome, not just a little nick, but a broken one, that's a very serious problem for the cell. If it doesn't fix that chromosome, either the cell will die or the animal will get cancer.

1:57:20So you have to fix it. So that's why it's panic for the cell and this comes apart if you break a chromosome but usually what happens with dna damage is just a little bit gets broken half of it gets broken here okay and you can easily fix that that's not a big problem but if your six feet comes apart into three feet and three feet that's a big problem that's called a double-stranded dna break but how do i know like what am i doing on an everyday basis because this sounds oh how do you know scientific like how do i know that what I'm doing is actually making me better or damaging me? Yeah. Well, I would go with the evidence, which is that we know the healthy fasting practices from human studies.

1:58:05We know the healthy sauna practices. So for instance, with sauna, you can definitely overdo it. There's temperatures that you don't want to go and you can dehydrate. But if you look online, if you go to pubmed.org, you can read papers about saunas. And those papers will tell you that like 20 minutes, three times a week is associated with less heart disease. So my point is, you don't need to know molecular biology. You don't need to understand this fully. In fact, I don't even understand this fully. So I go based on human studies, what works and what seems to work. Do you, because you're talking about sauna, did you see the new thing that you need to freeze your balls before, like when you're going to the sauna?

1:58:52Well, keep them cold. If you want to procreate. Yeah. Yeah, I would wrap them in a cold. Well, for sure. We know that sperm requires cool because that's why it's, it's a reason that's outside the body. And now I saw some videos where people are keeping a cold ice pack on their head as well. So they're keeping it on the head, they're keeping it on the balls. Why the head? Oh, that part I don't know about. I actually think that a bit of stress to the hair follicles could be good for hair. I use red light to stimulate my hair growth. But yeah, a little bit of stress on the head is good for you. But freezing the balls, you're saying if someone's going to the sauna is not putting an ice cold pack down there, then is it a problem for a long time?

1:59:39uh not long time but but in the short run you'll make less sperm if you're even if you wear tight pants and get hot down there uh it's known that you need to be less than body temperature to make sperm you know in a productive way um at my age it doesn't matter but for for men that want to have children yeah i would think it would make sense to have i wouldn't freeze them that would be worse but just a cold towel down there probably i think that makes a lot of sense let me you know when when you look at young people because you said young men right now so typically from 20 to 30 it's 10 years of hardcore hustle bad work timings toxic food just you're in financial insecurity you're in struggle like you're your these 10 years you don't know what you're doing even if you're actually very ambitious and things are going right for you you don't know when you're eating when you're sleeping what you're doing and you're perpetually alive so this 10 year of all these bad environment according to you like according to aging right can we reverse this damage We're working on it.

2:00:55We can in animals. And I think one day we will be able to reverse it. But today, we don't have it. So let's say if anyone has gone through these 10 years or is going through these 10 years of putting themselves, will this become permanent damage and they will never be able to reverse? uh no we think that all aging is reversible theoretically uh we're doing it in the eye we think it'll work everywhere but right now there's there's nothing that really reverses aging by more than a year or two it's still early early days so all these habits of 10 years they're actually damaging us yeah yeah that's why i tell young people even teenagers don't go out and party don't drink so much alcohol, don't just eat pizza, because what you're doing now will affect the rest of your life.

2:01:50But how do people stop partying? How do people stop just working really hard and sleeping for four hours? Because that's fair. Well, working hard and sleeping for four hours is pretty common. I still do that myself. It is hard, but it's the really bad habits, the over-drinking. So I used to drink every day some red wine. I don't do that anymore. I think there are a lot of young people that have stopped drinking alcohol if they, like yourself. Did you ever drink alcohol? No. Great. I did and I regret it. Smoking is the big one. Smoking has chemicals in it that break DNA. So you're going to be like that mouse that got older faster if you smoke.

2:02:38So I would say there are some pretty easy things to avoid doing. There was a study from Harvard that showed that the men who lived the longest, they actually had 14 years of extra healthy life if they just did five things. And this is what I remember. It was don't over drink, don't smoke, don't be overweight, don't stress and eat healthy. Those are what your grandmother would tell you probably yeah yeah if you just do the basics that's already 14 extra healthy years but how do you get rid of the part which is no alcohol is easy no smoking is easy yeah no well stress is such a part of your life today if you're young and living in a large city like this yeah you're stressed about financial insecurity you're stressed about ai taking your job you're stressed about what's going to happen, you're stressed about your health, you're stressed about reversing the damage with all the sugar and alcohol that you've consumed over the past couple of years and you're stressed about finding the partner, starting a family.

2:03:45You can't get, or probably if you have a toxic boss, you're stressed about that as well. How do you get rid of that? It's difficult and I was not good at it until I was 50 and this is when I met Serena. What I've learned to do is to have faith in myself. That's the key. I was hard on myself and you probably are because you're very successful. You're probably, I could do this better. I should do this better. Why am I not doing this better? Why didn't I sleep more? Why didn't I? You got to stop that. That is destructive. What I do now is, yeah, I'm concerned that my lab could run out of money. Yeah, I'm concerned that the trial might not work.

2:04:28I'm concerned that some newspaper will make up a story. Yes, but I don't dwell on it. It comes to my mind and I push it away and I tell myself, I believe in myself. I can't control what they're doing, but I can control what I am doing. And this is what I'm going to focus on. And I am older, so I have a little bit more experience that I know that I can do it. But I wish earlier in my life I had had this attitude, which is, I believe in myself and I'm not going to worry. I will figure it out. I will face trouble, but I know that I'm strong enough to get through it and I will defeat whatever comes my way.

2:05:12And that's how I live now. So I don't get upset with these things. It's good to hear. It's very difficult to practice. It is. I'm trying. It took me 50 years, but yes, try. It's so important. Your life will be completely different if you can master that. What do you think? What are the top three things that young person is doing, which is damaging them the most? Oh, well, overeating. Number one, being obese and is the number one globally. Okay. We know that that accelerates aging. The second would be not moving enough. We sit down too much. We play computer games. We're at a desk job. And then the third would be the quality of the food is terrible.

2:06:00It's easy and cheap to buy fast food. And the food is engineered to be addictive. And it's not as much fun eating, you know, hummus or lentil curry. These are not as exciting things. And I thought of plants as the side dish to meat my whole life until recently. But those are the three things if you can maintain a healthy weight. So for me, as soon as I start to build up more than that much on my body, on my chest, I know I need to get fast and get rid of it. So there's that. Then there's move, move, move, move. Just get a standing desk. Go for a walk. Go for a run. Get to the gym. Do something, anything.

2:06:52Just don't sit all the day. So in my office, I have a standing desk. I'm rarely sitting the whole day. My feet get a little bit tired, but it's great. It's very good for my muscles. My legs are strong and all I'm doing is standing. And then the third one is quality of food, fresh food, fresh colored food. You'll feel so great. Don't overcook things. I know most cultures, including India, overcook their vegetables. maintain it, make it crunchy. It's not bad. It actually tastes better. So, because you're destroying a lot of these polyphenols if you overcook it or over microwave it. So yeah, just slightly steam, slightly boil or eat fresh vegetables.

2:07:37Salad is great. All day salad. I also, I was in, until last to last year, I was exactly like you. I used to see vegetables as a side thing. It was not the main dish, it was a side dish, even though I'm vegetarian. Because I would eat like overly cooked lentil soup, which we call dal in India. So I would eat that or like vegetables, which are filled with oil and curries and like just mixed everything. And I always used to think that that's healthy, I'm eating vegetables. That's so true. There are studies that show that vegetarianism is pretty good for longevity. But what's really interesting is if you break it down into healthy vegetarian and not healthy vegetarian, there's a big difference.

2:08:27The healthy vegetarians are way ahead of the non-healthy vegetarians. So just being vegetarian is not sufficient. Give me differences between healthy vegetarianism and not healthy vegetarian. Oh, well, so an unhealthy vegetarian would eat French fries, chips, bread, and overcooked soups and other things. It's kind of winter food is not healthy vegetarian. Healthy vegetarian is, yes, salads, obviously, but also the legumes. So baba ganoush, hummus, these things are also full of protein and vitamins as well. So a typical meal for me and for Serena would be some fresh fruit, fresh vegetables, maybe a bit of olive oil, balsamic vinegar.

2:09:22And if we steam the vegetables, it's very quick, very light. So the asparagus would still be crunchy. The broccoli would be crunchy. But yeah, if your vegetables start to lose the color a lot, you've gone into the unhealthy side. Yeah, that's a good metric. if the original colors is no more the color then you've made it unhealthy you know why because these chemicals these polyphenols are the colors and they're the health so that the color disappears the health disappears interesting okay tell me the ideal protocol for a young person well how many hours of sleeping like this is the most basic thing but still i want to know All right.

2:10:06Well, I am going to say a few things, but the detail is in Lifespan, my podcast. Okay. So everyone tune into that for the detail. But the cheat sheet would be try to eat less than three meals a day. See if you can join a gym so you can lift weights. If not, get some weights at home. That's pretty easy. If your gym has a sauna, great. If you can afford a sauna, get one at home and move, move, move, move. So walk upstairs, don't take the elevator, get a standing desk, walk to the shop. These small things add up and monitor yourself, right? You have a ring on, I have a couple of rings on. I'm always looking to do better.

2:10:55more steps, lower heart rate, more heart rate variability, better sleep. Speaking of sleep, we haven't touched on that. What I've learned and Serena also taught me is it's not the number of hours that you sleep, it's the quality and you can measure deep sleep. And the amount of deep sleep you get is really what determines the brain fog in the day and how energetic you are. So she and I can go for a week with only a few hours sleep. And that's not a problem, for us because we are very efficient at sleeping. We get into sleep quickly, we dream, we get deep sleep and we wake up fresh even after just a few hours.

2:11:33Now, we don't do a few hours forever. We do catch up on weekends usually, but I do want everybody to know that you can still have healthy sleep as long as it's efficient. And some of these devices like this one will tell you your efficiency and over 90 % is typical for us. I need the sweet dreams. Sweet dreams is Serena's, we were talking about this earlier, sweet dreams is Serena's product that I take pretty much every night to get into deep sleep. And then the protocol that you talked about and the things that you talked about, is it true for a 25-year-old, 45-year-old, 65-year-old, all or do they do it differently?

2:12:17um well the exercise and the sleep um and the diet they're universal but when we get into the next higher level of detail about which supplements which medicines um then it changes over time and then we then there's stem cells and peptides and blood transfusions there's another level of complexity, which we talk about on my podcast. But I would say in your 20s, what we've talked about today is a very good start. And I know that your listener demographic is 20 to 30. So start with the basics, get those right. And then consider some supplements. The ones that I take, for example, resveratrol in the morning, NMN in the morning for the NAD boost.

2:13:07Should young people take that? Well, I don't ever make recommendations because I don't know everybody's blood work. I would say the science is strong that taking it can have benefits at any age, though we haven't tested it on people in their teens and 20s yet. So there's an unknown. But based on mouse research, which we've done for the last 15 years, it should be fine. I wanted to say though, and it's important that everybody listening knows, I measure everything. I know when something's changing. I know if it's doing good or bad and it's all done under doctor's supervision. And that's important.

2:13:55We don't want to just take something and hope for the best. And we don't want to do it without our doctors knowing about it. So I would encourage everybody to do what I do and what my father does and what Serena does is we measure things and we talk to doctors. Serena and I talk to three different doctors every week about things. That's a bit excessive because that's our life. But I do encourage people to not just trust what you hear on the internet. Research it yourself. Talk to your doctor. Take one thing. See if it works for you, measure it, look for a change. If you don't see a change, why do it?

2:14:34Fair. Is there, actually, this is a better question. While I was asking, I just turned my question. One supplement that young people should never take, which is specifically for people above the age of 40 or like under 40 or under 35, people should not take at all.

2:15:01there are medicines that people my age sometimes take for longevity. There's a diabetes drug, metformin, which lowers blood sugar. That one I think is extreme for someone in their 20s to be taking. Why? Unless you have a history like you, your body is still very sensitive to insulin, able to deal with a lot of metabolic changes. So it's not necessary. And so why take the risk with a medicine? There's another drug that's even more risky called rapamycin. Have you heard of this drug? No. So rapamycin is a favorite of the longevity field because when you feed it to animals, different types of animals, they live longer.

2:15:52but it also affects the immune system if you take too much it makes your immune system go down and that one has a lot of side effects if you take high doses so that one for me would be if you were to force me to say what not to take that to me seems too extreme and unnecessary in young people to be trying that because the risk is too high versus the reward that's my opinion um some may differ some people love um rapamycin um even i am cautious with rapamycin at my age because it has toxicities it affects the immune system um and i am concerned about the long-term side effects of this drug um the ones that i take like the resveratrol and the NMN.

2:16:44These are natural molecules. They exist in our food. They exist in our bodies. So the risk is really low and the potential gain is great. But is there any specific supplement which is easily available and people are taking right now and which we should not take? Shouldn't I see what you mean as a supplement that's out there? Well, there is some scientific debate about one particular supplement. It's an amino acid called taurine. And there was one study that gave taurine to mice and they lived, I think it was 15 % longer. So I started taking taurine and didn't see much benefit to me based on my blood work.

2:17:24And then a study, I think it was last year, came out and found that there was no decrease in this amino acid in older people. And so I've stopped taking it for that reason. So I think if people are taking high dose taurine, they should look at the science and make a decision for themselves. Is there a point where someone could get obsessed with all these longevity tools and protocols and at what point it is detrimental for your body? It's actually damaging, not helping. Like you're waking up certain point, you're tracking this you're tracking that you're doing cold plunge you're doing sauna you're doing eating you know how you have these ninjas yeah i mean there are definitely people who obsess about it yeah i don't know if it's overdoing it but they're obsessed for sure i'm not in that category i'm a scientist and i do it for a learning exercise i want to learn i want to teach and it's also enjoyable it's like a hobby so i think that if you read up about it You become knowledgeable about it and you follow, let's say, follow me on social media.

2:18:34It can become enjoyable. It's like something that you do as a hobby. But hobbies can become detrimental if you become obsessed with anything, right? You can collect a few cars, but if you want to spend all your money on cars, it's detrimental. Same with longevity. If it is taking too much of your salary, too much of your time, if you're taking too many supplements at once without testing them on yourself, then you've gone too far. I'll tell you, for me, I have a bag of supplements that I take with me on my travel. I've worked with these and tested them on my body for some of them for over 15 years.

2:19:14And it's like a symphony of supplements. I know what I'm taking. I'm at a point where I've adjusted my life and I know what to take and I'm happy with it. Occasionally I try something new. Occasionally I stop taking something. So I think that's a healthy way to exist is you do it for fun. And then if I skip it or I forget my supplement, I'm not going to worry. If I eat some meat, I'm not going to worry. If I have breakfast, I'm not going to worry. But it's the consistency. I've been taking resveratrol almost every day for 15 years or more. I've missed a few days, but it's consistent. Exercise, walking, all these things.

2:20:00Longevity doesn't come overnight. It can take decades to appear, but you can't decide at my age, oh, I'm going to suddenly live long. Not yet. We're working on it. But to get to my age and have my kind of a heart rate and heart rate variability, you do need to start, I think, decades earlier or at least 10 years earlier and optimize, preferably your age. I wish that I started at your age. I didn't really get into it until my 30s. And in my 30s, that was the 2000s. We didn't know much. There was not much you could do. Now there's so much information. It's a wonderful time to be alive. And we can actually, I think have a big impact on our future health by what we do, what we eat, what we swallow.

2:20:48And it's fun too. True. If people are listening to it, right, like whoever's listening to it right now and feels overwhelmed by all the information in the world, by this podcast, by all the things to do in the world, right? Yeah. And they could just change one thing in their life tomorrow morning, which will have drastically the biggest impact on their aging, on their life, on making them better? What would be that one thing? All right. The first thing I'm going to say is it's not confusing if it's presented clearly. And what I'm building is a community where people will learn how to live their longest life.

2:21:30It's called lifespan. Yeah. So that's what I'm doing. I want everybody to experience this, but it can be overwhelming. so we need to explain it simply so i would i would start with eating less often and within those meals eating fresh that's the start okay and then learn from this so much to learn it's really fun and you'll feel so great perfect done i have the last question which i ask all my guests which is what is the cost of becoming David Sinclair? Oh,

2:22:17I rarely have time for myself. I was not the father to my children that I wanted to be, I'm trying to make up for that. but I was often away and I wasn't focused on the present and I did not appreciate my life and the I wasn't grateful for the joy that I could have had in my 30s and 40s because I was so focused on making the impact testing the science getting the molecules into people that I didn't stop and appreciate that I had three amazing kids and a house and a career that I loved. It was just go, go, go, always problem solving. I'm different now. But I missed probably 20 years of joy that came with being David Sinclair, of working, being obsessed to perfection.

2:23:21Thank you so much for sharing that. I really appreciate it. Thank you. Thank you for spending time with me, explaining me the science, which was my nightmare today. I understand much better. I love this balls analogy and this structure. Thank you so much for doing all of this. I really, really love our time here. Raj, I appreciate you having me on. And this was a really great chance to tell people about what's typically very complicated science. And I think your questions were perfect to be able to explain something that I rarely have a chance to explain at this very simple level, but very interesting level as well.

2:23:58Thank you so much. Thank you. Yeah, thanks. So, you know, with me, how I got exposed to your work, there was one guest on my podcast. He ended up talking about the stuff that you have written in the book. And then there was another guest who also spoke. And then the third, I was like, what is going on? Oh, that's interesting. Yeah. And I was so fascinated. Thank you for doing this. It's a pleasure to host you. Well, no, it's a pleasure to be here. I love how you educate. This is not a podcast about advertising. It's not about making ourselves look good. It's for your listeners to learn. Yes. That's why you've been so successful.

2:24:37Thank you. That's the whole goal. Today we're going to learn, as you can see. We have the whole classroom set up here right now. Yes, exactly. Thank you for watching this episode till the end. We would love to know what you liked or disliked about this episode and which guests you would like to see on the show. Let us know in the comments. Your feedback help us improve and make every episode a little better. I'll see you next time. Until then, keep figuring out.