Essentials: The Biology of Slowing & Reversing Aging

00:00:00.000 | Welcome to Huberman Lab Essentials, where we revisit past episodes for the most potent and

00:00:05.400 | actionable science-based tools for mental health, physical health, and performance.

00:00:10.000 | I'm Andrew Huberman, and I'm a professor of neurobiology and ophthalmology at Stanford

00:00:16.020 | School of Medicine. And now, my conversation with Dr. David Sinclair. Thanks for being here.

00:00:21.240 | I have a ton of questions for you about aging, longevity, lifespan, actionable protocols to

00:00:27.620 | increase how long we live, et cetera. And I just want to start off with a very simple question.

00:00:32.180 | What is the difference between longevity, anti-aging, and aging as a disease? Because

00:00:38.540 | I associate you with this statement, aging is a disease. Right. Well, so longevity is the

00:00:46.020 | more academic way we describe what we research. Anti-aging is kind of the same thing, but it's got

00:00:51.900 | a bad rap because it's been used by a whole bunch of people that don't know what they're talking about.

00:00:55.800 | So I really don't like that term, anti-aging. But aging as a disease and longevity are

00:01:00.620 | perfectly valid ways to talk about this subject. So let's talk about aging as a disease.

00:01:05.980 | When I started my research, disease here at Harvard Medical School, it was considered,

00:01:12.760 | if there's something that's wrong with you, and it's a rare thing, has to be less than 50% of the

00:01:19.300 | population, that's definitely a disease. And then people work their whole lives to try and cure that

00:01:24.740 | condition. And so I looked up what's the definition of aging. And it says, well, it's a deterioration

00:01:29.560 | and in health and sickness, and you can die from it. Typically you do. Something that sounds

00:01:34.920 | pretty much like a disease. But the caveat is that if more than half the population gets this

00:01:40.760 | condition aging, it's put in a different bucket, which is, first of all, that's outrageous because

00:01:45.920 | it's just a totally arbitrary cutoff. But think about this, that we're ignoring the major

00:01:50.860 | cause of all these diseases. Aging is 80 to 90% the cause of heart disease, Alzheimer's.

00:01:56.860 | If we didn't get old and our bodies stayed youthful, we would not get those diseases.

00:02:01.020 | And actually what we're showing in my labels, if you turn the clock back in tissues, those diseases

00:02:05.900 | go away. So aging is the problem. And instead, through most of the last 200 years, we've been

00:02:12.220 | sticking band-aids on diseases that have already occurred because of aging, and then it's too late.

00:02:17.900 | So there are a couple of things. One is you want to slow aging down so we don't get those diseases.

00:02:21.900 | And when they do occur, don't just stick a band-aid on, reverse the age of the body,

00:02:25.740 | and then the diseases will go away. That clarifies a lot for me. Thank you.

00:02:29.500 | Can we point to one specific general phenomenon in the body that underlies aging?

00:02:35.660 | Fortunately, during the 2000s, we settled on eight or nine major causes of aging.

00:02:41.580 | These eight or nine causes, at least for the first time, allowed us to come around and talk together.

00:02:47.340 | We put them on a pizza so everyone got equal slices. But I think that there's one slice of the pizza

00:02:53.260 | that is way larger than the others. And we can get to that, but that's the information in the cell

00:02:58.540 | that we call the epigenome. Well, tell us a little bit more about the epigenome. Frame it for us,

00:03:04.700 | if you will. And then we'll get into ways that one can adjust the epigenome in positive ways.

00:03:10.700 | Yeah. So in science, what I like to do, I'm a reductionist, is to boil it down. And I actually

00:03:16.940 | ended up boiling aging down to an equation, which is the loss of information due to entropy.

00:03:23.500 | It's a hard thing to overcome the second law of thermodynamics. That's fair. But this equation

00:03:27.900 | really represents the fact that I think aging is a loss of information in the same way that

00:03:34.140 | when you Xerox something a thousand times, you'll lose that information, or you try to copy a cassette

00:03:40.460 | tape, or even if you send information across the internet, some of it will get lost. That's what I

00:03:45.660 | think is aging. And there are two types of information in the body. There is the genetic information,

00:03:50.860 | which is digital, A-T-C-G, the chemical letters of DNA. But there's this other part of the information

00:03:57.020 | in the body that's just as important. It's essential, in fact. And that's the systems that

00:04:03.020 | control which genes are switched on and off, in what cell, at what time, in response to what we eat,

00:04:08.460 | etc. And it turns out that 80% of our future longevity and health is controlled by this second

00:04:14.300 | part, the epigenetic information, the control systems. I liken the DNA to the music that's on a

00:04:20.540 | DVD or a compact disc. For the younger people, we used to use these things.

00:04:23.900 | I recall.

00:04:24.700 | Yeah. And then the epigenome is the reader that says, okay, in this cell, we need to play that

00:04:29.900 | set of songs. And in this other cell, we have to play a different set of songs. But over time,

00:04:34.860 | aging is the equivalent of scratching the CD and the DVD so that you're not playing the right songs.

00:04:40.300 | And cells, when they don't hear the right songs, they get messed up and they don't function well.

00:04:45.900 | And that is what I'm saying is the main driver of aging. And these other hallmarks

00:04:50.220 | are largely manifestations of that process.

00:04:53.180 | What are the scratches that you're referring to?

00:04:56.060 | So DNA is six foot long. So if you join your chromosomes together, you get at six foot per cell.

00:05:00.540 | So there's enough to go to the moon and back eight times in your body. And it has to be wrapped up to

00:05:05.580 | exist inside us. But it's not just wrapped up willy-nilly. It's not just a bundle of string.

00:05:11.660 | It's wrapped up very carefully in ways that dictates which genes are switched on and off.

00:05:15.980 | And when we're developing in the embryo, the cell marks the DNA with chemicals that says,

00:05:22.140 | okay, this gene is for a nerve cell. You, you cell will stay a nerve cell for the next hundred years,

00:05:27.740 | if you're lucky. Don't turn into a skin cell. That would be bad.

00:05:31.020 | And those chemicals, there are many different types of chemicals, but one's called methylation.

00:05:36.860 | Those little methyls will mark which songs get played for the rest of your life.

00:05:41.100 | And there are other marks that change daily. But in total, what we're saying is that the body

00:05:46.700 | controls the genome through the ability to mark the DNA and then compact some parts of it, silence those

00:05:55.500 | genes, don't read those genes and open others, keep others open. That should stay open. And that pattern of

00:06:02.860 | genes that are silent and open, silent, open is what dictates the cell's type, the cell's function.

00:06:09.660 | And then the scratches are the disruption of that. So genes that were once silent,

00:06:14.700 | and you could say it's a gene that is involved in skin. It's starting to come on in the brain,

00:06:21.340 | shouldn't be there, but we see this happen. And vice versa, the gene might get shut off over time during

00:06:26.060 | aging. Cells over time lose these structures, lose their identity. They forget what they're supposed to

00:06:32.300 | do. And we get diseases. We call that aging. And we can measure that. In fact, we can measure it in

00:06:38.780 | such a way that we can predict when somebody's going to die based on the changes in those chemicals.

00:06:43.820 | Are these changes the same sorts of changes that underlie the outward body surface manifestations

00:06:50.620 | of aging that most of us are familiar with? Graying of the hair, wrinkling of the skin, drooping of the

00:06:55.980 | of the face? Or are we talking about people that are potentially are going to look older, but simply live longer?

00:07:02.300 | Well, it's actually you you are as old as you look if you want to generalize. So let's start with

00:07:08.860 | centenarian families. These are families that tend to live over 100. When they're 70, they still look 50

00:07:14.780 | or less. So it is a good, good indicator. It's not perfect because you can like me grow up in Australia

00:07:21.660 | and accelerate the aging of your skin. But in general, how you look, no one's ever died from gray hair.

00:07:28.380 | But overall, you can get a sense just from the ability of skin to hold itself up, how thin it is,

00:07:34.220 | the number of wrinkles. Very interesting. So I started off in developmental neurobiology. So

00:07:40.460 | one of the things that I learned early on that I still believe wholeheartedly is that development

00:07:47.180 | doesn't stop at age 12 or 15 or even 25, that your entire life is one long developmental arc.

00:07:58.060 | So in thinking about different portions of that developmental arc, the early portion of infancy,

00:08:04.620 | and especially puberty seem like especially rapid stages of aging. And I know we normally look at

00:08:11.580 | babies and children and kids in puberty and we think, oh, they're so vital. They're so young.

00:08:15.900 | And yet the way you describe these changes in the epigenome and the way you have framed aging as a disease

00:08:24.220 | leads me to ask, are periods of immense vitality the same periods when we're aging faster?

00:08:33.740 | Yes. Really good question. So those chemicals we can measure, it's also known as the Horvath clock.

00:08:39.980 | It's the biological clock. It's separate from your chronological age. There are some people that are

00:08:44.220 | 10, 20 years younger than other people biologically. And it turns out if you measure that clock from

00:08:50.460 | birth or even before birth, if you look at animals, there's a massive increase in age based on that

00:08:56.220 | clock early in life. So you're right. So that's a really important point that you have accelerated aging

00:09:02.780 | during the first few years of life. And then it goes linear towards the rest of your life. But there's

00:09:08.140 | another interesting thing you brought up, which is that we're finding that the genes that get messed

00:09:11.820 | up, that get scratched, that are leading to aging, are those early developmental genes.

00:09:17.420 | They come on late in life and just mess up the system. And they seem to be particularly susceptible

00:09:23.260 | to those scratches. So what's causing the scratches? Well, we know of a couple of things in my lab we

00:09:28.460 | figured out. One is broken chromosomes, DNA damage, particularly cuts to the DNA breaks.

00:09:34.700 | So if you have an X-ray or a cosmic ray, or even if you go out in the sun and you'll get your broken

00:09:40.140 | chromosomes, that accelerates the unwinding of those beautiful DNA loops that I mentioned.

00:09:46.540 | We can actually do this to a mouse. We can accelerate that process and we get an old mouse,

00:09:53.580 | 50% older, and it has this bent spine, kyphosis, it has gray hair, its organs are old. So we now can

00:09:59.980 | control aging in the forwards direction. The other thing that accelerates aging is massive cell

00:10:05.580 | damage or stress. So we pinched nerves and we saw that their aging process was accelerated as well.

00:10:12.940 | Incredible. Yeah. This is more of an anecdotal phenomenon. It is an anecdotal phenomenon, but

00:10:19.820 | at this experience of in junior high school, you know, going home for a summer and you come back and then

00:10:26.220 | some of the kids, like they grew beards over the summer or they completely matured quickly over the

00:10:32.540 | summer. Do you think there's any reason to believe that rates of entry into and through puberty have,

00:10:39.660 | can predict overall rates of aging? Well, yeah, I don't want to scare anybody. Sure.

00:10:44.700 | There are studies that show that the slower you take to develop, it also is predictive of having a

00:10:51.260 | longer, healthier life. And it may have something to do with growth hormone. We know that growth hormone

00:10:57.660 | is pro-aging. Anyone who's taking growth hormone, you know, for a short amount of time, you'll build up

00:11:03.420 | muscle, you feel great, but it's like burning your candle at both ends. Ultimately, if you want to live

00:11:09.100 | longer, you want less of that. And the animals that have been generated and mutants that have low growth

00:11:15.340 | hormone, sometimes these are dwarfs, they live the longest by far. Can we say that there's a direct

00:11:21.500 | relationship between body size and longevity or duration of life? Well, there is, but that doesn't

00:11:29.260 | mean that you're a slave to your early epigenome nor to your genome. The good news is that the epigenome

00:11:36.860 | can change those loops and structures can be modified by how you live your life. No matter what size you

00:11:42.620 | are, you can have a bigger impact on your life than anything your genes give you. 80% is epigenetic, not

00:11:48.860 | genetic. So let's talk about some of the things that people can do. And I've kind of batched these into

00:11:53.820 | categories rather than just diving right into actionable protocols. So the first one relates to food,

00:12:04.220 | blood sugar, insulin. This is something I hear a lot about that fasting is good for us,

00:12:09.980 | but rarely do I hear why it's good for us. I think understanding the mechanism will allow people to

00:12:16.460 | make better choices and not simply to just decide whether or not they're going to fast or not fast,

00:12:22.060 | or how long they're going to fast. I think should be dictated by some understanding of the mechanism. So

00:12:27.340 | why is it that having elevated blood sugar, glucose and insulin ages us more quickly?

00:12:33.660 | And, or why is it that having periods of time each day or perhaps longer can extend our lifespan?

00:12:41.900 | Well, let's start with, with what I think was a big mistake was the idea that people should never

00:12:47.900 | be hungry. Some people never experienced hunger in their whole lives. It's really, really bad for them.

00:12:53.180 | It was based, I believe on the 20th century view that you don't want to stress out the pancreas

00:12:58.460 | and you try to keep insulin levels pretty steady and not have this, this fluctuation. What we actually

00:13:06.060 | found, my colleagues and I across this field of longevity, is that when you look at first of all,

00:13:13.820 | animals, whether it's a dog or a mouse or a monkey, the ones that live the longest by far 30% longer and

00:13:21.980 | stay healthy are the ones that don't eat all the time. It actually was first discovered back in the

00:13:27.820 | early 20th century, but people ignored it. And then it was rediscovered in the 1930s. Clive McKay did

00:13:34.300 | caloric restriction. He put cellulose in the food of rats, so they couldn't get as many calories,

00:13:39.340 | even though they ate. And those rats lived 30% longer. But then it went away and then it came

00:13:45.420 | back in the 2000s in a big way when a couple of things happened. One is that my lab and others

00:13:51.260 | showed that there are longevity genes in the body that come on and protect us from aging and disease.

00:13:57.260 | The group of genes that I work on are called sirtuins. There's seven of them.

00:14:01.420 | And we showed in 2005 in a science paper that if you have low levels of insulin and another molecule

00:14:09.340 | called insulin-like growth factor, those low levels turn on the longevity genes. One of them that's

00:14:15.500 | really important is called sirt1. But by having high levels of insulin all day, being fed means your

00:14:22.780 | longevity genes are not switched on. So you're falling apart. Your epigenome, your information that keeps

00:14:28.860 | your cells functioning over time just degrades quicker. Your clock is ticking faster by always

00:14:34.060 | being fed. The other thing that I think might be happening by always having food around is that

00:14:42.300 | it's not allowing the cell to have periods of rest and re-establish the epigenome. And so it also

00:14:50.620 | is accelerating in that direction. There's plenty of other reasons as well that are not as profound such as

00:14:56.540 | having low levels of glucose in your body will trigger your major muscles and your brain to become more

00:15:03.580 | sensitive to insulin and suck the glucose out of your bloodstream, which is very good.

00:15:08.780 | You don't want to have glucose flowing around too much. And that will ward off type 2 diabetes.

00:15:14.060 | What is the protocol that people can extrapolate from that?

00:15:17.820 | Well, if there's one thing I could say, I would say definitely try to skip a meal a day.

00:15:23.260 | That's the best thing. Does it matter which meal?

00:15:26.140 | Or are they essentially equivalent?

00:15:27.340 | Well, as long as it's at the end or the beginning of the day, because then you add that to the sleep

00:15:32.460 | period where you're hopefully not eating. Beware that the first two to three weeks when you try that,

00:15:37.260 | you will feel hungry. And you also have a habit of wanting to chew on something. There's a lot of physical

00:15:42.460 | parts to it, but try to make it through the first three weeks and do without breakfast or do without

00:15:47.500 | dinner. And you'll get through it.

00:15:49.740 | Do you ever do longer fasts like 48 hours or 72 hours or week long fasts?

00:15:55.420 | Not very often. I find it quite difficult to go more than 24 hours.

00:16:00.540 | But when I do it, maybe it's once a month, I'll go for two days. After two, and actually even

00:16:06.140 | better if you go for three days without eating, it kicks in even greater longevity benefits.

00:16:12.460 | So there's a system called the autophagy system, which digests old and misfolded proteins in the

00:16:18.940 | body. And there's a natural cleansing that happens when you're hungry. Macro autophagy,

00:16:24.060 | its name is. But a good friend of mine, Anna Maria Cuervo at Albert Einstein College of Medicine,

00:16:29.420 | discovered a deep cleanse called the chaperone mediated autophagy, which kicks in day two, day

00:16:35.340 | three, which really gets rid of the deep proteins. And what excites me is she just put out a big paper

00:16:42.780 | that said, if you trigger this process in an old mouse, it lives 35% longer.

00:16:49.500 | When you are fasting, regardless of how long, I know you're ingesting fluids like water and

00:16:54.780 | presumably some caffeine. I heard you had several or more espresso today. Are you also ingesting

00:17:00.540 | electrolytes? Like I know some people get lightheaded, they start to feel shaky when they fast,

00:17:05.020 | and that the addition of sodium to their water or potassium, magnesium is something that's becoming a

00:17:11.580 | little more in vogue now. Is that something that you do or that you see a need for people to do?

00:17:15.660 | Well, it makes sense, but I haven't had a need to do it. So I don't, I just, I drink tea during the

00:17:22.140 | day and coffee when I'm first awake and I don't get the shakes. So, you know, I don't fix what's not

00:17:27.580 | broken. Okay. You've told us that there's ample evidence that keeping your blood sugar low for a period

00:17:33.980 | of time each 24 hours can help trigger some of these pro longevity, anti-aging mechanisms. And that

00:17:42.220 | extending them out two or three days can trigger yet additional mechanisms of gobbling up of dead cells

00:17:50.940 | and things of that sort. How is it that blood glucose triggers these mechanisms? Because we've said, okay,

00:17:57.100 | remove glucose and things get better. You've talked before, maybe we could talk more now about some of

00:18:03.180 | the underlying cellular and genetic mechanisms, things like the sirtuins, but how are glucose and the

00:18:07.980 | sirtuins actually tethered to one another mechanistically?

00:18:10.620 | Yeah, there's a really good question. That proves you're a scientist or the world leading one.

00:18:17.820 | So what we, what we've now know is that these longevity pathways, we call them these longevity

00:18:23.100 | genes talk to each other. And we used to say, oh, my longevity genes more important than yours. It was

00:18:27.740 | ridiculous because they're all talking to each other. You pull one lever and the other one moves.

00:18:31.980 | And the way to think of it is that there are systems set up to detect what you're eating.

00:18:35.900 | So the sirtuins will mainly respond to sugar and insulin. And then there's this other system called

00:18:43.260 | mTOR, which is sensing how much protein or amino acids are coming into your body. And they talk to

00:18:49.660 | each other, we can pull one and affect the other and vice versa. But together, when you're fasting,

00:18:55.020 | you'll get the sirtuin activation, which is good for you. And you also through lack of amino acids,

00:19:02.140 | particularly three of them, leucine, isoleucine, valine, the body will down regulate mTOR. And

00:19:07.980 | it's that ups or two and down mTOR that is hugely beneficial and turns on all of the body's defenses,

00:19:14.780 | the pro chewing up the old proteins, improving insulin sensitivity, giving us more energy,

00:19:19.660 | repairing cells, all of that. And so these two pathways, I think are the most important for longevity.

00:19:25.180 | You mentioned leucine. It's clear that because of leucine's effects on the mTOR pathway, that there are

00:19:32.300 | many people, not just people in these particular fitness communities that are actively trying to

00:19:37.260 | ingest more leucine on a regular basis in order to maximize their wellness and fitness, and in some

00:19:44.220 | cases, muscle growth, but also just wellness. But what I interpret your last statement to mean is that

00:19:50.460 | leucine, because it triggers cellular growth is actually pro-aging in some sense. Is that right?

00:19:57.420 | That's what the evidence suggests. And again, it goes back to the debate. Should you supplement

00:20:01.740 | with growth hormone or testosterone? All of these activities will give you immediate benefits. You'll

00:20:08.940 | bulk up more. You'll feel better immediately. But based on the research, it's at the expense of long-term

00:20:15.900 | health, so my view of longevity, the way I treat my body is I don't burn both candles. I have one

00:20:24.380 | end of the candle lit. I'm very careful. I don't blow on it. But I also do enough exercise that I'm

00:20:30.700 | building up my muscle, but I'm not huge. Anyone who's seen me knows that I'm not a professional

00:20:36.540 | bodybuilder. But I tried to actually... Here's the key. And I haven't said this publicly that I can

00:20:41.820 | remember. I pulse things so that I get periods of fasting, and then I eat. Then I take a supplement.

00:20:48.700 | Then I fast. Then I exercise. And I'm taking the supplements and eating in the right timing to allow

00:20:57.260 | me to build up muscle sometimes. Because you can't just expect to take something constantly and do

00:21:04.140 | something constantly for it to work. And that's why it's taken me about 15 years to develop my protocol.

00:21:09.340 | And there's a lot of subtlety to it. What you want to do is to get the cells to be

00:21:13.500 | perceiving adversity. Because our modern life, we're sitting around. We're eating too much.

00:21:20.940 | We're not exercising. Our cells respond. They go, "Hey, everything's cool. No problem." And they become

00:21:28.700 | relaxed, and they turn on their defenses, and we age rapidly. We can see it in the clock.

00:21:32.780 | People who exercise and eat less have a slower ticking clock. It's a fact.

00:21:36.940 | One of the questions I get asked all the time is, "Does ingesting blank break the fast? Does

00:21:43.180 | eating this or drinking this coffee?" If I walk in the room and someone else is eating a cracker,

00:21:47.980 | does it break my fast? People get pretty extreme with this. My sense, and please tell me if I'm wrong,

00:21:53.740 | but my sense is that it depends on the context of what you did the night before, whether or not you're

00:21:59.580 | diabetic, lots of things. So for instance, if I eat an enormous meal at midnight,

00:22:03.820 | go to sleep, wake up at 6:00 AM, I could imagine that black coffee or coffee with a little bit of cream

00:22:12.140 | might "break my fast." But the body doesn't have a breaking the fast switch. The body only speaks

00:22:17.580 | in the language of glucose, AMPK, mTOR, etc. So do you worry that ingesting these calories is going to

00:22:25.340 | "break your fast"? And more generally, how do you think about the issue of whether or not you're

00:22:30.460 | fasting enough to get these positive effects? Because not everybody can manage on just water

00:22:37.260 | or just tea, or we should say not everybody is willing to manage on just water or just tea for

00:22:42.380 | a certain part of the day. Well, my first answer is not scientific. It's philosophical. If you don't

00:22:47.820 | enjoy life, what's the point? And so I'd like a cup of coffee in the morning, a little bit of milk,

00:22:53.420 | spoonful of yogurt's not going to kill me. Olive oil doesn't have protein or carbs in it, not many.

00:23:00.620 | And so I'm probably not affecting those longevity pathways negatively. But without that,

00:23:06.700 | first of all, I wouldn't enjoy my life as much. Well, the olive oil is not as great as the yogurt,

00:23:11.660 | but I'm trying to optimize. And there's no perfect solution to what we're doing. And we're still

00:23:18.540 | learning. We don't know what's optimal for me, let alone everybody else. But I'm with you. I don't

00:23:24.220 | believe that taking a couple of spoonfuls of something, unless it's high fructose corn syrup,

00:23:29.580 | is going to hurt you. The point about doing this is that you try to do your best. If you go from

00:23:36.780 | regular living to don't eat the whole day, you're going to fail. Like quitting smoking cold turkey,

00:23:43.180 | it's easier to chew gum and stick the patch on, because your body has to get used to all sorts of

00:23:47.100 | habits. And it's social, it's physical, putting stuff in your mouth, chewing, not just the low blood

00:23:52.620 | sugar levels, and your brain will fight it. Your limbic system is going to go, "Hey, do it, do it, do it." And

00:23:58.700 | you're going to have to fight it. But once you get through it, you'll be better. But you do it

00:24:03.260 | in stages. Don't go cold turkey, because everyone knows it's a fact that if you try to do a strict

00:24:09.420 | diet right out of the gates, you'll almost always fail. That captures the essence of fasting rationally

00:24:17.100 | and a rational approach to supplementation very well. Along the lines of supplementation,

00:24:21.980 | what about NMN? How does one incorporate that into a supplementation protocol, should they choose to do

00:24:28.380 | that? All right. Well, disclaimer is that I don't recommend anything, but I talk about what I do.

00:24:33.500 | So a bit of scientific background, these sirtuin genes that we discovered first in yeast cells,

00:24:37.340 | when I was at MIT, and then in animals, as I moved to Harvard in the 2000s. And one of my first postdocs,

00:24:44.940 | actually literally my first postdoc, Chaim Cohen, published a great paper and found that turning on

00:24:50.300 | the sirtuin 6 gene, remember the 7, number 6 gene is very potent. It extended the lifespan dramatically

00:24:56.620 | of mice that he engineered, both males and females, which is great. So what you want to do is naturally

00:25:02.620 | boost the activity of these sirtuins. They are genes, but they also make proteins. That's what genes typically

00:25:08.220 | make or encode. And then those proteins take care of the body in many different ways. NAD levels are

00:25:13.420 | really important for keeping those sirtuin defenses at a youthful level. I take a precursor to NAD

00:25:19.980 | called NMN, and the body uses that to make the NAD molecule in one step. And so I know from measuring

00:25:28.620 | dozens of human beings, that if you take NMN for the time period that I do, I've been taking it for years,

00:25:35.660 | but if you take it for about two weeks, you'll double, on average, double your NAD levels in

00:25:40.860 | the blood. So I just want people to be aware that what I do may not perfectly work at all for others.

00:25:47.500 | But I have studied, as I said, dozens of people who take NMN at a gram, sometimes two grams. And I know

00:25:56.620 | by looking at all those people that without any exceptions, that if you do what I do, your NAD levels go

00:26:02.220 | up by about twofold or more. Anecdotally, because I've been taking this for a long time. If I don't

00:26:07.340 | take it, I start to feel 50 years old. It's horrible. I can't think straight. It may be placebo, but who

00:26:13.740 | knows? But what we're doing now are very careful clinical trials. I want to talk about iron and iron

00:26:20.060 | load. I don't think we can get right down into how much iron somebody needs because it'll vary person to

00:26:24.700 | person. But I was surprised to learn that iron is actually going to accelerate the aging process in

00:26:32.060 | various contexts.

00:26:32.940 | This is a new finding out of Spain. Manuel Serrano's lab has found that excess iron will increase the

00:26:42.060 | number of senescent cells in the body. And senescent cells are these zombie cells that accumulate as you

00:26:48.060 | get older. And they sit there and they cause inflammation mainly, and also can cause cancer.

00:26:52.540 | And it's found that if you get rid of these cells or never accumulate them,

00:26:57.500 | you stay younger in animals. And there's some really interesting studies out of Mayo Clinic in

00:27:03.180 | humans as well. And what I find, for example, is people who are really healthy and live the way I do

00:27:09.340 | and have a diet that's fairly vegetarian, but not strict, still have slightly low hemoglobin levels,

00:27:18.060 | slightly low iron, slightly low ferritin, but we have super amounts of energy. We're not anemic

00:27:23.900 | and we're getting along with great in life. But a doctor who just looks at that might say,

00:27:28.940 | oh, we need to give you more iron. So what I'm getting at is an example of we need to personalize

00:27:35.580 | medicine and look at people over the long run to know what works for them and what's healthy for them.

00:27:42.300 | And not just work towards the average human, but work towards what's optimal for human.

00:27:46.620 | I love that answer. You mentioned tracking and tracking over time. And this is a

00:27:52.380 | really interesting area that I know you have been focused on for a long time.

00:27:56.700 | I've been getting blood work done about every six months since I, frankly, since I was in college,

00:28:01.100 | I just got, I like data. Are there any things that you pay attention to that you think are particularly

00:28:06.780 | interesting for people to just take note of? I mean, we're not asking you to go against anybody's

00:28:11.020 | physician, but what sorts of things should people start to educate themselves about in terms of what these

00:28:16.460 | molecules are on their charts if they choose to get them? And what do you, what do you look at?

00:28:20.140 | Yeah. Yeah. Um, the first is that you should be tracking things, um, because one measurement

00:28:25.420 | isn't enough. These things vary and over time, and you, if you can have a decade or more of data,

00:28:29.980 | it's super informative as you know, but there were some main ones. I would say, uh, your blood sugar

00:28:34.620 | levels. You want to do your HbA1c, which is your average glucose levels over the month. There's a CRP,

00:28:40.460 | which I mentioned for inflammation. Let's talk about C-reactive protein for a second. Cause I think,

00:28:44.860 | um, it's been shown to be an early marker of macular degeneration of, of a heart disease,

00:28:50.540 | a variety of different things. Um, CRP is something that we don't hear enough about. I think it is a,

00:28:56.300 | the best marker for cardiovascular inflammation and is also, we use it as a predictor of longevity and

00:29:03.340 | it's levels go up and with mortality. Um, and so this is an association, but there's enough data that

00:29:11.020 | I would say, if you have high levels of CRP, you need to get your levels down quickly. And the levels

00:29:16.860 | usually go up with age, uh, and with levels of inflammation. So the ways to get it down would

00:29:22.460 | be to switch the diet, eat less, uh, try to eat more vegetables. You'll find it will come down.

00:29:27.340 | There are also drugs that can do it. Uh, anti-inflammatories, um, can do it as well.

00:29:31.900 | But CRP is, it's actually HCRP. There's a high sensitive or HSCRP. Your doctor will know,

00:29:38.540 | get one of those readings. Cause if, if you've got normal blood sugar levels,

00:29:43.020 | your doctor or fasting blood sugar levels, um, your doctor might say you're fine, but a lot of people

00:29:48.780 | have normal blood sugar, but have high CRP, which is just as bad for you long-term, um, and can predict

00:29:55.260 | a future heart attack. Zooming way out. What are the behavioral tools that one can start to think

00:30:02.860 | about in terms of ways to modulate these, uh, you know, basically the way that DNA is, is being expressed

00:30:08.540 | and functioning. In other words, what are the sorts of things that people can do

00:30:12.780 | to improve the sirtuin pathway? And I, I realized that there are caveats. We can't go directly from

00:30:17.980 | a behavior to sirtuins, but in the general theme, what can, what can people do? What do you do?

00:30:23.100 | Well, we know that, that aerobic exercise in mice and rats raises their NAD levels and, and their levels

00:30:28.940 | of SIRT, one of the genes goes up to actually number one and number three. I, I based my exercise on the

00:30:36.060 | scientific literature, which has shown that, uh, maintaining muscle mass is very important for a number of

00:30:41.980 | reasons. The two main ones are, uh, you want to maintain your hormone levels. I'm an older male

00:30:47.820 | losing my testosterone and muscle mass over time. And by exercising, I will maintain that

00:30:53.260 | and have, uh, in fact, I've, I've, I probably haven't had a body like this since I was 20. So that's

00:30:59.180 | one of the benefits of having this lifestyle. What about estrogen? Because women are different

00:31:04.940 | in the sense that they do, uh, the number of eggs that they, and the ovaries change over time.

00:31:10.460 | Right. Uh, do you think that they can maintain estrogen levels at, in, uh, over longer periods

00:31:16.780 | of time using some of these same protocols? I don't want to get too much into the anecdotes,

00:31:20.860 | but I'll tell you the science, which is, um, that if you take a mouse and put it on fasting or caloric

00:31:28.540 | restriction form up until the point where it should be infertile. So that's about it. At a year of age,

00:31:35.580 | a mouse gets infertile female mouse. Due to, due to fasting or due to simply to aging. Due to aging,

00:31:41.100 | due to aging, the fasting it's, it's not an extreme fast. It's just less calories. Got it.

00:31:46.860 | Then you put them back on a regular food and they become fertile again for many,

00:31:52.220 | many months afterwards. So the, the effect on slowing down aging is also on the reproductive system.

00:31:59.260 | Interesting. And so that I wouldn't say to any woman, I wouldn't think that they should

00:32:03.980 | become super skinny to try and preserve fertility. That's not what I'm saying.

00:32:07.660 | But these pathways that we work on, these sirtuins are known to delay infertility in female animals.

00:32:14.300 | Case in point. Um, I'm one of the lead authors on a paper where we used NMN. Remember this is the gas,

00:32:20.380 | the fuel, the petrol for the sirtuins. We gave old mice, uh, one group of mice was 16 months old.

00:32:29.660 | Remember they became infertile at 12. Gave them NMN. And I think it was only six weeks later,

00:32:36.540 | they had offspring. They became fertile again, which goes against biology, a textbook biology.

00:32:44.220 | Which is that female mammals run out of eggs. Turns out that's not true. You can rejuvenate

00:32:51.260 | the female reproductive system and even get them to come out of mouse-a-paws as we call it.

00:32:56.380 | So that's a whole new paradigm in biology as well. What I think is really interesting is that what we're

00:33:01.660 | learning from work that you and your colleagues have done and in my lab as well, is that the body has

00:33:07.180 | remarkable powers of healing and recovering from illness and injury. And what we once thought was

00:33:14.620 | a one-way street and you just can't repair, you can't get over these diseases. You can reset the system

00:33:21.180 | and the body can really get rejuvenated in ways that in the future we'll wonder why, why didn't we work on

00:33:26.300 | this earlier. And thank you for talking to us today. I, I realized I took us down deep into the guts of,

00:33:33.420 | of mechanism and, and as well, talking about global protocols, everything from what one can do and take

00:33:40.220 | if they choose or that's right for them, um, to how to think about this whole process that, that we, uh,

00:33:46.860 | talk about when we talk about lifespan as, um, as always in incredibly illuminating. Thank you, David.

00:33:52.940 | Thanks, Andrew.

Essentials: The Biology of Slowing & Reversing Aging | Dr. David Sinclair

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