Lifespan Book Club (Casey Means & David Sinclair)

When the Levels community comes together with thought leaders in metabolic health, many interesting things can happen. That was the case when Dr. Casey Means, Chief Medical Officer and co-founder of Levels, sat down with Dr. David Sinclair, the author of Lifespan and one of the leading experts on longevity in the world. In this episode, Dr. Sinclair took the time to have a mini “book club” meeting with our community, complete with thoughts on the ways that we can continue to extend our lifespan.

3:18 – The concept of death

You can’t let the thought of death keep you from living fully. It doesn’t matter if you live 40 years or 1,000, you can still maximize your experience.

There are those who think about death a lot, those who don’t. I’ve met a lot of people who don’t get excitement out of life because they think about death, they get excitement out of life because they love life. And I’m one of those people, I don’t care if I’m going to live 100, or 1000, or a million years. Every day is exciting and new and I just want to learn more and do more…I mean, if you all thought you were going to live for 1000 years, would you be bored? Would you not show up to this? Would you not be listening to me? I don’t think so. I think we take every day as it comes and try to do our best, most of us do. And the other thing, imagine if I said to you, “Oh, well let’s all die at 40 like we used to, like many of us used to,” would that make your life better? Because we can go back to those days if you want, we can take away antibiotics, and vaccines, and sanitation, is life better then? I would guess that it would not be and none of us, I don’t think would want to go back 200 years and live those medicines. So if you extrapolate that, the longer we lived healthy we are, it actually makes life better and you want to live longer because the future looks even brighter.

06:22 – Extending youth vs old age

Poor physical and mental health are the only reasons that any person would decide they are “ready” to die; not reaching an arbitrary age.

It’s all about extending the youth, not extending old age. And when I tell people that they typically go from, “Oh, I don’t want to live beyond 100” to “Yeah. I’ll keep living, I don’t have a real limit. And it turns out if you’re healthy and happy, let’s say you got friend, you’ve got your health, you’ve got productivity, you’re doing something that you enjoy, it can be community service, whatever, nobody wants to die. Can you imagine that you wake up one day, you’ve turned 80 and suddenly you’d say, “Okay, I want to die.” No, people want to die because they’re sick, they’re depressed, they don’t have any meaning in their lives, they’re alone. And we’re trying to make people avoid that.

08:11 – Health needs to start young

Just because someone is young doesn’t mean they can have bad health habits.

It is a tragedy that kids are being overfed and fed the wrong foods largely due to marketing, largely due to the saying that the biggest and most important meal of the day should be breakfast, which I don’t necessarily agree with. And what that does to kids is that it sets them up for a bad epigenetic clock and bad epigenetics for the rest of their life. We know that the clock is ticking from conception. In fact, it goes very rapidly when you’re young and then becomes linear. So what that means is that yeah, if you say, “Oh, it’s just puppy fat, Jimmy will lose it when he turns 18 or whatever.” Even if Jimmy does, it’s done permanent damage to the epigenome and that 5, 6, 7 decades later Jimmy’s body will feel it. So that’s something that most people don’t understand, and certainly, I would say most parents don’t get.

13:45 – Using Inside Tracker

Inside Tracker is a service that analyzes your blood for various biomarkers — from sugar and cholesterol levels to liver enzymes — and tells you how you are faring in terms of health and fitness.

I still use Inside Tracker and I just posted on Instagram that I think I broke the record at the company. I didn’t realize I was, but they saw my post and they said it, “Holy crap, you’re a decade younger, more than a decade actually.” So that was pretty cool. So what have I done to achieve this? Well, it is in the book and I think most of you have read it, but I have changed some things since 2019, and I’ve added some things, and I’ve taken some things away… I’m monitoring myself also epigenetically to see if I’m actually reversing my epigenetic age, which from my book is one number that’s very important. And I am going backwards according to a number of those clocks. So that’s good news that you can send your age backwards, is not just slow it down. But actually the biggest change since 2019 is my food intake, I have cut myself back to one and a half meals a day, a very small lunch, a snack, maybe late in day, and then a healthy regular dinner.

29:22 – Chronological vs. biological age

While chronological age is out of our control, biological age can be manipulated.

So there are two numbers that we have, there’s the chronological age and the biological age. Chronological age is simply the number of times the earth has gone around the sun, that’s hard to stop. So that’s going to tick over no matter what we do. But the revelation and realization of scientists and revelation in the public is that our biological age is different than our chronological age, and that we can change it backwards and forwards. In my lab, we can drive aging forwards in a mouse and backwards, that will, it’s easy. We have control over aging very precisely now. So what does that mean? It means you can choose your own biological age, in the future you can choose to be 30 and stay 30, choose to be 50 stay 50, but being 50 and biologically 40, which is basically what I am, doesn’t mean I have the wisdom of a 40 year old, I have a wisdom of a 50 year old. So if you extrapolate, I could be 100, you could be 100, still have a 40 year old body and have the wisdom of 100 years living, that’s what’s exciting me. So you’ve got the biological clock you can control. And then the chronological age in my view just gets better and better with wisdom and experience. So I don’t want to stick to any particular chronological age, I don’t mind that that advances, as long as my biological age is slow or even steady.

44:42 – How Levels will help make longevity research more equitable

In general, the scientific community is in sore need of data that looks behind white males.

We as a field, we’ve only just started using females in our studies let alone, people in different races. And we live in a time where that’s very for the forefront of our conversations, but because it takes a while to get results from clinical trials, we’re still in the dark actual about that. Now, I’d be surprised if there are not ethnic differences, racial differences in mice even strains of mice, have different effects when it comes to calorie restriction, some calorie restriction protocols will support certain strains of mice and others will live longer. And that’s until we have the data on effects of different ethnicities, it’s even more important that individuals measure themselves to make sure that what works for a white male will also work in an African-American female, for example. We also look at data typically at Levels and at Inside Tracker, from the wealthier part of society and they skew ethnically as well, and so we have to remember that there’s a whole other group of people that are not typically being equally measured. And my goal would be hopefully yours too, it’s to democratize this and get it out to everybody as fast as we can and as cheap as we can.

48:19 – Research is evolving quickly

David says that he’s optimistic about the coming advancements in the field of epigenetic reprogramming and age reversal.

I really think that it’s possible now that we will be able to reset many parts of our body within our lifetime. But yeah, I think I’m much more optimistic, I now believe that with this infusion of research dollars and development of drugs, that’s going to happen, we might, within the next 10 years have the ability to reverse the age of certain organs, perhaps within 20 years, the whole body. Already there are people, doctors that are claiming to have sent their age back by 10 years based on the blood methylation plot. I’ve seen it in myself that I’ve gone back according to those clocks by at least a couple of years. And that’s all you need to do every year to have a big effect on lifespan.

55:26 – The role of biomarkers

David shares his thoughts about how long before we can take certain biomarkers of aging, (e.g. the epigenetic clocks) and use them to make future predictions.

So you’ve got to look at that data and say, okay, the clock is valid, it’s got 5% error, but still, you got to believe that it’s measuring something related to your actual aging and your future health. So I think we’re already there, I think that these clocks need bit more development. We need them in more people, but I have no doubt that we’re going to be able to use these clocks to predict someone’s future health and longevity, it’s already done in various studies. Which means that if you reverse the clock and in multiple clocks, I don’t just mean a blood test because your blood might improve but your brain might not. We need a way to actually test multiple tissues, it could be a cheek swab spit, might be a muscle biopsy in some people, just a test and also blood. But at least you need to see it happening in the multiple parts of the body to be more convinced that this is true. But with that, I think that at least, if you’re not skeptical in the next five years, we have a number of interventions that are well established and well accepted to slow down and if not reverse, and also reverse aging, including alpha acute glute, which looks promising senalytic molecules look promising for true age reversal.

59:42 – The impact of COVID

David says that the virus depletes NAD, which can accelerate aging.

COVID very likely accelerates aging, it accelerates cellular senescences, we see that in my lab. We can counteract that by deleting the senescent cells, and there are Fisetin and cosentino are two possible ways at least in the supplement world, so that’s one issue. The other thing that the virus does is it depletes NAD massively, if you Google it, you’ll see there’s a lot of papers on this. And there are some case studies at hospitals where patients have been given NMN and they’ve recovered rapidly. And so we are doing well, Metro biotech is doing a COVID-19, NMN trial right now, and also kidneys as well, which is a problem for some patients. So those are the two things I think NMN might help certainly recovery and cellular senescence is a problem, is a senolytics might address long COVID. But yeah, I think it’s important that people know, tell your family and friends that if you get a bad case of COVID, it might accelerate aging. If they don’t haven’t had the vaccine, they’ll probably go get one after they do that.

David Sinclair (00:00:06):

Imagine if I said to you, “Oh, well let’s all die at 40 like we used to, like many of us used to.” Would that make your life better? Because we can go back to those days if you want, we can take away antibiotics, and vaccines, and sanitation.

David Sinclair (00:00:22):

Is life better then? I would guess that it would not be, and none of us, I don’t think would want to go back 200 years and live those medicines. So if you extrapolate that, the longer we live healthy we are it actually makes life better, and you want to live longer because the future looks even brighter.

Ben Grynol (00:00:45):

I’m Ben Grynol, part of the early startup team here at Levels. We’re building tech that helps people to understand their metabolic health, and this is your front row seat to everything we do. This is a Whole New Level.

Ben Grynol (00:00:58):

When the Levels community comes together with thought leaders in metabolic health, many interesting things can happen. Well, that was a case when Dr. Casey Means, Chief Medical Officer and co-founder of Levels sat down with Dr. David Sinclair, author of Lifespan and one of the leading experts in the world when it comes to longevity, so Dr. Sinclair took the time to have a book club with our community.

Ben Grynol (00:01:34):

He did some Q&A at the end, and the interview started off with Casey just talking to him about the book. What are his thoughts on longevity and how does he think about the ways that we can extend our lifespans? It’s a very interesting conversation, here’s Casey.

Casey Means (00:01:56):

Dr. Sinclair, thank you so much for taking the time to be with us today. This is the massive gift and I am so thrilled to get to chat with you about some of the burning questions that I have after being a huge appreciator of your work for many years.

Casey Means (00:02:11):

So I wanted to jump in with one that’s a little off the wall and focuses on death. In your interview in June with Lex Friedman, which is an amazing conversation, there was a discussion about how people largely don’t want to think about death, I think you said that for most people, it’s extremely distressing for us to think about our own mortality and we’re actually maybe genetically wired to not think about death.

Casey Means (00:02:35):

A trend that’s been interesting to see recently is that this mindset might be shifting a little bit in part because of the psychedelic renaissance, there’s people, especially young people who are seeming to be seeking and finding a sense of existential relief about death through these experiences.

Casey Means (00:02:52):

We also have a lot of stoic fans on the team and who are sort of this concept of Memento mori, remembering that you’ll die, how that can add to our fulfillment of life. And I’m just curious to hear your thoughts on these trends, like particularly how the booming trend and investment in psychedelics and existential experiences will impact also the concurrent longevity conversation that’s happening?

David Sinclair (00:03:17):

Yeah. So there are those who think about death a lot, those who don’t. I’ve met a lot of people who don’t get excitement out of life because they think about death, they get excitement out of life because they love life. And I’m one of those people, I don’t care if I’m going to live 100, or 1000, or a million years, every day is exciting and new and I just want to learn more and do more.

David Sinclair (00:03:38):

So there is a group, I would say, it’s more than half of people that are not excited about life because they know they’re going to die. And the other thing I would say is… So I’ve been alive now for 52 years, which went by super quickly, that’s like a blink of an eye. And what would 100 years be like? Well, it’d be two blinks, so what would be 1000 years if we could live that long? That’d be 20 blinks of an eye, still really short.

David Sinclair (00:04:05):

And so absent immortality, which I don’t believe will have any time within the next few 1000 years, we’re all going to die, and I think we’re going to get, be just as excited about life. I mean, if you all thought you were going to live for 1000 years, would you be bored? Would you not show up to this? Would you not be listening to me? I don’t think so, I think we take every day as it comes and try to do our best, most of us do.

David Sinclair (00:04:28):

And the other thing, imagine if I said to you, “Oh, well let’s all die at 40 like we used to, like many of us used to,” would that make your life better? Because we can go back to those days if you want, we can take away antibiotics, and vaccines, and sanitation, is life better then? I would guess that it would not be and none of us, I don’t think would want to go back 200 years and live those medicines. So if you extrapolate that, the longer we lived healthy we are, it actually makes life better and you want to live longer because the future looks even brighter.

Casey Means (00:05:01):

I think that’s a beautiful way of putting it and I think it’s interesting, similar to what you’re saying, I think hearing testaments of people like in the Johns Hopkins studies and whatnot who have done some of these very deep existential experiences that have really relieved a lot of their anxiety around death, you don’t end up having this sort of feudalism where people say, “Oh, I’m fine with dying, and so I’m not going to try and live it also.”

Casey Means (00:05:25):

It almost seems like the opposite where people in engendering in awe for the cosmic journey or whatnot, it makes people even more maybe excited or in awe of this existence that we have here. So I think that your points really resonated.

David Sinclair (00:05:41):

Is one of the things Casey, which is we tend to think that old age is going to be horrible, and God forbid, that we become old like that. And so when I say, “Oh, well, we can make people live longer,” people generally immediately jump to that image that I’m going to spend more time in a nursing home, and be sick, and depressed, and suffer.

David Sinclair (00:05:59):

It’s in fact, again, it’s the opposite, it’s that by doing what Levels is doing for people and what I do, it’s about keeping people younger for longer, so that in your eighties and nineties, you can still be productive and have a life like you had when you were 40. My father’s 82, he lives no life differently than he did when you was in his thirties and forties, in fact, in some ways, many times better.

David Sinclair (00:06:20):

So yeah, it’s all about extending the youth not extending old age. And when I tell people that they typically go from, “Oh, I don’t want to live beyond 100 too.” Yeah. I’ll keep living, I don’t have a real limit. And it turns out if you’re healthy and happy, let’s say you got friend, you’ve got your health, you’ve got productivity, you’re doing something that you enjoy, it can be community service, whatever, nobody wants to die.

David Sinclair (00:06:46):

Can you imagine that you wake up one day, you’ve turned 80 and suddenly you’d say, “Okay, I want to die.” No, people want to die because they’re sick, they’re depressed, they don’t have any meaning in their lives, they’re lone. And we’re trying to make people avoid that.

Casey Means (00:07:00):

Yeah. I think this gets into the topic of health span, which you address so beautifully in the book. There’s a difference between lifespan and health span, we really want to extend healthy years. And one of the questions that I’m still grappling with is really sort of what the limits are of longevity therapy.

Casey Means (00:07:18):

And one thing that comes to mind is that we have this epidemic of children now who have severe metabolic disease, we’re seeing fatty liver disease, we’re seeing obesity, we’re seeing even type 2 diabetes in children, atherosclerosis at young ages, presumably all from really diet and lifestyle, since genetics haven’t changed rapidly.

Casey Means (00:07:38):

So just by being young and useful, theoretically having high NAD levels in their cells or whatever’s going on in their cells too, to make us young, we’re still seeing essentially this morbidity. So just because we can make someone younger doesn’t necessarily mean we can make them healthy.

Casey Means (00:07:56):

So how do you think about the limits of longevity and aging treatments given that the bodies, that these future therapies are going into are highly dysfunctional for the most part due to our food and lifestyle norms in the US?

David Sinclair (00:08:10):

Right. Well, it is a tragedy that kids are being over fed and fed the wrong foods largely due to marketing, largely due to the saying that the biggest and most important meal of the day should be breakfast, which I don’t necessarily agree with.

David Sinclair (00:08:24):

And what that does to kids is that it sets them up for a bad epigenetic clock and bad epigenetics for the rest of their life. We know that the clock is ticking from conception. In fact, it goes very rapidly when you’re young and then becomes linear. So what that means is that yeah, if you say, “Oh, it’s just puppy fat, Jimmy will lose it when he turns 18 or whatever.” Even if Jimmy does, it’s done permanent damage to the epigenome and that 5, 6, 7 decades later Jimmy’s body will feel it.

David Sinclair (00:08:54):

So that’s something that most people don’t understand, and certainly, I would say most parents don’t get. I’m looking to write a book about that, about using these technologies earlier, of course not malnutrition or starvation, nothing like that but the damage is not just temporary. So that said, these longevity treatments, let’s take the NAD boosters that we work on.

David Sinclair (00:09:14):

And it’s true for many of the other interventions is that when you slow down aging, you also improve metabolism and you tend to lose weight. So in animal studies and we’ll know in humans, hopefully sometime within the next 12 months, that you tend to lose weight as well, Metformin does this for a variety of reasons, it’s thought to be a longevity drug.

David Sinclair (00:09:35):

And so what I think we can do for people is not just for kids, but even when they’re older, and there are plenty of older obese people as well, that we can give them added years but also improve their metabolism because they go hand in hand. In the case of Resveratrol, which is the old story from red wine, we are able to protect mice from a high fat diet, even though there were still obese.

David Sinclair (00:09:57):

And so there are ways to actually prevent some of the inflammation and damage that’s caused by obesity, but it’s far better to have a healthy diet, eat less often and combine it with the interventions, because there we find is that the biggest bang for the book, and in the case of the mouse study with [resveratrol 00:10:15], when we gave resveratrol and food every other day, that’s when we got the extreme life span extension. But yeah, I’m with you, I really feel bad about what’s happening to the kids, and I would love to be able to help them more.

Casey Means (00:10:25):

I think a framework that I’m often thinking about is what is the cell made up? What are the… When we think about diet, it’s really just molecular information, right? That’s like going into our body, that’s building our cells, and unfortunately right now we’re using core building blocks, people are vitamin D, magnesium, selenium deficient.

Casey Means (00:10:45):

We’re not getting these things from a diet or we have excess of omega-6 or whatever, and that’s literally the construction of the cell. And so how to reconcile that this like poor molecular sub straight of the body with therapies that shift metabolism.

Casey Means (00:11:02):

And one of the things I think I’m really excited about with your work, with Inside Track or/and other sort of biological observability type work, is that we can start to understand what we’re made of, what is the vitamin D level? What are the other micronutrient levels? So we can hopefully create that synergy between these therapies, but also our molecular structure and see more insight into that, which right now we have very little of. So curious if any thought?

David Sinclair (00:11:27):

Well, yeah. So Inside Track where I helped start that company about old years ago, at the time, it was considered crazy that you would measure your body. That’s something that you do every year with your doctor. Now we know that that’s very medieval way of thinking and things change month to month, if not day to day.

David Sinclair (00:11:46):

And you cannot optimize what you don’t measure, and that’s why Levels are super important on a key parameter. And Inside Tracker isn’t continuous, right? So that’s the disadvantage here. But continuous is the way it has to go because measuring yourself three, four times a year, it’s okay, but it’s not allowing you to change your lifestyle and see what happens with immediate feedback, whereas of course, I’ve got my levels monitor or I do that every day, but yeah, the future has to be like that.

David Sinclair (00:12:13):

The idea that you go to your doctor once a year is really quite scary and very soon we’ll certainly seem medieval. Not only that, what I find is that my doctor at least wants to have the data but the insurance company won’t let him pay for it.

David Sinclair (00:12:27):

And so when I showed him my data, whether it’s the glucose or the Inside Tracker, he loves it, we go through the data on Zoom and everything. So there’s this unwillingness of insurance companies to pay, which I’m sure you’re thinking about. But yeah, if humanity doesn’t go in that direction, then we’re going to continue to fly in the dark and we don’t know what’s working and what isn’t.

David Sinclair (00:12:48):

And it is really bad that for most people now, 99.9% of people, they might try diet, they might try exercise, they might change other aspects of their lifestyle, take a supplement that they buy off the web with no real guarantee. And they have no idea if it’s damaging your liver, it’s working, it’s contaminated, and the only way to know that is to measure things.

Taylor Sittler (00:13:08):

Do you mind if I jump in here for a second, Casey, to ask a question?

Casey Means (00:13:11):

Sure.

Taylor Sittler (00:13:11):

Dr. Sinclair, Taylor Sittler, just joined Levels as head of research. Just wanted to push that a little bit further and ask, in terms of your health dashboard, when you think about what is important to measure, when you talk a lot about it in the book and the specific things that Inside Tracker is doing now, what is your health dashboard look like in 10 years? What do you think are the important things that you need to be thinking about now so that we can both… It sounds like we need to do both behavior change in terms of eating the right diet, maybe doing a cold planche once in a while, as well as taking the right therapies. So what does that dashboard look like for you?

David Sinclair (00:13:44):

Well, I still use Inside Tracker and I just posted on Instagram that I think I broke the record at the company. I didn’t realize I was, but they saw my post and they said it, “Holy crap, you’re a decade younger, more than a decade actually.”

David Sinclair (00:13:58):

So that was pretty cool. So what have I done to achieve this? Well, it is in the book and I think most of you have read it, but I have changed some things since 2019, and I’ve added some things, and I’ve taken some things away. What I’ve added are Oleic acid, I’m taking some [inaudible 00:14:16] now, gram a day, and some senolytics, so fisetin and cosentino, we discovered back in 2003 were lifespan extending molecules. And those appear to not just activate, so one like resveratrol does, but also kill [offness 00:14:29] and cells at high doses, so I have done that.

David Sinclair (00:14:31):

And I’m monitoring myself also epigenetically to see if I’m actually reversing my epigenetic age, which from my book is one number that’s very important. And I am going backwards according to a number of those clocks.

David Sinclair (00:14:44):

So that’s good news that you can send your age backwards, is not just slow it down. But actually the biggest change since 2019 is my food intake, I have cut myself back to one and a half meals a day, a very small lunch, a snack, maybe late in day, and then a healthy regular dinner. I’m a struggling vegan at the moment, I don’t eat meat but occasionally I’ll take a slice of cheese or an oyster or something.

David Sinclair (00:15:07):

But generally, I’m plant-based and I’ve been doing that only for three months, one of my inspirations and I think some of you have heard of Serena, who and I met her a few months ago and she’s been inspiring me with back to knowledge. So I’ve done that and I’ve cut out alcohol to see what happens.

David Sinclair (00:15:23):

There are social occasions where I miss it, and I think you don’t have to cut it out, but I’m doing experiment. And so that’s my life. Now, I’ve lost a fair amount of weight, I used to be 149 pounds, 150 at max, and I’m now 132 and I feel great, I look great, I have a lot better energy. So that’s really the thing.

David Sinclair (00:15:43):

And then the Inside Tracker data also says that I’m doing really, really well, I’ve gone down in age by a few years since I’ve started on this diet. I miss meat, I wish meat extended lifespan, I would eat meat all the time, but the data just says, that’s not going trying to help. You will feel great in the short run, there are a lot of carnivals who tell me, I don’t know what I’m talking about, because they feel great.

David Sinclair (00:16:04):

And if you feel great, that must mean it’s good for you. Well, that’s not true, what you have to think about is that there are two states of the body, well, there’s three, I guess, there’s homeostasis, but then you’re either an adversity or abundance. Abundance will make you feel energetic and grow your body, so more muscle.

David Sinclair (00:16:23):

And then there’s the adversity nomedics or the adversity signals, which it supplements and my lifestyle are aimed at mimicking. And you still have the energy because your body adjusts, but your body fights against aging, because it’s worried that it might die in a couple of weeks time. And that’s what fasting, and exercise, and the supplements, and cold, and heat are designed to do is to get the body to be afraid of dying in the near future.

Casey Means (00:16:48):

That’s an awesome overview. And I think one of the things I’m most excited about with personal real time monitoring is to just totally pull the rug out from under these diet wars, carnivore vegan, I’ve been plant-based for a long time and it’s one of the things that’s been so interesting is showing on social media or whatnot, like these are flat levels with a plant-based diet that it shocks people.

Casey Means (00:17:07):

And I think when we can dial that up another notch, like what’s happening with your MTOR signaling on a carnivore diet versus a plant based diet? What are your branch chain amino acid level? Whatever it is to actually start getting more clarity on the longer term sort of lagging indicators aside from just glucose stability. So I think we’re very excited about those things as well.

Casey Means (00:17:27):

And I want to shift gears a little bit and ask you about the future of really evidence based medicine. You said something on Joe Rogan, an amazing interview that everyone should watch, three hours with David Sinclair, but it was about how a lot of your lifestyle, food, and supplement choices, or some of them are extrapolating from animal research and from observations of cultures who have lived a long time. And we can’t wait for science to prove it all, we’re sort of in urgent moment where you got to get this figured out.

Casey Means (00:17:56):

And I think this approach certainly can be chastised by the conventional metal community, like if you’re just extrapolating from animals, it’s not evidence based, where’s the RCT, randomized control trial, et cetera.

Casey Means (00:18:05):

So given the new era, that’s emerging, that’s inevitable of personal tracking and monitoring, I’m curious about what your model is for thinking about future validation of therapies and what you think the future should look like in terms of process for validating and regulating new therapies, is it all going to be end of one? Is it going to be different type of RCT? Where do you see it going in this new era of monitoring?

David Sinclair (00:18:30):

Well, I don’t see the FDA changing in a hurry, so that’s not where the innovation’s going to come from. As much as they say, they’d like to speed the process up it’s still a few 100 million dollars per drug at a minimum because of all of the regulations, which of course, in place for good reason, there have been some terrible historical events where a drug has killed people, we don’t have that to ever happen again.

David Sinclair (00:18:50):

But at the other end of the spectrum, we have 100,000 people dying every day from age related diseases that I think could be tackled if we had better ways of getting drugs on the market that were more efficient. And by more efficient, I mean less costly, it’s so expensive to make a drug, that’s the problem. And sometimes people say, “Well, why don’t you just stick to your lab? Why do you have to start these companies?”

David Sinclair (00:19:11):

Well, that would be great if I could get 500 million dollars in my lab and run a clinical trial, but I just can’t and get a drug in the market. So if I’m going to make drugs, I have to go out of the academic circuit. But I think we now live in an era where we are able to take our health into our own hands and see what works for us and what doesn’t, both as individual buying products that are legal and available online or in shops, of course that’s nutraceutical area, there are some cosmetics that are active as well.

David Sinclair (00:19:41):

And then when you get into pharmaceuticals or regulated molecules, you can work with your doctor, such as it’s becoming more standard to ask your doctor for Metformin before you have type-2 diabetes. And those two models will continue to play out.

David Sinclair (00:19:54):

But the biggest innovation is going to be at least until the FDA declares aging a true disease, which hopefully will happen in the next five to 10 years, where the innovation’s going to come is that people can look at what works for them. And so when the traditional medical establishment says, “Oh, we have to wait till it’s proven in a clinical trial,” I would push back and I would say, “Nothing is proven in biology.”

David Sinclair (00:20:16):

And until you take it, we don’t know what’s going to happen. And all drugs are unsafe in fact, and while it may be safe in 1000 people, there’s going to be one and it could be you [inaudible 00:20:26] that reacts better. And so it’s all about individual personalized medicine at this point, but to do that you need to measure things and be very careful about what you choose to put into your body and who’s supervising you.

David Sinclair (00:20:38):

And my approach has been, and I think this is the one that is becoming more popular, only change one thing at a time and then take a reading and see what happens to your body, do things get worse? Do they get better? Is your liver okay? Are your kidneys functioning okay? Is that product from that company okay?

David Sinclair (00:20:55):

And if it is, keep taking that and try something else. And that’s why my regime that I have, it wasn’t just made up yesterday, it’s taken over a decade to get to this point, even with the particular brands that I take. It’s not perfect but it is all we have right now, we have to work within the law and technology.

David Sinclair (00:21:13):

But I’m not one of these people that says I’m going to wait another 20 years till it’s proven because first of all, there’re going to be a lot of people who die tomorrow. Second of all, I’m probably going to be fairly sick at that point. My father will be dead for sure if we don’t do something.

David Sinclair (00:21:28):

And it’s like, people say, “Oh, I don’t know what’s going to happen if I take supplement X?” Okay, nevermind the fact that it’s already been taken by 100,000 people for the last five years, that it’s been clinical trials, it’s been in animals for years.

David Sinclair (00:21:41):

There are still some people that say, “I need proof,” but let’s face it. If you wait for that proof, it’s going to be too late for most people. And so I think just choosing molecules and vendors of very high quality and seeing what happens, you can escalate the dose carefully, that’s what’s done in clinical trials.

David Sinclair (00:22:00):

I think that’s the way to go and that’s far better than taking a handful of pills and never measuring anything, you could really be doing yourself some harm. But I would say that’s important is first of all, I’m not a physician, I don’t recommend anything, but you do want to tell your physician that you’ve taken these molecules so that they can make sure that if anything bad happens, they know what to do about it.

Casey Means (00:22:20):

Yeah. I’m certainly excited for maybe also a future world that bridges these two, the standard way that we validate things through randomized control trials but also what does that look like when all of the participants are wearing lots of monitoring technology? They’re totally hooked up, and so we start to be able to some stratify within these populations right now, it’s all about the averages.

Casey Means (00:22:41):

For the average person, this had a clinical effect and didn’t have side effect, which doesn’t really work for the individual. But if we have that metadata of all the people taking some drug, or therapy, or lifestyle intervention, be able to sort of sub phenotype, how are different groups of people responding based on different biomarkers? Maybe there’s an avenue there towards moving within our conventional system of validation towards a little bit more of a biological observability framework.

David Sinclair (00:23:08):

100%. Do you have a million hooked up with bio monitors? You’re going to learn within a matter of months what works and what doesn’t. And you can have doctors who agree to do a trial off label to see if a drug works or a supplement with a manufacturer that guarantees that it’s pure, and the amount in the capsule is what you say.

David Sinclair (00:23:25):

But 100% that’s the way it needs to go. It’s just been slow, I tried to do this years ago, 15 years ago, I tried to do this and it’s just hard, I think the main barrier is that we don’t have good monitoring and we don’t want to just ask questions, is how do you feel? All of that’s really not good, but yeah, Levels is the company that can do that for the population, and not just help an end of one, totally agree.

Casey Means (00:23:51):

In terms of that, in terms of more mainstream adoption I think another question I wanted to chat about is a lot of the movement towards being able to see inside the black box, the body increasing biological durability right now is really direct to consumer. We’ve got like Levels, Inside Tracker, or a Whoop to monitor yourself, you’re kind of going outside the system.

Casey Means (00:24:10):

And so I have two questions. One is that I think if one insurance company starts using some of this tracking stuff and realizes that it’s helping make people healthier and costs are cut, it’s going to just be inevitable that the others are like, “Oh gosh, we should get on board with this, we can have costs savings.” But how do you see the domino effect happening from direct to consumer into the system and semi-relatedly, what are you seeing right now in your world that is most exciting and promising in terms of biological observability?

David Sinclair (00:24:40):

Well, the other area are obviously these external bio monitors, and those are advancing really rapidly. There’s one company I know of, it’s called BioIntelliSense, you may have spoken with them. I know the CEO, well, they have made a couple of product ones with sticker on the chest, the other one is a double bigger sticker.

David Sinclair (00:25:00):

They both do ECGs for the heart, they measure motion, coughing, breathing, and they have algorithms that are able to know through machine learning, detect whether you have the flu, or pneumonia, or COVID, and it was originally designed for the hearts.

David Sinclair (00:25:16):

Well, the other reason that they’re important to mention is that their FDA approved and hospitals are starting to use them to send patients home early to monitoring. So they’ll just get better, and better, and better. And there’ll be a point where doctors don’t just want to send people home with them, but we’ll send them a monitor to where a couple of weeks before the annual checkup so at least they have some data to look at when they come in other than being blind.

David Sinclair (00:25:39):

But where I see the tipping point is that if a device can save a life, for instance, this bio sticker can predict a heart attack a week early, theoretically, maybe it can, maybe it can’t, I don’t know, but let’s say it can. And someone dies from a heart attack, and a hospital did not provide it, and it costs $20.

David Sinclair (00:26:00):

The family will sue the hospital and say, for $20, you could have saved my father or mother’s life, why didn’t you do it? And they the going to get millions of dollars in compensation because their father is dead from then on, of course every patient will go home with a $20 monitor because it’s too dangerous to risk somebody dying without it.

Casey Means (00:26:18):

I think that’s really interesting. You can imagine a similar situation, even for something like a continuous glucose monitor, as we start to have in the last 18 months, more adoption of this as a proactive measure, you can imagine people potentially developing diabetes down the road and saying to their doctor, “What the heck, you’re giving me a CGM now, this would’ve been really nice 15 years ago or something,” and it’s like… But as the bottom line also starts, we know how expensive it is, the healthcare system when someone has developed a chronic disease like diabetes, heart disease, et cetera.

Casey Means (00:26:52):

And this is where I think some really evidence in this space of showing improved outcomes over time with these preventatively are going to hopefully help move this forward even quicker. But even those conversations like what you’re talking about, maybe not a lawsuit but just people just starting to say to their doctors and be aware of like why didn’t I have this earlier? This would’ve been so, so helpful. And hopefully shifting from the bottom up through awareness.

Casey Means (00:27:16):

Well, Dr. Sinclair, we are so excited to work with you to build this world and this vision that I think we both have, and that you described so beautifully in the book. I mean, in the book, just hearing about what your vision for futures, doctors appointments are going to look like and how it’s all going to work, it’s truly exhilarating, and we could not be more supportive of your work and more aligned.

Casey Means (00:27:37):

So thank you for taking the time to chat for a few minutes with me. And I want to turn it back over to Ben because our members have some amazing questions for you. And so we’ll dive into those, but thank you so much for chatting.

Ben Grynol (00:27:48):

Perfect. Thanks, Casey and thank you, Dr. Sinclair, very fascinating to listen to the discussion thus far. The first question from Tracy is around eliminating aging as a disease. So Tracy, if you want to dive in a little bit further.

Tracy (00:28:02):

Hi. Thank you, Ben, and thanks to you guys. I’m just so honored to be able to be part of this, this is awesome. I love the book. The podcasts are great but they left a lot of questions that even in a long podcast like that you don’t get time to answer, so a lot of the detail in the book really helped clarify for me your thinking.

Tracy (00:28:20):

And one of the questions I had was about, if you talk about aging as a disease as opposed to how we generally think of aging as the inevitable decline, what words do you use to describe advancing in years versus if you’re reserving aging to imply like disease and this decline as we normally have, what words do you use to talk about that? And in a future world where you can actually eliminate all of these negative physical aspects of aging, then what’s left?

Tracy (00:28:52):

If you think about someone being born, and maturing, and then getting to a point, and then aging, and the decline, if you could eliminate all of those causes of disease of aging, where do you get left in theory in terms of your chronological age and is there optimal chronological age that you would theoretically stay up forever? I’m trying to get my head around, what does this actually look like? If everything you said is true and we could figure it out, what does that lifespan look like?

David Sinclair (00:29:20):

Right. Good question. So there are two numbers that we have, there’s the chronological age and the biological age. Chronological age is simply the number of times the earth has gone around the sun, that’s hard to stop. So that’s going to tick over no matter what we do.

David Sinclair (00:29:33):

But the revelation and realization of scientists and revelation in the public is that our biological age is different than our chronological age, and that we can change it backwards and forwards. In my lab, we can drive aging forwards in a mouse and backwards, that will, it’s easy. We have control over aging very precisely now.

David Sinclair (00:29:51):

So what does that mean? It means you can choose your own biological age, in the future you can choose to be 30 and stay 30, choose to be 50 stay 50, but being 50 and biologically 40, which is basically what I am, doesn’t mean I have the wisdom of a 40 year old, I have a wisdom of a 50 year old.

David Sinclair (00:30:11):

So if you extrapolate, I could be 100, you could be 100, still have a 40 year old body and have the wisdom of 100 years living, that’s what’s exciting me. So you’ve got the biological clock you can control.

David Sinclair (00:30:24):

And then the chronological age in my view just gets better and better with wisdom and experience. So I don’t want to stick to any particular chronological age, I don’t mind that that advances, as long as my biological age is slow or even steady.

Tracy (00:30:40):

Got it. Thank you.

Ben Grynol (00:30:42):

Very cool. Well, April is on the call, but she is having some trouble with her audio and video, so I will do my best to provide some color for her question, but it’s a really interesting question around, she works in healthcare and a lot of times when people are in a certain field, it’s hard to communicate broader knowledge to people to make it accessible.

Ben Grynol (00:31:03):

So the book is very technical, there’s a lot of great information, but it’s one of those, I’m going to read it three, four times so that you can start to be a sponge. Her question is around, how do you make this information more accessible and more digestible to people so that they can start to relay it back to the greater community?

David Sinclair (00:31:20):

I’ll address your question, the first comment is I didn’t want to dumb it down, because I believe in the intelligence of humanity and that’s been born out, it was not dumbed down and it still became a best seller, which to me is just great news.

David Sinclair (00:31:35):

I’m writing my second book, I’m not making it as technical but I’m certainly not going to talk down to anybody. And I am very pleased to hear that many people do read it multiple times and get more out of it every time, I still read it and get stuff out of it, believe it or not. That’s the good news.

David Sinclair (00:31:51):

The way to reach more people is to get to the people who don’t read books, I don’t know what percentage of people read books, at most it’s got to be 10% at this point. What about the rest of people? So you can read since through podcasts, which I’ve been doing, and I did decide, and I’ve recorded my own podcast which is coming out in January, and you’ll hear me every episode reading an advertisement for Levels Health, I can recite for you all the good things about Levels and why I use it.

David Sinclair (00:32:21):

So there’s podcast and then there’s going to be, I’m going to see if I can venture into more mass media without ruining my reputation, I haven’t decided yet how to do that, but it might be a documentary or some sort of series on TV. Because that’s really the only way to reach truly millions, tens of millions of people, and that’s really the goal here.

David Sinclair (00:32:39):

But you know people digest information differently, and we are all in the top 1% measuring ourselves, reading a book about aging, there’s still a lot more people to reach, and we’ll just keep going down the various levels of media. I didn’t mention social media, but that’s probably the best way and that’s why I have built up a following on social media not because I care about the numbers and for my ego, it’s because it’s a platform to reach people that you normally wouldn’t be able to reach.

David Sinclair (00:33:09):

And that has been a real revolution in my ability and scientists ability to talk to the public directly, before you know what it was like 10 years ago to be a scientist, it was a nightmare. We would talk to a newspaper, they would have an agenda, they’d write a stupid title, especially with aging.

David Sinclair (00:33:25):

Harvard researcher says we’re all going to live to 200 and it would just be embarrassing to my colleagues, to me. It’s different now, I barely ever talk to a newspaper, I talk directly to the public through social media and through podcasts, and that’s the best way.

Ben Grynol (00:33:38):

Love the headline that you provided some color on because you can visualize it exactly happening, but now there’s more agency and license by you owning the platform, by you having the platform to provide color so that the information you put out is on your behalf as opposed to something that might be misconstrued in the way it’s approached from a media standpoint.

Ben Grynol (00:33:58):

To highlight one thing you said, so very cool about thinking the way we can make information more digestible with other forms. I listened to the audio book and loved how you had the standalone pieces of just discussing it with your co-author, and it made it feel more digestible to think, how did you come to some of these conclusions for each chapter?

Ben Grynol (00:34:16):

So really enjoyed that and thought that was quite beneficial. Lisa has a question that I think regardless of the industry somebody is in, we all wonder who do the thought leaders look up to as thought leaders? So Lisa, if you want to jump in, it’s a very interesting question.

Lisa (00:34:31):

Yeah. I’m just wondering who is your HG Wells or gene run very up the day? Who are you listening to? What are they saying? What are you finding intriguing, or interesting, or maybe something that is not confirming, something that’s against where your thought process is going?

David Sinclair (00:34:50):

My answer is going to shock some of you and for the rest of you, it’s going to disappoint you. I go around the world giving talks and often I’m told you should read this book or you should watch this movie, it’s exactly what you’re talking about.

David Sinclair (00:35:03):

I went to the Pentagon many times and they said, “Oh, this is just like this movie.” And my answer is I haven’t read the book and I haven’t seen the movie, but it sounds great. The closest I’ve seen probably is Gatica, but here’s the sad thing is that I used to have a lot of time to read fiction and a lot of science fiction, but I don’t do that anymore, it’s partly because of time, but it’s also because I like imagining my own future, I’m very good at imagining things.

David Sinclair (00:35:31):

And I’d rather to be honest, not be contaminated by other people’s visions of the future I might get locked into something that’s someone else’s idea. And it’s the same for science, I like going to conferences, it’s great. But I try not to get distracted by too much other stuff and get locked into the dogma because dogma is typically wrong and I’d rather be this free flowing mind and just let it expand.

David Sinclair (00:35:53):

So usually what I do when I’m talking about the future is with people, guys like Brian Green and like Friedman, George Church who’s in my department. We talk and dream about the future together. And that’s my main inspiration, the rest is just what I dream up and when I’m lying in bed at night, thinking about what the future should be like, if it was a perfect world.

David Sinclair (00:36:13):

Speaking of perfect world, I got to chat with William Shatner last night, which was a real thrill for me because as a kid, I was inspired by that somewhat perfect world. And I still feel like we are aiming to get there, and that, that may be what drives me each day is that knowledge that humans can do better, and I just want us to get there as fast as possible.

Ben Grynol (00:36:33):

Awesome. Thank you for that. Next is Eva. So Eva has, maybe a bit of a philosophical question around how longevity pertains to things like natural resource consumption, climate change, and our impact on the world so Eva, if you want to jump in?

Eva (00:36:50):

Yeah. Great. Thank you so much, Dr. Sinclair. I know that you’ve talked a bit about this in the second part of your book, answering the question of, if we live longer, what happens to our planet and can it sustain us so many people at once? It’ll be awesome to see your great, great, great grandkids, but are we perpetuating the decline of our planet in that process as well? I know you’ve touched on this quite a bit in the book, but I’d love to hear any current thinking that you have on miss as well.

David Sinclair (00:37:19):

Yeah, thanks. I do think about this every day. And since I published the book, somebody said something that stuck in my mind, which I want to repeat. They said, when you hear about the news for a cure for childhood leukemia, the reaction isn’t, “Oh, that’s going to ruin the planet with all these kids staying alive.”

David Sinclair (00:37:37):

So why do we have that reaction when we are trying to keep middle aged and older people alive? So that’s one, the second thing is I’ve put some numbers where my mouth was or my head was and published a nature aging article on the cost savings of extending lifespan by a year or 10 years in the US, and the value to the economy over the 30 years after that discovery would be in the trillions of dollars. And I mean, the numbers are actually 86 trillion for a year and 365 for 10 years.

David Sinclair (00:38:11):

Now that’s a lot of money, that’s currently wasted on what I call sick care, not healthcare. And that money can be put towards education, developing new technologies to treat [inaudible 00:38:23] or prevent climate change, that’s a lot of money. And it really is all about the allocation of resources and money.

David Sinclair (00:38:29):

Now, humans can achieve anything and they can either be making widgets or repairing crash cars, or I don’t know, pumping oil out of the ground, but if you have money to spend on other things, you can put people to work on really productive things rather than things that are just currently perhaps too expensive.

David Sinclair (00:38:49):

And if we say this money, we can use that wisely. In terms of population, both a lot of people worry that we’re going to be overpopulated and the numbers just don’t pan out, we’re already in most of the world approaching levels of replacement and actually in the US and Europe, we’re actually declining.

David Sinclair (00:39:06):

Japan’s already in that process and that’s a disaster for the economy, if we don’t do something about it, our kids and our grandkids are going to suffer badly economically if we don’t do something to keep people productive for longer, and that’s what we’re talking about here today.

Ben Grynol (00:39:19):

Perfect. Dolph has a question around the potential downsides to taking NMN later in life. So Dolph, if you want to provide some color?

Dolph (00:39:28):

Yeah. I thought it was a really compelling story in the book and a better build a swallow, and you talked about your dad and his experimentation with that. I’m just curious, when he told you that he was going to go down that road, what scared you about that? What were you worried about?

David Sinclair (00:39:43):

Yeah, if I was worried about it, I would advise him not to do it. Most of my, actually all of the things that I do are based on the knowledge that it’s extremely, extremely unlikely that it’s going to do any harm. I typically take molecules that have been in the body already for millions of years.

David Sinclair (00:40:01):

NMN has been in the body for billions of years, and what we are doing by giving NMN is replacing what’s lost with age. Speaking most generally, tissues decline in their NAD production, NMN being a precursor by about 50% by the time you’re my age, and I can raise those back up. And I actually know a lot more than the public thinks about the effects of NMN on the human body, they’ve been helping do clinical trials for about three years now.

David Sinclair (00:40:29):

And we know it’s safety, to some extent, we know how much it raises NAD in the body in which tissues, and we’ll even have some efficacy results tell you about next year, in mice, it extends their lifespan, it appears we’re doing more mice, but it looks really good, especially in females, and it reduces obesity, improves lean mass, improves their metabolic flexibility, and delays their frailty, which is based on 20 measures of health, including hearing and eye sight.

David Sinclair (00:40:58):

So based on all of that, I’ve had no issue with my father choosing to take it, I couldn’t stop him, he’s a grown man, he’s a scientist himself. But I don’t have any concerns, there is something on the internet, unfortunately, that like a lot of stuff on the internet, that’s just hype. It’s in the same realm as Metformin prevent you from building muscle, this one is that NMN will make your cancer grow more.

David Sinclair (00:41:18):

It comes from a study from Washington University where they depleted NAD from brain cancer cells and they grew slower, and the PR department of Washington put out a press release saying NAD makes cancer cells grow. Well, yeah, right. That’s kind of a misreading of the data, especially when you need a NAD for life.

David Sinclair (00:41:39):

So having less of it, of course, is going to make cancer cells grow slower, but giving them more doesn’t seem to do that in our hands, we’ve tested it in a couple of cancer models. In an abundance of caution, if you had a tumor, I wouldn’t take NMN because we don’t know, but if you’re healthy right now, there’s no evidence that it should have any negative side effects.

David Sinclair (00:41:57):

The biggest side effect that we’ve seen anecdotally is in perimenopausal women, it might improve the health of the ovaries and put out more hormones, they tend to have shorter menstrual cycles and heavier ones, but other than that, and that’s consistent with our mouse study showing you can reverse infertility in old mice. But other than that, I don’t know of any downsides taking NMN, and we haven’t seen anything in the clinical trials either.

Ben Grynol (00:42:20):

That’s great. Maria has a question around lifespan and any research pertaining to mental health. So anyone who has a genetic predisposition towards mental health. Maria, you can provide more color to the question, but teeing it up of you.

Maria (00:42:36):

Hi, thank you so much for being here and taking discussion. I think extended lifespan and health span is so remarkable and I love the book and really am excited about it. But and I didn’t even really think about this, but I do have a brother with severe mental health challenges and daily life is really a struggle for him, and I wondered if in all of your research or thinking about this, I mean, it’s really exciting when you’re really healthy and you have everything going for you, but if daily life is a struggle in that respect, and it’s probably environmental, probably genetic, he’s had it for a very long time, but I just wondered what your thoughts were in that area?

David Sinclair (00:43:21):

Yeah. Well, we talk a lot about aging, but actually what we’ve discovered are the body’s defenses against disease and that’s not just age related diseases it can be applied to enhance the resilience and defenses of the body, even in children. NMN or at least a version of NMN is being tested now in a disease called Fredric ataxia as part of a company that I started out of my lab.

David Sinclair (00:43:44):

And that’s just an example. And that disease affects kids in their teens through their thirties, they end up in wheelchairs. And so what gives me hope is that these molecules should be able to help people of any age, with potentially, I wouldn’t say any disability, but it’s pretty broad from reducing inflammation, we’ve seen results in humans already within a certain one activating molecule through to mental problems, we do see improvements in blood brain flow in animals.

David Sinclair (00:44:10):

And we’re testing this in people now and perhaps even changes in mood, we see some evidence that it improves positivity as well. But yeah, I would say that we talk a lot about helping healthy people stay healthier, but that’s really just one part of what we’re hoping to do with the science.

Ben Grynol (00:44:28):

That’s great. We’ve got another question here from Natalie. So Natalie, I think you’re still on, on the call here, but it’s around ethnicity and some of the research pertaining to lifespan and longevity.

David Sinclair (00:44:41):

Yeah. We’re still in the dark ages there, we as a field we’ve only just started using females, now studies let alone, people for in different races. And we live in a time where that’s very for the forefront of our conversations, but because it takes a while to get results from clinical trials, we’re still in the dark actual about that.

David Sinclair (00:45:05):

Now, I’d be surprised if there are not ethnic differences, racial differences in mice even strains of mice, have different effects when it comes to calorie restriction, some calorie restriction protocols will support certain strains of mice and others will live longer.

David Sinclair (00:45:21):

And that’s until we have the data on effects of different ethnicities, it’s even more important that individuals measure themselves to make sure that what works for a white male will also work in an African-American female, for example.

David Sinclair (00:45:35):

We also look at data typically at Levels and at Inside Tracker, from the wealthier part of society and they skew ethnically as well, and so we have to remember that there’s a whole other group of people that are not typically being equally measured. And my goal would be hopefully yours too, it’s to democratize this and get it out to everybody as fast as we can and as cheap as we can.

Ben Grynol (00:45:59):

Awesome. There’s one last question here. And Taylor is going to jump back in with a few questions, but there is one part in the book and then now I can’t remember if it was the book or the side conversations that you had with the co-author, but you said it’s so interesting to write a book that is research based because it’s just evolving so quickly that it’s like by the time you’ve written something, the last chapter you wrote, you’re like, “I want to go back and change that,” but you have to button it up and put a bow on it eventually.

Ben Grynol (00:46:23):

And so Tina had a question around, is there anything that you wrote in the book that your outlook has drastically changed just because research is evolving so quickly? And it sounds like when you were saying it, it was like on a daily basis you’re like, “Oh my goodness, this is brand new.” So would love to hear some thoughts on that?

David Sinclair (00:46:41):

Sure. Well, the good news is that the basic scientific principles, if anything are much stronger than 2019, many of you will have seen that the field of epigenetic reprogramming and age reversal since our paper came out in nature a year ago is just the field’s exploded, with the likes of Jeff Bezos and Brian Cunningham from Coinbase, getting involved with lots of money, there’s been at least 20 billion dollars invested since our paper came out, I can’t take credit for it all, but it certainly didn’t hurt.

David Sinclair (00:47:09):

So that’s been a big change since the book, but the fundamental science is the same, so that’s great. Because I wrote the book when epigenetics and aging was not even on the radar for most people, so that’s held up. The interesting thing though, was that the science that’s in the book was written and published in the book before the scientific paper came out in nature, which I think doesn’t happen very often.

David Sinclair (00:47:29):

Luckily, I didn’t get destroyed there by my colleagues for doing that, talk about scooping yourself. But if you ask me, what’s the big change? Well, I predicted that there was going to be a pandemic at the end of 2019, three months later, it came out or months later. I wish I was wrong about that.

David Sinclair (00:47:47):

So my thinking about that was that this was going to be some time in the future, maybe 10 years I was wrong, it came months later. My thinking actually has evolved also to be, I think I was too conservative, I didn’t realize that the amount of attention and money would come into this field and you can achieve a lot with 20 billion dollars, that’s like putting the whole NIH on one topic.

David Sinclair (00:48:11):

And so I think my timelines might have been out. I thought I was already optimistic, Met Laplant was pushing me to be super optimistic and I did, but I really think that it’s possible now that we will be able to reset many parts of our body within our lifetime.

David Sinclair (00:48:25):

But yeah, I think I’m much more optimistic, I now believe that with this infusion of research dollars and development of drugs, that’s going to happen, we might, within the next 10 years have the ability to reverse the age of certain organs, perhaps within 20 years, the whole body. Already there are people, doctors that are claiming to have sent their age back by 10 years based on the blood methylation plot. I’ve seen it in myself that I’ve gone back according to those clocks by at least a couple of years. And that’s all you need to do every year to have a big effect on lifespan.

Ben Grynol (00:48:56):

That’s great. Well, we’ll turn it over to Taylor, he has a few questions and if anyone else has questions, please put them in the chat and we will get through a couple more.

David Sinclair (00:49:05):

I see a question from Julie in the chat.

Ben Grynol (00:49:08):

Oh sure. We can do that first. Let’s do it.

David Sinclair (00:49:10):

So I don’t know what 14.5 is for telomeres, but so telomeres were the old way of measuring aging and they’re still somewhat relevant, some aspects of aging do seem to be important for the health of the body, the immune system, the liver.

David Sinclair (00:49:25):

But what we’ve, the scientific field has found is that telomeres actually do grow and shrink, you can’t link the in them, they do bounce around a lot more than the epigenome does. I think ultimately, if we’re going to live for hundreds of years, we have to address telomere length.

David Sinclair (00:49:39):

But I think that the best path too, to this is to work out how to reprogram the epigenome and that’ll actually take care of things. We find that we can regroup telomere is when we reprogram cells to get younger, then telomeres will grow longer. The gene expression gets set back to 80% of what it was, or at least 80% of age.

David Sinclair (00:49:57):

There are some drugs and some supplements that are in clinical trials that look somewhat promising as well, but I know that, that’s not a perfect single binary answer, but the summary would be that, yeah, we have to address those at some point, but I think that what we’re working on in the reprogramming space can take care of that and the other eight pull marks of aging.

Ben Grynol (00:50:18):

That’s great. And that’s actually a really good segue to where I was hoping it could go for a little while, I mean, I think you’re actually you are pioneering this work, but if we do so let’s zoom ahead a couple of years, and medical societies and the FDA are finally accepting that aging is disease, right?

Ben Grynol (00:50:35):

We now have that designation, we now just like with cardiovascular disease, with diabetes, we need to establish what the biomarkers are and the subclinical to clinical it’s a chronic disease, right? So it goes over some period of time, and then we need to have diagnostics and therapeutics that are going to be given over that course.

Ben Grynol (00:50:53):

So what’s the process like if you had to, none of us love the way that clinical trials are designed, you talked about the fact that lots of different people are left out of those trials. What would be the process that you want to implement for this new designation, and in uncovering, and treating this new disease, would you stick with the randomized control trial? Would you do the R1 trials? Should we be thinking about something else?

David Sinclair (00:51:19):

Yeah, I can think of at least a few stages. The first stage is what we’re doing now, which is NF1 studies showing at least in some individuals that with your own self, as your negative control starting point, measuring blood biomarkers, including glucose, but also and including epigenetic edge, and telomere length, that’s still part of the determinant of your ultimate longevity.

David Sinclair (00:51:43):

And learn that way very quickly already in over the last year we’ve seen some successes, we’ve actually seen also some published papers where changing lifestyle, Mediterranean diet, exercise, some supplements, advocated gluco rate, seemingly reversing, slowing if not reversing age.

David Sinclair (00:52:00):

So that stage one, that’s self experimentation or in a small clinical trial with each person being their own control. The next stage would be to have hundreds, and perhaps I said, millions of people who are being monitored, and then you give them intervention A and not intervention or a group that has not no intervention.

David Sinclair (00:52:20):

And then you can learn that way in lots of people. And that would be done perhaps by the public rather than in a hospital setting, and that would be a lot quicker and cheaper, of course.

David Sinclair (00:52:31):

And then the third way would be the traditional way, but that’s expensive, a trial would be 30 to 50 million dollars, but the standard way would be a double-blind, placebo-control, intervention, people come into the hospital, get measured and you have to do multiple hospitals and run it for four or five years and have a look at their frailty, of course, all the biomarkers that we’d want to measure in the previous studies I mentioned.

David Sinclair (00:52:53):

And then if you do enough people, you can actually also do lifespan, but that’s a lot of people, that’s thousands of people over age 70 that we need to do that. But at a minimum through all of those three steps, we’ll have a good idea as to where the aging can be slowed in humans.

David Sinclair (00:53:11):

Will it be proof that you can extend lifespan? No, there you need really a lot of people and under double-blind, placebo-controls, which is tough, right? If you’re doing it for a decade, it’s not easy. So that would be stage four, but I think we’ll get there in our lifetimes, so we’ll be able to say that this molecule extends lifespan.

David Sinclair (00:53:29):

And in the meantime, we are relying on these epidemiological studies, such as Metformin where tens of thousands of people have been looked at and they live longer on type-2 diabetics live longer on Metformin than people who don’t even have type-2 diabetes and take the probe, which is an astounding observation. But the real proof, if you want to call it proof has to come from prospective studies not retrospective.

Taylor Sittler (00:53:54):

No, that’s super helpful. And then let me push a little bit on that second type of study that we talked about coming, where we can monitor millions of people in order to do that well, we need to be able to draw some kind of a conclusion that’s beyond just a correlation, right? We need to be able to get some type of evidence that’s not randomized control trials.

Taylor Sittler (00:54:15):

So rather than go into the mechanics of clinical trials, I think there comes a point in time with many diseases where biomarkers can be synonymous with the progression [inaudible 00:54:26], so like you were saying, it’s very difficult to get to the point where we could definitively show that we’re improving lifespan, or we’re improving healthspan.

Taylor Sittler (00:54:34):

But if we take it for granted now that for instance, if I give a population statins and I’m able to reduce the cholesterol, that’s taken as reducing the incidence heart attacks, how long do you think it will be before we can take certain biomarkers of aging, e.g the epigenetic clocks that you’re doing and have enough confidence that those will actually be reducing or extending outstand.

David Sinclair (00:54:56):

Right. Well, we already know from Horvath’s work and others, that certain lifestyles will accelerate the clock and others will reduce it. And that’s looking at thousands of people. So unless you’re a total skeptic and you’re just a glass half empty person, you’ve got to look at that data and say, and by the way, Horvath’s clock, like GrimAge predict your longevity that way and even how long you you’re going to live from that point.

David Sinclair (00:55:26):

So you’ve got to look at that data it and say, okay, the clock is valid, it’s got 5% error, but still, you got to believe that it’s measuring something related to your actual aging and your future health. So I think we’re already there, I think that these clocks need bit more development. We need them in more people, but I have no doubt that we’re going to be able to use these clocks to predict someone’s future health and longevity, it’s already done in various studies.

David Sinclair (00:55:49):

Which means that if you reverse the clock and in multiple clocks, I don’t just mean a blood test because your blood might improve but your brain might not. We need a way to actually test multiple tissues, it could be a cheek swab spit, might be a muscle biopsy in some people, just a test and also blood.

David Sinclair (00:56:06):

But at least you need to see it happening in the multiple parts of the body to be more convinced that this is true. But with that, I think that at least, if you’re not skeptical in the next five years, we have a number of interventions that are well established and well accepted to slow down and if not reverse, and also reverse aging, including alpha acute glute, which looks promising senalytic molecules look promising for true age reversal.

David Sinclair (00:56:30):

That’s different than saying, “Oh, the mainstream medical establishment and the FDA agree that will take many more years.” And we know from the team study, the Metformin study that near [inaudible 00:56:43] life’s heading, is that the while the FDA is open to the idea of calling aging a disease, they need to see that you can reduce markers that are agreed upon that represent age, which includes frailty, cognition, and some blood biomarkers as well.

David Sinclair (00:57:00):

And that’s a lot of work it’s very expensive, so it’s different. I think acceptance within our community is pretty much going to happen in the next few years. Doctors will probably take maybe seven to 10 years and then the FDA could be even longer, but I hope I’m wrong about that.

Taylor Sittler (00:57:16):

Yeah. I think it’s a question of how quickly we can get the medical societies engaged.

David Sinclair (00:57:21):

Yeah. I sounded a little bit conservative there. I think with the pace that we’re learning to educate people with the books, with the podcast, with just people talking about this, it’s just a lot of buzz. I hope that we can accelerate this, but so far it’s happening at a grassroots level rather than the top down.

Taylor Sittler (00:57:39):

Yeah. That was actually my next question was, do you see any signs yet from the traditional medical community at moving? Because I mean, you’ve got a couple doctors here on the call who are in, but we certainly don’t look up the majority.

David Sinclair (00:57:50):

Well, talking to my circle of advisors and friends, there’s been a paradigm shift in the way they think, but of course my circle is not representative. I haven’t taken a survey, that would be a good thing to tweet today to see what happens, if you’re a doctor, what do you think?

David Sinclair (00:58:04):

I have faced the opposite, I faced criticism, particularly from one doctor through direct messaging that nobody should be allowed to use a glucose monitor unless they have type-2 diabetes to which I replied and then tweeted, that’d be like saying, people shouldn’t have bathroom scales in their bathroom to monitor their body weight, who’s to tell us what we can measure and what we cannot?

David Sinclair (00:58:27):

But anyway, you know where I sit on this, there certainly are these really strict opponents, even with calling aging a disease there’s, I had to just, I’m going to be publishing in a Lancer, a letter saying, “Please don’t reverse the decision to call aging a disease at the World Health Organization,” because there are some limitedly opposed doctors that say aging shouldn’t ever be considered disease.

David Sinclair (00:58:47):

And I don’t even know what it hurts. I don’t know why they’re offended, it doesn’t [inaudible 00:58:52] funny. I think just people don’t like change, and this is an example of that. But I couldn’t tell you, you might have a much, you probably have a much better idea of what percentage of doctors are on board with home monitoring of blood glucose versus those that are not.

Taylor Sittler (00:59:04):

Well, I mean, I have to say it’s been a slow shift, but the numbers are increasing, and I think part of it is that these services that incorporate glucose monitory are now getting traction across the board, and they’re now publishing studies, and I feel like the key to shifting doctor’s minds is just to, you just have to have this formula for producing the output and creating studies in a way that they can understand. And then it becomes part of the medical education. And it will be slow but it’s coming.

David Sinclair (00:59:32):

I see a question that’s interesting. I’ll go quickly and answer them all virtually. So the question in the chat is about whether anything that we work on can impact COVID. So, first of all, COVID very likely accelerates aging, it accelerates cellular senescences, we see that in my lab.

David Sinclair (00:59:48):

We can counteract that by deleting the senescent cells, and there are Fisetin and cosentino are two possible ways at least in the supplement world, so that’s one issue. The other thing that the virus does is it depletes NAD massively, if you Google it, you’ll see there’s a lot of papers on this. And there are some case studies at hospitals where patients have been given NMN and they’ve recovered rapidly.

David Sinclair (01:00:11):

And so we are doing well, Metro biotech is doing a COVID-19, NMN trial right now, and also kidneys as well, which is a problem for some patients. So those are the two things I think NMN might help certainly recovery and cellular senescence is a problem, is a senolytics might address long COVID.

David Sinclair (01:00:31):

But yeah, I think it’s important that people know, tell your family and friends that if you get a bad case of COVID, it might accelerate aging. If they don’t haven’t had the vaccine, they’ll probably go get one after they do that. Let’s see, the blue zones.

David Sinclair (01:00:43):

Yeah. So I totally agree that the science says that the environment is important, your social environment, your stress levels cortisol, we measure, I measure in my body, I try to keep that law. Now, it’s very clear that the data says that you need a social environment to live really long.

David Sinclair (01:00:59):

Now it can mean having a great partner you can rely on, or if not, or/and have a pet that you come home to. These are all shown to be great for longevity. And actually there’s a study that’s worth noting, which is that at Harvard, they followed, these were men, they followed them after world war I, I think it was maybe it was world war II.

David Sinclair (01:01:20):

Anyway, it was for their whole lifespan and looked at their health. And the one thing that was in common with the people that lived a long time was to have a reliable partner. And to me that’s striking it, wasn’t just what they ate, how much they exercised it was the partner, it was important. So yeah, I think being lonely really will accelerate aging. So big emphasis on that, big emphasis on the mind, meditation, peacefulness, mindfulness, calming yourself, not stressing about life too much.

David Sinclair (01:01:49):

That’s a quick way to accelerate at aging. Plant-based yeah, definitely a fan of eating, at least one fewer meals a day, I skipped breakfast, I’ve done most of my life skipping breakfast. And in the last year I’ve started skipping lunch, if I can, most days I do that, I’ll have some nuts or a supplement drink, athletic greens or something like that, or just add water as another product.

David Sinclair (01:02:14):

And then I get through to dinner and I have a nice dinner that’s hopefully big and if not vegetarian, and then let’s see all the stacking, so I do think that taking multiple supplements and doing multiple things, such as exercise and cold back has an added benefit.

David Sinclair (01:02:30):

Now, do I have proof of that? No, because try to do that clinical trial is never going to be possible, you’d need a billion dollars to do all of that and individually, but what I’ve done is I’ve added things on sequentially.

David Sinclair (01:02:43):

And so I’ve been slowly stacking these things over my adult life to a point where I’ve gotten to where I probably take 10 supplements a day, and my health has never been better. Literally never been better, since I was in my thirties and my age is calculated to be much younger.

David Sinclair (01:03:04):

I doubt that would be possible by taking one thing. In fact, I know that it’s not true because when I only took one thing was Virtual, I wasn’t this healthy. And then I added NMN and Metformin, it was great, but I didn’t get down to these levels. So all of these things, including my diet and my excess have gradually been getting the younger and younger over the last decade.

David Sinclair (01:03:23):

There’s a real question around athletes. I don’t agree that Metformin should be cut out of any plan, unless maybe you want to be Mr. Universe or Miss. Universe, actually, Mr is the only way that’s an issue. So Metformin, if you dig into the data, Metformin only reduces the size of muscles by about 5%.

David Sinclair (01:03:39):

And it probably only because you feel a bit weaker on that day, because it interferes with your mitochondria. But other than that, you can take Metformin on days you don’t exercise seems to be fine, and it’s only a 5% different. So unless you’re Mr. Universe or extremely Vain, 5% you won’t even notice.

David Sinclair (01:03:55):

And those muscles actually on Metformin were healthier just as strong and had less inflammation, some proponent of actually reading the data and not going on these rumors that are on the internet, cutting meals as an athlete. Well, I think that you can still do it, you don’t want to do it on the day that you’re running probably, but it’s amazing what the liver can put out in terms of glucose, you see those levels might a very steady that’s because of glucogenesis in my liver.

David Sinclair (01:04:21):

But on days that you run, you want to have more energy than just in your liver, especially if it’s a long distance one. So I would say you don’t want to skip meals on super training days or competing days. But I would encourage you to look at the documentary, what is it called? Somebody, remind me something games, the one [without 01:04:39] on Schwarzenegger?

Taylor Sittler (01:04:41):

Game changer.

Ben Grynol (01:04:41):

Game changer?

David Sinclair (01:04:41):

Pace changers. Yeah. And now you’ll see that a lot of athletes do just as well, if not better on a plant based on. So any thoughts on the impact of C-60 florins? So I’m open to the possibility, I know the lead author I am, I’ve talked to him about it. I’m currently… Interestingly, no one knows this, but I’m currently trying his product, which has Oleic acid fused to C-60.

David Sinclair (01:05:08):

And I’m going to see if it helps or not. If it doesn’t I’ll stop, if it does, I’ll keep doing it. But the effects were dramatic, I think it was close to 30%, 40% life span extension, it was crazy. So I’m open to, “Oh, you’re 90%? There you go.” That is truly insane if it’s true.

David Sinclair (01:05:25):

What’s the mechanism? Well, iron, thinks that it’s also [Methylprednisone 01:05:29] in the same way, exercise, hyperbaric, oxygen and Metformin create a disruption in their electron transport chain that release every radicals that creates [Mitoromisis 01:05:40] and you get health that way.

David Sinclair (01:05:41):

And he could be right about that, I really don’t know if that’s true, but that’s his theory, but I am, just to give something that is useful, more and more mechanism points to [Mitoromisis 01:05:53] as a productive way to boost longevity. And that’s why I’m bullish on exercise and Metformin as ways to do that.

Ben Grynol (01:06:01):

So this is fully qualitative in the sense that in places like the blue zones, let’s make an assumption that most people they’re very laid back, they consume different food, it’s a very different lifestyle, but there’s also this sense that in these smaller communities, there might not be the same media consumption that we have in North America, or in Europe, or any of these countries are on the continents where people almost get obsessed by media consumption, which is raising cortisol levels and you become consumed by, we saw it happen with the pandemic. How much of what goes on in the blue zones do you think has to do with versus, let’s just say North America has to do with longevity, or is that something that comes to mind?

David Sinclair (01:06:43):

I mean, that access to social media and other types of media affects them [crosstalk 01:06:47]

Ben Grynol (01:06:47):

Becoming obsessed, like as a society, there’s a societal obsession with always consuming, maybe things that aren’t positive in the news, and aren’t, everyone’s just immersed in this, and when you’re in that mind, say something you alluded to, when you’re in that mindset, you’re elevating your cortisol and you become wrapped up in the negative of the immediate versus having a 10,000 foot view of I’m present in this world.

David Sinclair (01:07:13):

I think there’s a lot to that. Your cortisol levels and possibly other molecules we haven’t discovered yet are circulated in your body when you’re in this heightened fright or flight state, which you based on my surveys of people that I meet, reached its height during the Trump administration and the election.

David Sinclair (01:07:33):

And since then, a lot of us, including myself, have gone cold Turkey on consumption of the news. And I’ve been just speaking to myself, much healthier, my cortisol levels have gone down and my mental state is so much better. I even talk slower than I used to. I mean, a more Zen like state, but before it was, “Oh my goodness, how many people have died today? What’s going to happen? World’s going to blow.” That’s not healthy at all.

David Sinclair (01:07:56):

And I can easily imagine it to be true that that reduces the longevity of an entire country, that’s watching it versus, or at least communities that focus on it, versus those that don’t. And what you hear also from people who live a long time is that they don’t worry about things and they don’t consume huge amounts of media.

David Sinclair (01:08:16):

And often they say it’s their sense of humor that has gotten them through. And that’s a common theme with these centenarians and actually it’s one of the few things that’s common, often they smoke, they drink, they do bad things, but being relaxed and having brushing off problems and not worrying is one of things that they all share.

Taylor Sittler (01:08:36):

It’s like we have one more question here from Casey. If you want to wrap it up, Casey.

Casey Means (01:08:41):

This is just kind of an off the wall. I went to this talk this weekend at a longevity conference, and it was talking about this grim Reaper clock in the pineal hypothalamus. And that pineal calcification, which can happen from long term exposure to melatonin is sort of upstream, the theory in this talk was it was sort of upstream of everything else with cellular aging.

Casey Means (01:09:00):

Just curious, how structural changes like that, that maybe irreversible, like pineal gland calcification relate to what’s happening more on the cellular and epigenetic level. And if we can bypass maybe central changes with more downstream therapeutic that affect the epigenome and whatnot.

David Sinclair (01:09:18):

Yeah. There’s a bunch of problems with melatonin. I’m guilty as anyone is taking melatonin, I probably do that three, four times a week. But I also am paying attention to this new data that looks like calcification is a major problem, not just for Alzheimer’s disease, but for normal aging as well.

David Sinclair (01:09:37):

You get calcification reduced volume of the pineal gland, and then you get decreased melatonin, and then you take more melatonin, it just makes things worse. And you’re going to reduce neurogenesis in the brain, increase inflammation, it’s just not a good feedback at all.

David Sinclair (01:09:52):

In some countries, they don’t allow you to have melatonin, I’m Australian originally, and you just can’t buy melatonin. It’s funny that it’s available over here and it’s hormone. So I’m cutting back my melatonin consumption and using other methods to go to sleep. I now, am mostly using gaba, and el thine, and some magnesium if needed.

David Sinclair (01:10:11):

I’ve taken myself off alcohol and Ambien that I used to need to get to sleep, which of course are extremely toxic and addictive substances. And so that’s the overall thing, which is to get away from the things that we know about and replace them with things that are at least apparently safe.

David Sinclair (01:10:27):

And I’ll tell you from my experience, I was in my late thirties and I was suicidal because I couldn’t sleep. It was really, really a bad thing. And through arming thoughts, I didn’t meditate, but I’m trying now. But just by reducing my levels of stress and taking these supplements nowadays, I have no trouble sleeping, it’s really quite something to have gone from that state to this. And I think it’s entirely due to that shift.

Casey Means (01:10:55):

Yeah. He touched a little bit on melatonin, like oral melatonin, the main focus was endogenous melatonin, just that we, because we’re producing it throughout our lifetime, it naturally causes in theory calcification, and it’s almost like this is our way of nature, controlling our lifespan by naturally producing something that then calcifies a part of our body that then leads us to essentially no longer to have hypothalamus dysfunction and then aging.

Casey Means (01:11:17):

And in trying to reconcile that with your book and the word was trying to figure out that model, like if this is happening and if that’s true, sort of more centrally, let’s say we really, throughout our lifetime, our pineal gland or hormone production glands become toast because of things like this, is that a block towards some of this stuff working or is it a different mechanism that we can kind of bypass what might be happening centrally through going straight to cellular epigenic modifications and whatnot through longevity therapies?

David Sinclair (01:11:47):

Do you mean specifically about the pineal gland calcification?

Casey Means (01:11:50):

Well, if there’s irreversible changes that happen with the aging like that.

David Sinclair (01:11:54):

First of all, what I’d say is there’s nothing that’s irreversible in aging, at least there’s no reason to believe that it’s irreversible, there are two things that people think are irreversible, well, three things that we’ve proven are not irreversible, blindness, dementia, protein aggregations in tissues, they can get eaten up.

David Sinclair (01:12:15):

And of course, we’ve reversed vascular aging as well, that was pretty easy, did that two years ago. But is pineal calcification reversible? I don’t know, we can try it, I think that it probably is if we just make the tissue younger, that’d be something to try.

David Sinclair (01:12:30):

You might know Casey, I don’t, but I do know melatonin will impact calcification even in the cardiovascular system, which you can try to slow down using vitamin K2, which will keep the calcium out of the arteries and put it into the bones. But do we know if K2 will help unloop them?

Casey Means (01:12:49):

I don’t know, that’s a really interesting question, not sure, future directions.

David Sinclair (01:12:54):

Yeah. Right. The thing mouse pineal glands, we throw them away. But do you remember if mouse pineal glands get old and calcified as well? Because we can easily check that.

Casey Means (01:13:04):

I think so. I think so. Yeah. And I think some of this work was in mice but I think the point you make that is so hopeful is that this idea of irreversibility maybe a more limited, our paradigm of your reversibility may need to be updated and modernized. So I think that’s a really good point for us to end on of just the body at the remarkable adaptive capability when it has the right conditions.

David Sinclair (01:13:34):

One more thing that we reverse that I’ve forgot to say is the ultimate irreversible aspect of aging, which is senescent, once you know the trick, it’s easier to make a senescence sell healthy again.

Ben Grynol (01:13:46):

Wow. Perfect. So never say never.