The Manosphere Report

0:00For the first time, we could take an old brain and we could give factors

0:03from a young organism and ask, is that going to change the age of the

0:08brain? And that's indeed what it did.

0:10So we saw that there are stem cells in the brain of these mice, that

0:14they got reactivated. There was less inflammation, more activity that we can measure in the

0:22brain. And then most importantly, we actually saw that their memory function improved.

0:27Welcome to the Huberman Lab Podcast, where we discuss science and science -based tools for

0:32everyday life. I'm Andrew Huberman, and I'm a professor of neurobiology and ophthalmology at Stanford

0:41School of Medicine. My guest today is Dr.

0:44Tony Weiss -Corey. Dr. Tony Weiss -Corey is a professor of neurology at Stanford School

0:48of Medicine and an expert in identifying factors that can help prevent and reverse organ

0:54degeneration and aging. Today, we discuss the factors that are present in young blood.

0:59Yes, you heard that right.

1:00And the factors that are present in blood after exercise that have been shown to

1:05rejuvenate the brain and other tissues in older individuals.

1:08Dr. Tony Weiss -Corey's lab has discovered several proteins that are present in high amounts

1:13when we are young and that circulate in the blood and that diminish with age.

1:17And if these are supplied to the aged body and brain, can reverse key features

1:22of aging, including improved cognition, tissue recovery from stress, damage, and more.

1:27We also discuss how aging is non -linear.

1:29It does not progress uniformly across the lifespan.

1:32And we discuss the fact that there are certain phases, such as puberty, your early

1:3740s, and your early 60s, when aging is accelerated and then slows again.

1:41We also discuss how different organs in your body age at different rates and how

1:45you can measure that. Today's discussion is a very important one because so often these

1:50days we hear about anti -aging and longevity.

1:52But today, you're going to hear about the real science of organ rejuvenation.

1:56We also are going to talk about the role of sunlight, fasting, hormones, and the

2:00use of specific molecular approaches to improve your vitality and health.

2:04We also, of course, discuss exercise and social interactions, but in the context of the

2:09specific molecules they release into your blood to promote and enhance health and how you

2:14can leverage that information. Tony Weiss -Corey is a celebrated pioneer in the science of

2:18these topics because of the rigor he applies to the work.

2:21He's not just talking about some molecule that someday there'll be a drug or some

2:25activity that we already know promotes health.

2:28He's an avid tool developer for measuring and reversing aging.

2:32So today we discuss all of that, and you're sure to come away from the

2:35discussion with both tools to improve your immediate and long -term health, as well as

2:39a deeper understanding of the biology.

2:41Before we begin, I'd like to emphasize that this podcast is separate from my teaching

2:45and research roles at Stanford.

2:46It is, however, part of my desire and effort to bring zero -cost -to -consumer

2:50information about science and science -related tools to the general public.

2:54In keeping with that theme, today's episode does include sponsors.

2:57And now for my discussion with Dr.

2:59Tony Weiss -Corey. Dr. Tony Weiss -Corey, welcome.

3:03Thank you. Dr. Tony Weiss -Corey, great to see another Stanford colleague here.

3:07Yeah. You're a true pioneer.

3:09Your work is the first work that I heard of where somebody did a serious

3:13experiment taking blood from a younger organism, putting it into an older organism, and observing

3:19very interesting things. If you would, could you tell us about that experiment and what,

3:25if anything, has been done in humans to examine whether young blood, such a loaded

3:30term, but young blood can be a rejuvenation factor for the more mature body or

3:36brain? Yeah. So we were actually not the first ones.

3:40Okay. But we collaborated with the person who, in sort of, in more modern times,

3:47used this model again. It's called parabiosis, where you have a surgical model where an

3:55old and a young mouse are paired, and their circulation allows for exchange of blood

4:01from the young to the old animal.

4:03And my colleague who recruited me, actually, to Stanford, Tom Randall, used this model to

4:10study aging of stem cells in the muscle.

4:13So he discovered that with old age, the muscle sort of deteriorates and doesn't regenerate.

4:21And when he used the mouse, an old mouse, and paired it with a young

4:25mouse, and now this young circulation infusing, if you will, the old muscle, he regenerated

4:34that muscle. And it looked almost like a young muscle.

4:38And at the same time, he also observed effects in other tissues, including in the

4:42brain. And that's when we started to collaborate and explored what could the effects of

4:50the brain, of young factors on the brain be.

4:54And in part, we were also intrigued by that because we had separate studies in

4:59humans where we tried to find blood signatures of Alzheimer's disease.

5:04And what we noticed is that we could see proteins that were correlated or even

5:10predictive of Alzheimer's disease. But the most striking difference was between younger and older people.

5:17So we thought that the concentration of their proteins was very different in young people

5:23and old people. And when you see something like that in biology, always ask, is

5:28this cause or effect? So do the proteins in our body change because they respond

5:35to the aging of the brain, for example, or do they actually drive the aging

5:40of the brain? And here Tom had this model that allowed him to ask that

5:45question or that allowed us together to ask that question.

5:48Because for the first time, we could take an old brain and we could give

5:52factors from a young organism and ask, is that going to change the age of

5:58the brain? And that's indeed what it did.

6:00So we saw that there are stem cells in the brain of these mice, that

6:05they got reactivated. There was less inflammation, more activity that we can measure in the

6:12brain with electrical activity of neurons.

6:16And then most importantly, we actually saw that their memory function improved.

6:21And so to your question, is that relevant for humans?

6:25We actually try to translate that.

6:27And we can talk more about this, where the stage of that field is right

6:32now to see whether it can be translated.

6:34Yeah, I would love to hear more about that.

6:36I realize in your description that most of us think about blood, of course, delivering

6:42oxygen and red blood cells, et cetera, et cetera.

6:44But of blood that's drawn as a good, not the only, but a good window

6:51into the health status, the age status of an organism, including us.

6:56But what I'm hearing is that it's also delivering nutrients or proteins of some kind

7:02that can reverse some sort of clock.

7:06And we'll get into later whether or not it's an organ -specific clock or a

7:09body -wide clock. But I think blood -borne factors generally I think of as a

7:14readout, not as a medicine.

7:18But you're talking about blood -borne factors as medicine.

7:20Yeah. I think that's really the fascinating aspect of this work that over the past

7:26few years people started to look at, that many of these proteins and probably other

7:33molecules in the blood, they're not just reflecting the status of the body, if you

7:40will, but they're actively influencing how it works.

7:44And the composition changes dramatically from young to old.

7:49We have this picture that I always like to show when I give a talk

7:53about our work where we have several thousand individuals and we measure 3 ,000 proteins

8:00in them. And then we use colors to show low levels or high levels of

8:04proteins. And you see this dramatic change from young people to old people in a

8:09way that you can pick one sample and you can say, this person must be

8:14about that old. And we can talk more about what people call clocks.

8:18But to your question, yes, there are factors in the blood that clearly can change

8:25the function of cells and organs.

8:27And what the field is trying to figure out is what are the key ones?

8:33Which ones could we use to slow down aging or to keep the body healthy

8:39as long as you live?

8:40So what has been done in humans in terms of an equivalent or pseudo equivalent

8:45experiment to the parabios experiment you described?

8:49To try to translate that, we started a company, Alkahist, to see whether factors from

8:58the blood of individuals could influence, first of all, aging of a mouse brain.

9:04So we took blood from young people or old people and injected it into mouse

9:08brains so that we could show that young blood could, in fact, mimic the effects

9:15of young mouse blood. So there were similar factors in humans as in mice.

9:20And then we went a step further and worked, collaborated very closely with a company

9:26called Griffos who is producing clinical medicines for hospitals based on plasma donation.

9:38So they have centers where volunteers donate plasma and then they pool this and they

9:45isolate, for example, antibodies. So if you're immunodeficient or you have cancer therapy and you

9:53are immunosuppressed, you will get regular infusions of antibodies that are sourced from healthy people,

10:02from these volunteers. Also, if you lose a lot of blood, you may get albumin,

10:06which is the main protein in our blood.

10:09So this company had this manufacturing process where they collect thousands of donations and they

10:15process it into different medicines.

10:18And this allowed us to test these different fractions and see which ones have an

10:23effect in the mice. And again, we could find some of them that really were

10:28more powerful than others. And so we started some clinical trials in patients with Alzheimer's

10:33disease and Parkinson's disease and infuse them with these fractions that we've shown have effects

10:42in mice. And these were small trials, but they looked promising.

10:47And they're related to what people have been observing.

10:52previously that if you get a blood transfusions, often people have sort of feel invigorated

10:59or their mind, they say their mind got cleared or they improved.

11:04And this company actually, Griffols, had also run a clinical study that was blinded, placebo

11:11controlled in patients with Alzheimer's disease where they first removed their plasma.

11:17This is called therapeutic plasma exchange and then infused them back with a major blood

11:25component, this albumin, which also contains other factors.

11:28And they saw clear significant benefits.

11:31And this was in 500 patients.

11:33So the field is trying to figure out next steps and hopefully do really one

11:40of these large clinical studies where you can then say this actually works and could

11:45get FDA approval. Have you done one of these?

11:49I haven't. I haven't. Are you close with anyone who has?

11:53I know people who have done it, yes.

11:56And I know people who as a response actually then supported the research that we

12:01have been doing in this field.

12:05There are companies now that offer this what is called therapeutic plasma exchange.

12:10And there was a small trial that was again placebo controlled in 40 individuals from

12:16a company called circular therapeutics.

12:19And they then looked in these individuals.

12:22These are healthy, older people.

12:24And they use some of these measures that allow us to assess how old an

12:29organ is, how old the body is or how old an organ is called epigenetic

12:34clocks. And they could indeed see that some of the organs looked younger or the

12:41body overall looked younger. There's some improvements in function, not dramatic, but suggesting that there

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15:28I can imagine a situation where there are factors in blood that can damage tissues

15:37that arise when there's some sort of injury.

15:40Let's say a heart attack or even a hip fracture, you know, pick an injury.

15:47I can also imagine a situation where the blood of very healthy, vigorous, younger organisms

15:55is devoid of all of that.

15:58So when I'm thinking about what could be in young blood that could be rejuvenating,

16:02I can imagine that there's sort of a possible double dissociation there, that as we

16:06get older, we're having little, let's just call them micro injuries that we're not aware

16:11of all the time. And that infusing young blood into that person would make them

16:17feel better. So you're counteracting the bad.

16:19stuff. But there's another picture where you're supplying something that's pro -youthful.

16:25Do you know whether or not the proteins that are contained in young blood are

16:29inhibiting the damage -induced bad stuff, or it's supplying something that is really a kind

16:36of a youthful factor? Two different things.

16:39And you could see where they'd interact, but the reason I'm getting granular here is

16:43because I think ultimately for a therapeutic, you'd want to be able to dissociate between

16:50these two. Yeah, yeah, yeah.

16:51No, it totally makes sense.

16:52And in a short answer, it's all of the above.

16:56So what we see is with age, there's an increase in many of what we

17:01call inflammatory proteins. And we actually identified some.

17:06And in mice, if we knock them out or if we neutralize them, then cognition

17:11improves in the mice, in old mice.

17:14So there you have examples of factors and actually natural factors that can inhibit some

17:20of these detrimental factors. But then you have also active pro -growth factors, growth factors

17:29that stimulate the activity of cells and might maintain stem cells better.

17:36So they're truly beneficial factors, right?

17:39The challenge in this field has been to figure out which ones are the most

17:45important ones. And is there a smallest possible number of factors that you would need

17:52to have an effect, right?

17:54Sort of a cocktail. Now you could say our blood is nature's cocktail, right?

18:00It's the elixir of youth.

18:02It just sort of, or it's a fountain of youth that lives in us, but

18:06it dries out as we get older.

18:08But it also accumulates. There's also an accumulation of bad stuff.

18:12So it's not just a loss of that fountain.

18:15We have now tools where we can, in mice again, we can look at every

18:21cell in the body of a mouse and we can ask, how do the cells

18:25in an old mouse respond to young blood?

18:29And what you see is that almost every cell changes their behavior when we measure

18:34their transcripts, so their gene expression in these cells, but they respond in different ways.

18:40And it's expected because they have different what we call receptors.

18:44So one cell may respond to one factor and another cell to another one.

18:50And what's also interesting, we see a lot of stem cells seem to be targets

18:56of these young factors, which sort of proves what we originally described.

19:02But now in an unbiased way, we look at everything and we ask, what are

19:06the major effects? And then what you also see that some organelles, such as mitochondria,

19:12these are the energy producer units in inside cells.

19:17They are key targets of these rejuvenating effects.

19:20So it all makes sense based on what we know from the aging field, what

19:24we know from stem cells and maintenance of stem cells.

19:29But pinpointing which factor you would need to have this rejuvenating effect or which one

19:35you have to block has been extremely challenging because you almost have to go into

19:39the organism. And then we call this CRISPR tools where you can knock out one

19:44gene after another and ask which one is the important one.

19:47We can't really do this easily in vivo yet, but that's almost what we need

19:52to do. So unfortunately, in the past 10 years, you know, there's individual factors that

19:58people keep describing. But I think we have not really come up with a good

20:04method to integrate multiple different factors that could provide or serve an amplified benefit and

20:12mimic what nature is doing.

20:15Should I be banking my blood?

20:16You don't have to. Because what we find, even though there's differences, clear differences from

20:22one person to another, overall, if you have the blood of a young person, that

20:28blood has overall a similar concentration from another young person, and it would still be

20:35beneficial to you. So all the blood that we ever used in our studies was

20:40always a pool from multiple individuals, and that still has the beneficial effect.

20:46So for these type of studies, you would not have to bank your own blood.

20:51Is the lore around Dracula based on this general logic?

20:55And if so, how do you think that lore arose?

20:58Meaning, I don't think somebody sat back and thought, oh, I can make up this

21:01story about this Count Dracula who, you know, drank youthful blood.

21:05And I mean, does that mean that experiments were being done long ago?

21:10I'm not trying to get gruesome here, but we know, for instance, bloodletting and a

21:14bunch of other, you know, scientifically dubious things have been used throughout history.

21:21But then again, to reduce iron load in the blood, some people will give blood.

21:26It's also a nice thing to do for your blood bank.

21:28They need blood in hospitals.

21:29And too much iron load isn't good.

21:31We know that. So what's known about the origins of the Dracula story, vis -a

21:36-vis the science that we are now aware of?

21:39Yeah, sort of in retrospect, I think where they came from is maybe more that

21:44people realize that, you know, blood is this essential fluid.

21:48If you get a cut and you bleed too much, you're dead, right?

21:53But then maybe also associated it with age or youthfulness.

21:59I don't know exactly how.

22:01We have not done, and this question came up many times before, we have actually

22:05never fed mice young blood.

22:08You could try that, right?

22:10Because it would have to be absorbed.

22:12The factors would have to be absorbed into the body.

22:15I wouldn't be surprised if some of them wouldn't have beneficial effects and survive sort

22:21of the stomach, the acid environment of the stomach, but nobody's ever done it.

22:29I don't know where it comes from, but it's, yeah.

22:32I mean, there's a lot of these questions and bloodletting too.

22:36It's blood thinning also, right?

22:38These leeches release factors into the blood and they must have done something.

22:44Otherwise, people would probably not have done it.

22:46I mean, it's pretty wild.

22:48Again, I'm not trying to be gruesome or medieval here.

22:50It's just now and again, something from the historical text shows up in modern science

22:58and we kind of go, well, there's sort of a mapping of the past to

23:03something that is clearly a scientific validation.

23:08I'm not promoting drinking blood.

23:10I'm interested in organ -specific rates of aging.

23:15And then I also want to circle back to organ -specific delivery of nutrients, because

23:21what you're talking about is blood infusion.

23:24It goes everywhere. It goes into the general circulation.

23:27You've mainly focused on the brain, but it's possible that certain organs are more receptive

23:33to these youthful factors than others.

23:36I mean, even the brain has a blood -brain barrier.

23:39The gonads have a blood gonad barrier for interesting reasons.

23:42What is known about the rates of aging in different organs?

23:46Do they happen in parallel or no?

23:48And how different organs respond to these youthful factors?

23:52Yeah. So it's really interesting that intuitively you think an organism just ages sort of

23:59as a whole in synchrony, we would say, right?

24:02But what researchers have discovered, and this was first, I think Monica Driscoll was the

24:09first to show in worms, that when she looked at the ultra -structural level, that

24:14some of these organs in the worms seem to look more aged than others.

24:19And over the years now, we have molecular tools where we can look at a

24:23single cell level or within an organ.

24:26And what we clearly see is that organs and cells within an organism can have

24:32slightly different rates of aging.

24:34And the way we conclude that is if we look at all these tissues in

24:39many different organisms and every period of weeks or months in mice, for example, we

24:46harvest tissues from different animals, we can see these trajectories that some of them are

24:53relatively stable for a long time and then they start to decline, where others continue

24:58to decline from early adulthood.

25:00And yet others, you know, may maintain almost until the animal expires.

25:07So that allows you then on an individual level to ask, if you compare now

25:16one individual to another, do their organs age exactly in the same way?

25:22Or is maybe they're a person whose heart ages a little bit faster than their

25:27actual, the rest of their body.

25:29And in another person, it would be the lung or the brain.

25:32And that's indeed what we seem to be seeing.

25:36And the way we did this in humans, and maybe we can talk about this

25:40now is, again, we look at these proteins and there's companies now that can look

25:46at thousands of proteins in a drop of blood.

25:50And this is not seranos.

25:51This is actually real platforms, real science where in just a drop of blood, there's

26:00companies that measure 11 ,000 proteins now, the concentration of these 11 ,000 proteins.

26:06And there's large population -based cohorts where people follow healthy people over two decades or

26:16even longer now, and they collected blood.

26:19And so we can profile this blood now, and we can ask, are proteins in

26:24that blood related to what diseases people develop or how they age?

26:29And the way how we make this, what people call a clock for a specific

26:34organ is, we look in your blood for proteins, for example, from the brain.

26:40So out of these thousands of proteins that we can measure in the blood, some

26:45of them originate from your brain.

26:47Some originate from the lung, from the liver, from the heart.

26:51And we've always used that in clinical medicine, but we measure only a handful of

26:55proteins, usually a few liver proteins, a few heart proteins.

26:59And we use them to assess injury or loss of function.

27:07So if your liver is damaged, that's what we detect.

27:10But here we have now an opportunity to look in thousands of people.

27:15At proteins that come, for example, from the liver and ask, how do they change

27:20with age? And that allows us to then estimate the age of the liver in

27:27an individual. And what we find is that for most people, the age of your

27:32organs is pretty much in sync with your body.

27:36But for some individuals, you have more or less of a deviation.

27:40So your liver may age faster than that of the rest of the population and

27:48the rest of your body.

27:49And what is really super exciting, we call this an age gap.

27:53So the difference between your actual age and the estimated age of your organ.

28:00And that's a very strong predictor of your future risk to develop disease in that

28:05organ. So in other words, if your heart shows to age faster, you're more likely

28:11to get heart disease or a heart attack.

28:13If your kidney ages fast, you're going to get kidney disease.

28:17If your brain ages faster, you're more likely going to get Alzheimer's disease.

28:22Is this a test that anyone can now take?

28:25Is it commercially available? Yeah.

28:27So that's a great question.

28:28We started a company with Paul Coletta called Vero Biosciences.

28:35Vero. Vero Biosciences. And the mission is really to profile the age of organs to

28:43ideally eradicate chronic diseases and to maintain or to predict which organ is going to

28:52age. Because what we find is that if you have an organ that ages faster,

28:58if you can detect that and you can do an intervention, you can potentially delay

29:06aging, right, and extend healthspan.

29:09And this is really the mission of Vero.

29:12So the Vero compass uses a combination of this biological signature together with clinical and

29:20wearable data to create a platform that can predict how you respond, which organ, first

29:27of all, which organ is the most sensitive, which intervention you can use.

29:32And then whether your organ responds or not by repeated testing and sort of creating

29:38a continuous loop where I tell you which organ is of concern, you get medical

29:47advice based on other data that we can obtain from you.

29:50And then you may get an intervention, could be a classic medical treatment, but it

29:57could also be a change in your lifestyle, exercise, change of diet, type of exercise,

30:04but have it tailored to your specific needs.

30:08And then we can test, does that intervention actually change the age of your organ?

30:14It seems spectacular. I realize in addition, let's say I were going to start a

30:19new medication, maybe taking a new drug for ADHD.

30:24Not for me. I don't have ADHD, fortunately.

30:27But, you know, people are doing this all the time now, trying different drugs for

30:29different things or taking something to lower their ApoB, as it were.

30:33And then you could monitor how that impacts, for better or worse, the age of

30:38a particular organ or set of organs.

30:40Exactly. Absolutely. So in many diseases, complex diseases, Alzheimer's disease in particular, we know that

30:48people have probably different forms of Alzheimer's disease.

30:52And we know there are risk factors that predispose you to have Alzheimer's disease.

30:58But most of the trials now are done in all comers with the disease who

31:04already have the diagnosis. And so you could imagine that if you have these predictors

31:11of change, the predictors of risk, and you get actually more resolution, and we can

31:18talk about that in a minute, what the next stages of this type of research,

31:21you may get different profiles in people and say, okay, let's test this new drug

31:28in this type of Alzheimer's disease who has a very particular risk profile rather than

31:35in everyone. And then the drug fails.

31:36I think we may have tested a lot of drugs out there that might actually

31:42be beneficial, but because we apply them to everyone and we apply them too late,

31:47they fail and we throw them away.

31:49We had David Fagenbaum, Dr.

31:52David Fagenbaum, he's an MD, University of Pennsylvania, professor of medicine, who himself was diagnosed

31:59with Castleman's disease and took it upon himself to try essentially every approved drug as

32:04a last ditch effort. He was dying, basically.

32:06And he came up with a combination, a small kit of already approved medications, and

32:11he's now been alive 11 years since his essentially death diagnosis, or excuse me, death

32:16prognosis. And he has a not -for -profit called Every Cure, where people with diseases

32:26that have resisted all other forms of treatment, people can go there and they use

32:30AI to come up with reasonable candidates to try.

32:33Because as he said exactly what you said, which is that many of the solutions

32:37to diseases that are common may already exist, but they've been swamped by the variation.

32:42in those diseases when looked at in clinical trials.

32:46So the idea that we're already sitting on good treatments and cures that wouldn't have

32:50to pass through all the testing is very interesting.

32:53There's also very little incentive for drug companies to invest in those because they've passed

32:56through their patent window. So there's not a lot of money to be made.

33:00Yeah, that's sometimes another problem.

33:02I have a question that I promise I'm just going to be...

33:06I've had this podcast long enough to know that I don't tap dance around things

33:09anymore. David Sinclair has been very...

33:13I'm not trying to attack David, but I want to know...

33:15David has been very vocal about NAD and the NMN pathway, which is upstream of

33:20an NR. Others have talked about NR.

33:23There's, you know, True Niagen.

33:25I'm not trying to go after any one person or company, but for a while,

33:28there was a lot of excitement, mainly generated by David, that NAD, which goes down

33:36across development into adulthood, might be a pro -longevity treatment.

33:42I confess I take NMN powder.

33:46I don't get paid to say this.

33:47I know it doesn't even matter what company I get it from because I buy

33:50it like everybody else. I don't have any belief that it's going to increase my

33:54lifespan, but it seems to have a pro -energy effect that I like.

33:58And for some reason, it makes my hair grow very fast and my nails grow

34:01very thick, which is a side effect I wasn't looking for.

34:03Okay, maybe I should try it too.

34:05My sister experiences the same thing, but, you know, this is all anecdata, right?

34:08Again, I make no money for saying this, but I've seen a lot of criticism

34:12of the NAD hypothesis of longevity.

34:15And so is there any evidence that increasing NAD levels, either through NMN or through

34:23NR or direct infusion or injection of NAD, any of those things, can actually extend

34:28the lifespan of humans and or experimental models?

34:33Yeah, I mean, this is not my area of expertise, but just as a blank

34:38statement, there is no human intervention that can extend lifespan that has been tested or

34:45validated. There are many that have shown beneficial effects in animal models, including NMN and,

34:52you know, all these metabolites.

34:55There's actually a clinical study that shows that if you take these supplements, they increase

34:59your levels in the blood.

35:01That's a good clinical study, but it doesn't show that it has an effect on

35:05lifespan or even on frailty or any other tangible outcome.

35:11And this is the case with many other medications that might be beneficial, but they

35:17have simply not been tested in a clinical trial.

35:20They have been tested in disease sometimes, and they are, you know, very good drugs

35:26to treat a person who is sick, but they have not been tested in healthy

35:31elder people and see whether they reduce aging or increase health span.

35:37And there's really nothing out there except exercise and diets.

35:42Those have sort of proven effects.

35:46There's a very good study from a researcher in Singapore who tested 10 different preparations

35:52of NMN, and she found that many of them actually don't contain what is on

35:58the label. That doesn't surprise me.

36:00And that's the case for most supplements, for half the supplements.

36:04There's, you know, many resources out there you can check or you can just ask

36:07ChatGPT. There's not in there what it says.

36:11And with NMN, apparently, and according ChatGPT, it's very unstable, and so it degrades quite

36:18quickly. So you want to make sure, I think with any supplement, if you want

36:22to try it, make sure it's from a good source.

36:26Third -party tested. That it has been third -party tested, yeah, and you use it

36:31within the, you know, time frame.

36:34Yeah. No, I appreciate you saying that.

36:37Like I said, I don't expect to live longer because of taking NAD.

36:41I just sort of like the effect that it appears to give me.

36:44I'd like to talk about the relationship between things that increase vitality that are abundant

36:49in youth versus their possible role in decreasing longevity.

36:55I've been fascinated by this for a long time.

36:57So bear with me here, and I'll try and set the stage, and then I'll

37:02be quiet. Puberty is perhaps the fastest rate of aging that we undergo in our

37:09entire lifespan. Within two years, we transform as an organism, right?

37:13Some people progress through puberty much faster.

37:16Other people seem to have a more protracted puberty.

37:19And here I'm defining puberty as the acquisition of secondary sex characteristics.

37:22You know, facial hair, et cetera, reproductive ability, et cetera, okay?

37:28So puberty is a constellation of things that obviously differs in males and females.

37:34It's correlated with hormones like testosterone, estrogen, gonadotropins, et cetera.

37:40But really it's a brain thing that switches on that then initiates all of this.

37:45So there have been many attempts in the kind of health and wellness space to

37:50take the hormones usually, testosterone, estrogen, and growth hormone being the three primary ones, and

37:58then supply those to people in adulthood.

38:00Perimenopausal women taking estrogen and or testosterone nowadays quite frequently.

38:04This happens a lot. Men taking testosterone either because they need to quote -unquote replace

38:09it or they're just trying to.

38:10augment what they already have.

38:11Growth hormone, certainly all of these things dosed appropriately, we know will increase vitality, energy,

38:18libido, recovery from exercise, in some cases, maybe cognition, et cetera.

38:23But it's also been demonstrated that when you increase growth hormone in IGF -1, that

38:29you decrease lifespan. This is seen in large dogs versus small dogs.

38:33The reason larger dogs live so much shorter lives than small dogs is because of

38:39the dosing of IGF -1.

38:40So how do you look at the balance between vitality and longevity?

38:44And are there factors that can increase both vitality and longevity?

38:50Because to my knowledge, the things that these hormones mainly that increase vitality, well, if

38:56they allow you to exercise more and perhaps be leaner, then perhaps they buy you

39:00some time, additional time in life, but they also decrease the amount of time you

39:05have alive. So it's a very interesting interplay.

39:08And most people conflate longevity and vitality.

39:13That's an excellent question. And short answer is we don't know.

39:19We don't really know. And in the aging field, this is called antagonistic playotrophy.

39:25So something that is good when you're young can be bad when you're old, right?

39:29It relates to this concept.

39:31And humans are, of course, you know, they're sort of exempt from evolution, if you

39:38will, right? So our natural lifespan is probably around 30 to 40.

39:43If you look back in history, that's how long people lived.

39:46I mean, there were always individuals who had, you know, exceptional lifespan, but most people

39:51would die much earlier. And infections.

39:55And it was probably mostly infectious diseases.

40:02But, you know, you could argue from an evolutionary perspective, once you're sexually mature, you

40:09reproduced and you guaranteed your offspring, which is around 30 to 40 years.

40:14Nature doesn't care about you anymore.

40:16And so there's no longer, it's very brutal to hear, but - As long as

40:21your kids are sufficient enough to raise it.

40:22Exactly. I mean, an infant can't raise itself.

40:25That's right. A seven -year -old maybe could, if they were very industrious, you know,

40:31but kids need us at least until they're in their late teens, right?

40:36And then, you know, you may have some evolutionary pressure to maintain individuals who have

40:42knowledge and wisdom to help the, you know, the group to survive.

40:47But that's probably a much weaker, um, force of evolution to keep you alive, right?

40:54And so that's why people increasingly see now that there are these inflection points that,

41:00you know, menopause, but also in men around age 30 to 40, dramatic changes in

41:07the composition, again, of the blood.

41:09We just looked at this, as I mentioned earlier, if you look at the composition

41:12of the blood across human lifespan from 20 to 90, we call these waves of

41:17aging. The first wave is around 35 years of age.

41:21Dramatic changes in concentrations of lots of factors, and not just in women, in men

41:26as well. 35. 35 to 40.

41:29Degradation? Any improvements? Some go up, some go down, and, you know, it's, it's speculative,

41:36but does that have something to do with, this is how long nature needs us,

41:41and then it doesn't care.

41:42And, you know, the, the fact that we live now 80 or even longer on

41:47average, right, is really thanks to hygiene and, you know, um, certain medications that, you

41:54know, blood pressure and, and heart disease that are antibiotics.

41:58I have a friend who's, who called me over the weekend, he's got some -

42:01Antibiotics, absolutely, yeah. I mean, he's got a brutal infection that, that could, almost took

42:05out his vision in one eye.

42:08Antibiotics, infused, boom, done. I know some listeners don't like antibiotics and they're concerned about

42:13it. I'll tell you, if you have a brutal infection that's aggressive and it's near

42:16your brain or your eye, and you get on systemic antibiotics and they're the right

42:20one, you are one lucky individual.

42:22And if you don't, you're, you could be looking at excavating one or both eyes.

42:26It's absolutely brutal. Yeah. Yeah.

42:28Yeah. Yeah. Wonderful. I mean, for many different infections, antibiotics are, you know, a lifesaver.

42:33Absolutely. Yeah. So, um, it's a really good point.

42:37And actually my, my, my friend, Tom Randall, uh, mentioned earlier, he always makes that

42:44point that, you know, a lot of the study look at lifespan as an outcome

42:48in animal models, but they don't really look at how active or, you know, what,

42:55what is sort of the, the, the level of that extended lifespan is, are they

42:58just hanging in there, these organisms, or are they still strong and, and, and vital,

43:05right? Is the vitality still there?

43:07And, and I think we don't, we haven't found a magic that would keep everything

43:13together for a longer period of time, and certainly not in humans.

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45:22Lately, I've been somewhat surprised, although not entirely, by some of the data on sunlight

45:28exposure and lifespan. There's this really interesting large -scale study out of Sweden where the

45:34more sunlight exposure people got, the longer they live.

45:37Even smokers who get more sunlight appear to, on average, these are averages, folks, seem

45:42to, so overlapping distributions, but live longer than non -smokers who don't get sufficient sunlight.

45:48Now, getting a lot of sunlight is also correlated with outdoor activity, fresh air, a

45:53number of things, so it's far from perfect study.

45:56But, yeah, the interplay between vitality, and I think of sunlight as pro -vitality, and

46:03longevity is such an interesting one because the dance that we seem to be playing

46:07now with medications and, you know, could be supplements, but really medication and lifestyle is

46:13what can we do and take to get more life but also to enjoy that

46:18life more? And there are certain things like growth hormone which will make people feel

46:22much more youthful, much more youthful.

46:25Skin, hair, even cognition, etc., ability to maintain or put on muscle, lose fat, and

46:31on and on. But higher IGF -1 and growth hormone, broadly speaking, means a shorter

46:38life. Yeah. Maybe comes at a price.

46:41Yeah. Yeah. So I guess, I mean, that can be determined individually whether or not

46:45somebody wants to make that trade -off.

46:46But what I'm excited about are the things that are possibly in these blood transfusions

46:52that come from younger humans, maybe us, but younger humans, you said pooled, that are

46:59getting to cellular function in a different way, that are restoring vitality and longevity.

47:05And maybe there are a few candidates that you could discuss with us and what

47:09pathways they impinge on. I probably won't be familiar with the specific molecules, but are

47:15they impacting DNA, the epigenome?

47:19Are they impacting mitochondrial function?

47:22If you would maybe pick your two or three favorite candidates, if you can.

47:25I know some of these are still under study.

47:27The factors often are growth factors.

47:31GDF -11 is one of them that has been described, growth and differentiation factor 11.

47:37There is, you know, IGF -1 actually also has been described to be in young

47:42blood is higher. There are factors that have been identified through an approach that is

47:49similar to transferring young versus old.

47:53So what one of my trainees did, Saul Vileda, when he was a graduate student

47:57in my lab, he did these parabiosis experiments.

48:00And then his lab and my lab independently did an experiment where we exercised mice,

48:08young mice. We took their blood and we injected it in non -exercise mice and

48:13we could show that the beneficial effects of exercise on the brain were transmitted again

48:18by blood. Were you going young to young?

48:21We went young to young.

48:22Saul went young to old and could show that he can have a stronger effect

48:28on these brains than just young blood.

48:33If it's exercised young blood, it's even better.

48:35So surprising to me because I think of exercise as a purposeful stress that induces

48:44inflammatory molecules that then induce an adaptation.

48:47Are there factors that are liberated during exercise, brain -derived nootrophic factor, et cetera, that

48:54are pro -health and vitality, that are not designed to get an adaptation, that are

49:01just good stuff coming out of the cells when we exercise?

49:04Yeah. What... What... Both actually he and my lab found is that somehow this exercise

49:11seemed to trigger the release of factors from the liver that then go to the

49:16brain and make the brain function better.

49:18In our case, we described a protein that's called clustering.

49:22It has many different roles.

49:25It can bind to lipids.

49:26It's also called apolipoprotein J.

49:29It's involved in coagulation and complement pathway.

49:33Very complicated. We couldn't quite figure out how does it have these effects, but we

49:39could show that if we make recombinant synthetic clustering and inject it into mice, we

49:45could mimic some of the effects.

49:47This is clustering? Yeah. It's in the complement pathway.

49:50Yeah. Complement initially identified as part of the immune system.

49:55Coat cells as a part of the eat me signal in the immune system or

50:00the eat me system, but does many other things too, right?

50:04Involved in synapse formation and remodeling, and we know from Beth Stevens' work and others.

50:08Wild. Wild, yeah. Wild. And then Saul found another factor that's called GPLDH that, again,

50:17he can clearly show has an effect, but how exactly does that is not clear.

50:24Most recently, he did another really creative experiment where he did caloric restriction of mice,

50:30and again, that's sort of an accepted beneficial effect and longevity promoting potentially, and takes

50:40the plasma from mice, puts it into other mice, and again, can isolate factors that

50:46mimic this effect. Because of intermittent fasting.

50:49Yeah. What this tells us is that this is physiology, right?

50:53We call this physiology. But organs in our body communicate with each other, and there's

50:59an orchestration of effects that leads to factors that are released into the blood, and

51:07then they go to different organs and have, in this case, beneficial effects.

51:12So the exercise effect is not just because you think you're exercising, but there are

51:19actually factors released that seem to benefit your brain.

51:23So interesting. There's this idea that was, at least to me, first put forth in

51:29a book called Spark. Do you know John Rady's book?

51:31It came out some years ago.

51:34He's a physician, I believe, trained at Harvard Med.

51:39And he talked about the essential requirements for movement in brain plasticity.

51:44This was early days of understanding neuroplasticity, but he talked about brain derogative nootrophic factor,

51:49other things that are liberated by exercise.

51:51But he described some interesting experiments in there of, for instance, there's a sea -dwelling

51:58creature that swims around and has a fairly elaborate nervous system, at least for it.

52:03But then at some point in its life, settles down on a rock and eats

52:07its own nervous system, basically.

52:10And there's been some interesting experiments looking at what happens when you get that organism

52:15or other organisms, I believe.

52:16I think it was that organism.

52:18But other organisms to continue moving.

52:19It seems like there's feedback from the process of moving the musculature.

52:25And it could be neuromuscular in origin.

52:27It could be hormonal in origin.

52:28I don't think we know that it comes from muscle.

52:31But there's something about the requirement for movement that signals to the brain that it

52:36needs to continue to exist and not just the motor portions of the brain or

52:41the portions of the brain controlling motor activity, but that the body may supply chemical

52:48or other types of feedback to the brain that if it's moving and continues to

52:53move, that the brain needs to continue to be robust, which I find very interesting

52:59because few things, to me, explain how movement to the body would signal vitality of

53:06the brain, aside from hormone -borne factors.

53:09But it kind of makes sense, right?

53:11Continuing to move the body is essential for keeping the brain healthy.

53:15Yeah. And, I mean, exercise interventions, you know, there's thousands of studies that show that

53:21exercise is beneficial, cardiovascular, but also other exercise.

53:25Yeah. Now it seems everyone's excited about resistance training.

53:27I mean, I think both is clearly the answer.

53:30I mean, you look good.

53:32What's... I mean, you're not in your 80s, but...

53:35I might be. Do you exercise?

53:37Right, right. Yeah. That would be impressive.

53:38Um, what, what is your exercise regimen?

53:41People want to know. Yeah.

53:43I, I, I run. I like running outdoors.

53:46I like the sun. Um, I, I try to get two runs, five to 10

53:52K per week. Yeah. That's the main exercise I do.

53:56I do some Pilates in the morning.

53:57I'm struck by how quickly the body degrades after an injury, especially if that injury

54:03occurs after age 60. When we are injured as kids, we heal up.

54:10It's amazing, right? I mean, kids getting cuts and they're just like, what happened?

54:14It's just, they heal right up.

54:15Do we know why we heal more quickly as kids than as adults?

54:19We do know that the immune system ages like everything, and it has this bias

54:26that it goes from a more specific response to a non -specific response, and that

54:30is often associated with inflammation.

54:32inflammation. Okay. So it's possible that part of it is that if you have a

54:40wound, there's too much of an inflammatory response and less of a healing response.

54:45But we also know from aging organisms that if you have a cut, there's proteins

54:57in the extracellular matrix like collagens and things like that that are often overproduced.

55:02And they may interfere with a quick healing response.

55:06So I think everything is a little bit out of tune and that might be

55:09the reason, but it's not really something I would know the details.

55:14I've always been fascinated by the fact that if we get a cut on the

55:18surface of our body, that it may or may not heal with a scar.

55:22But if we get a cut on the inside of our mouth, which is loaded

55:28with bacteria and warm and moist and in contact with the outside world all day

55:35long, it tends to heal with either zero or much less of a scar.

55:40There has to be something in the mouth that's pro -healing.

55:45And I believe people are studying this, but someone's got to figure this out.

55:48Yeah, yeah, that's true. It could be saliva.

55:51Yeah. Wild, right? I mean, the rate of healing.

55:54I know there's a lot of blood supply, but there's also a lot of blood

55:57supply to the nose and to the hands.

56:00And there's scars form on the hands and on the nose.

56:03Yeah, it's also scarring in babies, right?

56:05May not leave, or a cut in a baby may not leave any trace.

56:09But the same type of wound in an older person may leave a scar for

56:16the rest of their life, yeah.

56:18So how do we move past correlation and to really understand causative stuff?

56:25So we'll get back to lifestyle factors, but I mean, it's so very clear from

56:28the animal studies and from the human studies that you described that there's something in

56:32young blood or things in young blood that are pro -rejuvenation for the brain and

56:37other tissues. How do we get to a real pro -longevity molecule medication treatment?

56:45Or pro -health maybe more, right?

56:48I think most people in the field are not really interested in extending lifespan, which

56:54would be longevity, but healthspan.

56:56So, and we talked about this before, right?

56:59That you try to maintain the function of your organs until you die, so that

57:05your brain would still be functioning, you're cognitively intact.

57:09All your organs would still be functioned relatively well.

57:12And then, you know, you fall asleep and that's the end of your life.

57:17And not necessarily extending lifespan.

57:20As you said, it could be that we extend lifespan and you just have 10

57:23more miserable years. That's certainly nobody would want that, right?

57:27But I think to get to causation, we need these types of experiments, physiological experiments

57:34in animal models first to isolate individual factors and then test them on an individual

57:40basis with very rigorous methods, which we can do.

57:44And say, okay, this factor has the capacity to maintain, for example, brain function in

57:53the mouse. And then we have to test it in humans and do it in

57:58a careful, clinically controlled trial where people are blinded, whether they got the treatment or

58:05not, and do a big enough study that we can say, okay, this truly works.

58:11And then we have a drug.

58:12How close are we to the clinical trial?

58:16There are different molecules. Clotho is actually another one.

58:20It's this protein that has been described to have beneficial effects on multiple different organs.

58:29The biology, again, not exactly clear.

58:31K -L -O -T -H -O, Clotho.

58:34That's right. Yeah, yeah. And, you know, there's companies trying to move this into humans,

58:43into human trials. Some of these other factors, I think, their companies are trying or

58:51inhibiting detrimental factors. And with, you know, individual clinical trials, you could get there in

59:00the next five, 10 years.

59:01There may be something that has an effect.

59:03I think we will not have a factor, an individual factor that just has, you

59:09know, this miracle effect on everything.

59:12This is very clear from the studies of young blood.

59:15It's many different factors. And they target different pathways, different cell types in different tissues.

59:24So you really need to, you may have to decide, you know, for this organ,

59:29we need this treatment. For this organ, we need that treatment to optimize its function

59:34and keep it, you know, running at full capacity until you're 100 years old.

59:40I'm not suggesting anyone do this, but I do seem to hear now and again

59:44that people are taking Clotho already.

59:47Not surprising. People will, you know, get ahead of the curve, so to speak.

59:52Yeah, I've also read people taking this GDF -11.

59:55I don't know where to get it.

59:57I'm guessing it's just Mexico and San Francisco.

1:00:01In South America, there are a lot of clinics that do this sort of thing.

1:00:04I will put out a true story, cautionary note, a friend who, whenever people say

1:00:11I have a friend, this is a medical doctor who had a back pain that

1:00:17was giving him a lot of issues and he went to a stem cell clinic

1:00:22in Mexico, got an injection of stem cells into a spinal disc, which my neurosurgeon

1:00:28friends tell me is a terrible idea.

1:00:30It turns out the disc cannot accept cellular injections.

1:00:33A chair of neurosurgery told me that.

1:00:37So you can come at me if you want, folks, but he's the chair of

1:00:40neurosurgery at a prominent medical school so that the disc cannot accept direct injections of

1:00:46foreign cells. Anyway, this guy, a different guy, different MD, went and got this injection

1:00:52and ended up with an egg -sized infection that left him paralyzed.

1:00:58He was fortunate enough to be airlifted to a certain clinic in the United States

1:01:04and told he was, that's it, you're done.

1:01:08We're going to have to just sever your spinal cord.

1:01:10He was taken to another clinic where fortunately they were able to excise this infection

1:01:17and he's mobile today. He will tell you and I'll tell you that you have

1:01:22to be very, very careful getting injections of cells in anywhere, but the regulations out

1:01:28of country often are not as stringent.

1:01:31And I tell that story because a number of people are excited about stem cells.

1:01:35They're excited about these technologies, but it really can be quite dangerous.

1:01:40And again, this is what we discussed earlier, this experience that we have in the

1:01:48medical field that you really need to test something in people in a very controlled

1:01:53fashion, very carefully with the dose and then test it in a blinded fashion ideally

1:02:01so that you know it really works and it's safe.

1:02:04And what you mentioned earlier with stem cells, there are no such treatments that have

1:02:09been tested rigorously. And for many of these other factors, they work in some animal

1:02:16models. There are some mouse studies that showed they might have an effect, but you

1:02:21cannot translate that to humans.

1:02:23It's just a long road.

1:02:25And I would be extremely cautious to take anything that is not really prescribed to

1:02:31you from a clinician that you trust.

1:02:35Thank you. By way of contrast, platelet -rich plasma, PRP, is approved by the FDA.

1:02:42People who are undergoing fertility treatments will get injected into their ovary.

1:02:47People are getting PRP injected into their shoulders, their knees, their whatever.

1:02:51I'm not trying to be disparaging of this.

1:02:53It is FDA approved. To my knowledge, platelet -rich plasma does not contain stem cells.

1:02:59That's correct. But it seems to be beneficial enough and safe enough that the FDA

1:03:04has approved it. What is the deal with platelet -rich plasma?

1:03:08What has it been shown to be actually useful for?

1:03:11Because just because something is allowed for one indication and is used broadly for a

1:03:15bunch of things doesn't mean that there's evidence that it works for all those things.

1:03:19That's right. That's right. So platelet -rich plasma has these platelets in there that are

1:03:25full of growth factors. They have these granules that help in wound healing as a

1:03:31primary function. And somehow that seems to be beneficial in sports injuries.

1:03:37It's often given. And as far as I know, I think it's from your own

1:03:41blood. You concentrate these platelets.

1:03:44And then they release these factors.

1:03:46So you may have a massive load of growth factors that help you heal these

1:03:51various tissues that you mentioned.

1:03:53Yeah. Yeah. I haven't tried it, but I know people who have and reported some

1:03:57positive effect. I've heard also a lot about exosomes.

1:04:01And there are some clinics, I believe, where I think exosomes are FDA approved as

1:04:06a treatment. What are exosomes and what have they been shown to be useful for

1:04:11in studies and or clinical?

1:04:14I don't know in clinical studies how they're used.

1:04:17But so cells can release sort of little packages of material that is filled with

1:04:25proteins. But there's also RNA molecules in there, lipids, metabolites.

1:04:30And some cells do this all the time.

1:04:33Cancer cells, for example, do it.

1:04:35But also some immune cells have a very active release of these little, sort of

1:04:42like little packages, vesicles, we call them, that are filled with, again, all these different

1:04:47molecules. In the blood, you find large numbers of these exosomes.

1:04:52And that's where they're usually purified from.

1:04:55Different cells have different cargo in these vesicles.

1:04:59And it seems that they function to some extent to deliver information from one cell

1:05:06to another. It's still a very new field.

1:05:09But people explore, you know, whether they can be used for treatment purposes, but also

1:05:15for diagnostic purposes. Do they tell you something about a specific organ or a tumor

1:05:21that is developing? So when we measure these proteins that we talked about earlier in

1:05:26the blood, the blood, the blood, the blood, the blood.

1:05:28We actually measure what's in the exosomes also.

1:05:32So these exosomes, they float basically like immune cells.

1:05:37They float in the blood.

1:05:38And we open them up and we measure what's inside.

1:05:42We should probably talk about some of the things that damage vitality and longevity.

1:05:49Accident and injury aside, we know that smoking, especially nicotine, damages DNA, increases inflammation, and

1:05:59will shorten your life. I don't think there's any debate about that, right?

1:06:02But what about some of the other things that might produce low -level DNA damage?

1:06:07In particular, these days I'm very interested in EMFs.

1:06:11I don't actually believe that the low levels of EMFs that are present in most

1:06:15technologies are damaging in the acute way that being near them is going to harm

1:06:22you. But there is the idea that things can be cumulative, right?

1:06:26I mean, I get one X -ray every few years when I go to the

1:06:29dentist, but there's a reason the technician runs behind the wall.

1:06:35He or she doesn't want to be exposed to that on a daily basis.

1:06:38So how do we feel about things that at a low dose don't damage DNA

1:06:43or mutate proteins either, but that if we are exposed to them over a lot

1:06:50of time could very well do that?

1:06:52What are your thoughts on this?

1:06:54A very difficult question. I mean, you could ask the same question about any chemical

1:06:59that we invent and we put into food or we get exposed to, right?

1:07:05The, you know, the plastic, we, you know, we drink out of cups, hot stuff

1:07:10out of a cup that is coated with plastic and, you know, we're full of

1:07:14plastic. How is that going to change our lifespan?

1:07:18It hasn't in a measurable way so far, right?

1:07:23But we don't know what's going to happen in 20, 30 years.

1:07:26Or if people, you know, synthesize a compound that is detrimental, it doesn't look detrimental.

1:07:32It has been tested and is safe.

1:07:34But as you said, if it accumulates maybe or in combination with other stuff, it

1:07:39may be detrimental. I think about this from time to time and I wonder about

1:07:44what's in my environment that I can easily control.

1:07:46I try not to drink out of plastic.

1:07:50You know, I try and drink out of cans that don't have BPAs and things

1:07:55like that if I can.

1:07:55Yeah, if you go down that route, you know, it drives you crazy and you

1:08:00could, you know, sort of not do anything anymore or not eat anything.

1:08:05Well, it's getting harder nowadays to live a clean life.

1:08:09I mean, how long were you in Switzerland before you came to the States?

1:08:12I was 26. You were weaned in a very clean environment.

1:08:18You know, that's not just a stereotype about the Swiss being a thing that things

1:08:23are, yes, very tidy and clean.

1:08:24The streets are remarkably clean.

1:08:25You could drink out of the lake in Zurich, right?

1:08:28Maybe not the lake, but, you know, most, most, there's still fountains with groundwater where

1:08:33you can drink in any village, basically.

1:08:36Yeah. If you're lucky enough to grow up in a place where the tap water

1:08:40is clean, the food tends to be pretty devoid of dyes and preservatives and your

1:08:49home is centered around eating mostly whole foods, foods that you cook.

1:08:55Yeah, fresh fruits and vegetables are freshly prepared, right?

1:08:58Even desserts that are fresh, that are prepared, right?

1:09:00As opposed to a lot of packaged foods.

1:09:02It seems that that's a far and away different experience than most, certainly Americans get

1:09:08nowadays. Right. Yeah. And you wonder what the effect of that is going to be.

1:09:12We simply don't know. Yeah, we don't know.

1:09:14And I know now there's a big, you know, kind of attack on food dyes

1:09:17as the thing. And there's no smoking gun data on any of those.

1:09:20But, yeah, I think the cumulative effects of things are worth considering, I think, for

1:09:25most people. I try not to think too much about it.

1:09:27But I also, I mean, growing up in an environment where, you know, we had

1:09:32a big vegetable garden. I have a vegetable garden, you know, I have lots of

1:09:36fruit trees and try to get, you know, stuff out of my own garden.

1:09:41That's a luxury, of course, for a lot of people.

1:09:44But as you said, you can, you know, you can also buy fresh fruit.

1:09:48It's more work, right? It's more work than just buying ready -made food.

1:09:53But you know what you're cooking and what's in there.

1:09:56I'm fascinated these days by the data on organic versus non -organic fruits and vegetables.

1:10:02I spend the extra money on organic.

1:10:04But the more I look into it, the more you find that the differences aren't

1:10:09that great. Now, taste can be different.

1:10:11And ideally, you're sourcing from local farms.

1:10:13But I have a friend.

1:10:15Actually, I'll just, he will be okay with me saying this.

1:10:18We had, he's a physician, Dr.

1:10:19Teo Soleimani. He's a derm oncologist whose son ran an experiment for his school project

1:10:27looking at the differences between organic and non -organic fruits and vegetables in terms of

1:10:32what contaminants and things are on them, pesticides, et cetera, and found, this is one

1:10:38kid's study, but essentially no significant differences in that particular set of batches of fruits

1:10:47and vegetables. And so that is, I would say, reassuring on the one hand, because

1:10:52it means that people who can't afford organic will probably.

1:10:56be doing about as well as people who can.

1:10:58But I think if you can grow your own or access from local farms, I

1:11:02mean, surely it's cleaner. I mean, the highest rates of endocrine disruptors are found in

1:11:07rural areas. I always thought that being in a big city was the most dangerous

1:11:11for your lungs and endocrine health.

1:11:13And we had Shauna Swan on the podcast, serious researcher in this area.

1:11:17And she said, no, I mean, if you live in an area where they're spraying

1:11:20crops, cancer risk, endocrine disruption, it's very serious.

1:11:24It's also association with Parkinson's disease and the past, yeah.

1:11:27Right. I'd like to take a quick break and acknowledge one of our sponsors, Function.

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1:13:16Well, as long as we're talking about food, we should talk about not eating.

1:13:19We should talk about fasting.

1:13:20So many studies now showing in worms, in mice, in monkeys, and perhaps even in

1:13:25humans, that subcaloric intake for long periods of time, or perhaps intermittent fasting, we can

1:13:33talk about how we define that, can extend life.

1:13:36How is that thought to work?

1:13:38Is it the reduction in this mTOR, mammalian target arabomycin?

1:13:42Is it reduction in inflammation?

1:13:45Is it clearing of senescent cells?

1:13:47Give us the overview and any specifics about intermittent fasting, and perhaps start by saying

1:13:54how you define intermittent fasting.

1:13:56Is it daily, or is it two, three days?

1:13:59I think you should just answer that.

1:14:01There is no definition. Okay.

1:14:03There is no definition. And the whole field is also a mess.

1:14:07You know, it's again, taking studies in mice, for example, and then translating them to

1:14:15humans, you know, the lifespan, their whole rhythm, their environment is so different from our

1:14:24environment, right? That to translate these is always a stretch.

1:14:30And there's no clinical studies that show a clear benefit of fasting in humans.

1:14:35And some studies in monkeys actually suggest that it's detrimental for monkeys to fast, for

1:14:42example. They had more, I think, worse kidney function and things like that.

1:14:51So, overall, from animal studies, it's very clear that you activate sort of beneficial pathways.

1:15:00They're very diverse. Again, we can now use unbiased assessment of many different cell types

1:15:08in an organism, you know, gene expression across thousands of genes.

1:15:13And we see that different cells respond in different ways, and you get functional improvements.

1:15:19But they're very broad. They're, in part, reduced inflammation.

1:15:25Other cells, you get benefits on their energy metabolism, protein turnover, how they handle sort

1:15:32of what we call the garbage that accumulates in cells.

1:15:37Overall, from these animal studies, clearly benefits from reducing calorie intake, also less what we

1:15:45call oxidative damage. So, it's like you burn a fire, right?

1:15:50And if that fire is really intense, you may cause more damage.

1:15:55But how you translate this really to tangible benefits in humans, I'm not sure.

1:16:02Do you practice intermittent fasting?

1:16:04Rarely. Rarely. You like breakfast.

1:16:06I tried, you know, Longo's diet a few times where I reduce calorie, Walter Longo.

1:16:16I'm familiar with him. What's the contour of the diet?

1:16:19So, it's mostly you switch to a ketogenic diet, so a fat -rich diet.

1:16:24So your metabolism changes basically from a regular sort of glucose -driven diet to burning

1:16:30fat. And you feel that when you start to starve, that somehow it's almost like

1:16:38your body changes a little bit and you get a bit more alert almost.

1:16:44And in a way that makes sense, right?

1:16:45If you think you're out there in the wild, whether you're an animal or a

1:16:50human being, if you don't have enough food, the last thing you want is that

1:16:55your brain doesn't work well.

1:16:57I imagine the catecholamines, dopamine, norepinephrine, and epinephrine increase.

1:17:01Yeah. So you get more alert.

1:17:02You're a little hangry. Yeah, hangry, exactly.

1:17:07But I'm not sure how long that lasts and how beneficial this is in the

1:17:11long run. But, yeah, I've done it a few times.

1:17:14You know, you do one week, you lower your calories, I think, down to 1

1:17:18,000 per day. So it's pretty brutal.

1:17:22But only for five days and then we go back to normal.

1:17:25I know of a few people who've done long -term fasts, so three or four

1:17:30days with just water and electrolytes, maybe some ketones.

1:17:33And they were very overweight, carrying a lot of excess body fat.

1:17:36And when they returned to eating, claimed that their appetite was forever changed, in particular,

1:17:43the types of foods they were hungry for.

1:17:45Sure. And that's thought to be an effect on the gut microbiome, which then impacts

1:17:50the brain. So there may be a place for those longer fasts, what do they

1:17:54call them, medically supervised fasts.

1:17:57Yeah, yeah, exactly. I generally just like caffeine, electrolytes, and water until about 10 or

1:18:0211 a .m. And then I like to eat no later than nowadays at 7

1:18:08p .m. because I go to bed a little earlier.

1:18:10So is that intermittent fasting or is that just being a busy person who wants

1:18:16to still sleep well and exercise?

1:18:19Yeah, it is sort of a fast, right?

1:18:21I mean, in English, you call it a break fast.

1:18:26And it is, you know, 12 hours maybe where you have no food.

1:18:29And I think that that probably triggers some metabolic activity that is different than if

1:18:35you continue to eat. I think the worst is probably for the body to eat

1:18:39all the time, like a lot of people snack the whole day.

1:18:42That's not how we were, how we evolved, right?

1:18:46We evolved being starved on a regular basis.

1:18:50But is that a good thing or a bad thing?

1:18:53For sure, our body is used to it.

1:18:55That's a fair statement. It can handle it.

1:19:00I can't do the one meal per day thing because that meal ends up being

1:19:03so large that I get a lot of gastric discomfort.

1:19:06And then it disrupts my sleep.

1:19:07And that's what I'd like to discuss also is sleep.

1:19:09If there's been at least one, there's probably been three in my mind, but at

1:19:14least one major triumph in the public health discussion over the last, let's say, 10

1:19:20years. And we can really, truly thank the great Matt Walker for this, who wrote

1:19:26Why We Sleep. He was the first person to really say, hey, these are all

1:19:30the terrible things that are going to happen to you if you don't sleep enough.

1:19:32And everyone needs different amounts.

1:19:34I'm fine on six hours, so I don't believe everyone needs eight.

1:19:38Seven, I'm great, but I'm fine on six, especially with a little nap here and

1:19:42there. But Matt got people scared.

1:19:44Then he got people thinking about how to improve their sleep, and I and others

1:19:47have spent time on this.

1:19:48I think that's one of the great victories of public health communication around the best

1:19:55science. The other would be the importance of exercise, both cardiovascular and resistance training.

1:20:01But during sleep, we know that there's this so -called glymphatic clearance, the clearance of

1:20:06junk from all the tissues, but in particular from the brain that's facilitated by the

1:20:13glia, hence glymphatic. Have you guys looked at lymph between young and old animals?

1:20:21I'm fascinated by lymph. I have not.

1:20:23That would be very interesting to do.

1:20:25Because it's the debris from the blood, right?

1:20:27Well, it's the debris from the extracellular space that doesn't get picked up by the

1:20:31blood. I mean, it's essentially the extra bad stuff, all the ammonia and cellar debris

1:20:38and fragments. I would love for you guys to do an experiment looking at lymph

1:20:41from young and old animals.

1:20:44I mean, we looked at the cerebrospinal fluid, but it's, of course, different.

1:20:48And that, again, differs dramatically with age.

1:20:52The composition changes dramatically. And I had a fellow who was heroic enough or crazy

1:20:58enough to collect young CSF from animals, from mice.

1:21:04Trying to do any little?

1:21:04Yeah. Wow. And then infuse it via a pump over a month into old animals.

1:21:11And she could show that you can regenerate the brain, improve cognitive function in these

1:21:17mice. And oligodendrocytes, these cells that wrap the connections between neurons, it's like they produce

1:21:26the plastic around the wire, right, if you will.

1:21:31They were the strongest target if we looked in an unbiased way.

1:21:36And so she's studying that now in her own lab.

1:21:38But it shows you in another way how a fluid changes from young to old

1:21:44and the young fluid somehow has beneficial factors that benefit the old brain.

1:21:51And so I wouldn't be surprised that there could be beneficial factor in the glymph

1:21:58or the lymphatics that might benefit an old organism.

1:22:03We thought about it, but I think in mice, it's extremely difficult.

1:22:09There's also the interstitial fluid itself that people have collected, but they usually collect it

1:22:15by infusing artificial spinal fluid.

1:22:19And then you almost wash out what it's in there.

1:22:23People have used that in the neurotransmitter field and also more recently to look at,

1:22:27you know, A -beta or accumulation of protein deposits in the brain.

1:22:33Why not just go straight to humans?

1:22:35I mean, I feel like I ran a mouse lab for a long time.

1:22:38I've worked on so many different species, including humans.

1:22:40But it seems like given the relatively equal expense of doing exploratory science in mice

1:22:47and humans, that unless there's a question you can only address in mice, why not

1:22:51just take CSF from young and old humans?

1:22:53Oh, yeah. That's what we have done.

1:22:55Yeah. Oh, okay. CSF is no problem.

1:22:57Yeah. Okay. So we measure proteins in the CSF and, again, thousands of proteins.

1:23:03And we ask, are there proteins that correlate with cognitive function with resilience or decline?

1:23:11What's really interesting is, so we did this in a completely unbiased way.

1:23:16You find proteins that go up and go down together with cognition, so that positively

1:23:24or negatively correlate. And almost all the top proteins are synaptic proteins.

1:23:29We then use the top two, the one that goes up the most and goes

1:23:34down the most and made a ratio of the two.

1:23:37And that ratio is a very strong predictor for cognitive resilience or decline.

1:23:44And what's scary is that ratio continues to change from early adulthood.

1:23:51So you get a continuous, basically, degradation of that signal.

1:23:57And we get very prominent risk prediction between the top and the bottom quartile.

1:24:06And this is based on 3 ,000 individuals where we had CSF from.

1:24:09And it's independent of pathological markers.

1:24:13So we also had people with Alzheimer's disease in there at different stages of disease.

1:24:19So if you look for what is only predicted of cognitive function based on a

1:24:25memory test, we find these synaptic proteins are very strong predictors.

1:24:32So again, suggesting that the composition change.

1:24:35And then you can ask, is this a reflection of the change or is it

1:24:40actually driving the change? And it seems to be both again.

1:24:45It's always tough to get to causality.

1:24:48But anytime I see a study that looks in a correlative way at, you know,

1:24:53like which athletes live the longest, it's very interesting, right?

1:24:56I mean, I have no desire to run a marathon.

1:25:00But if I knew that it was going to add 20 years to my life

1:25:04or 15 years, I might start becoming a marathoner.

1:25:06But a recent study showed that it's the pole vaulters, not going to get into

1:25:11that, and the gymnasts, and I think the high jumpers and the sprinters.

1:25:16So the fast twitch muscle folks, they get a substantial longevity effect, you know, five

1:25:22to eight years on average, more than their age -matched cohorts, even compared to other

1:25:27highly trained athletes. So I see a result like that.

1:25:32And then, of course, the reductionist scientist in me says, okay, so is it the

1:25:35running? Is it the jumping?

1:25:36Is it anything like, oh, using the Weiss -Corey model, I mean, you can essentially

1:25:43look at the blood from sprinters versus marathoners.

1:25:47And, of course, they're going to differ.

1:25:48These are different people, after all, very different lifestyles in a number of different ways.

1:25:52But you have to kind of wonder, again, whether or not the feet – I

1:25:55wonder whether the feedback signals from the body, there's some feedback signal in the form

1:26:00of a chemical that says, okay, this body is moving fast, jumping, and doing explosive

1:26:09activity, essentially, on a regular basis, that supplies the brain with a cocktail of things,

1:26:14presumably, that keeps neurons healthy, keeps them – you know, keeps the oligodendrocytes proliferating, right,

1:26:22that make sure that, you know, you've got plenty of myelin for those fast transmission

1:26:27signals. And to me, that's where I – like, the field of healthspan and lifespan,

1:26:34but especially healthspan, really needs to go.

1:26:37Because otherwise, it's just like, pick the exercise you're going to do regularly.

1:26:40That's great. That's a great first step.

1:26:43But then ultimately, it really does become about quality of life.

1:26:47And if – so the importance of doing these kinds of studies to me is

1:26:53immense, because otherwise, it's just sort of like, well, you do a little cardio, you

1:26:58do a little this, do a little that.

1:26:59And I don't know. I mean, that's like saying, oh, you can get the same

1:27:03level of social connection from social media as you can from in -person – it's

1:27:08two totally different landscapes. So anyway, I'm struck by the idea that exercise is not

1:27:15one thing, and that there may be – there are certain forms of exercise that

1:27:19are – Much more potent, which means there are probably molecules associated with certain forms

1:27:23of exercise that are much more potent in terms of brain function.

1:27:27Yeah, that's very interesting. So John Long at Stanford has a lab, and he looked

1:27:32at metabolites in the blood of dogs, sprinter dogs, horses that do races, and then

1:27:42also humans, sprinters. And he found this interesting modified amino acid that is conjugated to

1:27:51lactate, LAC -Phi it's called.

1:27:54And that compound seems to spike with these extreme bursts of muscle activity.

1:28:00And he could then show in animals that it's actually beneficial and mediate some of

1:28:06the beneficial effects. He identified the receptor.

1:28:09So it's a really very exciting direction of research.

1:28:12But it speaks to what you're saying, right, that there's different ways, different forms of

1:28:18exercise, and they may have different effects.

1:28:21And they may all be beneficial, better than not doing anything, but they may have

1:28:26different effects. And you may be able to harness one or the other.

1:28:31And also some of us may benefit more from one or the other.

1:28:35It's extremely hard to do a rigorous clinical study on any of this, right?

1:28:41Because obviously if you exercise, you always know it.

1:28:44So you can't be blinded.

1:28:45And if you hate it or if you love it, your brain is probably going

1:28:50to send very different signals, right?

1:28:52I mean, I have friends who just hate exercise and they never want to do

1:28:56it. So how are you going to tell them, you know, you should do this

1:29:00or that? Well, if it buys you life.

1:29:03Anyway, I'm fortunate that I've always loved exercise.

1:29:07I've always loved it. I feel great going into it.

1:29:09I feel great during and I feel after.

1:29:10I mean, sometimes it's painful, but I always enjoy it.

1:29:13But I realize that not everyone feels that way.

1:29:17Gets that reward, right? Our colleague Robert Sapolsky told me about a study where they

1:29:20have rodents run on a wheel regularly and rodents love to run on wheels, as

1:29:27you know. And they, of course, experience reductions in blood pressure, blood lipids improve, et

1:29:35cetera, after the exercise, right?

1:29:37During the exercise and immediately after there's inflammation, but you get the adaptation, they improve.

1:29:41But if you tether the running of that animal, sort of like your parabiosis experiment,

1:29:48if you tether the running of that animal to another animal that's trapped in a

1:29:51running wheel, it can't leave the running wheel and it has to run when the

1:29:55other one runs, they're doing the same exercise and they're genetically identical animals.

1:30:01And the one that's forced to run experiences long -term increases in blood pressure, markers

1:30:08of stress, and deficits in memory associated with hippocampal, not damage, but rewiring.

1:30:14So you realize that the choice is big in all of this.

1:30:18That's for me running on a treadmill in a room versus outside.

1:30:22I'm exactly the same way.

1:30:23I mean, not to spin off into every study, but a lot of Stanford citations

1:30:26here, our colleague Joe Parvizzi, neurosurgeon, did this amazing experiment where he stimulates, for other

1:30:33reasons, he landed in the anterior mid -cingulate cortex.

1:30:36And when he stimulates there, people feel as if there's some impending pressure on them,

1:30:42like they're driving into a storm and they feel motivated.

1:30:45They feel the, subjectively, tenacity.

1:30:49And it turns out that the anterior cingulate cortex grows in people who successfully diet,

1:30:54who push through challenges in exercise and cognitive things.

1:30:57So pushing ourselves, you can tell your friends that if you enjoy doing something, you

1:31:02actually get less benefit. Yeah, maybe.

1:31:04If you hate it, you get more benefit, but not if you're forced to do

1:31:08it. So choosing, electing to do things that you hate and doing them anyway is

1:31:12where the real, where you get the double benefit.

1:31:17So in any case, this is the brain structure associated with super -ageers.

1:31:21If you motivate yourself to do a marathon, right?

1:31:23And you go through the torture.

1:31:25That's right. I think I'll sprint instead.

1:31:26I now do this thing where I hop on the Airdyne bike, the one with

1:31:29the handles, and I'll go warm up a minute and I'll go hard for 20,

1:31:3330 seconds and then rest 10 seconds and just repeat.

1:31:35And it's over in like seven minutes.

1:31:38But it's amazing where the brain goes.

1:31:40You're like, I hate this.

1:31:41I want to get off this thing.

1:31:42But afterwards, it feels pretty great.

1:31:43Well, I would love for you guys to look at CSF or other factors in,

1:31:46let's just call it high intensity versus long endurance type exercise.

1:31:50It's also hard to do in animals, but you can do it very easily in

1:31:53humans. I'm trying to think about the ways that we can use lifestyle interventions until

1:31:58you come up with the magic pill.

1:32:01Yeah. And, you know, it's interesting that you say that.

1:32:04Jill Livingston and others, you know, they have studied sort of how lifestyle influences the

1:32:13development of dementia and Alzheimer's disease.

1:32:15And it's a dramatic component that you can influence, easier or not, right?

1:32:22I mean, some of them are very hard to get out of.

1:32:25But, you know, poverty is a risk, of course.

1:32:29There's childhood obesity, lower education, smoking, excessive alcohol use, many of these things that we

1:32:39know, you know, they're good or bad.

1:32:41If you have all these, if you optimize everything, your risk for dementia is much

1:32:47lower. I mean, there's now, you know, countless studies that show that.

1:32:52So there are things that you can do, the lifestyle factors, right?

1:32:57And they're easier to do for some people than for others.

1:33:00But it's clear that there's incredible power in lifestyle and what we do.

1:33:08Are you aware of any correlates to the exercise thing we were just talking about,

1:33:12whereby certain cognitive exercises can help us hold on to cognition?

1:33:20For instance, we've heard doing crossword puzzles or, you know, reading good books.

1:33:25I mean, I think this is becoming increasingly important because it's so easy to have

1:33:29one's time sucked away on the internet or on social media nowadays, which requires essentially

1:33:36no work, right? You just scroll and read.

1:33:38I mean, articles have become very brief.

1:33:40Is there any known benefit of trying to tackle cognitive gymnastics?

1:33:48Is there any data? Not to my knowledge.

1:33:51Unfortunately, you know, the studies that looked in patients who already have cognitive impairment and

1:33:58you try to give them sort of exercise and mental exercise, they don't do much,

1:34:05unfortunately. It's probably more complex.

1:34:08And you, of course, also have, again, you know, what we discussed earlier with exercise,

1:34:13right? Some people just love to be stimulated.

1:34:16And, you know, they want to learn something new, you know, want to learn a

1:34:20new language or a new instrument.

1:34:23And their mind is already attuned to that, right?

1:34:26They crave for this. And for others, that might be much harder and they may

1:34:33not benefit from it. But you're the neuroscientist, you know, what, you know, what could

1:34:40you get out of something like that?

1:34:42And if somebody is really excited about, you know, doing any of these mental exercises

1:34:50versus, you know, it doesn't speak to them.

1:34:54Yeah, I think that if we should all find the things that we want to

1:35:00do enough that we would elect to do them, but that are challenging.

1:35:03There are data coming out now showing that handwriting is very important to development of

1:35:08certain brain circuits. It's kind of a no surprise, but this is important for the

1:35:12younger generation who's no longer handwriting so much.

1:35:15The phrase use it or lose it makes perfect sense to me.

1:35:17I mean, if you don't walk enough or run enough or cycle enough or do

1:35:21anything with your legs, eventually the neural systems that control your legs will atrophy, as

1:35:27will the muscles. We tend to think about the muscles, but we don't think about

1:35:30the neural control over the muscles.

1:35:31So I think since I'm 50 now, I think, you know, I make it a

1:35:36point to read at least, it's going to sound so paltry, but at least one

1:35:40page and ideally one chapter of a book every day.

1:35:44Sometimes it's just one page, but just with a book, with my phone out of

1:35:47the room, and I do, and I read papers and things like that.

1:35:50But doing things that feel unnatural, but that I know I will benefit from when

1:35:55they're over. There's such a deep feeling of satisfaction from having done that sort of

1:35:59thing. And for me, the higher intensity cardio is that I'd much rather jog than

1:36:04sprint. So I'd make it a point to sprint, you know?

1:36:06So I think maybe we should think about exercise and cognitive stuff the same way.

1:36:10Who knows? Yeah. I mean, is there anything in Switzerland that they do that they

1:36:15don't do here in terms of food and exercise and lifestyle?

1:36:18Because the Swiss are very healthy.

1:36:20The Swiss also, as I recall from something in The Economist a few years ago

1:36:23when I used to, I no longer subscribe to them, but the highest caffeine intake

1:36:28in the world is the Swiss.

1:36:29Really? They drink so much caffeine.

1:36:31Also chocolate. Yeah, yeah. Good chocolate.

1:36:33Chocolate and cheese. And people eat a lot of it.

1:36:36I eat almost every day I eat chocolate.

1:36:38Do you? Yeah. You're making some people very happy.

1:36:41I eat 100 % chocolate.

1:36:42It's part of my diet.

1:36:43When? When do you eat it?

1:36:45Usually after, you know, with a coffee after lunch or so.

1:36:48High in polyphenols. Mm -hmm.

1:36:50Yeah. And tastes delicious. Very hot and tasty.

1:36:53Yeah. Stimulates your brain. Makes you happy.

1:36:56I eat the raw or roasted cacao beans.

1:36:59Yeah. Because I like bitter, bitter things.

1:37:01Yeah, those are good too.

1:37:02Yeah, those are a good, a good, a good punch.

1:37:04You own a winery. That's right.

1:37:06That runs counter to everything I understand about longevity, but it runs.

1:37:10No, it doesn't. Okay. All right.

1:37:12Here we go. Educate me.

1:37:14Alcohol itself is probably not good for our body, right?

1:37:18Just pure alcohol. Right. But a lot of drinks are part of a social environment.

1:37:25And I think one of the major benefits that people have attributed to, you know,

1:37:30wine is the social aspects of it.

1:37:34I mean, some people may drink a bottle of wine by themselves.

1:37:37But I think the majority, you know, they have a meal together and you share

1:37:42a bottle of wine. And that's, we talked about this earlier, you know, how you

1:37:46dissociate one thing from another.

1:37:49I think, you know, there's this complexity that you see actually in almost all studies

1:37:55that look at centenarians, you know, where people lived the longest.

1:38:00One of the most common aspects is that they're all very social.

1:38:04They're not left alone when they're old.

1:38:07They have a community and they meet other people, right?

1:38:11And so I think that's part of the wine culture is really.

1:38:14And so I think that's part of the wine culture.

1:38:15being social, being together. Yeah, I mean, the data on social connection and stress reduction,

1:38:21huge. Yeah, I've gone on record saying that the data say zero alcohol better than

1:38:27any, two drinks per week is probably the upper limit for a non -alcoholic adult,

1:38:32after which I just say, you know, make sure you're doing other things correctly.

1:38:36One thing that I want to be really clear on is, since I'm talking to

1:38:43someone from originally from Switzerland, although you're a U .S.

1:38:47citizen now, is that the United States has never had a history of healthy food

1:38:54or drinking habits. You know, if you think about classic American cuisine, it's all unhealthy

1:39:00stuff. Apple pie, French fries, hamburgers, hot dogs, pizza, which was originally not ours, right?

1:39:08And on and on, right?

1:39:10There's been a culture of volume and abundance and kind of amusement park food, frankly.

1:39:20And the same is true for drinking.

1:39:21I mean, certainly not speaking for everybody, but there's been a culture around alcohol in

1:39:25the United States of drinking a lot of beer or a lot of spirits.

1:39:29Whereas I think in Europe, the food, including the desserts, have a tradition of nourishment,

1:39:36of social connection. And sure, we have bars in the United States and people drink

1:39:41beer while they watch games and things like that.

1:39:43But I think sometimes that gets lost in the conversation, that the United States has

1:39:49never been a particularly healthy place, except for its level of engagement in sports and

1:39:55exercise until recently. So I totally agree with what you're saying.

1:39:59If you're getting together with friends and having a couple drinks or something like that,

1:40:03that sounds entirely healthy. But the problem is that's usually not how it looks on,

1:40:10certainly not on college campuses, but that's another thing.

1:40:13Well, excess is right. Anything.

1:40:15If you also with food, I mean, I eat any food.

1:40:18You can eat any food, but you don't want to just eat one food.

1:40:22I mean, I eat French fries or a burger.

1:40:25There's nothing wrong with it.

1:40:26But if that's your only diet, that's not good.

1:40:29If you eat no fruit, that's probably not good if you have no vegetables in

1:40:33your diet. And the same, I think, with drinks.

1:40:36I mean, I have drinks, but I try not to get drunk every day, right?

1:40:42So I think moderation is really, I think, the magic.

1:40:50I'm going to get a little wacky here.

1:40:54Not woo, wacky. There's some really interesting stories about improving health and vitality, maybe lifespan,

1:41:04with things that adjust blood flow.

1:41:05So, for instance, in the literature around Qigong breathing, and there's a lot of different

1:41:11forms of this, but we can distill things down to the fact that inhales, vigorous

1:41:15inhales, increase the heart rate.

1:41:17Exhales, deliberate exhales, extended exhales, decrease the heart rate through something called respiratory sinus arrhythmia.

1:41:23So in a number of cultures, they'll do Qigong, Tai Chi, which is deliberate breathing

1:41:29and movement, of course. And the idea is that you're improving circulation, that it feeds

1:41:33the brain, you know, in the language of these things, that it's feeding the brain

1:41:36nutrients. And it all makes perfect sense, given what you're saying.

1:41:40It's also interesting. I've been looking at how patterns of breathing change as people age

1:41:45and talking to people who work in hospitals.

1:41:48And there's actually a little bit of data around this.

1:41:51As people get older and their cognitive function goes, they tend to become mouth breathers.

1:41:58That's interesting. They're having trouble oxygenating their brain.

1:42:01Now, it could be the mouth breathing is the cause, or it could be reflective

1:42:04of something else. It's kind of interesting to think about because the relationship between breathing

1:42:09and blood flow is an obvious and well -established one.

1:42:12So there are all these things about the young blood versus old blood that might

1:42:17be independent of pure biochemistry of aging that could be controlled with lifestyle factors.

1:42:23And we say exercise improves health span, but exercise increases breathing rate.

1:42:30So have you, are you at all interested in, I'm trying to get a bunch

1:42:35of studies going here, you can tell, and people that do some sort of deliberate

1:42:38deep breathing. It doesn't have to be Tai Chi.

1:42:40That would be super interesting.

1:42:42Right? Yeah. Because you're changing the chemistry of the blood.

1:42:44I mean, anything, you know, what we discussed earlier is this cause and effect.

1:42:48And really the way to show that something has an effect is you have a

1:42:53study where some people, you take their blood, they do an exercise, and then you

1:42:59take their blood again. And you look, does it change something?

1:43:02Very easy to do. Can we do this experiment?

1:43:06Absolutely. Because I ran a study with David.

1:43:08It just costs money. Money we can get.

1:43:10Money we can get. I'm not worried about that.

1:43:12David Spiegel and I ran a study on breath work.

1:43:15But we didn't look at how different patterns of breathing change a blood chemistry.

1:43:20Yeah, that would be super interesting.

1:43:21Absolutely. Because these are things that people can do at any age.

1:43:25Absolutely. And they're zero cost.

1:43:27But we don't have mechanistic data.

1:43:29We just have, oh, you know, people who do Qi Gong or Tai Chi live

1:43:33a long time. But then there's so many variables.

1:43:35They're outdoors. They're moving. It's social.

1:43:37And so the thing that concerns me about the health span, longevity space, if you

1:43:42will, is that we keep going around the merry -go -round and we keep going

1:43:45exercise, sleep, nutrition, social connection, sunlight, and don't smoke, drink in excess, play a contact

1:43:53sport where you hit your, we just keep going around and around and we need

1:43:57tools. Right. So I think that's exactly what we recognize at Vero, where we want

1:44:06to have tailored interventions that, you know, you give very specific advice based on, you

1:44:12know, if your heart is showing accelerated aging, this is the exact exercise that will

1:44:17help you based on studies that we just discussed, right?

1:44:21Where you say, okay, here we had 50 people who did this exercise and 50

1:44:25who didn't or something different, and it had a clear benefit and made their heart

1:44:30younger or made their brain younger.

1:44:33That's really what I think we all want, right?

1:44:36Rather than these broad sort of, oh, live a healthy life.

1:44:39How is that going to help you?

1:44:41You want really tailored advice and then also validating that it actually does something.

1:44:49And this is not a promotional.

1:44:51I just learned about Vero today, really.

1:44:54I'd heard of it, but I'm learning in detail.

1:44:56So it's now a company that anyone can access these tools?

1:45:00We are live. It's currently a small number of clinics that we're working with, and

1:45:07we hope to, you know, grow and expand it quickly.

1:45:11Do you measure your steps or make it a point to walk a lot each

1:45:15day or both? I measure my steps.

1:45:18I have a Garmin. I find it useful.

1:45:21I find also the sleep measurements really useful.

1:45:24Talked about sleep earlier. You know, it tells me how well I slept, how much

1:45:29deep sleep. Yeah, I think that's useful.

1:45:31Yeah, it's wild. Nowadays, people just accept, oh, yeah, we track our sleep, et cetera.

1:45:36I remember when I was a postdoc at Stanford in 2005 to 2010, people getting

1:45:42into quote unquote wearables. That's what they call them.

1:45:45They didn't quite work yet.

1:45:46Yeah, there was one graduate student in the neuroscience program, this woman, Rachel, who I

1:45:51think went to go work for a wearable company, and she had like seven or

1:45:53eight different watches. This is like Mike Snyder at Stanford.

1:45:57Yeah, we had him on here.

1:45:58Yeah. And way ahead of the curve with all these wearables.

1:46:00And I remember thinking, who's going to wear all those watches?

1:46:02And she said, no, no, eventually it will all be condensed to one watch or

1:46:05maybe even just a small ringer device.

1:46:08And I thought, all right, whatever.

1:46:09I've always been into health and wellness, but nah, and sure enough, she was right,

1:46:13but far smarter than me.

1:46:15I think we're going there.

1:46:17I think we're going to a place where soon many, many things will be measured.

1:46:23Like I would love eyeglasses where the frames have a measure the amount of photons

1:46:32I get during the day to make sure I get sufficient sunlight.

1:46:35Yeah, that's always something that I don't understand.

1:46:38There's a lot of people in this country have shades, right?

1:46:40They wear dark glasses all day long.

1:46:43This is so bad for your brain.

1:46:45And for your mental health, we know 80 ,000 plus subjects in this, in this

1:46:50UK study, the brighter your days, ideally from sunlight, but the brighter your days and

1:46:55the darker your nights, the less susceptible you are to every single mental health condition.

1:47:00And if you have a mental health condition, it gets way better.

1:47:03So you need bright days and dark nights and artificial lights during the day are

1:47:07not sufficient. And at night, a small amount of artificial light is too much.

1:47:12So these things should be straightforward to measure.

1:47:15Aren't people in the South happier?

1:47:17You know, in Europe, if you look sort of, they enjoy life more, they have

1:47:22more food, they sit together, they have fun.

1:47:24And the more North you got, the more serious and the more depression you got.

1:47:29I have Danish relatives. I don't want to insult them.

1:47:32And they're very cheerful. But it's interesting.

1:47:36People vary a great deal in their susceptibility to artificial light at night.

1:47:41So I've long said, you need to dim the light.

1:47:43Some people should even wear short wavelength blocking glasses, you know, maybe even red light.

1:47:47Some people, a small amount of artificial light at night increases their cortisol really substantially

1:47:52and could disrupt their sleep.

1:47:54Other people less so. So there seems to be some divergence and it doesn't correlate

1:47:58with, with light eyes or dark eyes.

1:48:00I am very, very sensitive to light at night.

1:48:03It will really disrupt my sleep.

1:48:05Some people, not so much.

1:48:06But in terms of temperament, I'm going to inspire some family arguments here, but I

1:48:11don't know. Yeah. Yeah. I mean, even growing up in Switzerland, you know, we had

1:48:15four very short days in the winter and then often fog.

1:48:22It's hard to get up in the morning.

1:48:25And then coming to California, it's sunny all day, you know, most of the year.

1:48:31It just makes it easier to get your day started.

1:48:34And yeah, I love the sun.

1:48:37Yeah. I think if people don't have access to sunlight, enough sunlight, there are great

1:48:41data that a 10 ,000 luxe artificial light placed in the kitchen or in the

1:48:45bathroom when you wake up in the morning, you don't need a lot of time

1:48:47in front of it. You don't have to stare at it.

1:48:49That can help offset some seasonal depression.

1:48:52And some people just need more photons to get that morning spike in cortisol, which

1:48:58is good to get the catecholamines going, dopamine and so on.

1:49:01I mean, the power of light over our mood and metabolism is huge.

1:49:05Amazing. Yeah. Should do another study on that.

1:49:08I mean, listen, I... I don't know.

1:49:10Do for a sabbatical. Can I do a sabbatical in your lab?

1:49:12Tell me, is there anything that you're particularly excited about that I did not ask

1:49:17you about? You've been publishing so well for so long now, and you really put

1:49:21this whole field of looking at bloodborne and other factors correlated with youth as a

1:49:30therapeutic, you really put that on the map in a serious way.

1:49:33And I really want to congratulate you for doing that on a backdrop of Dracula

1:49:38stories and kind of sensationalism around that.

1:49:41You're clearly a serious scientist taking things on seriously, and also measuring multiple factors from

1:49:47blood, as you know, has a kind of a complicated history, but you've really moved

1:49:50this forward in a very rigorous way.

1:49:54And so that's awesome. What are you thinking about these days that I wouldn't know

1:49:59about? Thanks for the opportunity.

1:50:01Yeah. So one thing that should later this week actually be publicly available on a

1:50:08preprint server. So we took this idea of looking at organs and, you know, getting

1:50:16an estimate of how old is your brain or your heart.

1:50:19We took this to the next level and ask, can we build similar models and

1:50:24estimate how old cells are in your body?

1:50:27So we have many different cell types, right?

1:50:30That's how we have specialized organs.

1:50:32So we were able to, with the current technology that measures these thousands of proteins,

1:50:38we were able to assign proteins to 40 different cell types.

1:50:43And so we can now make estimates of specific cell types in your body.

1:50:49One of the most striking findings was we looked in people with different neurodegenerative diseases

1:50:55and ask, how old are all their different cell types?

1:50:59And we find in this rare disease called amyotrophic lateral sclerosis or ALS in the

1:51:08US, we often call it Lou Gehrig's disease because Lou Gehrig was this baseball player

1:51:13who got this devastating disease.

1:51:15It's a muscle weakness that often progresses extremely quickly and people die.

1:51:21And what we found is that these individuals had extremely old, an enrichment in extremely

1:51:28old muscle cells, skeletal muscle cells in particular, and also heart muscle cells, cardiomyocytes.

1:51:36So there was this very strong association.

1:51:39And then we looked in a progressive, in a longitudinal study, cross -sectional, but where

1:51:47we had 20 years follow -up.

1:51:48It's called the UK Biobank.

1:51:50So we had blood samples from people when they entered their study healthy.

1:51:55And then a number of people developed, about 250 developed ALS over the course of

1:52:0015 years. And we found a strongly increased risk to develop the disease if they

1:52:07had these extremely old muscle cells.

1:52:10So here we have now a much finer resolution and granularity where we can get

1:52:18more predictive power. We can get more precise prediction of what type of disease you

1:52:26might get. And of course, at the molecular level and the cellular level, we know

1:52:31where the problem might be, right?

1:52:33It's not just the whole organ, but now we know which cell type.

1:52:37Another one was there's these cells we call astrocytes in the brain.

1:52:42We find a very strong association of the age of astrocytes and development of Alzheimer's

1:52:48disease, much stronger than just the brain age, so the age of your whole brain.

1:52:54When we look now at these individual cells, they are a very strong predictor of

1:52:59Alzheimer's disease, especially together with a genetic risk factor.

1:53:03So that's something that we have been developing and really excited about.

1:53:08But my ultimate greatest stimulation right now is to build a map of the human

1:53:18proteome across different genetic diseases.

1:53:21So what I'm trying to do is to ask, if somebody has a disease that

1:53:28is caused by a single genetic mutation, and there's about 6 ,000, 7 ,000 such,

1:53:34we call them monogenic diseases, where if you have a mutation, you will get a

1:53:38disease, childhood disease or an adult disease.

1:53:42So what I want to do is to look at individuals with these mutations and

1:53:48profile their plasma, basically measure all the proteins and see, are they different from healthy

1:53:55people? And if you do that across hundreds of diseases, you basically get a picture

1:54:01of how our body responds to the disruption of specific genes.

1:54:07And the idea is that this will allow us to look at any type of

1:54:13disease, or we don't know how it's caused, and then say, this looks like this

1:54:18genetic disease. Basically, what we've been doing in animals with worms, right, where we knock

1:54:24out every gene or in flies, use the human experiment, if you will.

1:54:30And this may be a bit disparaging.

1:54:32These are obviously people who have diseases.

1:54:35But there are repositories. where people volunteer to make these samples available for research.

1:54:43And so we have had the opportunity already to look at 25 different genetic diseases,

1:54:49and we find these very specific patterns.

1:54:52So that's what I want to build, and then make it publicly available so that

1:54:57any researcher can ask, how does my protein of interest that I want to study,

1:55:03how does it change in these different genetic diseases?

1:55:06And learn about how they're related to each other and which biological pathways they may

1:55:13change. That's what motivates me the most.

1:55:17I love it. It's so clear that you're a driven person, and learning about what

1:55:23the next vista is is always exciting.

1:55:27And again, thanks for the incredible work that you've been doing for all these years,

1:55:32bringing a level of rigor and seriousness to something that prior to that was just

1:55:37kind of tossed around as kind of an observation and something to discuss at parties,

1:55:43you know, young blood and this kind of thing.

1:55:44You're clearly shedding light on real mechanistic knowledge.

1:55:50And the ability to measure aging of different organs now, I think, is a tremendous

1:55:55technology. I'm very curious about that.

1:55:56I know a number of other people will be.

1:55:58We'll put links to the various things in papers, et cetera.

1:56:02And I also want to thank you for coming here, taking time out of your

1:56:05busy schedule, your lab, your family, your vineyard, this is a plural, to educate us

1:56:11on health and on healthspan and on the relationship between youthfulness and aging and what

1:56:18we can do to really ameliorate the degradation of healthspan.

1:56:23You're developing the things that change lives for the better.

1:56:27So thank you so much.

1:56:28I really appreciate you. Thank you so much for having me.

1:56:30Yeah, and come back again and tell us about all the other discoveries.

1:56:33And I'll buy a bottle of the wine from your vineyard and I'll gift it

1:56:35to one of the drinkers in my life.

1:56:37Sounds good. All right. Thank you very much.

1:56:40Thank you for joining me for today's discussion with Dr.

1:56:42Tony Weiss -Corey. To learn more about his work and to find links to the

1:56:46various resources we discussed, please see the show note captions.

1:56:49If you're learning from and or enjoying this podcast, please subscribe to our YouTube channel.

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1:57:22I do read all the comments.

1:57:24For those of you that haven't heard, I have a new book coming out.

1:57:27It's my very first book.

1:57:28It's entitled Protocols, an Operating Manual for the Human Body.

1:57:32This is a book that I've been working on for more than five years, and

1:57:34that's based on more than 30 years of research and experience.

1:57:38And it covers protocols for everything from sleep to exercise to stress control, protocols related

1:57:44to focus and motivation. And of course, I provide the scientific substantiation for the protocols

1:57:50that are included. The book is now available by presale at protocolsbook .com.

1:57:55There you can find links to various vendors.

1:57:58You can pick the one that you like best.

1:57:59Again, the book is called Protocols, an Operating Manual for the Human Body.

1:58:04And if you're not already following me on social media, I am Huberman Lab on

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1:58:13And on all those platforms, I discuss science and science related tools, some of which

1:58:17overlaps with the content of the Huberman Lab podcast, but much of which is distinct

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1:58:23Again, it's Huberman Lab on all social media platforms.

1:58:26And if you haven't already subscribed to our Neural Network newsletter, the Neural Network newsletter

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1:58:34call protocols in the form of one - to three -page PDFs that cover everything

1:58:39from how to optimize your sleep, how to optimize dopamine, deliberate cold exposure.

1:58:43We have a foundational fitness protocol that covers cardiovascular training and resistance training.

1:58:47All of that is available completely zero cost.

1:58:50You simply go to HubermanLab .com, go to the menu tab in the top right

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1:58:56And I should emphasize that we do not share your email with anybody.

1:59:00Thank you once again for joining me for today's discussion with Dr.

1:59:03Tony Weiss -Corey. And last, but certainly not least, thank you for your interest in

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Restore Youthfulness & Vitality to the Aging Brain & Body | Dr. Tony Wyss-Coray