#359 ‒ How metabolic and immune system dysfunction drive the aging process, the role of NAD, promising interventions, aging clocks, and more | Eric Verdin, M.D.

26:20And I think the intensity of the peaks of insulin is a reflection of your glucose intake, fast absorbing glucose. And that's the reason why we advocate, advocate people to go on a CGM, continuous glucose monitor, and to really learn to understand what spikes them. The whole idea is to mitigate these peaks of insulin secretion. I'm just going to play this for all of our patients. We have this discussion with every one of our patients, so it'll be nice to just play this video and let you do the talking. The whole idea there is to, again, mitigate these peaks, and either dietary, or, for example, the JLP1 icon is playing a role in this as well.

27:00Let's talk about this, because there is at least for me a great deal of confusion around this point. Now, we understand today the role that the gut plays in metabolism, and we understand that a lot of it is transduced through GLP1. So endogenous production of GLP1, according to Ralph DeFranzo, the world's authority on this, is what's driving 80 % of beta cell activity with respect to insulin. And therefore, or when we have insulin resistance, the GLP1 we're making is insufficient to generate the insulin that's required to manage the glucose. Make sense if that's the case, that giving exogenous GLP1, you take a shot of Teresepatide or Semaglutide, you're going to put more GLP1 in the system, you're going to overcome the resistance at the beta cell, you make more insulin, you now have better glucose control, everybody wins.

27:56Now it's not clear that that has anything to do with the weight side of it. That's a separate issue and I want to actually talk about that because there are two very interesting theories as to why these things cause weight loss. But point here is, wouldn't you expect to see higher levels of insulin in someone taking a GLP1 agonist to achieve that better glycemic control? Yes, and that's not what you see. And I don't have an answer for this. I've seen the same thing, including personally, I've been experimenting with Tuzapatite. My insulin is five now. which is lowest that you can possibly get it.

28:30There was a part of me that I was worried that I was going to go against my own whole theory about. Have you checked post -prandially? Have you done an oral glucose tolerance test? Because that might be something to do to see what is happening to post -prandial insulin, along with post -prandial glucose, which of course will be better. No, I haven't. That would be an interesting test to do, yeah. I've won a CGM. my A1C has gone from 5 .45 .5 to 5 .0 and my insulin is down to 5 .0 as well. And did you lose any weight? I lost a little bit of weight, not a huge amount, 6 or 7 pounds, which was never the goal to start with and no loss of muscle mass, which actually is the big bugaboo that people will have you fear, no loss of muscle mass if you are exercising.

29:17So for me, it's an experiment. I haven't decided this is something I'm going to continue. But I just wanted to really experiment it for myself to try to see, okay, what is this job really doing? And it's been nothing short of remarkable, I think, in some way. One of the most surprising has been for me this feeling of satiety. You hear about satiety. I was never in my whole life, the type of person that felt full. I could always eat more. And all of a sudden after about two weeks on this, is I just looked at my plate, I said, I'm full. And I heard myself saying this and it just felt like, well, this is really completely different.

29:50And for me, not the reason why I'm excited about these drugs is, and by the way, this is not an endorsement, this is something to deserve. Yeah, this is self experimentation. It's self experimentation, which is a long part of the tradition of our field. The whole idea is really, the thinking was one of the biggest advance in longevity medicine, in this, this idea that a range is meaningless. And as a practicing physician, you know this. I went to medical school and we were told that your blood pressure has to be 130 over 90. And I was still the normal range. So you could be 128 over 88. And you were still considered normal.

30:28The same thing I went to see my personal physician and told him, my blood sugar is creeping up every year that I'm doing it. And now it's 96 fasting blood sugar. And I'm worried because soon I'm going to be pregnant. He said it's below 100. It's okay. It's only your normal. Don't worry. And I told him I said, what is normal? And I think this really is where I think Longevity Medicine is going to make an important impact. It's really sort of revisited. I can't tell you how many times I've had this argument with people about glucose. And here's the funny thing. We have the literature. In other words, we have literature in non -diabetics.

31:01Your A1C. That says the lower the A1C, the lower the all -cause mortality. It's a monotonic reduction that knows no lower limit. I'm with you. So we say that up to 5 .6 is normal, and if you're at 5 .6 you're fine, but 5 .5 is better than 5 .6 and 5 .4 is better than 5 .5 and 5 is better than 5 .4 and 4 .8 is better than 5 .1. I'm not there yet. But my point is I also find it, I don't know what the word is, maybe sad. I find it sad that we've simplified this problem in an effort to communicate but have lost the essence of where is lower better? Because it's not always true in biology. When you look at TSH, for example, when you look at thyroid hormone, much more narrow band in which we would say there's optimal.

31:48If it's too low or too high, it's problematic. But it turns out that when it comes to average blood glucose in a non -type one diabetic or someone who's taking insulin, under natural physiologic circumstances, it's just better to be lower. And as you age, it just keeps creeping up. same thing for blood pressure. Yes. They're revisiting the number every five years in terms of making it lower. I think if your blood pressure is a 105 over 65, you're better off than if you're 115 over 75. That's right. Provided you're not symptomatic, lower is always better. You know, I'm frustrated, but I'm also excited by the fact that this is now becoming norm in a whole new field of physicians who are more aware of actually what is health.

32:29and the same for your weight, we know that the thing that is really interesting in the whole aging field is this idea that everything is a J -curve. So there is a sweet spot where you want to be and quite often it's broad enough that you can maneuver this in a way to optimize people's health. What do you think is the relationship between, I mean, body weight is so crude, but maybe we can even talk about it through adiposity, body fat, and longevity once correcting for metabolic health. So it's obvious that so much of the relationship we see between body fat and poor health is really just a proxy for something that's harder to measure, which is metabolic health.

33:07It's very easy to measure body fat, and we estimate body fat from BMI, and so that's why we have all these population data from BMI. But if you have the luxury of working with actual patients, I couldn't tell you the BMI of one person I take care of, but I know everybody's body fat, everybody's visceral fat, and everybody's oral glucose tolerance tests. we know what we know and we know what matters. Are you convinced that at a positive per se is problematic? Or do you believe that a person can have excess body fat but be metabolically healthy and confer the same longevity benefit as a metabolically healthy lean person?

33:44We know there are people who are considered overweight who are metabolically healthy. Yes. Easily 20 % in my experience. Yes, and these are facts. No one can dispute them. You can be overweight and metabolically healthy. What I worry about is the long -term effect. Do you mean from an orthopedic perspective with the other complications that come from excess weight? Or are you saying that they're basically increasing their probability of eventually going off the metabolic slide? Both. Honestly, I don't know what the data says, but my worry would be that you might be metabolically looking healthy when you're 40, but if you sustain this for 20 years, clearly visceral fat.

34:25It's a highly predictive of everything. The other thing I'll say also, the BMI itself is, my BMI is at the border of being overweight. I am overweight by BMI. I'm four pounds. If I lost four pounds, I would get down to a BMI of 25. And I have 11 % body fat. So I don't worry about it because I know all in all, I'm metabolically healthy. My numbers are good and all this. So in some way, it's not a particularly helpful. I mean, it serves its purpose at the population level, but it can't be used to make a decision about an individual at all. Exactly. But it can also sometimes become a confounding variable, and when people do studies and they use these numbers and they make predictions or they draw conclusions that are really not based on the fact that IBM, my fraction of the population is heterogeneous in terms of metabolic health.

35:12So my colleagues at the buck Nathan Price and Lee Hood have actually published a paper. I didn't realize they were at the buck. Yeah, both of them. They were up in Seattle before weren't they? Yes, we recruited both of them actually in the last two years. Congratulations. Yeah, thank you. I think this is transformative for us. Fantastic guys. Lee is still partially in Seattle. Okay. So it's partially at the buck. We've established a collaboration with Phenomen health. And Nathan was a thorn and still a CSO at thorn, but faculty member at the back. And they're really helping us to do something really exciting along these lines.

35:46For example, they had a paper describing this BMI, but biochemical BMI based on biological markers that essentially assess you metabolic status. So I think that those tools are available and it's a question of educating the physicians. Can you know what makes up that biological BMI? No, I'll give you the paper. Okay, we spent a little more time on metabolism than we did immune health and the immune system overall. I'd actually like to go back and talk about it a little bit more. I think, again, the listeners of this podcast are very familiar with the metabolic stuff. We haven't had as many discussions on the immune system.

36:23Talked about it length with respect to cancer. I had Steve Rosenberg on a few years ago. That was a fantastic discussion explaining the role of the immune system in cancer, which I think we're going to have to talk about here, because I certainly feel convinced that a big part of why cancer incidents goes up exponentially with age is the declining immune system, not just the accumulation of mutations, although I imagine they both play a role. But I will tell you something else, Eric, which is, you know, I wrote a book a couple of years ago about this space, and in the book I talk about these things called the Four Horsemen.

36:56And I describe them as the four things that are basically coming for us all. If you manage to outlive youth, this is not to diminish the role of trauma and other things that are deadly. But for many people living in OECD nations, it's going to come down to ASCVD, cancer, dementing and neurodegenerative diseases and metabolic diseases. And people often say, Peter, is there anything you wish you'd written in the book that if you go back in time, you would do? And I say, yeah, there are probably many things if I thought about it. But the first thing that jumps out is I really should have added a fifth horseman and that is immune health.

37:30and the types of infections that ravage people in old age that a young person would laugh at. Thank you for bringing this up. Immunology and aging have been not really mixing very well. One problem is that immunology is an extremely complex and advanced field, along with neuroscience, one of the most complex. So when you go to an aging meeting, there is no one talking about immunology. You go to immunology meeting, there are very few people talking about aging. We try to navigate even that nomenclature is being used differently. People in immunology talk about immunosinescence, meaning aging of the immune system.

38:07They don't mean senescence the way we talk about aging. So that yields all kinds of crazy communication problems. Yeah, because if you're in the aging field and you hear immunosinescence, you think of sasps and things that are being secreted by T cells. It just means aging of the immune system. Now, the reason why I think this is a tragic failing for both field is what happened during COVID became obvious that your risk of infection was not linked to your age. The virus infected everyone across, but the outcome could be completely different with 84 excess, 84 fold excess mortality if you were above 75, 84 fold.

38:45Now when this happens and we can go in terms of trying to understand why did this happen, What are the reasons for this? I went and started to look at the literature Influenza, it's exactly the same thing R is V same thing So all of these viruses that you can contract in later years will kill you with really significant rates Influenza I think 30 ,000 people die every year from influenza the mortality in terms of COVID was really highly segregated into the older part of the population or in that part of the population that showed excited aging obesity and so on. Do you think that most of the mortality, any time we saw a gap in mortality, whether it was young versus old, whether it was obese versus non -obese, diabetic versus non -diabetic?

39:33Anytime you looked at that, you saw a difference in mortality. Do you believe that it was always a difference in immune function? I mean, with young versus old, it's very obvious, but do you think that was also true in the other comorbidities? I would say so. And it comes from two reasons. One is there are two broad immune systems where we call the innate and the adaptive immune system. I don't know if you want me to. I would. I actually was going to say I think it is worth going full bore on this. I think it is time for people to roll up their sleeves and understand arguably the most interesting system in the human body.

40:06I am biased. I spent two years at the NCI doing immunology, but I think this is such an interesting field. But our immune system is built to recognize foreign elements. That's really is why it evolved. It has two lines of defense against microbes, bacteria, viruses, fungi, all of those. We are constantly bombarded by those. It is actually amazing because the evidence of this is if your immune system doesn't function, the bubble would be... It's incompatible with life. It's incompatible with life. So we are colonized with bacteria in and out and our skins everywhere. So we constantly respond to them in an appropriate manner.

40:43And we survive everything, including disruptions to the barriers. Absolutely. Absolutely. So we have two lines of defense in the immune system. First is so -called innate immune system, which is your macrophages, your dendritic cells, but also pretty much every cell has a whole series of mechanism that are not pathogen -specific. That is, they will recognize an intruder, be it a virus, be it fungi, bacteria, and it will activate a first line of defense. Those line of defenses are non -specific and therefore they're less effective. And they give time to the so -called adaptive immune system, which is the second part, which is made up of T cells and B cells.

41:27And both of those cells have a highly selective defense mechanism. The B cells make antibodies, bodies, which will go recognize a bacteria or fungus or virus, and the T cells, which are able to actually kill the infected cell itself. So we'll recognize when the cell is colonized by a foreign pathogen and we'll kill it. So the time course of these is that once you encounter a pathogen, you will be activated your innate immune response. Typically, it can be fever, it can be all kinds of symptoms, but activation of this defense and this gives the whole organism a couple of weeks to actually build the defense for the specifically recognized this organism.

42:10Let's talk a little bit about memory within that system. So the innate immune system does not really have a true memory. It will always react in the same way no matter how many times you... If your kids are ping ponging the same respiratory virus at you from school, your innate immune system has the same playbook fever. You're going to get red. inflammation. You're going to get sore. All of those things are going to happen regardless. And that's in contrast to the adaptive immune system because once the initial response has been generated, either via an infection or a vaccination, this is what a vaccination is, it presents you with a given fraction or the whole virus or a part of it, your body will mount a response and this will lead to the amplification of a subset of cells that are selective.

42:59So think about your T cells or your B cells. None of them are the same. We have a process by which we generate so -called diversity, which is billions of different forms of antibodies or T cell receptors that are recognizing, in principle, every chemical structure, every protein, from a microorganism. Now what happens during the initial encounter, either being a vaccination or an infection, is those B cells or those T cells that have a receptor that is able to recognize the pathogen will become amplified. And they will turn out large amount of the antibody or the T cell clones. Once the job has been done, they will contract, but they will not contract back down to the same level.

43:48They will become what we call memory T cells or memory B cells, so that if you encounter the same antigen in the future, the reactivation process is shortened. The maturation happens faster. So eventually the whole idea of the vaccination is to sort of get yourself ready with a subset of memory T cell clones or B cell clones that once the true virus will come, you will be able to mount the response within a few days or up to a week. And so that's how vaccination works. Now what's interesting during aging is, and people are not aware of this. If you're above 70, most vaccinations do not work. So people then will ask, they actually, your immune system has aged and your vaccination rates really decreases very strongly.

44:35For what I remember, this might be different in different populations, but vaccination rate successes close to 30 % if you're above 70. During COVID, what was the risk reduction for a person over 75 who was vaccinated versus not vaccinated. It was almost complete reversal of the effect in terms of the protection. Meaning it was highly highly protective. Yeah, it was protective. So how do we reconcile those two facts? That's true. To be honest, I don't know how this has been studied. I would be happy to read about this. Because the COVID vaccine seems to have had a remarkable risk reduction in very old people.

45:16didn't seem to have an impressive risk reduction in younger people because the absolute risk was so low it didn't seem to matter that much but boy did it matter in older people. But did it matter at the population level or at the individual level? This is what I'm not sure about. I certainly don't want to go on record saying something. I think we can find the answer and put it in the show notes. My recollection, which could be wrong, is that the older a person got the greater the benefit they got from COVID vaccines with respect to mortality. So I guess the question is, let's maybe talk about other vaccines.

45:53Is that not the case with influenza? Is that not the case with pneumococcus or any of the other vaccines that are used primarily in older adults? In general, and I'm not a vaccine specialist, but the thinking is that there's a dramatic decrease in the efficiency of vaccination against influenza, against RSV, against all of those as you age. The thinking then is how does it work at the population level? And this is where the whole concept of herd immunity works, is that if you limit the spread of the infection in a family, for example, you're much less likely to infect grandpa. So that's been my understanding of how most of these viruses, these viruses work.

46:34Yeah, I'm asking a different question. That's an important question. I guess I was asking Obviously, they didn't probably do a randomized control trial, so you've got all these confounders in it, but I wonder if they just looked at all comers to the hospital vaccinated versus none. Let's try to control for all the confounders. If the hazard ratio is 1 .2, it means nothing or 0 .8. But if the hazard ratio was 0 .2 or 8, well, you'd say even with the confounders, there must be some high degree of protection that came from that. So anyway, I'm sure someone listening to this knows the answer to that.

47:10We'll try to find the answer and put it in the show notes. But let's go back to the why. Why is it that as a person ages, they're less likely to respond to a vaccination. Is it because A, the immune system, the adaptive immune system is less able to recognize the foreign pathogen and build up a high enough reserve of T cells and B cells that will respond. or is it B that they can do that, but the ability for those cells to stay in a memory state and B reactivated is somehow impaired. I think it's both. It's in everything you're aging. But there's one aspect which is really unique, at least in terms of T cell, which are really instrumental in terms of most vaccine response, is the fact that these T cells are the diversity of the T cells is generated by the thymus.

48:03And the thymus, a small organ behind a sternum. How big is your thymus and my thymus right now? I'm 68 so it's probably very, very embryonic and it's probably not much left after age 50 and most people you find it very small. Whereas when you're young, it's actually you can see it on an imaging scut study and I would imagine if you and I had a CT scan of the chest, you'd barely be able to pick it up. Exactly and it's replaced by fat actually in most people as you age. Although there is somewhat controversial evidence that there might still be some clones that can be reactivated, even in older people.

48:39And human growth hormone, as you know, is one of the interventions that has been shown to actually re -induce thymogenesis. So, let's talk about that a little bit. Are you referring to that phahey paper from about seven or eight years ago that looked at growth hormone with metformin and DHEA or something like that? That's one, but that Faye paper was actually inspired by work of a colleague of mine when I was at the Glatzon Institute who did this actually Mike McHughan and colleagues did this in patients with HIV were chronically infected with HIV where they lose a lot of their city for T cells and there was an interest.

49:18So there's a big lesion initially in infection, and there was an attempt to actually try to see if you could regenerate these populations to bring them back to a normal. Because even though we had great drugs against HIV, they could not bring those patients back to normal. There was a remaining original insult. So they did a trial with a human growth hormone that were able to show some degree of timeogenesis and increase in naefty cells in these patients. And I believe the phoenix trial actually tried to reproduce this. I think there's a second phoenix trial that is ongoing, but I haven't seen the results.

49:57Yeah, I mean, the first one was, I don't remember the results. The cocktail was a little suspect. I agree. So the GH made sense if that's your hypothesis. I believe, I've never spoken with Greg, but I believe reading the trial, the metformin, which was really given at a homeopathic useless dose. I think it was only given at 500, so apologies if it wasn't, but I think it was only given at 500, was meant to offset the glucose metabolism disturbances of GH. Do you remember why the DHA was given? No. There was some reason for it that made sense on paper, but didn't make sense physiologically. Now, the more important question is, my take on that trial was it was a single active agent, which was growth hormone.

50:41Like, I don't think DHA does anything. I don't think 500 a metformin does anything. So the question is, and it was a very small trial, and I think it was open label. I have significant problem with the readout of that trial. So that's what I wanted to ask you about. Remind me of the readout. The readout was one of the clocks. Ah, that's right. This was Steve Horvath was the other author of that paper. Exactly. And actually this whole story sort of pushed us into a whole project that we've published down on what we call Entrant Clock, because they was in the experiment in the patients, they'd indeed observe some increase in the fraction of naifty cells, which tells you and me that something worked.

51:19The fraction of naifty cells increased with respect to the memory. The naifty cells are the ones that are generated in the time is the naiv because they have never met their cognate antigen and they sit there waiting for something to happen. So the whole idea of treating with human growth hormone was to induce timeogenesis and to restore the pool of these naïvetes. So I think to some degree it works at low level. Then they use the clock on the whole blood. And my worry when I saw the paper, which is a worry that actually existed, predated this, and was also a worry when people were using telomere length, is the idea when you sample the blood as an immunologist, I know this is a highly dynamic organ.

52:02Think about the blood as an organ. We enumerated this point today with the best technology more than 500 different populations of cells in the blood. Suppose that these cells vary in response to any intervention and that these cells individually have a different epigenetic age, you would have the impression that you are rejuvenating, which was the claim of that phahepip, or that they had rejuvenated people. But in effect, what you would do is simply change. Yeah, it's like you're on a sine wave that goes like this and you take two sample points. They could be here, they could be here, they could be here.

52:39And by the way, as you probably know, Matt Cabralen has famously purchased, I think, four or five of the commercially available aging clocks. He bought them in duplicate and did all of them sampled them all simultaneously. Two of this, two of this, two of this, two of this simultaneously take 10 samples and not only do all the clocks disagree with each other, but even within the same clock, there was disagreement, significant disagreement. So, yeah, I mean, I want to actually come back and talk about clocks in some detail, but given that that study was done years ago with an older clock, I think the clock part of it is not even remotely interesting.

53:16I think the more interesting question is, was there genuine thymac regeneration? If so, how do we reconcile a very pressing and vexing question within neuroscience, which is the role of growth hormone? So I've never taken growth hormone. I've never, I shouldn't say I've never prescribed it. I've prescribed it in very rare circumstances for injury, healing, but I've never prescribed it for quote unquote longevity benefits. But a lot of people are out there doing so. And as such, I've had lots of patients who come to my practice who have been taking or are on growth hormone. And I will say this to a person every single one of them has said, I feel so much better when I take growth hormone than when I do not.

53:57I mean across the board 100%. And I can't actually point to evidence that tells them it's bad to take. I can just say it doesn't make sense to take. If our goal is to reduce the risk of cancer and if our goal is to slow the aging process. So what is your take on that? Just your intuition, or is there any data you're aware of that would lead one to think that, well, maybe we could pulse a little bit of growth hormone here and there if we get some phymic regeneration. We don't have to be on it all the time. I mean, how would you think about that? I do worry about it. I'm not a specialist on growth hormone itself.

54:33It induces diabetes. It induces glucose intolerance. So from that angle, I do worry about what it would do chronically, especially in someone young. It's a bit like increasing your protein intake. There's clear evidence that increasing your protein intake, especially as you age, becomes beneficial. and the people who have higher protein intake actually do better in terms of muscle mass and so on. So in someone who is 65 to 70, who is starting to feel the effect of manifests some form of sarcopenia, there might be a benefit for that person to actually increase muscular mass and all the benefits with this, especially if it's not done continuous.

55:16But I mean, I would argue there's no doubt that there's benefits, but you're going to get far more efficacy from testosterone or anabolic steroids when it comes to mitigating sarcopenia. Growth hormone actually is not remarkable at inducing muscle mass. It's nowhere near as effective as testosterone. It's more effective at eliciting fat loss, but I wonder if there's something that goes beyond that. Because I think when people tell me they feel better on it, I think they're talking about less aches and pains. joints just feel better. I don't think anybody's saying they feel better because their thymus is more plump, but I wonder that to me would be a reason to potentially consider a schedule, an intermittent schedule of something if it's again going back to my macro thesis here which is I've been harping on these four horsemen, four horsemen.

56:04Well, if we introduce a fifth horsemen, what is the strategy? Because I can give you chapter in verse, the strategy for how you will mitigate heart disease, cancer, all of these other conditions. What is our strategy for mitigating immune decline? I would say the same as a strategy that would mitigate decline in every other organ. It is clear evidence that the effect of exercise on immunology is the same as in everything. So I'm not familiar with it. So tell me a little bit about that. I don't know specifically how exercise It's impacts the immune system. I cannot speak to specific papers. Clearly, there's evidence that people who exercise actually respond to infection, better respond to vaccination, better.

56:45So that's all been documented. I see. I cannot speak to specific studies. Do you have a sense of mechanistically why that's the case? It is so complex, I would say. I would not be able to tell you. But that being said, I think the whole line of investigation to induce Theimic rejuvenation, I think is an important one area, especially if we're thinking about increasing lifespan further for what we are doing now. That's in the future, it will become one of these rate limiting step. It's a bit the same situation as the ovary, where the ovary and the thymus, we call them the canary and the coal mine.

57:21I mean, there really are specific organs that show, et cetera, ageing way earlier than other tissues. Now the question is, why is the thymic invuluding so early? I think it's probably because of evolutionary we would never meant to live this old. And so that really is one of the thinking that goes on. That's going to be in the long term one of the problems that we have to face. And this is something we actively studying in the lab is trying to, we just completed a study where we are looking for novel biomarkers that are predictive of whether you will respond to a vaccination or not. And it's something done in collaboration, Mark Davis at Stanford using the 1000 Immunom project, which is one of the largest studies studying aging and immune system only in humans.

58:05So we've been able to studying people to identify some metabolites that are associated with poor response to vaccine. And so those are not only markers, but they could also become tools that we include in as adjuvant or as a pre -cheat metery. I'm sure you're familiar with the work of Joan Manic. Of course, yeah, I was going to ask you about Manic and vaccine in a moment. Before we do, I want to Go back to this point here, which is biomarkers are so important when I think about cardiovascular disease. And even though it's the leading cause of death, why I tell my patients, it's the one you need to be least afraid of if you're willing to be proactive in management.

58:43And it comes down to the fact that we just have such a clear understanding of how the disease works. And we have exceptional biomarkers. So we can measure the things that are causing the disease. We can measure inflammation, we can measure APOB, we can measure VLD, cholesterol, LP, little A, we can measure blood pressure, we can measure metabolic health, and we know how to address those things. And we know that when we address those things, we can measure whether what we're doing is working. Okay, so problem solved, basically. When it comes to the immune system, we're going to talk about manic and clix -dean in a moment, But as we saw from their paper 10 years ago, they gave a rapamycin analog to people, people who were in their 60s, vaccinated them and demonstrated that, oh boy, you got a much better immune response.

59:32Okay. They were able to demonstrate that using laboratory techniques, I'm sure they used flow cytometry or something like that to measure it. How close are we to being able to do that sort of thing commercially? By commercially, I mean over the counter. not close. I think in that study they actually measured antibody titers. So even more complicated than close cytometry? Yes. Okay. In that case they definitely showed an enhancing effect with a known giro protector. This was a suspected giro protector at least in humans. Exactly. A rapid log and they showed not only increased titers but also protection, increased protection.

1:00:11Eventually the clinical child failed for a whole series of other reasons, which were in parts due to the way that the FDA imposed the trial to be generated. I think it just complicated the whole picture. Yeah, by the way, for folks listening to us who were confused by that Matt Cabralin and I had a specific discussion because it wasn't the 2014 trial. It was a later trial. It wasn't the RAD001 trial. It was the other trial that failed. And I actually don't remember the reason, but Matt explained that it was very clear that it was a tragedy of bureaucracy. It is. And it shouldn't be viewed as a black eye on that molecule.

1:00:51Yeah. Matt is a more of a specialist in the whole weaponized and so will differ to what he said. We'll link in the show notes to where Matt and I had that discussion. Yeah. What I've heard from anyone that I've talked to including Joan is that this was in some way bungled, which is sad because sometimes things like this can put a field back for a number of years, discourage investors. We have a startup that originated at the Bako Leovian, which has raised $50 million. Again, coming up with RapaLogs, novel RapaLogs that are going to be, I think, revisiting that whole picture. So, quite excited.

1:01:23The field is far from being dead. Well, we ever be able to measure this in people the way we measure hemoglobin A1C or things like that, or is it going to be one of those things where it's a bit of a leap of faith? And you're going to have to look at the clinical trial where the outcome was there. And then And you're just going to have to say, well, even though there was probably massive heterogeneity amongst the participants in the trial, we're going to dose this thing individually. I mean, it's a little bit like you brought up vitamin D earlier. I mean, one of the problems with the vitamin D trials is that they're all garbage because they all just give people a given dose.

1:01:56They don't measure their response. They don't measure compliance. The vitamin D trial should be done based on target level, not target dose. And we run the risk here of the same thing in a much more complicated system. Agreed. That being said, measuring pathogen -specific titers is done routinely in the clinic. I don't know if you did this, but I just had my measles titer measured. It was born 1957, which is right the age. Before 1957, everyone was exposed to to measles, so you're typically safe, but you should measure your tighter to determine whether you need to be re -vaccinated. I find out that, yeah, you can do this very easily.

1:02:40You get a tighter. But with the tighters by themselves tell you, so what would you predict? If I measured every tighter right now, yes, if I measured polio, shingles, that a pan tighter on you, and then started you on rapamycin for eight weeks and then stopped it, and then re -measured your titers without vaccinating you, what would you expect to see? I would not expect them to change. Yeah, exactly. So how do we know we're improving your immune system if, indeed, we have? Oh, I see what you're saying. So in terms of if we were to start you on RAPOMISIN, why would happen? So that's... How could we measure the improvement in immune function?

1:03:17By the way, the manic trial showed that first they did a one -month treatment with the RAPOMISINATION. They demonstrated not an effect on existing but only demonstrated on denover vaccination. And I think what would be the effect on existing titers against all of the other pathogens? I don't know. I don't think this has ever been done. Yeah, interesting. You want to just say a little bit more about that trial. So that was, at least for me, a pivotal moment in my journey in this space and in understanding this world. So that was December of 2014 that paper came out and And if I recall, roughly 300 plus participants divided into four groups.

1:03:56So placebo group, a group that got one milligram every day, a group that got five milligrams once a week, and a group that got 20 milligrams once a week. Two people were pulsed, one much higher than the other, and then one given daily than a placebo. I believe they were all over 65. I think the study was done in Australia. And as you said, they were put on their, whatever treatment was for four weeks immunized. I think it was another four weeks and then a six week wash out and then the titers were checked. The best response I think was in the five milligram pulse and the 20 milligram pulse. The one milligram daily still had a better response than the placebo but not as strong as the two pulse doses.

1:04:37But the five in the 20 weekly were nearly identical but the 20 had much more side effects. I don't remember perfectly so correct. You're not pretty well. The takeaway was basically The 5 milligram pulse was the sweet spot. You get all the benefit without the side effects. That's how I remember that trial as well, although I'm always impressed by how you remembered all the details of these clinical trials. What was remarkable about that data was the fact that this is from a drug that is known. It's supposed to be an immune suppressant. An immune suppressant. It's been a long road for the longevity field to try to get our colleagues who are actually using a RAPAMISON as a linear suppressant to have them believe that this actually has an effect on immunity and not only not immunosuppressive, but actually a promoting immunity.

1:05:24How do you reconcile that? Not their disbelief, which is warranted, but how do you reconcile that one molecule? So if you think about the doses we used to give RAPAMISON, it's not actually used that much, by the way, today in the transplant clinic. So FK506, I'm blanking on what FK506's real name is, but anyway, whatever. It's largely displaced, Sirola must which is Rapa, but that said when we used to give it out, we were giving two to four milligrams a day. Now, let's just assume that it was indeed contributing to prevention of organ rejection. Do you think it was doing so because that's a high enough dose of constitutively giving a drug that it suppresses the immune system?

1:06:04Or do you think it was only suppressing the immune system because it was being given in combination with two other drugs? and it was only as part of that sea of other drugs that it has the immunosuppressive effects. I think there's clear evidence it is immunosuppressive by itself. I can tell you that for the period when I was on Rapa Mice and I would take either four, six milligrams a week, every morning, once a week, the biggest difference between the immunosuppressive and the geoprotective effect is really the amount, the frequency and the amount. And the reason why people adopted this once weekly dose is to first not have any immunosuppression and second to mitigate the secondary effect, which are thought to be caused by inhibition of M .T .R .G.

1:06:49II, which is the second complex. Right, the glucose effect. And that seems to be working largely. What was in my case remarkable is that every time I took my dose, not two, I only did two for a couple of weeks, but either four or six. The next morning I would have a pimple on my nose. So I was immunosuppressed, clearly, every single time. For a day. Yeah, for a day or two. I sort of made peace with it. In the fact that if I had a really heavy workout, I would have exactly the same thing. Exercise is immunosuppressive. If you go all out, you can get a cold. You're temporarily fragileized after a really heavy exercise.

1:07:26So I think the difference between these two worlds of immunosuppression, which clearly has been documented by clinical trials, it is immunosuppressive by itself, versus the beneficial effect on the immune system to me as a question of dosage and frequency. And yet, I cannot reconcile the unambiguous success of the interventions testing program, where those mice were eating rapamycin in every single bite of food they took. In fact, And they were consuming it more continuously than even the most immune compromised patient. And without exception, every single ITP study of Rapa Mison, whether they started an old mice or young mice, Rapa alone, Rapa with another drug, it just doesn't matter, it always worked.

1:08:16How do we reconcile that? Well, I don't have the answer, but I can sort of talk about it. There's something that worries me about our reliance on the mouse as a model system for aging, for studying aging, and how relevant it is to us as species. Even mice, because we would all admit that the ITP mice are the best, they're the Ferrari of mice. Exactly. The ITP is the best way to address this question because they're using mice that are crossed. So it's not in bread. Not in bread. in black six, you're essentially doing the experiment on N of one. And the whole world, I mean, 80 % of the work that's being done in mice is done on black six.

1:08:58We're all studying the same person. So obviously when you go and try to transfer this to a human population with all of its variation. So the ITP did the right thing. That being said, and this is not an attack on ITP. I think ITP is a great program and should be funded and she continued to study this. I just worry about the overreliance on ITPO loan, and I think we should have another system that studies primate interventions with drugs. There are a number of primates, non -human primates that are actually much closer to us. The reason I worry about mouse is something that actually Steve Austat, you've had on the spotcast as well.

1:09:36Steve is a good friend, and he came up with something called the longevity quotient, which I think is something that people do not pay attention enough. So the longevity question is this idea that if you look across the animal kingdom, the larger you are, the longer you live. Okay, so you can take thousand species and you can on the x -axis you have their size on a y -axis their life expectancy. It largely rises to the right. And you can see a monotonous curve. Now there are exceptions to this. One of them is making mole rats, for example. They punch above their weight, dogs tend to punch below their weight.

1:10:12Exactly. Although in dogs, again, this is within the size of the disease. This is between species. Then when you look, interest species, it gets even more complicated, which is the larger dog live shorter than the smaller dogs. The great day versus the Chihuahua. And that is down, actually, that's driven mostly by growth hormone, which is, again, another reason why we should look at taking growth hormone as an anti -aging drug with some degree of circumspection. because in dogs, the more growth hormone you have, the larger you are, and the shorter you live. We know also in humans, the larger you are, the taller you are, the shorter you live.

1:10:48So, are these effective growth hormones? Yes, are they only important while during the growth phase? That's a possibility, but it's something that really gives me pause to go back to our discussion about growth hormone. So, going back to the longevity equation, mice are also an exception. They punch below their weight, so they live shorter than they should based on their size. And humans is the biggest exception. We live about 5 to 6 times longer than we should based on our size. Which tells me that we are an naked mole rat of primates. We do incredibly well, which means that we already have optimized a lot of these pathways that are promoting aging.

1:11:29I suspect the mice is exactly the opposite. I don't know that someone has really compared sort of intrinsic tour activity and mice. Are they, for example, living mice are, especially laboratory mice, are engineered to reproduce and grow as quickly as possible. They have large later size. They do everything very quickly. Now we know all of these activities are requiring a lot of anabolic strength, which is driven by tour. So the question is, are the mice examples of animals that are maximizing tour activity to do everything they do very quickly. And we are maybe at the other end of the spectrum where we have low basal tour activity.

1:12:08So that's where I worry when people just transfer everything we know from tour from mice into humans is saying it's going to show and work in humans. I don't know if you are. Such an interesting point. Yeah. And this is frankly why I stopped taking rubber mice in. I thought I did not really see anything in terms of anything metabolically physically muscle strength. that could not in contrast to G .O .P. when I got this where I saw all of my numbers get better and functionally strength all of this I saw everything getting better on G .O .P. agonist with rapamycin I never could tell whether I was taking it or not.

1:12:43Yeah although it's not just that I would say where rapamycin acts I don't know that we would see anything getting significantly better because if we think that the main places that rapamycin is going to act would be on a top of G Well, there's no way you're going to measure a topology. You're not going to feel a topology. You're not going to see it or measure it. Does it tamp down on certain subsets of senescent cells? That's certainly plausible. Again, I don't know how we're going to see or measure or necessarily even feel that. Does it reduce some of the tonic, low -grade, unhelpful inflammation?

1:13:20Probably. But again, if a person doesn't have much to begin with, it's going to be tough to measure. conversely, GLP1 agonists act directly on a thing that is so easy to measure, which is glucose metabolism and body weight for those who are losing weight as well. So it might not be a fair comparison. I guess the other thing I would add to this interesting observation is that, of course, the mice in the ITP are still in a relatively sterile environment. And it might be that even if they incur some immunosuppression, it's not going to be as maladaptive as it would be if they were wild animals as we are.

1:13:55They live in a sterile environment, they live a group in a cage with no ability to move, to exercise. They eat a diet which makes the American diet look like the most healthy thing ever. I mean, have you ever seen the pellets that these mice are eating? Do the ITP mice eat the crappy pellets as well? I suspect they're eating a... Okay, I don't actually know what their diet is. I don't know what the diet is. I can guarantee you they're not eating salad and fruits and vegetables. In some way, they are an incredibly artificially bad sort of environment. These mice actually doing everything that is conducive to a poor health.

1:14:37And so the fact that we see something that works in that system might have some value for the fraction of the population that has a very poor lifestyle, I do worry about transferring this to someone like you and I who are exercising or trying to eat well or trying to sleep and all of this. I take these observations with some degree of caution and frankly when people ask me should I go on rapamaisin, I do worry. Now this is a different story if someone a patient comes and sees you at 40 years old and tells you I think I want to go on rapamaisin, I would strongly argue that you should not do this because even in the studies that have been conducted, they still sign the fact in mice that were the equivalent of 65 to 70 years old.

1:15:18Now, if you're 75 years old and you have the feeling you're chronically inflamed, you have the feeling that things are not doing well, there are a number of anecdotal cases where people have described really feeling a lot better and a lot stronger very quickly. On rapamysin. On rapamysin. But I would predict it would be the same thing with I grew through a moment or somebody's intervention. So I really put those in different categories. My argument to people is today we have one intervention that is very profoundly anti -aging and it is physical activity exercise in all of its forms. Once you have optimized this, I think let's talk about doing something else on top of that.

1:15:55Earlier you brought up the Sir Two End story in NAD. I'd love to spend a little bit of time there. I was at a talk recently and as always I get asked questions about stuff like that and I got asked the question about NAD and I said, look, this is one of those things where if I tell you the following facts, I'm going to tell you three facts. NAD is completely ubiquitous throughout the body and it is absolutely essential for the most important chemical reactions that happen in the body. You cannot undergo redox reactions, metabolic reactions without NAD. That is point one. point two is a class of proteins called stertuins rely heavily on NAD as the substrate in the process of repairing DNA.

1:16:44That is fact two. Fact three is as you age, NAD levels decline precipitously. Okay, those are three facts and I don't believe is there any dispute to any of those facts? No controversy. Okay. Armed with those three facts, how could it be that supplementing NAD does not lead to a longer better life or some health benefit. That's a logical conclusion, right? Well, not completely, because it depends also what is the reason why NAD levels decrease, and it depends also what supplements are you remedying the reason. Yes, yes, yes. And this is something I'd love to talk about CD38. So it could be that NAD levels go down because their consumption goes up.

1:17:29As we age, there's more DNA damage, there's more consumption, the suituins need more of it, and it goes up. And then, of course, the question would become, is the current level of NAD that we have rate limiting to that reaction? If not, then all the extra NAD in the world should have no benefit because you're just adding more substrate to a reaction where it's not needed. Conversely, if NAD levels are going down because there's a production issue, and if you provided more of it, you could actually do more good. but well then it could be the exact opposite story. So let me pause there for a moment and have you fill in the edges of everything I just said so that we can go deeper into this discussion.

1:18:06So let me explain a little bit what NAD is, explain what it means in redox, and obviously let's talk about Sir Twoons and the role that NAD plays there. Lots to unpack there. It could be a two -hour podcast. It's one area that we've worked on for the last 25 years. We were responsible for cloning the human Sir Twoons actually after Lenny Garanty published as paper on Sir 2 and Yees, but the graduate student was the first to publish, is wasn't it? Kajolin. Yeah, Sir Matt and Brian, I mean David, I mean that whole gang was the original gang along with Lenny Garenti were paved the way for a lot of what we know.

1:18:40One thing that I would just start by saying is that it pains me in some way in a field that is so rich and has generated so much data that there's a whole cloud lying on top of Sir 2 in the NAD. There's nothing there. I just tell people it is an incredibly studied system. We are still juggling the complexity. And I would argue that any field where the same degree of investigation will be conducted will have the same controversy. This is the nature of science. The beauty of science is that it's incredibly messy on the way up, but eventually things are getting clarified. And I think in the terms of the Sotuin's, we're still right in the middle of it.

1:19:21So there's some complete garbage. Yeah, and by the way, I'm not completely dismissive. What I will say has made this field complicated is that the leading proponents of it have all opted for a commercial pathway. And therefore, they have opted not to study this in a rigorous way, but to study it in a commercial way. And I mean, I understand why you would do that. Like that's the nature of it. And this is not a molecule that you're not going to generate intellectual property in the same way that you would around an awful drug. And so it poses a limitation to how these things can be studied, but unfortunately that coupled with the risk -vera -trol fiasco, unless you think otherwise Eric, we don't need to talk about risk -vera -trol.

1:20:03I remain completely convinced that risk -vera -trol had zero benefit whatsoever. I think it is an absolutely useless molecule. So I think that risk -vera -trol debacle, the over -hype, complete debacle of that, coupled with the fact that all of the participants in the NAD landscape are doing it through their own commercial enterprise with their own proprietary blend has resulted in this inability to drive forward in this field. I agree. Identified the problems to hype and the commercialization. I mean, commercialization can be helpful if the companies are actually willing to invest in clinical trials and so on.

1:20:40I always use the example of timeline, uralith and a, I mean, that we've worked with them. They do clinical trials, rigorous, they publish them in the best journals and at the end, you know what you're measuring. That being said for the so -to, and so let's try to be step back. And given the controversy, I would say I would encourage you listen, not to just discard it all, we're still in the middle of it. And I think there's something interesting really merge out of it. So NAD is a critical intermediary metabolite. It has two big roles. First is it plays a key role in Redox reactions. Again, we've talked about these reaction reduction oxidators.

1:21:15Any time electrons need to move around. Exactly. So it exists in two form, an AD, an ADH, and it's critical to intermediary metabolism. There are more than 600 of these enzymes that use an AD in the whole metabolism. So it stands to reason that if you losing an AD levels, you go below a certain critical level, these enzymes are going to suffer. Your whole metabolism is going to go down. And we know, by the way, that decreasing metabolic efficiency at all levels is one of the hallmarks of aging. So in addition to these enzymes that utilize the NAD NADH couple. There's a whole series of other enzymes that actually are digesting, cleaving NAD.

1:21:55And these would be the parps, polyadepyrabors, polymerase. So these are enzymes mostly involved in DNA repair. So it plays a critical role. Acertoins, seven -certoins, all doing different things within the cell. And we can go back and dig into this a little bit in terms of what are the Sertunes doing. There's also another two enzymes called CD38 and CD157. These are also NAD hydrolases and we are studying them a lot. So that's, I guess, the background of what these enzymes are doing. One thing that you'll listen to should know about NAD levels and why the decrease in NAD levels are relevant to aging with respect to the Sertunes.

1:22:37The Sertunes have a relatively narrow range of KD for NAD. So if the NAD levels change, as we know they do during aging, it will lead to a change in the activity of the Sartouins. And I think this is something that was proposed by Lenny Garante back in the days and showed, for example, even during fasting, your NAD levels will increase and this will activate Sartouins. So I think this This is something that's really unique to the Sartouin, is there. And we know this in a really acute way because there are Sartouins that are present in the cytoplasm versus in the mitochondria versus in the nucleus.

1:23:16And the NAD levels in each of these organs are very different, for example, much higher in mitochondria. It turns out that 33 as a KD for NAD, which is much higher than 31. And so variations are, that really is the indication that they are sensors of NAD levels, which goes back to the initial model that you mentioned, NAD levels change during aging, therefore we can expect the activity of the sort to ends to change. Now, what else if I not address in your initial batch of questions? I think we're now ready to then move on to, if we believe with some conviction that restoring NAD levels in an aging individual is beneficial, we now have to deal with the same problem you deal with any small molecule or large molecule for that matter.

1:24:09How do you get it in the body? So what are the ways in which you could get NAD into the body directly or indirectly? So that brings me to maybe another element of the biochemistry. So one thing that is emerged is this idea that the question is to why do an AD level decrease? And there's been lots of theories. activities. Activation of the parps, that seems to be happening in sea elegance. In mammals, this is the work of Eduardo Chini, was the first one to show that CD38 appears to be the major driver of the decrease of NAD during aging. And the way he's demonstrated this and we've actually repeated some of his results and published on this as well.

1:24:50If you study a mouse that's knocked out for CD38, you'll find that any D -levels actually do not decrease during aging. And that's pretty much across all the organs. And I think what this does is really brings the whole question in terms of what should we be targeting. Did we talk about what CD38 is doing specifically? Yeah, so CD38 as a membrane anchored protein, some of it is facing outward on the outside of the cells, some of it is facing inward. For example, in T cells, it's mostly facing outward. In macrophage, it's mostly facing inward. And it isn't an AD hydrolyze. Now, what is it doing in the immune system?

1:25:28Why do we have it? Not entirely clear. One idea is that because it is present in T cells, and the theta cells as well. One idea at least for the immune system is that it might come up and eat up all the NAD that's local in the extracellular fluid, although there's not much of it and limit the abilities, is part of the innate immune response and limit the ability of bacteria and other organisms to actually access these micronutrients for their own growth. That's one thinking. And I think it's a lot more complicated and this and we're really in the middle of it. I have a good part of my lab actually studying the rule of CD38 in the immune system and in the theoretical cells and in the brain as well.

1:26:12Now you mentioned a moment ago that the CD38 knockouts do not see a decline in NAD with aging. Zero, and they live longer. I was just about to say, what is the phenotype of a CD38 knockout? What deficiency do they have? Nothing that we can tell, and they live longer. How much longer? 15%. That's comparable to rapamycin. Yeah, it's pretty significant. This has been published by Eduardo Chini. Do you think that that is true, true, and unrelated to the increased pool of NAD? Now, CD38, that's a key question, and that's one that's not been answered. And I would say, if I had to go on the limb, I would say it's not linked to the NAD decrease.

1:26:51Just to make sure everybody understands what you're saying. Your belief is that the CD38 mouse, the knockout does not live longer because he has more NAD. That's just another issue we're seeing and that there's something else about that mouse. Yes. Or it might be partially the NAD and partially the other mechanism. I'm about to discuss. One thing that's remarkable is that as we age, us and mice, we see an increase in CD38 level across the organism, especially an immune system. We've published a paper showing that the SASP from Cinescent cells is a very powerful inducer of CD38 expression in macrophages.

1:27:27So that's one mechanism by which we're linking Cinescent and the SASP to increase CD38 leading to a depletion of an AD and other effect. And yet we have no idea what it's doing other than hydrolyzing NAD. It has a cognate receptor on other cells. They don't seem to be immune deficient. It's really one of these players that people are hundreds of papers. You can get plays a role in inflammation, a negative role in inflammation. One idea about it is that it plays a suppressive role in the immune response, because we see it being induced latex in the immune response and the idea it comes on to tampon down.

1:28:04So it's actually the exact opposite. it. It's so pro anti -inflammatory that it can be harmful in that way, as opposed to contributing to sterile inflammation, which is the more typical problem we see in aging. Yeah, we did not discuss this. The other side of the immune system is that it has to be incredibly balanced between reacting appropriately towards exogenous pathogen, but not reacting against the self. As you know, as a physician, there are so many conditions that are a manifestation of an excess of immune response against the individual. All of the autoimmune diseases, which by the way, increase during aging.

1:28:42So, except for type 1 diabetes. Yes, that's the one young. I know that you used to study that. Why do you think that is? It's really an interesting question. Although there's something called Lada that I'm sure you've heard about that is emerging that we might have been diagnosing some type 2 that were actually late type one. The thing that is really unique about type one is the fact that I remember a number of papers that highlight the fact that there might be something happening during development that exposes the immune system to the developing beta cells and that might trigger more to immunity at that time.

1:29:21It could also be linked to the fact that there's been for many years of discussion of the role of viruses infection and molecular mimicry between some of these viruses and beta cells. So it could be that a subset of infections that happen during childhood actually puts you at risk of activating your immune system inappropriately. That's the whole idea. But there's clearly an increase with metoemunity throughout life. By the way, CD157, do we see the same effects? Do we have a CD157 knockout? No. Much less study. there is some interesting effect also, but CV38 is garnered most of the attention.

1:29:57If you think about, I'll go back about CV38 in terms of what it's doing. It's taking an AD and cleaving it into ADP ribose, which is sugar and nucleotide and nicotinomide. Nicotinomide is a precursor to an AD. And so this nicotinomide, which is generated by CD38, but by the sort of twins, by the the parps, normally gets recycled in a two -step reaction all the way back to NAD. Now what's really interesting is if you block this, it's called the salvage pathway for nicotinamide, if you block it within a few hours, your NAD levels go down to zero. So the system, wow, heavily dependent on recycling.

1:30:38Incredible actually. And there's a specific inhibitor of the enzyme called NEMPT. you can add it to cells with done the experiment within 46 hours and ED levels down to zero to cell die. So there's an incredible churning through that whole pathway, which is a reflection of the activity of so -toins, CD38, CD157, the parps and so on. So you have a situation during aging where CD38 increases, you increase the degradation. So you decrease the pool of NAD. But you're increasing in theory the metabolites. You're increasing the metabolites nicotinamide. Now one important thing is nicotinamide metabolism is either salvage back to an AD or methylation by an enzyme.

1:31:23And this is important for supplementation because it turns out CD38 not only cleaves an AD but it also cleaves an amn which is one of the two precursors an amn NNNR. So when you actually are, I have increased CD38 activity and you take NMN, you turn through this pathway and you actually increase your nicotinomide and you increase its methylation. So NMN is also cleaved by CD38 into what? Nicotinomide plus something is not ADP virus. And so when you do this, you're increasing your level of nicotinomide to the point that But it's shanting to methyl nicotinamide starts depleting your one carbon cycle.

1:32:04So what you see in a number of people actually on an emin is their homocysteine level going up. Including me. I stopped taking it when I saw this. I thought this is not, I was taking about a gram of an emin for a while and then I saw my homocysteine level going up. I think it's a reflection of this pathway and basically stopped it. Now, why is it, Eric, that the increased pool of nicotinamide preferentially goes down a methylation pathway as opposed to the salvage pathway to give you more NAD? Yeah, I don't think it goes preferentially. It just depends how much. It's just the more you put in, even if it splits stoichiometrically or stochastically even, you're going to take away one carbon.

1:32:45Yeah, and I do not know what the relative proportion is, but clearly the more you drive the system with NMN, the more you're going to yield these. How much did your Hema system go up, by the way? Up to 15. From, from typical seven. Wow, that's a big job. And then how long did it take to resolve once you stopped the NMN? I measured typically every three months. After three to six months, they had gone back to normal, seven to eight. What about NR, nicotine and my ribosite? How is that treated by CD38? It's not metabolized by itself. and are eventually in the cell has to make it back to an MN, which is on the salvage pathway that we talked about.

1:33:27So NR is less bulky, less big than NMN, so it is able to get into the cell, but eventually it makes it into nicotinema, NMN, and then goes back into the same pathway. So eventually they all come back to the same. So do you think that there's no difference between the same amount of NR and NMN? No, there clearly are some differences, especially in all the really complex biochemistry that happens in terms of getting them into cells. The problem with NR and NMN is that if you think about what the approaches, you essentially, you have a pool of NAD, which is a sink, think about a sink full of water.

1:34:04It's leaking. That's your CD38. That's the leak at the bottom of the sink. And you keep pouring more NMN, more NR inside of it. You're just going to accelerate the leak. You're not going to solve the problem, basically. Maybe you'll reestablish the level at a normal, somewhere normal, but the turning through is problematic. Now, why is the turning through problematic because some of the byproducts of CD38, for example, are cyclic ADP ribos. So there's two forms of ADP ribos, not cyclized and cyclized. the cyclist activates calcium signaling. And so there's a whole aspect of the biology of CD38 that's linked to calcium signaling.

1:34:45So I think I do worry about the supplementation with the NRNMN. I do worry about it. I'm not discounting them. I think clinical trials are ongoing. There's dozens of clinical trials. So we will soon identify something in which it has a benefit. it. Again, if you think about the metabolism of these metabolites, it's incredibly complicated. There are effects on the microbiome, there are effects on different absorption by different cells, just literature hundreds and hundreds of papers, I think, way beyond what your audience party wants to hear. But I would say at this point, most of what you can buy a supplement have doses that are so low.

1:35:28This is where there's an important discordance also. When we do experiment. We've seen amazing things in laboratory animals in terms of supplementing with an RNA and an MN. This is where the excitement comes from. But typically these animals are getting 10 times more than what you're buying as a supplement. And the reason is, I think, grass status is given to these companies to give a small amount. Grass meaning generally, regardless of the safety, FDA's criteria for giving something that is naturally occurring. Yes. Yeah, but doesn't require it to go down the IND pharmacologic pathway. Eric, if you were taking one gram a day of NMN and your homocysteine went from seven to fifteen, I guess two questions would be, has that been reported elsewhere?

1:36:10Is that a known phenomenon? In the trials that are testing NMN, are they measuring homocysteine to see if that's... I must have read it somewhere because I was looking for it. We were looking for it. And then the second question is, how would you then tolerate 10 grams of NMN? I mean, if one gram is doing that, you would deplete all one carbon. Does that mean you wouldn't even be able to alter your epigenome in ways that might be favorable? You've run all kinds of risk and a number of people that I've seen the same thing and start taking trimethyl glycine to try to supplement this. I do worry about this.

1:36:42I think for me, I want to reiterate the fact that I think the data and unemoral models of some of the things that we've seen with some of these precursors is really interesting. And this is why there's so much interest. Did you ever try using TMG to see if it would offset the? No, I didn't. I've never been interested in the whole self -experiment. Okay, what about intravenous NAD? So that is one of my pet peeves. I try and everything to remain open -minded to things that I don't know and don't understand. My prediction is that first, NAD is not an extra -centred molecule. And AD does not exist, almost does not exist at all in the opalasma.

1:37:25It is an intracellular. And as I mentioned, high concentration in mitochondria, much lower in the cytoplasm in nucleus. So the whole idea of injecting intravenous NADs, first it's too big to be absorbed by cells. So what is the body doing with it? There is a famous paper by Joshua. Joshua Benowitz. Robin of it. That showed that if you inject it actually intravenously, you actually get it mostly the catabolized by the liver and to nicotinomide. Nicotinomide is one of the fractions of niacin. You can buy this at the pharmacy for very cheap. You can go into an IV clinic and get a $700 injection of NAD.

1:38:05Very few studies. 102. I've read both of them. They're interesting. My opinion is that NAD intravenously is not something that should be done. The same thing for subcutaneously. I've seen another company that sells it subcutaneously. Really no evidence for doing this. Now that being said, I've heard, and this is where I try to remain open -minded. Obviously, we don't know everything. I have heard anecdotal evidence of dramatic effect in some patients with Parkinson's. People really describing not a miraculous, but near miraculous effect right after the infusion having increase in motor performance that you can really assess in someone who's a severe Parkinson's.

1:38:49So not studied systematically. Mechanistically as there are reasons you could explain that through dopamine or something else. There's a whole literature on the effect of NAD precursors and so on Parkinson's, mostly animal models. And I think there are lots of clinical trials going on in Parkinson's as well. But more using the standard NR and NMN. The thing that I've described is more a couple of friends who've told me I've seen this. Not enough to make a product, but enough maybe to question maybe there's something more to it than what we truly know. But the proliferation of these intravenous clinics frankly is how complicated is it to produce a bag of intravenous NAD?

1:39:29I don't think it's very complicated. I mean, I've never made it. I know making NMN purely took some effort to scale it up and for some of the companies that have been doing this right now, there's like one major supplier out of China that pretty much everybody uses. But in terms of an AD, I don't think this is an industrial process. I can tell you, it's not $700. Yeah, I'm sure it's not. So if a person was going to supplement with one orally, do you think there's a case for NR being superior to NMN? I would say no. I would say take them both. If you're going to do something and you want to a bit of an insurance, I did this for a while, I'm not doing it right now.

1:40:08Take 250 milligrams of each and you'll have a half a gram. You are in a safe relatively safe dose, follow your homocysteine. If you are 60 or above, you could make the case. This could be part of a stack. Although this is the same thing that we see with so many of these supplements right now, which one do you take, which ones are beneficial. There's one a little bit of a dark cloud linked to NAD supplementation is the demonstration that the SASP is actually dependent on an AD levels. And so when you are actually increasing NAD levels, you might be increasing these pro -inflammatory markers. Let me make sure I understand why because the SASPs, which for folks listening, these are the soluble products made by the Sinescent Cells that effectively are doing all the bad things that we don't want to see Sinescent Cells doing.

1:40:57So now they are dependent on CD38 to some extent. So as CD38 goes up, they go up, and are you saying as you give more NR and more NMN, you might turn it up. You might be turning up this ASPs. Yeah. You finish your point, then I want to make a broader point. There's also some worry about the fact that supplementing with some of these precursors might also accelerate tumor growth. So this would not have an effect in you and I. We don't have a cancer, but if it's someone out there who has an early form of a cancer, this could lead to an acceleration. This is something that's been shown in animal models that giving some powers to some people in terms of recommending this to be taken over by everyone.

1:41:40The folks who make this have strenuously denied that there is any validity to those animal models that have suggested that. And some of this has been done in vitro as well, correct? I'm not very familiar with that literature. I saw, I remember seeing one study, it was very small. My take on it was, I guess if you had cancer, this might be a bad idea to take, but I didn't find it that convincing. I agree with you. It is a general consideration for our whole field of longevity research. It's better as the enemy of good, as something that was sort of drilled into me as I went through medical school.

1:42:16We have a term in French, which is sort of like therapeutic overdoing it. doing too much. There's such a thing as overdoing it for your patients. In this case, the whole longevity field is embracing a whole series of these interventions. I mean, it is not a week that doesn't go by that I don't see a new supplement being touted online and so on. And I read about all of them. The question is which ones should you be taking? Which ones are actually risky? Which ones are not? And to me, this is part of the whole balance of the equilibrium and I'm trying to reach. There's something that really has a beneficial effect, you want to be on it as soon as possible, if not, why take the change?

1:42:55Yeah, that's the point I was going to make at the outset. You've said it so much better. Let's pivot a little bit to a couple of the things I want to chat about quickly. Let's talk about interleukin 11. Big trial last fall that looked at blocking interleukin 11, which is a molecule that's made by immune cells plays an important role in inflammation. This was done in mice and those mice lived longer. What do you make of the study? I read the paper like you. I don't have sort of an inside knowledge about of course when the paper came out It was like interleukin 11. I mean as an immunologist you talk about one interleukin one two four seven six seven But 11 never heard about it.

1:43:35It goes up to like 30 so I went and read the paper It's an inflammatory marker. So again, it could be on par with one in six No, I would say probably not so it came out of the left field But it sort of makes sense in the context of what we know about the inflammatory response linked to aging. And maybe this is where I can add one point is when we think about the chronic inflammation of aging, sort of, inflammation, it is both cause and effect. We talked about how the immune response helps you to protect yourself against the innate immune response against pathogen as a first line of defense. The innate immune response also has another important role is that it recognizes damage.

1:44:17any kind of damage. If you cut yourself, if you have a wound inside of your organis... A coronary artery. A coronary artery. This will act any kind of damage unfolded proteins. There's all kinds of things. So the anatomy and response will be triggered and will activate itself. So as we age and as damage slowly accumulates, which is aging is a slow irreversible accumulation of damage, eventually your immune system responds to this by becoming chronically activated. And so the problem is that you might think, well, this is great because you're actually repairing of this damage. The problem is the activation of the immune response by itself becomes problematic because these cells of macrophages, for example, a powerful tissue remodular, the immune system in this case is stuck to check in on mystic hide.

1:45:10It's helping, but it's facing an unsurmountable amount of damage. And eventually, its activation leads to an AD depletion. That's one of the things that it does. But many other things stem cell dysfunction and mitochondrial dysfunction. So the whole idea here is that 11, my simply B, is one of the key markers of this chronically activated immune system. So this is not something I imagine you're going to give to a 20 -year -old. But in someone who's getting rid in the part where chronic immune activation is present could really play an important role in the future. And what the paper showed was, again, in mice, but from what I understand is already an existing molecule.

1:45:49And there are actually recently was contacted by a company that has another novel inhibitors of IL -11. You can imagine this to become part of the whole armamentarium that we have against aging. And then how do you see playing that off something in the other aspect? Because we're really trying to deal with two sides of this system. and we want to tamp down the part that's overactive and we want to ramp up the part that's underactive. So we've got basically the only example we have over here is rapamycin. This one does this and then we now have IL -11 inhibition or use knockout mice, but block this.

1:46:26That did good thing. So is this one of those things where you need to do both, by the way, maybe you have growth hormone over here as well. Yeah, IL -1 there also. Yes. That's right, it says block IL. Yeah, block IL -1, block IL -11, and give growth hormone, give rapamycin. I mean, here's the problem. You get into this reductionist state, which is like the whole NAD world of NR and NMN. Hey, it sounds great, but what if there's unintended consequences we can't see? Like, even as much as I love thinking about this and want to do all of these things, I start to think, man, what is the probability we're gonna get this right?

1:47:02I agree. The immune system is an incredibly tenure system, which is in really delicate balance. So the balance is too much immunity. You might say, well, this is good protection against cancer, protection against microbes. Right. But then you get auto immunity. But then you get auto immunity. Not enough immunity while you run the risk of being killed by a pneumonia or some kind of infection. But at least you don't have too much inflammation. Yes. So it is a very fine balance. This is why I wish we had a dashboard. What are the biomarkers we can use for these things because we don't have this problem with blood pressure.

1:47:39We don't have this problem with thyroid hormone. We don't have this problem with so many things that we treat because we can measure what we care about. That's a good point and the question is the immune system is so complex, there's not going to be one single marker. My colleague David Thurman is this thing called IAGE, which is an immunaging set of tests and you can actually conduct. That was the first attempt and trying to measure immune aging. What do they actually measure? Is it all serum biomarkers? Yes, serum biomarkers and mostly cytokines. Validated how? Been validated in clinical studies.

1:48:15IA, immuno aging? Yeah, yeah. IAge. Oh, IAge. Yes. So this was developed in Pioneer by David Ferman and Mark Davis. So David Ferman is with us at the Bach, Mark Davis is still at Stanford. I guess this brings us to clocks. Yes. I don't even know if I have the energy to talk about this. Okay, where do you want to begin? There are so many of these things out there. Some of them are commercially available. Some of them are just tools of research at the moment. Some of them aim to tell you an actual age, an actual number that represents your biological age as opposed to your chronological age. Some of them don't aim to tell you that at all.

1:48:54They just want to tell you a rate of aging. some of them look only at the epigenetic signature and other they look directly at the methylation, sequence, others look at a host of markers, including some very simple serum biomarkers like glucose levels and vitamin D levels and things like that. So how do you make sense of all of those tools? Right now we don't. First statement is there are not ready for prime time in terms of patient management. There are research tools, which is interesting because they're far outside of research labs at this point. Yes, they are available commercially. I've done the same thing.

1:49:33I don't remember who told you told me someone actually it was at Matt Kaibberland measured his clocks. I do the same thing. Actually, I measured them every three months. It's just a scatter plot. It's a scatter plot in a way, you know, I'm between 25 and 68, which is of course I like the clock that show me to be young, but that being said, we know that we're learning. So we know that, for example, you alluded to the fact that they can vary the same clock. There's circadian variation, for example, five years. So your age can vary by five years using some of the clocks depending on when you measure.

1:50:07What time of day? Yeah, what time of day. That biology that just tells you in the epigenome is something that's highly dynamic. And so that's something as we learn, obviously, the companies will encourage you to measure it, you know, to draw the blood always at the same time. Now, the whole field by now is pretty much focused, almost completely focused on DNA methylation. Steve Horvat done beautiful work. I mean, it's really pioneering work, identifying all this and Morgan Levin and others have gone on. Dan Belsky, I think, with Danedin Pace, which is another a PGND clock that measures the pace of aging.

1:50:43By the way, I think this is probably my favorite because it really seems to be responding to interventions. If you change your diet or if you do something, you will see your pace of aging changing. So I think that one to me seems more promising. We don't know really how to use these tools clinically. That's the problem. They're nice gadgets to buy. The companies are selling you supplements and then they're selling you the tests with it. I don't know what to make of it. Personally, I think this is not ready for prime time. It's something that should be done in the future. Might become in the future.

1:51:17Would you agree with my stern words on this because I've made a lot of enemies by saying that if as a consumer you encounter a company that is selling you a test, especially a test that is not validated in any clinically meaningful way And then in the same breath, selling you a supplement to fix the result of that test, you need to run. I agree. I don't have the patience for that kind of behavior. Someone told me, actually, recently that one of these tests, actually, that you can measure almost everyone who gets their result is low. And of course, low being good or bad in this test. It's bad. Bad, yeah.

1:52:02It's insufficient. The next step is the recommendation you have to buy this supplement to solve the problem. So yes, again, it's the same thing with the certunes and the NAD. Let's not throw out the baby with the bathwater. There is a whole series of these players. I'm not disputing their honesty or their good intention from what I've seen. I think it's too early. And what do you think is the biggest problem? Is the biggest problem? The biologic noise in the system, which means even if you had the absolute perfect tool to measure. And you knew exactly what to measure. The movement of that thing is so great that the probability that you're capturing a meaningful value is irrelevant.

1:52:44In other words, imagine that there's a variable that moves like this, but on the small level, it's moving like this. I'll give you an example. Imagine you were measuring heart rate, but you could only sample it milliseconds at a time and what you were actually measuring was heart rate variability instead of heart rate. It would be useless. It's too noisy. I agree. Do you think that's the problem? No, I don't think that's a problem. I'll speak personal experience. I work with true diagnostic. They use the Epic array and you get not one clock. You get dozens. So I get all of them. And they tend to be reproducible, you know, every three months, unless I make some interventions.

1:53:22But in general, there is some consistency. I'm not the only one who's seen this. So my advice, if you really are determined to use them, use all of them. They all are different mirrors of your reality. The problem of the methylation clocks is that there's a very tenuous link between the change of methylation at any given site and the biology. Typically the clock each clock would rely on about 500 different methylation sites, but they're not attached to a specific gene, so you don't really know what it means. But how are they even doing that? They're not measuring with point arrays. They do this with the race.

1:53:59They're doing this with and right? About 20 million methylation sites that they're assessed, but each clock uses a subset for 500. Sorry, just to be clear, you're saying they're actually measuring point of methylation. Yes. Yes. The quantifying the level of methylation at each of these sites. The problem with the clocks is also where do you obtain them from? Typically blood, as I mentioned, it's a heterogeneous compartment. As you age, for example, you know that your fraction of naïve T cells decreases down to close to zero if you 80 years old your memory T cells increase. So we did a very simple experiment.

1:54:37We sorted all of these different T cell subsets, memory, naïve, central memory, time rather, termingly differentiated and measured their epigenetic age using several of the clocks, 20 to 25 year difference between the naïve and central memory T cell. In the right direction, the direction you would predict. Yeah, but I even much younger. Yeah. That's somewhat interesting. That was really interesting for me because it means also any conditions where you see a shift in the relative proportion of these cells. For example, you get an acute COVID infection. What happens? You have a massive expansion of your memory cells.

1:55:17So it looks like you're going to, and then you sample. And given that these cells look much older than the other ones, you're going to look like you're aging. And there's a whole literature that talks about Accelerated Aging and Rheumatarathritis, in COVID, in HIV, all of these conditions that are all associated with chronic immune activation. So, that's another confounding variable. So what we did to do this with a student in a lab, we made a new clock in which we eliminated all of these methylation sites that are linked to differentiation. Okay, so now this clock that we've done does not vary actually as a function of the types of cells that are in the blood.

1:56:01As a T cell goes from being a naive T cell to being a memory T cell to being a temra, the methylation patterns change as part of the epigenetic regulation. So we eliminated all of those sites, made a new clock called Intrint clock, which actually is impervious to your level of immune activation. And what's interesting is that that clock doesn't change anymore during COVID. It doesn't change very little during HIV. It doesn't change during a whole series of conditions where people have talked about aging acceleration, including the story that we talked about earlier in growth hormone. What does change it then?

1:56:36What does change it? Cancer? Cinescence, which is really interesting? What about short -term interventions that might be beneficial? So if you took an individual who is insulin resistant and you put them on a GLP1 agonist and three months later, their 20 pounds lighter and their insulin resistance has resolved, how does that change on the clock? Would not be able to tell you specifically for individual clocks, but Dan Belsky's, then it in pace, clock is the one that repeatedly people have shown seems to be responding to interventions, which is the two qualities that you want in a clock is one to be predictive and the other one to be predictive of ultimate income, sort of life expectancy or the occurrence of disease, but also you want it to be modulatable, responsive and reproducible.

1:57:28And reproducible, yes. reproducible I think is more a question of the laboratory that's doing it, so there are no. But also potentially the biologic noise still. Exactly. So biologic noise and and laboratory conditions speak to reproducibility. I agree with what you said. I mean, I've often made this case when people ask me about clocks is my gripe with the age clock. So again, the pace clock is different because it's just trying to give you a rate of aging and I agree with you. I think there might be more there. But these clocks that spit out, hey, Eric, congratulations, you're 25. I say to someone who says, isn't that wonderful?

1:58:00I say, maybe, but do you actually believe that you're 68 and your clock said you're 25. Should I expect you to live another 55 years? Yes. In other words, is it a better predictor of future life than chronologic age? And the answer is to my knowledge, no. There is no clock that has a better ability to predict lifespan than chronologic age does. And until that's the case, I worry that the biologic clocks are creating a bit of a distraction, at least this subset of clocks, and that we may be ought to focus better on clocks where the readout state is more about, is this intervention good or bad, or is this a net positive intervention or a net negative intervention?

1:58:52I agree. As we mentioned earlier, the field initially focused on the epigenetic clocks, because this is Steve's Horvath's empire and airing work, so it got everybody to start thinking. We can generate these tools, but the field is now moving into proteomics clock. So what makes up Dan's clock? Dan is a methylation. It's also methylation. Why do you think it's doing a better job than maybe Horvath's clock at the moment? Typically, it really depends on what the variable, what the cohort, what the question was. I don't know. I mean, I think the dance is the only one that's doing it in this way. Why is it working better?

1:59:30They're just looking at it in a completely different way. How much is AI facilitating this at this point of the week? Learning is the key instrument. Essentially what these clocks are is a regression analysis on to start with a variable, which is your age, and you regress each methylation site onto the age. You do this on enough people of different ages. You'll find an average. I wonder if that's the wrong way to do it. Wouldn't it be better to get biobanked data and instead of mapping it on to age, map it on to number of years remaining in life? Because if you'll know that in a biobank. They've done this.

2:00:06They've done this. They've done this in terms of life expectancy. They've done this in terms of morbidity. So this is like the third and fourth generation of these clocks now are looking at regression. The initial one was just chronological. Yeah. And Steve used to go around saying my correlation coefficient is 99. And I was like, well, that's because that's what you built it on. Yeah, exactly. I can look at a calendar. I don't need a maybe genetic clock to tell me how old I am. But the next generation clocks actually had a bigger spread. Of course, you have an average. That's right. Because they started to build it on a different variable.

2:00:39Exactly. So what really excites me right now is the whole idea that the field is moving on to the next stage, which is non -epigenetic clocks. Because I'm still frustrated as a biologists trying to understand what are these clocks? It can be everything. It doesn't make any sense to me whether we wouldn't look at the metabolism, the proteome, and the epigenome. There's no excuse today with the compute power not to do that. We have clocks based on fundus. We have clocks based on skin. We have clocks based on facial recognition. So the clocks are going to be measured using dozens of different biological variables.

2:01:14Any biome, a small company in the Bay Area is using it the tongue. A tongue picture, the old doctor looking at your tongue so you can actually use machine learning to recognize patterns of discoloration. And another exciting and really story was, I don't know if you're familiar with a Tony Whisk race paper using proteomics. He has shown, for example, proteome in plasma changes throughout life. Pretty dramatic matter, which is really completely mind -boggling for me to see that you can be so different as you age in terms of your whole blood proteome. Why? If the epigenome is changing, then gene expression is changing.

2:01:52If gene expression is changing, it's okay. No, it would. Yeah, yeah, yeah, it's okay. But that it would change to such a degree. Tony has a beautiful slide which shows all of the proteome in the blood and how the colors change across the... And do you think that most of those changes are post -translational? No, most of them are probably expression levels. It's expression. Yeah, it's expression. People are building transcriptomics clock. And so, Tony now has a study that is, I believe, in press or coming out soon, where they've gone back using this proteomics clock, and they've done this on a UK bio bank, more than 40 ,000 different people.

2:02:29And this is the study we started this discussion on, identifying what Tony did was actually remarkable. He looked at each of these proteins that are in the blood and selected some that were predictive to be coming from unique organs. Imagine what you know about how you measured tropomyosin for heart attack. So they did this, they went and looked at every single organ and said, okay, what proteins are specific of this organ and which ones actually can be measured into the plasma. And using this, they were able to generate what they call an organ specific clock. simply from a blood draw, they're able to really determine, do you have a frailty point when I look at you?

2:03:11Is there like suffering happening? And this is Tony's work through the proteo. Tony with Correy, it's a new startup called Vero for disclosure. I've joined the board of this company but I only joined the board because I was really excited about what they're trying to do. And I think it really brings a whole new dimension to these predictive biomarker which is more aligned to what you and I have seen as physicians. Got a simple mind that it's a protein that's released into the blood. It shouldn't be there. It might be indicating some suffering. And I discussed with some colleagues who have used this clocks and have identified some abnormal aging in a unique organ, only to go back and find that there was indeed one problem without going into what the issues were.

2:03:57The reason I tend to be a slow adopter of these things is even if that's the case, the question is how much noise is in the system. I go and do that test on a patient and it comes back and says, oh my God, there's something wrong with your liver, your kidneys a bit too old, you're this, you're that, you're this, you're that. So I have two fundamental questions. The first is, could I have figured that out another way? So if it's telling me your liver is angry or something's wrong with your liver, how do your transaminases look? If it's telling me something's wrong with your kidney, could I have picked that up on a urinary analysis looking at creatinine clearance or cystatin C or something else.

2:04:33In other words, is it giving me information that I can get elsewhere in a more reproducible, more validated fashion? The second thing is, let's say it tells me seven things are not perfect. And by the way, everything looks perfect. I have my standard assays. Everything looks awesome. This test says, oh my God, these six or seven things are problematic. And I go poking around, poking around, poking around. and I find out one of them is indeed not working, but the other six were perfectly fine. So now we have this huge false positive situation. That's the whole MRI. Yeah, exactly. It's the same problem we have with cancer screening, which is buyer needs to be aware of the Pandora's box you open.

2:05:12And at least with MRI, you're dealing with imaging. But this sounds like exciting, and yet it's a bit of a black box. Agreed. Where it's going to spit out, oh my god, there's something wrong with your left testicle. What do I need to do, you know? That being said, I think the essays are generated in a way that there are multiple. It's not like one single protein, like a triple -mycin. We know that's a clear indicator. There's something cell death in terms of your heart. In this case, the clocks are generated in a way that there are multiple centinels for each organ. Many. The story I was talking about early days, okay?

2:05:46We totally agree with this. It's a startup. I think they will deploy it. And obviously it's going to take again a group of physicians who are able to look at these tests, this is what research is. This is what startup and I can blame them for trying because I think it has a potential, for example, to highlight a frilty point, which is in aging research, for me, it's really critical. You could have the best mind and the best hearts in the world if something else is going to fail that you are completely unaware of. You want to know as soon as you can. My prediction is, I'll share the paper with you if you're interested in looking.

2:06:20It's quite exciting in terms of where this is leading, but I agree with you early this. Yeah. I will probably maintain a shockingly high degree of skepticism and probably enjoy some experimentation with it. But again, my experience in the real world is that that's just not how it works. There aren't people walking around that are insanely remarkably healthy where everything looks amazing, but they have some time bomb they don't know about. With the exception of a few things, I'm not sure it would pick up, for example. cancer is always that thing. And of course, there's an entire field of medicine that's going around with liquid biopsies that's exactly trying to solve that problem.

2:06:58We could reword the liquid biopsy industry through the lens you said, which is it's looking for that weakest link, which in this case is the earlier signs of cancer. And it could be that a cancer will manifest itself also in local organ suffering and again, leaching in might actually point along with the liquid biopsy It tells you you have some cancer cell. It might tell you and might point you to one place where actually this is actually happening. Yeah, it's interesting. The case that I've made about MRI is the same. I have a whole bunch of physician friends. I get a yearly MRI and they tell me, why do you do this?

2:07:31I say, well, because I would rather know. It's a, well, you're going to find all kinds of things. I said, we did find something. I had a tumor behind my jaw and a mass. It was not a tumor, but it took me six months of worrying about what it was. was and decided not to biopsy anything. My sense of all of this is that these are novel ways to practice medicine. I'm criticized heavily for being too much on the forefront of doing that, but probably not nearly as far as some. At the end of the day, I think about every time you do a test, one, you never do a test unless you're willing to act on an outcome or you have a sense of how an outcome will change your behavior.

2:08:12We don't order tests for the sake of information, we order tests to make decisions. Therefore, you must at a minimum understand the full suite of outcomes that can come from the test and how many of them will pose huge trouble for you. 20 % of my patients opt not to do whole body MRI. Yes. And I fully endorse that decision. And I try to talk patients out of it. I really try to highlight how many times we find thyroid nodules that we have to put needles into that ultimately end up being nothing. And all we do is subject them to that risk and the anxiety that comes along with it. So I'm eager to look at this because I do think that the proteome offers a lot, but I'm always worried about going a little too far on the clinical implication of a test.

2:08:58I'm with you in terms of being careful. I view this as another attempt. For example, we talked about the data showing that the two organs that appear to be rid limiting in terms of aging the immune system and the brain. That came out of that story. That's actually the title of the paper, essentially, that identifies the brain and the immune system. So they have a whole series of immune markers that are predictive of some degree of immune activation and so on. Well, Eric, there's a lot of other things I wanted to chat about, but I think what we'll do is we'll have you come back out to Austin for another day of driving a Coda and then We'll justify it by doing another podcast where we dive deeper into some of these topics, who we really take advantage of the fact that we have the best race course in the country here in our backyard.

2:09:43So I think you're going to have fun tomorrow and you'll be like, let's come right back and do it again every month. I'm looking forward to this. Thank you, Eric. Thank you. Thank you for listening to this week's episode of The Drive. Head over to peteratiamd .com forward slash show notes if you want to dig deeper into this episode. You can also find me on YouTube, Instagram, and Twitter, all with the handle Peter at TMD. You can also leave us, review on Apple podcasts or whatever podcast player you use. This podcast is for general informational purposes only and does not constitute the practice of medicine, nursing, or other professional healthcare services, including the giving of medical advice.

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