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The Truth About Today’s Hottest Anti-Aging Drugs with Dr. Matt Kaeberlein - E78
36 Plays14 days ago
Everywhere you look, there’s a new “miracle” anti-aging drug promising longer life and boundless vitality. With headlines hyping breakthroughs and social media feeds flooded with success stories and supposed shortcuts, it’s nearly impossible to know what really works - and what’s just an expensive myth. This episode pulls back the curtain on today’s hottest anti-aging drugs, revealing where the real evidence lies, what matters most for extending healthspan, and how to dodge the latest wellness fads designed to sell, not serve.
Dr. Matt Kaeberlein is a renowned scientist and mentor recognized for his research in aging biology, with more than 150 published scientific papers to his name. A fellow of the American Association for the Advancement of Science and the American Aging Association, Dr. Kaeberlein’s early work on sirtuins at MIT helped launch a new paradigm in longevity genetics. He is co-director of the Dog Aging Project and has led landmark studies on caloric restriction, mTOR, and rapamycin, making him a sought-after authority in translational aging research and healthspan interventions.
“In every animal where rapamycin has ever been tested, it is capable of not only increasing lifespan, but seemingly slowing the biological aging process.” - Dr. Matt Kaeberlein
In this episode you will learn:
- Why lifestyle habits must be the base for any drug or supplement if you want to boost healthspan.
- How Dr. Kaeberlein became a leader in aging research, including his work with sirtuins and mTOR.
- What the latest research says about rapamycin, SGLT2 inhibitors, and NAD boosters, including where the science is strong or mixed.
- The risks of overhyped claims in health and wellness and how to spot real data from noise.
- Why a strong mindset, social ties, good sleep, movement, and nutrition are top drivers of long-term health.
- How to set sustainable routines for healthspan, and why consistency beats extreme change every time.
Resources
- Connect with Dr. Kaeberlein on Instagram: https://www.instagram.com/mkaeberlein
- Learn more about what Optispan has to offer: https://www.optispan.life/
- Listen to Dr. Kaeberlein’s podcast, The Optispan Podcast: https://podcasts.apple.com/us/podcast/the-optispan-podcast-with-matt-kaeberlein/id1728587274
This podcast was produced by the team at Zapods Podcast Agency:
Find the products, practices, and routines discussed on the Alively website:
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Transcript
Introduction and Podcast Overview
00:00:00
Speaker
Lifestyle versus drugs, number one, it's not either or. Like I think there's a place for both. But lifestyle probably has to be the foundation on which you build a better Healthspan trajectory.
00:00:16
Speaker
This is the Home of Healthspan podcast, where we profile health and wellness role models, sharing their stories and the tools, practices, and routines they use to live a lively life.
00:00:29
Speaker
Dr. Kaverlin, I am personally so excited for this conversation. i've gotten more questions from our listeners than any other guest ever in the show. So i don't think we'll have time to jump in on all of them, but I can't wait for our conversation.
00:00:43
Speaker
um Before we jump into those, though, how would you describe yourself?
Meet Dr. Kaverlin: A Journey from MIT to Aging Genetics
00:00:47
Speaker
I'm a lively husband, father, scientist, mentor, trying to improve health for as many people as I possibly can.
00:00:57
Speaker
Yes. And i I think it's well documented. You are doing that at a tremendous scale. You know, more than 200 scientific papers published, part of the American Association for Advancement of Science, American Aging Association, so many others.
00:01:13
Speaker
But I guess it all started... before it now, right? This was years leading up to where you are now. Could we go back to some of your early work on Sirtuins at MIT and kind of what ended up launching you into this space?
00:01:29
Speaker
Sure. And I mean, it was really that time in my life that set the stage for the rest of my career. so i So I went to graduate school at MIT thinking that I would study protein structural design, X-ray crystallography, something like that, because that was really my my background. I had undergraduate degrees in biochemistry and mathematics, and I i looked at biology through a very sort of biophysical perspective or lens. And I heard a talk during my first semester at MIT by a professor there named Lenny Grunty, who I ended up doing my PhD thesis with.
00:02:03
Speaker
And Lenny gave a lecture about how his lab, within the last five or six years, had started studying the genetics of longevity. And in this case, it was in a single-celled organism, budding yeast, David Sinclair, who was in the lab at that time as a postdoc, had recently, within just the last year, published a paper on what really I think was the first proposed molecular mechanism of aging.
00:02:28
Speaker
And so that talk captured my enthusiasm and interest. I'd never thought about aging as, first of all, a biological process, and secondly, something you could use genetics and molecular biology and biochemistry to study. So I went and I talked to Lenny, um ended up joining his lab,
00:02:45
Speaker
And when I started in the lab, through a series of conversations with people in the lab, and in particular David, decided to really try to look at the role that a protein called SIR2 played in the aging process. At that point, nobody was thinking about SIR2. And this gets in the weeds a little bit, but Brian Kennedy, who's who's also pretty well known in the field, a fantastic scientist, had done early work. Brian was actually one of the two first graduate students who got Lenny's lab working on aging. along with Nick Ostriaco, who ended up becoming a Catholic priest after graduate school. There's a whole story there. Anyway, Brian and Nick had sort of looked at a different protein called SIR4, and they were focused on SIR4 as a key player for longevity um in yeast.
Understanding Sirtuins and Aging: Hype vs. Reality
00:03:31
Speaker
um and And David had published this model about the ribosomal DNA being very important for aging. That's that molecular mechanism. And so I kind of, through looking at the literature and through a little bit of detective work, developed the hypothesis that it really wasn't SIR4. It was this neighbor of SIR4. We'll just put it that way. They act in the same complex, SIR2, that was really the important factor because it was at the RDNA and at the telomeres and all of that was was kind of making sense, put the puzzle pieces together.
00:04:01
Speaker
And so I started studying that. And eventually, along with another graduate student in the lab named Mitch McVeigh, we did, I think, what was really the seminal experiment around sirtuins. And I'll talk about how SIR2 is related to sirtuins in a second, in case that's not obvious. But what we did was we overexpressed the SIR2 protein in yeast, and we showed that that was sufficient to increase lifespan and slow the aging process. And so that really established SIR2 as a central...
00:04:29
Speaker
player in aging in yeast, right? This is all in yeast. So, um you know, we don't want to get too excited yet about how relevant that is anywhere else. um And then it was a really exciting time in the lab because, you know, David was there. Another great scientist named Shin Ichiro Amai was there. Heidi Thissenbaum, who went on to do a lot of important work on on longevity, was in the lab.
00:04:51
Speaker
At this time, nobody knew what the biochemical activity of SIR2 was. shin and i was fortunate to be able to play a role in this as well discovered that it was a new kind of what's called histone deacetylase was a fundamentally new chemical reaction it's called n nad dependent histone deacetylation um and he found out that's what ser2 was doing it was carrying out this reaction and not only that there were a whole family of these proteins that look like SIR2 structurally. That's where the word SIR2N comes from. SIR2N, the family of proteins that look structurally like SIR2. So Shin basically discovered, I mean, obviously this is Lenny's work because it was all done in his lab, but Shin was the person who who did the actual research, discovered that SIR2Ns are this family of NAD-dependent histone deacetylases. And Heidi showed that
00:05:41
Speaker
The SIRTU from worms increased lifespan in worms. And suddenly we had this really, I think, compelling, exciting story that the whole field got enthusiastic about, that this isn't only a yeast-specific story. It connects epigenetics. That's what histone deacetylation is. It's an epigenetic modification. It connected epigenetics to aging through these SIRTU and family of enzymes, And another postdoc in the lab, Suju Lin, had developed a model that caloric restriction was working through sirtuins by affecting NAD levels. So it really created this whole complicated but elegant model for a potentially conserved mechanism of aging involving this family of enzymes called sirtuins. So by the time I graduated, when I joined Lenny's lab, nobody was studying SIRTU. I was the first person in the lab to really start working on it. And by the time I left the lab, four and a half years later, everybody in the lab almost was working on SIRTUans in one one you know shape or form. and so It was sort of a fundamental change in Lenny's lab's focus. And, you know, a lot of people in the field um got excited about sirtuins. And this led to probably 10 years or so where sirtuins were probably the most talked about and studied factor in the longevity space.
00:07:01
Speaker
Yeah. And so I guess like it's a initial study that launches almost a field, right, around all of this. Yeah. And I mean, we may talk about this in some ways it it was, it was a double-edged sword because, you know, I think as we learned that Sirtuin paradigm turned out to be overstated. I think certainly, you know, compared to 2005.
00:07:23
Speaker
two thousand and five so i was in Lenny's lab from, from to late early you know, by And a lot of people were excited about sirtuins and so from like two thousand three to 2010, it was a dominant paradigm in the field. I think if you ask anybody now, you know, some people still think sirtuins are important, but nobody thinks they're the quote unquote master regulator of aging. That's how people talked about them back then. And a lot of resources went into trying to prove how important sirtuins were. And I think we learned out
00:07:59
Speaker
a lot of they're they're they're not as important as people thought. Right. So yeah it did lead the field astray a little bit, I would say, because so much it sort of became a a dominant paradigm in the field that wasn't really as solidly backed up by the data as as as a lot of people thought.
00:08:17
Speaker
That makes sense. And so as you left, what was the the genesis of the path as we move over and look at mTOR and and maybe your work with rapamycin since then?
Beyond Sirtuins: New Frontiers in Longevity Research
00:08:29
Speaker
I mean, it's a really interesting ah ah path for me personally. so So I left graduate school. I spent about a year and a half in a startup biotech company called Longenity. This was in in Boston that was started by a guy named Pete Estep, who came from George Church's lab. And we were 20 years before our time because Longenity was about building technology.
00:08:50
Speaker
biological aging clocks before anybody had ever thought about aging clocks, right? We didn't call them clocks. We called them biomarkers of longevity, but that's what we were trying to to create were were these these tools that would allow us to predict future longevity for for individuals. um So anyways, 20 years too early. I spent about a year and a half doing that. And then when my wife completed her PhD, she was at Northeastern at the same time, we moved back to Seattle ah to the University of Washington, both doing postdocs there. I did my postdoc with a ah sort of famous scientist in the in the the cell biology world named Stan Fields. He developed something called the yeast two hybrid assay. But Brian Kennedy had relocated to the University of Washington. He was an assistant professor there. And Brian and I knew each other from the Boston days. And we had, of course, the shared background of of being in Lenny's lab, even though we didn't overlap as graduate students. And so we sat down, you know, very early in my time at the University of Washington and and and, you know, both continued interest in the biology of aging. And I think we both rapidly realized that we shared the feeling that the field had become way too focused on a very small number of genetic pathways, sirtuins being one of them, insulin-like signaling, IGF-1 being another.
00:10:08
Speaker
And there was a lot more to discover. And that we wanted to go and look more broadly instead of really trying to drill deep on these known pathways, figure out what we don't understand about the biology of aging.
00:10:19
Speaker
And so we set out to carry out one of the very early what are called genome wide screens for for for genes that affect longevity. And again, we were working in yeast. Other people at the same time were working in C. elegans.
00:10:33
Speaker
And so we created this system where we could screen a large number of genes one by one in yeast and find genes that when we deleted them increased lifespan. And we just started plowing through the genome. And we got kind of lucky that in the first year,
00:10:50
Speaker
500 or so mTOR happened to be in that set. We didn't pick it. I wish I could say we were really smart and we knew mTOR was going to be important and we went after it. Nope, we got lucky. It happened to be in the first 500 that we tested. When we knocked down mTOR, it increased lifespan in yeast.
00:11:06
Speaker
And again, through sort of what happens in science sometimes completely independently, three other labs stumbled on mTOR as a regulator of lifespan, two of them in C. elegans, one of them in fruit flies.
00:11:20
Speaker
And so there were these four papers that came out all within a year of each other reporting that when you turn down mTOR, you increase lifespan in three different organisms spanning billions of years of evolution. I mean, this had to be important, right? And the fact that we all independently found this, I think, also gave a lot of confidence that it was real, right? That it's not just one lab that that's doing all of the work in this area. And so...
00:11:44
Speaker
um So I immediately, when we found that deleting mTOR or TOR1 in yeast is the yeast version of mTOR, increased lifespan, I immediately went to the literature. I'd never heard of rapamycin before this. I went to the literature and like, what do we know about mTOR?
00:11:57
Speaker
um And it turns out that mTOR is regulated by nutrients. So it was a very reasonable hypothesis that this was... part of the caloric restriction effect on lifespan.
00:12:08
Speaker
And there's this drug, rapamycin, that's an inhibitor of mTOR. So we deleted one of the two TOR genes in yeast and increased lifespan. It made sense that the drug, which turns down TOR, should have the same effect if we gave it to wild-type cells.
00:12:20
Speaker
Turns out it did. So we published that in 2006, which was really the first paper that ever reported lifespan extension from rapamycin. um And then now, you know, What are we, almost 20 years later, we now know that in every animal where rapamycin has ever been tested, it is capable of not only increasing lifespan, but seemingly slowing the biological aging process at the organ, tissue, cell, molecular level. So this is sort of, and again, you know, I'm, I feel grateful that I've had a role in this, but this is lots and lots of labs, dozens of, dozens of really, you know, quality scientists, probably hundreds of papers at this point in many different model organisms showing that rapamycin or turning down mTOR through other ways can have this effect on aging. So it really is, you know, second to caloric restriction, the most studied protein
00:13:15
Speaker
pro-longevity intervention that's out there, and also second to caloric restriction, the most robust, probably even more than caloric restriction, the most reproducible. So it really is in many ways a gold standard intervention for slowing aging, at least
The Dog Aging Project: Trials and Discoveries
00:13:29
Speaker
in the laboratory. And I definitely want to dig on that and in that juxtaposition. Before you do, you you were saying in every organism is tested. You're doing work now with dogs.
00:13:40
Speaker
yeah Can you kind of speak to what you're seeing there? Sure. Yeah. I mean, I wish I could tell you I knew the answer. So this is this is as part of something that's called the Dog Aging Project, which is a large... mostly observational study of aging in companion dogs or pet dogs living with their owners. So this is very different than, you know, all of the work that I was involved in before we started the Dog Aging Project and that, you know, this is outside the laboratory, real world, dogs living with their owners.
00:14:07
Speaker
And so, as I said, most of the Dog Aging Project is observational. We're not asking owners to do anything different. We're collecting data, biosamples on the dogs and to try to understand what are the most important factors that influence health outcomes during aging. So as part of the Dog Aging Project today, there are more than 50,000 dogs and owners participating around the United States. It's a very large, probably the largest study of aging in the world. But a piece of the Dog Aging Project is a veterinary randomized placebo-controlled clinical trial testing whether or not rapamycin can slow aging in dogs. and And when that's fully enrolled, there will be about 580 dogs participating in the clinical trials, but half enrolled right now. The the goal there is to test
00:14:50
Speaker
whether or not rapamycin slows aging in dogs. And the primary endpoint is lifespan. So that's so that the number of dogs combined with the entrance criteria. So the dogs have to be at least seven years old and between 40 and 110 pounds, we believe gives us statistical power to detect a 9% change in lifespan. So that's the primary endpoint.
00:15:10
Speaker
um But of course, we're interested in healthspan and we're looking at a a variety of healthspan metrics, heart function, neurological function, activity, disease incidents, you know, really trying to to assess whether rapamycin can improve health, broadly speaking, in dogs.
00:15:27
Speaker
And so that study is ongoing. So what I can tell you is before we started this large, it's kind of equivalent to a phase three clinical trial. We aren't going for FDA approval, but if you were, it's kind of equivalent to that. We call it triad for tests of rapamycin in aging dogs. Before we started triad, you know, of course, the first thing we had to to determine and and establish is that this was safe, right? So we did two safety studies.
00:15:48
Speaker
ah One was 10 weeks of treatment. One was six months of treatment. in the In both studies, the dogs got echocardiograms before and after to look at heart function. And I would say the signals were were going in the directionally in the right direction, where we saw evidence for improvements in age-related heart function. In particular, some metrics of left ventricular function, which other people in mice had shown rapamycin could improve. So, you know, I don't want to make too much of it other than to say the arrows were going in the right direction. These were small studies.
00:16:19
Speaker
ah some of the measures were statistically significant. So so that was good. We definitely were able to establish safety. We didn't see any evidence for significant adverse events, and that still has held up, even though Triad is still blinded.
00:16:33
Speaker
We've got a ah monitoring committee, data safety monitoring board. We haven't seen any any evidence that rapamycin is having side effects and in the dogs. um The other thing, and and again, you know, it's not something I want to make a ah lot out of but in both studies, the owners were blinded, the veterinarians were blinded, we were blinded, and in both studies, the owners self-reported improvements in activity and quality of life. So, you know, it's...
00:17:01
Speaker
going in the right direction again. And that's really probably the biggest health span indicator, especially if it's blind saying, wow, my my dog's acting much younger. her Exactly. Yeah. So encouraging, I would say. And for that, the dosing, because I think this is, Peter Atiyah often mentioned with fasting, right? It's like, we have this miracle drug, but we don't know the dose and yeah frequency or anything. And with rap, I think that's a common question for a lot of people as well. What what is it for the dogs?
00:17:30
Speaker
So the the dose we're giving in the current trial is 0.15 milligrams per kilogram once a week. the first ah The first trial, the 10 week trial, we did two doses, 0.05 and 0.1 milligrams per kilogram given three times a week. And it's all guesswork. I mean, it's educated guess, but these are guesses. and And that's one of the hard things about clinical trials. I don't think people really realize this. You know, when you're designing a clinical trial, you're forced to make a series of educated guesses, right? and um And then you have to live with them. And so you hope you do a good job. And dose is one of them. I'll come back to dose in a minute. Another one people don't think about, but the one that actually keeps me up at night, not that it really does keep me up at night, but that I worry about with our rapamycin trial is...
00:18:17
Speaker
um because we wanted to make this a trial of healthy aging, one of the exclusion criteria where the dogs could not have a significant preexisting age-related condition. it makes sense and it creates a healthy cohort bias because now the dogs we're enrolling are healthier than the average population. It's harder to see a positive effect on health if you're starting from an overly healthy population.
00:18:40
Speaker
So these are all the kinds of things you have to try to do the best you can and then you live with it. So coming back to dose, the reason why we started with 0.1 and 0.05 mg per three times a week is because when when I was designing this trial, we had no information on rapamycin in dogs other than ah study two two groups were studying rapamycin for different types of cancer in dogs, one osteosarcoma and the other hemangiosarcoma of the spleen. And both of those groups were using this three times a week dosing. And so they were they were generous enough to share their safety data with me. And so I was trying to figure out like, what's a dose that might have efficacy, but that I'm very confident will be safe over the timeframe of the trial. And so that's why we started with those doses.
00:19:28
Speaker
And the reason why we moved to the once weekly dosing for the next two trials, including triad, is Joan Manick has published a couple of papers now with a derivative of rapamycin called Everolimus in humans, where they showed that you can get similar efficacy,
00:19:46
Speaker
with a better side effect profile at once weekly dosing versus daily dosing, roughly comparable overall total doses. And that's what most of the off-label use of rapamycin is gravitated towards is is once weekly dosing in humans. And like six to eight milligrams typically, yeah. Yeah, I mean, it's variable. So six is the most common. It's it's it's probably three to eight is ah is is the ballpark standard deviation range. But but six is the the most common dose. um A little bit of variation for women and men. Women usually taking a little bit less. But but almost, I would say probably 90% of people using rapamycin off-label. And what I mean by that is just not for the on-label indication, which is usually going to be organ transplant rejection. is once weekly. So probably 90% of people are taking it once weekly.
00:20:35
Speaker
And the, you know, normal curve standard deviation is going to be four to eight. Okay. And I mean, I, not that we give medical advice, obviously, you know, all the disclaimers on the show, but do you currently take rapamycin?
00:20:48
Speaker
Yeah. I mean, I'm not taking it right now. I usually cycle three months on and then three to six months off. And and my personal dosing has ranged between six and 10 migs a week. It turns out I'm a fast metabolizer. I know that because I measured it in my own blood.
00:21:02
Speaker
um So I probably can tolerate a little bit higher doses than other people can. And that's the other thing, you know, most of that, certainly for off-label dosing, very rarely does anybody personalize the dose to their own state. Right. And this is This is actually something that's worth saying about rapamycin. Unlike some of the other interventions we might get to that are popular in the ah the the longevity off-label community, we don't have great biomarkers for rapamycin.
Examining Drug Efficacy: SGLT2 Inhibitors and NAD Boosters
00:21:28
Speaker
We don't have a good way to say, yeah, this is the right dose for you because we don't really know what the right biomarker is.
00:21:35
Speaker
I've heard you say in the past, the the two that you see the most justification for are RAPA and then SGL2. Yeah, SGLT2 inhibitors, yeah. Genagliflozin and pagliflozin, yeah. So first of all, just for people who don't know what what those do, I mean, basically they just make you pee out more glucose. So they they're they're ah they're ah an inhibitor of a co-receptor, co-transporter in the kidney that causes reuptake of glucose. And so when you inhibit that,
00:22:02
Speaker
you pee glucose out in your urine. So the effect is it lowers circulating blood glucose levels over time, at least for many people, it will also lead to an improvement in insulin sensitivity, probably because you have lower average blood glucose levels. So it's um been approved for diabetes, also some evidence for benefits for a kidney function, potentially...
00:22:27
Speaker
ah cognitive function, cardiovascular. But the reason why people are excited about it for you know longevity is because it also has been shown in animal models, in mice in particular, to increase lifespan. This has come out of the interventions testing program. So it seems to slow biological aging in laboratory animals.
00:22:47
Speaker
Definitely beneficial for people who are metabolically impaired and some evidence for other other potential benefits in humans. Now, the nice thing about SGLT2 inhibitors is we've got a really, really great biomarkers to tell whether it's working for you. Is your average circulating glucose lower? And is your insulin sensitivity getting better? If it is...
00:23:06
Speaker
you're you're in the right range, right? So this is where I think it's it's kind of a very different beast than rapamycin. I personally feel a lot more comfortable about SGLT2 inhibitors because we know what the biomarkers are to look for. And if we're seeing improvements in insulin sensitivity for the vast majority of people, I think that's a pretty good bet that their health is going to be better. Maybe their longevity is going to be greater, but their overall health is going to be better going forward.
00:23:32
Speaker
One other one that has been mentioned kind of in passing since we started talking, but I think the question is as a supplement, does it actually work at NAD? So, you know people are doing IVs, doing shots, trying patches. I've gotten all this on social media from rows, like a zomal formulation. yeah What are you seeing there? Like it's one of those theory and practice issues, it seems. So, I mean, I think there's no doubt in my mind that the whole NAD thing is is way overhyped compared to the data. The data is interesting. It's also very mixed. So I think what I can say with confidence is NAD levels in laboratory animals decline in some tissues with age but but the idea that NAD declines globally with age is
00:24:16
Speaker
mostly bunk, but it's not supported by the bulk of the evidence. That's probably true in people as well. So that's overstated. There's probably some truth to it. And it's probably individual, right? So NAD, again, for people who maybe aren't aficionados, it's a cofactor in thousands of reactions in our cells. Many of them are metabolic, but not all of them.
00:24:34
Speaker
DNA damage, repair, bunch of other functions. So it's important for lots and lots of different cellular chemical reactions, and and it's essential for cellular function. um And so for that reason, nd levels are very well buffered in our cells, right? It takes a lot to to move NAD out of the the the range that it needs to be in for our cells to function. So the idea that NAD levels are dramatically declining with age just does not, it's not biologically plausible.
00:25:04
Speaker
So then a question is one question is, NAD levels decline enough with age that they're impairing cellular function? And I think in some people with significant metabolic perturbations, that's probably the case. So for example, in people who have mitochondrial, like severe mitochondrial dysfunction, mitochondrial inherited mitochondrial diseases, you will have a depletion of NAD to NADH, which is the reduced form of NADH,
00:25:33
Speaker
And then in order to restore NAD, your cells will make lactate. That's why lactic acidosis often happens in people who have impaired mitochondrial function. It's also why you get lactate buildup when you're exercising, you know, two extreme levels, right? That's to regenerate NAD. So that's um that's a mechanism that our body uses to maintain NAD homeostasis. This is all, i'm just trying to make the point. It's really hard to get our bodies to a place where NAD is limiting, right? Yeah. Yeah. So then the so so i think the real question is, what evidence is there that if we boost NAD, that that's going to be beneficial?
00:26:07
Speaker
And then I think a second secondary question there is, of the various ways that people are trying to boost NAD, which of them actually boost NAD? Because it's not always the case that that's clear. So I would say for longevity, the data in mice is very unconvincing that that n NAD boosters increase lifespan.
00:26:25
Speaker
um There was one study from the Alworks lab that failed to be replicated with nicotinamide riboside. There's a nutty another study from the Sinclair lab where the supposedly long-lived mice on NMN are actually shorter-lived than control mice should be.
00:26:39
Speaker
So... weak evidence, and that hasn't been replicated. um So I would say it's very unclear in mice that NAD boosting slows aging. There are some mitochondrial disease models or Parkinson's disease models where boosting NAD appears to have therapeutic value in laboratory animals. And that's the only data I find even moderately convincing in humans at this point is in Parkinson's disease. There's a signal. It's early, but there's a signal with nicotinamide riboside that it may have some benefits in people with Parkinson's disease. So my intuition is there are certain metabolic perturbations where...
00:27:19
Speaker
Boosting NAD, probably because you're you're restoring the NAD to NADH balance, is beneficial. Is that going to translate to the average person as as you're getting older?
00:27:31
Speaker
I don't know. I will say, anecdotally, in talking to physicians who use NAD drips, I've talked to some people who seem pretty credible who say in some of their patients, people have sort of remarkable improvements in quality of life. So I believe there are certain conditions where boosting NAD can be quite beneficial. I just don't think we know at this point who it's going to be beneficial for and who who it's not going to be beneficial for. yeah um And then there's a lot of noise around, you know,
00:28:01
Speaker
Is NMN capable of being taken up by cells? Is NR capable of being taken up by cells? It all gets broken down by the microbiome to to nicotinamide anyway, so does it matter? I find the the, again, the sort of bickering back and forth among people in the NAD space to be a bit comical when they have yet to establish that these things are actually useful.
00:28:22
Speaker
Yeah, it makes sense. And you you touched there, know, there's a couple that you say, hey, we actually have good evidence that these work and some we know the mechanisms can track.
Lifestyle vs. Pharmaceuticals: The Longevity Debate
00:28:35
Speaker
And then there's a long list of others. But before we talk about some of that, I'd be curious because you also compared it to, I think, the the number one intervention we do know or seem to know for extending longevity is caloric restriction.
00:28:50
Speaker
And this whole world of behavior and lifestyle change versus maybe molecules. Because I think yeah when we met at the TEDxBoston Unlocking on Longevity, you had the chart showing, hey, you know, rep is the best thing that we know.
00:29:05
Speaker
And here's where it sits next to caloric restriction. Caloric restriction is still outside in terms of extending life. So especially with your work at OptiSpant, where you're you're balancing both,
00:29:16
Speaker
What do you see the weighting on how we should think about these two? That's a great question. so So before I dive into that, i do want to i do want to explicitly make the point. so So in laboratory animals, caloric restriction can have the biggest effect on lifespan that we know of right? And it's about twice the magnitude of rapamycin.
00:29:36
Speaker
um which is the second biggest effect on lifespan. So that's just useful to understand in terms of, you know, what we're talking about. And that's lifespan. So when you start talking about healthspan, which is, I think, what most people are more interested in, or many people are, right? Yeah, they're, you know, it's harder to assess because...
00:29:54
Speaker
there aren't very many studies that look broadly at healthspan in laboratory animals. It happens sometimes, but usually it's ah you have to you have to you know aggregate a whole bunch of studies that looked at one healthspan metric for rapamycin or one for caloric restriction. The thing I would say is, and this is my take on the literature, but I think most people who are broadly read in the field would agree with this. Both caloric restriction and rapamycin seem to improve a variety of health span metrics across many different tissues and organs in mice. okay
00:30:25
Speaker
But when we go to people, I think we really wanna be cautious about caloric restriction because mice in the laboratory aren't dying from fractures or frailty or infections in general because they're in a relatively sterile environment.
00:30:39
Speaker
Those are the things that I get really concerned about. the The level of caloric restriction that we apply to mice, if we were to apply that in people, I would be very concerned that people are going to experience frailty, fractures, and high risk of infection, both bacterial and viral. Because we're talking about, you know, 60% caloric restriction, 800 calorie diet, right, a day. So I just want to make that point that when we get to the lifestyle discussion,
00:31:03
Speaker
I don't think that level of caloric restriction makes sense in humans, even if we could do it. I just don't think you're going to make people live longer. I think it's going to have detrimental effects outside of normal aging biology that are going to offset the the benefits. Do I believe caloric restriction slows biological aging in people?
00:31:21
Speaker
Yeah, I can't prove it, but my intuition is it does, given the data that we've got on, you know, clocks and other markers of aging. And it's not a long-term strategy for increasing your lifespan or certainly not for improving your quality of life in my view. So that's where I land on caloric restriction. I just think it's important to say that because because when you talk about caloric restriction in mice, all of the sudden people are are thinking that, you know, you extrapolate that to humans, they should start eating a severely calorically restricted diet. diet.
00:31:47
Speaker
Now to get to the question of lifestyle versus drugs, um number one, it's not either or. Like I think there's a place for both. But lifestyle really should be, probably has to be the foundation on which you build a better health span trajectory.
00:32:04
Speaker
And, you know, at OptiSpan, we talk about this as four pillars. You know, you can have your different, everybody has their different number of pillars. We talk about four. We talk about eat, move, sleep, connect. Active words. I like active words. So eat is, of course, you know, diet, nutrition. Move is exercise. Sleep is obviously sleep quality. And connect encompasses both mindfulness and the importance of human relationships, social network. And stress weaves its way through all of those. So some people like to put stress as its own pillar, but it really, all of those things influence the the stress you experience and the way you manage stress. So that's how I think about lifestyle. And I don't, again, you know, maybe I go back and forth a little bit in my own head over time, but but I can't say with any degree of confidence or emphasis that one is more important than the other. It's going to be different for different people, what the biggest levers are. But they're all super important. So I wouldn't try to put, you know, one above above the other. I think they're all they're all important. And I think where drugs come in is drugs can help if, because sometimes you can you can have a pretty good lifestyle and you still got metabolic challenges. I think drugs can help there. I think like GLP-1, we haven't talked about GLP-1 agonists. Those can also help in getting people to a better lifestyle.
00:33:24
Speaker
than they have currently because you can, you can see improvements. And if you can reduce body weight, you can improve your ability to exercise or maybe your sleep quality. If you reduce inflammation, like I think, so I don't want to say like, I'm definitely not one of those people who says you'll have to do it all through lifestyle and then you can try drugs. I think It should be a balanced picture. And and for each person, you try to find, you know, what are the biggest levers you can pull?
00:33:49
Speaker
and And often, most of the time, there's going to be a lifestyle component to that. But sometimes there's going to be a pharmaceutical component. Sometimes there's going to be a supplement component um that goes along with it.
00:34:00
Speaker
Yeah, I mean, that's very much what we see. You probably saw the recent study from Gallup. ah Obesity has gone down for the first time in 20 something years, thanks to probably GLP-1s and the cascading positive benefit from that. And so I think our we we have five pillars. We we have stress and mindset as its own, but the same on the others.
00:34:25
Speaker
And we say the most effective thing is the thing you'll actually do, right? So maybe it's take a pill, but if you're terrible at remembering to take a pill and you're never going to take a shot or anything, but you will do this walk after each meal, then that's the most effective thing because that's actually something. The theoretical doesn't matter if you're not going to do it.
00:34:45
Speaker
And I would simply add to that, it's it's also what you're going to be able to sustain, right? And that's why there really is no one size fits all solution for for any of the of the pillars, right? So some of this is figuring out, you know, what, I think exercise is a really obvious example, right? Where, you know, some people are never going to get on an exercise bike an hour a day, right? It's just, there's never going to do it. But they'll definitely go out for ah a hike two times a week. So find the the modality that's going to work for you and and be sustainable. And it can change over time.
00:35:20
Speaker
I would also equate it to compound interest on investing, right? You think about Warren Buffett and Charlie Munger, It's that they did it so consistently for so long is how you built up the money. And my gym, there were these two larger ladies working out with my trainer and they were crushing with clean impresses.
00:35:39
Speaker
And I said to him the next day, i was like, man, that was really impressive what they're doing. he said, oh, you have no idea. So one of those, when she came was over 400 pounds and the other was 370. And when we started, it was just a little step. All she could do was just go in the step box. She was on...
00:35:57
Speaker
32 medications and she's down to seven just in, in, in it's, you start with the smallest thing. It's not, Hey, I'm going to start with CrossFit. You just start where you are and you can compound. It's that she continued to show up day after day. You get those benefits.
00:36:11
Speaker
I think that's really important. Yeah. Yeah. I mean, I, I align completely with, with what you said and, and trying to help people recognize it as a trajectory and a long-term journey. Right. Again, you're yeah you're not going to immediately go from zero to 100. Right. And nor should you try. like the whole point is it literally lasts a lifetime.
00:36:30
Speaker
Yeah. And I mean, this is something that we try to emphasize and and and I personally try to try to communicate as well is, is, you know, the journey should be the reward, right? It's not, i mean, yeah, we all have goals that we want to get to in terms of our, you know, our future longevity and health, but you should be feeling the value the entire time, right? The journey is the reward.
00:36:52
Speaker
In health or anything, right? I have a nine-year-old daughter and I try to explain that to her as well. Like I was a swimmer, her mom was a swimmer. She didn't enjoy it and she was great, but she didn't enjoy it. And I said, say yeah you can be great as a novice, but you're not going to be great at the next level because you don't like going to practice. You're not going to put in the effort you need to find. like No one ever asked Messi to go practice.
00:37:10
Speaker
that All you ever wanted to do was play with the football. right And so it's the same with with the health. like You don't have to be carnivore. You don't have to be vegan. You just find something that's getting you good nutrition and stick with what works for you.
00:37:23
Speaker
That's really helpful and self-affirming that I'm thinking about it as someone similar that I respect so much. Well, and I think, you know, and when you see so many success stories with with people who are are taking taking that sort of approach, right, that also reaffirms the the power. And, I mean, you mentioned these two women, you know, that that your trainer's working with, right? I think that's, for me, that's one of the most rewarding things about doing this, right, is is seeing people. And it's very different. I mean, when you're a basic scientist, yeah of course, you all hope that that eventually, you know, 20 years from now, something you discover will make it into the clinic and improve people's lives. It's very different seeing in real time or close to real time, you know, these these these dramatic life-changing impact that you can you can have, right? And sometimes it's detecting a hidden condition. Sometimes it's helping people get on this new health span trajectory that's going to probably give them 15 more years of high quality life.
00:38:23
Speaker
And on that, I would like to talk, your talk was a lot around being honest in this space. And when you talk about these stories, i mean, there's so many stories, right? TikTok videos, whatever of this magical X, Y, and Z, Oats, Zipik to take this molecule, whatever it is that there's some fad people jump on.
00:38:44
Speaker
And is someone with such a credible voice, it's worked at the highest levels with some people that there are questions on some of that. What are your thoughts there? Cause I, I recently had heard there was a period of time that it was actually the wealthiest that died more younger than the kind of middle part of the population, because they were, it was a snake oil.
Navigating Misinformation in Health and Wellness
00:39:07
Speaker
They were the ones experimenting with all this stuff and and actually was shortening their life. And I certainly have a concern with that with,
00:39:14
Speaker
self-medicating with all sorts of stuff out there. I mean, it's super complicated. And the the noise definitely swamps the signal in in this space. And that's getting worse, right? So, you know, I'm i'm now ah preparing ah like a short just public service announcement on a YouTube channel that's basically completely AI generated, telling complete nonsense wellness advice and using...
00:39:38
Speaker
David Sinclair as the, the you know, his his image, right? and his and as and And as much as, you know, i struggle with some of what David says, you know, this is taking it to a new level. So this is just gonna get worse. Oh, it's like a deep fake of David. Yeah.
00:39:51
Speaker
Yeah. Oh, wow. that's what they say. i I'm going to give David the benefit of the doubt and assume he has nothing to do with it based on the content that's there. But but yes, it's a it's it's an AI generated, ah giving terrible, just absolutely terrible wellness advice. so And that's all just to make the point, this is going to get worse with AI tools and with the fact that a lot of people are getting rich and famous by spreading misinformation. So I think as consumers, I mean,
00:40:18
Speaker
to some extent, people are going to have to develop strategies for separating the signal from the noise. And I think there are, you know, there are a few general rules. Number one, if it doesn't align with the the pillar, the four pillars or five pillars or whatever that we talked about, it's probably bullshit because we know that's true, right? So that's one. If somebody lies to you,
00:40:42
Speaker
they're gonna lie to you again. Like stop trusting people who lie. i just don't get this. And you look at the largest names in this space and they are often documented repeat liars. I don't understand that, but, but I can guarantee you if somebody has a pattern of telling you things that aren't true, it's going to happen again. So just stop listening to those people.
00:41:01
Speaker
I think this is not a perfect one, but I think you should ask yourself, does this person have both credentials and expertise yeah on the topic that they are topic talking about? Credentials don't always matter because there are some people with credentials that spread misinformation. And there are some people who do their own research and I don't care if you have a PhD, if you've gone and done the research and you have the information, right?
00:41:24
Speaker
But I think those can be guiding principles where if somebody doesn't have credentials and they don't have experience in the space and suddenly they're a longevity expert, probably not, right? So those are the kinds of things I think people can use to to to guide themselves. And then the other one, of course, is what are they trying to sell you, right?
00:41:42
Speaker
If they're trying to sell you olive oil, I'd be a little skeptical of that person. And if they're using fear, if they're using fear to control you, if they tell you things like the air you breathe, everything you eat is poisoning you, they're they're manipulating you through fear.
00:42:00
Speaker
So I think people need to recognize the strategies that the dishonest people in this space are using. Certainly. and I mean, you also have to be careful, I would think, for confirmation bias, right? Whatever you want, you can find an argument for that as well.
00:42:15
Speaker
You can. I mean, that's a harder thing because, and this is true in the scientific literature, right? You can go find, especially now with the AI tools that are available, you can go find a study that will support almost any position you want to take, right? Especially when it comes to supplements or nutrition.
00:42:31
Speaker
So that's a harder thing. i it's hard for me sometimes. It's a harder thing if somebody says, look at this study, it shows that, you know, I don't know, taking cranberry extract four times a day is going to keep you from getting dementia, right? You can probably find a study that that that kind of hints at that, right? And you just over extrapolate it even though there might be eight studies that then failed to show any any connection. So again, i think this is where if somebody has a track record of doing that, of cherry picking studies,
00:43:03
Speaker
And I think also, you know, there's a push pull and I've noticed this in the influencer world, right? Where in order to maintain um your status as an influencer, you have to constantly have something new to to hype, right? And science doesn't move that fast. So if somebody is always on to a new thing every week, right?
00:43:23
Speaker
they're probably overhyping. that By the way, they're an affiliate for selling. so Or making it up, right? Yeah. So so again, i think um people just have to use a little bit of of common sense and and critical thought. And it's hard because you know this is where I recognize when I see stuff, I'm like, well, that's complete nonsense. Why do people believe that? But I'm trained as a scientist. So I immediately approach things from the perspective of, you've got to convince me, not... yeah I'm going to believe you, right? You started the null hypothesis and have to go through So I think looking for alternative explanations and not being gullible are really important in this in this space right now. Otherwise, you're going to constantly be misled,
00:44:06
Speaker
Maybe the last thing I'll say, i don't I don't want this to be too negative, and I realize it's taken a bit of a negative turn, but I think these are these are strategies that people need to should adopt if you really want to be able to to navigate this space. Be wary of hacks, right? Everybody wants to talk about this longevity hack. If somebody says doing this one thing is going to make you live longer, and it's not part of the pillars of HealthSpan, they're at best, overstating the data. At worst, causing you to do something that's harmful to you.
00:44:39
Speaker
And so be careful. I will kind of the the opposite of that or the the counter to that, which I'm sure you see with OptiSpan as well, is if it is in one of the pillars and you're moving one of those metrics, it tends to move a bunch, right? If we improve deep sleep, we start seeing all sorts of cascading benefits. Yeah. They're interconnected. Absolutely. Yeah. Yeah. Absolutely. Yeah. And I mean, I think a positive way to look at this, and again, I encourage people to take control of your own health span, right? So, so become informed.
00:45:09
Speaker
And again, that's, it's not easy. I'm not suggesting that it's certainly, you're not overnight going to get a PhD in biology, right? But become informed, try to find credible sources. And,
00:45:19
Speaker
um make sure you've got a good optimally medical professional, but, but, but, but a good resource that you can go to, to help, you know, what should I be measuring?
Making Informed Health Decisions: Accessibility and Investment
00:45:30
Speaker
What should I be looking for?
00:45:32
Speaker
And if you see your biomarkers going in the right direction, that's a good sign, whatever you're doing, right? So use data to guide you as opposed to deep fake AI based YouTube videos.
00:45:43
Speaker
yeah Well, Dr. Gablin, I cannot thank you enough for being one of those credible sources and helping. I'm trying to be a voice, you know, in the wilderness, but it's hard sometimes.
00:45:54
Speaker
And helping our listeners and so many others stay informed in this space as well. is incredible. Not as fast moving as maybe the influencers want us to believe, but with AI and others, it is faster moving than it's ever been in human history as well. Well, and like and again, i'm I'm very optimistic that we have um good tools today for assessing where people are at and helping people add 10, 15 years on average to healthspan. don't know about lifespan, but I think we we know enough where we can have a big impact, especially if we talk about the average American on healthspan. And I think it's not as expensive as a lot of people have been led to believe. Like there's this myth that it's only for billionaires.
00:46:36
Speaker
I mean, I think, yes, of course, the more resources you have the larger the spectrum of diagnostics you can get access to and of course you're going to get access to higher quality health care i mean it's unfortunate that's just the reality but it it's not tens of thousands of dollars i think you know in in our in one of our programs at optispan we have a corporate health care program right so we're we're doing corporate health care for for sebi corporation employees You know, for couple hundred bucks a month, I think that's about the 80-20 on the, you know, $100,000 healthcare programs.
00:47:12
Speaker
ah You can do a pretty good set of diagnostics and get access to reasonable healthcare care for about a couple hundred dollars a month. Now, of course, that's outside of insurance. And I think this is also one of the things that I try to encourage people to at least think about. I think there's a culture in the United States, at least, just because of the way our health care system is paid for, that people have this gut reaction, well, where if insurance doesn't cover it, I'm not going to do it.
00:47:38
Speaker
Right. And I think you've got to like your health is more important than that. Right. So I understand where that comes from. But you should be willing to invest, in my view, as much as you can in your health. And and so think about where you're allocating your economic resources and whether they're being allocated towards the things that are most important in your life. And I would argue health is probably more important than most people give it credit for.
00:48:05
Speaker
And we do see as societies get richer, right? The proportion of income that goes to health and healthcare is bigger, though it's typically sick care. But I would say the signal from OptiSpan, from Function, from Superpower, these companies coming out, people are starting, it hasn't gone to hundreds of millions of people yet, but people are more willing There is a ah ah broader recognition. And again, you know, for some of the people that I struggle with in this space, ah Brian Johnson, David Sinclair, um they also have done good in raising awareness around this topic, right? so
00:48:38
Speaker
So it's not as if it's all, you know, it's all... bad stuff. So it's great that more people are paying attention. i think now the question is, how do we actually help help those people get access to the real information? And I think Function Health is an interesting example. I'll be interested to see where they go. um I actually...
00:48:59
Speaker
think it is ah a net negative for people to give them access to data without giving them any way to act on that data, right? Without providing medical care. I understand why they do it because it's, you can make more money and it's easier to do it outside of the regulatory system.
00:49:15
Speaker
And I think it's detrimental to most people who don't have a good physician that they can then go to. This is what I was getting at, at having somebody who can help you navigate that that data. You know, if you get a function health report and you take it to your typical primary care doctor, they're gonna be like get out of my face.
00:49:30
Speaker
i don't know what to do with this. Is this where Gemini and ChatTBT can, because you could ostensibly upload the report. What should I be worried about? What should be working on? And they're they're reasonably good, but they make mistakes, right? And so, and even if they tell you what to do, if you don't have a way to get access to a prescription medication that you need.
00:49:49
Speaker
So it's ah it's, you know, again, i'm not I'm not trying to be hypercritical of function health. I just wish they would bite the bullet, do it the hard way, and give people medical care.
00:50:01
Speaker
Yeah, and maybe that's on the product roadmap, right? Like, you know, as building a company, you kind of have to start and get your initial land grab and then expand. Well, Dr. Kaeperlen, thank you so much. This has been a complete pleasure. i I could keep asking you questions for much, much longer, as I think you saw right before your talk when I was just peppering you. Yeah, yeah, no, we can definitely do a part two at some point.
00:50:22
Speaker
Oh, I would love that. Thank you so much. And I know you're traveling this week, so safe travels and look forward to continuing to follow your work. Thank you. Thank you for joining us on today's episode of the Home of Healthspan podcast.
00:50:36
Speaker
And remember, you can always find the products, practices, and routines mentioned by today's guests, as well as many other Healthspan role models on Alively.com. Enjoy a lively day.