all you have to do is look at pictures from the 1970s just look at the shapes of people right fundamentally different you did not see obesity or if you did it was extremely extremely rare in the 1970s now I don't know what the statistics are 50 plus% of Americans are obese right that is purely environmental genetics have not changed in 50 years so you probably don't know this but I have a long history with resveratrol Resveratrol of course is the miracle molecule in red wine and and I was one of the scientists who first debunked that whole long it piece again not saying there's no benefits to Resveratrol it is not a longevity gr but even then I rationalize drinking red wine my sort of current speculation around NAD precursors is I think that boosting NAD for some people if you have particularly you know a high level of mitochondrial dysfunction or metabolic dysfunction for those people it may be beneficial I I think for the average person is probably not going to move the needle there also may be some specific neurod deener diseases like Parkinson's disease where there's some intriguing clinical trial [Music] data now Today's Show with Matt caraline is loaded with amazing information I strongly suggest that you look at the show notes and the time stamps because towards the end we talk a lot about rap ayin met foran the current state of testing and different tools to assess your biologic age and pace of Aging he also talks about and debunks some of the the common myth about dietary supplements that have been purported to slow down your pace of biologic aging we talk about other lifestyle factors such as socialization exercise nutrition and more it's a phenomenal show brought to you by myoscience nutrition so as you know exercise is one of the best interventions that you can Implement right now to not only help improve your health right now but slow down the pace of aging and optimize and prevent age related chronic diseases such as obesity and diabetes and dementia and Beyond but one tool that can help your exercise session is the novel [ __ ] enhanced electrolytes by myoscience what makes this product unique and different from many of the other [ __ ] products out there or the isolated electrolyte products out there is this pairs the best of both electrolytes and [ __ ] together [ __ ] helps with cellular hydration and electrolytes help enhance the absorption and utilization of creatine so they work synergistically and they can help improve your exercise efficiency and exercise sessions there's close to 900 reviews over at myoscience decom from people just like you who are finding benefit from the novel creatin enhanced electrolyte sticks I strongly suggest you give these a try there's a 30-day money back guarantee over at myoscience doccom I'll put links in the description below most people find that they get the most benefit from using this before or during their exercise sessions there's a lot of great customer feedback and reviews that you can check out and you can take advantage of the fact that there's a 30-day money back guarantee they want you to get great results from the formulas that they produce so use the code podcast Tove over at myoscience decom so let's cut back to it with Matt Matt caran thanks for coming back absolutely how would you explain to people what you do in terms of the in the realm of longevity and studying the biologic processes of Aging yeah so I guess I would say uh by training I'm a scientist so I spent about 25 years actually doing basic research on the biology of aging and what are the mechanisms that connect the aging process with functional declines and diseases um and then about a year and a half ago I left my academic position I still have one foot in the academic world but now I uh am CEO of a company called optisan which is really at the far end of the the the other end of the spectrum when it comes to human health which is really all about trying to create tools and Technologies to enable Health span optimization for as many people as possible I love that and what are you go go to tools and Technologies I know you do functional things like dexa and V2 Max and how esoteric do you get with that yeah so I mean I think we start with the fundamentals so you know at optis span we talk about the pillars of Health I think you know lots of people have their pillars of Health um we like we like four because that's a nice easy number and we like action words so we look at eat sleep move connect as the foundation and those are really what you would think they are eat is nutrition move is exercise sleep is sleep and connect really refers to both uh your individual connection with the world around you you uh that would include things like mental health um and Al and also your human connection both of those things we know are super important for quality of life and we think that that's the foundation and so one of the first things we try to do is at an individual level identify you know what's which pillar is weakest and can we take action there of course we also do uh a very medical approach to health span so um for our clients we have what we call a Gateway day and that's the day where we really try to understand at a deeper level where each person is at on their own health span trajectory so we use things like comprehensive blood work Imaging so ultrasound dexa to look at body composition um uh assessments for physiological function like V2 Max and strength um and then of course part of part of this is also about making sure there isn't pre-existing problems that we need to take care of so we do things like advanc cancer screening or assessments for different age related diseases all with the goal of again figuring out where each individual is at and then trying to identify you know where's the where's the biggest bang for the buck going forward for how we can start to to modify either lifestyle or when appropriate uh medications to get people onto a better health span trajectory amazing you mentioned connection and I think that's really important but yet underrecognized especially within the mainstream medical community I know you're going to Brazil in next week and have presumably traveled throughout Europe it's amazing to me when you look at different parts of the world the diet doesn't appear to be that I mean obviously maybe a little bit less processed foods depending upon where you are but generally I found more higher prevalence of smoking for example in Europe but yet people are walking more and connecting more so um how much do you think that plays into the social aspect and connecting and and movement how does that how much of a lever when it comes to longevity do you think that pulls yeah it's a good question and it's it's hard to answer um so I'm a scientist so I'm always like can I answer this quantitatively what are the error bars right but uh I mean I think from a from a sort of more pragmatic perspective from for longevity um we know that human connection plays a role I don't think we know how big of a role so my guess is you know that may be less important from a pure lifespan perspective than things like what you eat and how much you eat and how much you exercise um but from a quality of life perspective it's huge and like like you said I think massively underappreciate and I think you know again this is a generalization for sure but I think particularly for men and I'm 53 uh in my sort of demographic I think it is um uh even maybe more underappreciated you know you hear about this epidemic of male loneliness again I'm not at all trying to say that connection isn't a challenge for some women as well but I think for men in particular particular this is an area that we tend to neglect which is hugely important and when I look at my pillars right again I try to practice what I preach eat I've gotten a lot better move I've been pretty good throughout my life I've gotten a lot better sleep fortunately I've never had a problem with connect is the big whopping you know this is where your weakest link is for me and so I'm trying to take steps to fortify that and I think there are lots of ways that um that you can do that and again you know I sort of grouped both your personal connection to the world around you your mindfulness along with human connections and relationships I think I'm weak in both but um but I think you know one of the things that I've started trying to do is to actually focus a lot more effort on not just connecting with other people but um rebuilding and strengthening relationships that I maybe haven't been very good at um keeping up with as I've you know gone through my life and so I totally agree I think it's hugely important I I don't know I don't know how much that um contributes to differences in health Span in different parts of the world certainly the United States culturally is uh less Adept at maintaining and nurturing relationships as we get older compared to other parts of the world I think particularly family relation ships extended family I think you know many people are very good and focus a lot on their nuclear family marriage kids we really don't have the same sort of extended family Connections in general in the United States that you see in other parts of the world and I think that is clearly important for quality of life um and could have a big impact on on differences around the world right and it's really hard for people to um it's it's very easy to eat better and to exercise more well I don't know that I would say that a lot of people struggle with it but I think you know what to do maybe exactly like it's harder to go out and make friends relatively speaking compared to changing your diet and exercising more that's where I was going with that so yeah I I I mean I I I don't know so I I think there are I think it's it it seems harder I think there are lots of things that almost anybody can do like I I agree you can't just walk out the door find some random person and say hey can I be your friend I mean you could you probably wouldn't get the reaction that you're going for but you might you never know it would be an interesting experiment but you certainly can take up new activities with with a group right so like one thing I I still need to do at some point right that I've talked about for years is uh I miss the sort of competitive team sports right that I used to do when I was younger and I've talked forever I I played softball a little bit when I was at the University of Washington I am but I've talked forever about why don't I I should join a softball league right that's the kind of thing you could go join a softball league you could join a hiking club right if and there you're actually ticking off two pillars move and connect right or you know any hobby maybe a hobby you don't have that you might like you know go join a book club or a sketch Club there's all sorts of stuff you can do where you can interact with people um and do something else that also brings you Joy and again I I I feel I feel almost like I shouldn't be talking about this because I I'm trying to figure it out for myself but um but I think you know we sometimes make this seem harder than really needs to be it's it's really about making a commitment and so you know one of the things that I think is a good um way to approach this is is to just take a look at your pillars identify the pillar you're weakest in and then really find one thing what is one thing that I can do to strengthen that pillar and then make a commitment to do it and do it for a month right and see if you can make a new habit I think a lot of this comes down to new habits and um and then re-evaluate and and maybe you find a different pillar that's now the weak link right now once you prioritize one move on to the next and be goal oriented I love that um speaking of one pillar of aging and one mechanistic aspect of Aging we talked in the sauna before we did how do you feel after that by the way I feel awesome yeah yeah amazing yeah your brain is just you're on fire which is great um so we were talking about mtor because if you look at the research on Aging especially when it comes to diabetes and obesity related condition I conditions it seems that mtor is this key pathway that's overexpressed and can cause cells to misbehave and age more rapidly so that's one end of the spectrum on the other end we know that we should preserve strength span or strength as we get older preventing muscle loss in sarcopenia so I think there's a lot of confusion for people when it comes to well these are sort of com competing ideas right on the one hand we want to periodically Express mtor prevent muscle loss on the other hand we know that potentially overexpressing this mechanistic target of rapy could be problematic how do you reconcile this and help people navigate the Waters of protein and resistance training yeah I mean it's really complicated um I think there's a couple things to just sort of level set right so one is uh we know that mtor is this fundamental gatekeeper of growth really what mtor does is it senses the environment around us and helps the cell or the organism based on the environment make a decision should I grow or should I shut down growth and become stress resistant and so what we've learned from studies in laboratory animals is that if you turn down mtor signaling you can slow aging and increase lifespan I I think it's important to say we don't know for sure that the same thing is going to be true in people yet I think it probably is to some extent but we don't actually have that data um but it's also important and I kind of said this to recognize mtor is not an onoff switch think of it more like a dial that you can turn up or turn down it's also uh not necess necessarily turned up or down to the same level in every tissue and organ so you talked about muscle function you're talking specifically about mtor signaling in the muscle um whereas we also have mtor in our brain and it's important for different functions in the brain we have mtor in our liver our kidney our heart so the optimal level of mtor signaling for health and function may be different in different tissues and organs and then the third thing I would say is the idea that mtor becomes hyperactivated with age I would stay say is still a little bit um a little bit unclear uh I would say we can be pretty confident that mtor activity is not optimized for longevity but being optimized for longevity is not necessarily the same as being optimized for function or certainly not the same as being optimized for Reproductive success which is really what evolution is driving a store so all of those are sort of caveats to say that um where I land is that mtor needs to be turned up and turned down in an appropriate way and you can accomplish both of those things by interventions like eating protein or exercise with both of which will turn up mtor at least transiently or turning it down by Ramy I think the question that people get stuck on is if I take Romy or if I eat a low protein diet will it will I be unable to gain muscle or will I lose muscle and will that become detrimental as I get older uh certainly I think I'm pretty confident saying that you can take Romy and not lose muscle I know this because I've experienced it and I know lots of other people who have um if you took enough Romy would you lose muscle probably but again this is about turning the dial as opposed to turning a switch on on or off um what I can't say with any level of certainty is that if you take rap ay say once a week which is what most people are doing and you do resistance training that you're going to gain the same amount of muscle that you would gain if you don't take rap ay you can still gain muscle but you might gain a little bit more if you weren't taking rapidy I just don't think we know there are clinical trials and we can talk about the clinical trials there are clinical trials that are starting to address that question but from my perspective I don't think it really matters because at least for most of us when you get in your 50s 60s it's not about how much muscle can I gain you're not most of us trying to be professional bodybuilders it's about how can I best maintain function as I get older so that when I get in my 70s 80s 90s hopefully hundreds I can do what I want to do or at least do most of what I want to do and so that's where I think you have to really think about this this cost benefit and I I really don't see any evidence in the literature that Romy is detrimental for lean mass if anything in the animal studies it preserves lean mass so mice and rats taking rapamycin are protected against age related sarcopenia but yes it might be that if you're trying to be a competitive powerlifter or bodybuilder you're not going to get quite the same gains you would taking rapy protein I think is a little bit of a different Beast right so and one way to think about this is rapamycin is a very very specific drug it has one biochemical Target and one only that we know of um protein on the other hand is a very very dirty biochemical drug it has thousands of different biological reactions that are impacted by dietary protein so I don't know what the answer is in terms of optimal protein levels my reading of the current sort of state of the the literature for humans is that a higher protein diet in general is better for preserving muscle function and muscle mass as we get older as long as you are ALS so doing resistance training I think a lot of times the confusion around the risks associated with a high protein diet come from studies where they look at people who are eating a typical American diet probably obese probably not exercising regularly I think in that context it's clear that a high protein diet does at least somewhat increase cancer risk and potentially metabolic um risk but in people who are eating a relatively clean diet exercising regularly not overweight I think the bulk of the data support the idea that a higher protein diet is probably better than a low protein diet what does higher mean it's all relative I I I don't I don't know that we have great data on this but I think the the rule of thumb of one gram per pound of body weight towards the upper end but being somewhere near that is probably about right that's what I try to do awesome and when it comes to protein sources are you worried about the saturated fat and cholesterol and red meat versus lean chicken where do you stand with that yeah I so I mean I do think it I do think it it's like anything else I'm not a guy who says don't ever eat red meat I like red meat um I eat red meat periodically but it's I think it's like anything else um uh moderation is important and certainly I I think that the and again I'm going to probably take heat from this from my wife but um I I think the uh negative reputation of red meat has been a bit overblowing um having said that I think if you only eat red meat that's probably not a great strategy for health so if you want to have it once in a while great I eat a lot of uh lot of chicken a lot of fish both are great sources of protein um probably healthier than than red meat but I think kind of similar to the the case that I laid out for high protein I think a lot of the epidemiology on red meat suggesting that that there are um significant uh health risks associated with red meat come from studies where most of the people eating a high amount of red meat were also eating a pretty crappy diet probably overweight probably not exercising regularly so I think con overall context is important when you're trying to look at the impact of one macronutrient or one food type you kind of have to look at the sort of overall health status of that population and it could be very different in different people who are have fundamentally different Lifestyles right really good point going back to the the romise and I think there's a lot of uh interest in this as of late what is the A lot of people are like micro do in this 2 to 6 milligrams like you said once or twice a week um what are the some of the clinical trials looking at now in terms of dosing frequency and then the target population yeah so there are um at least three clinical trials that I think are really interesting right now in this space and and asking very interesting questions um so one is related to muscle function which we already talked about actually there are a couple going on um where the the one that I have sort of uh helped uh just advised on design is a clinical trial out of New Zealand where they're looking at the impact of Ramy in older adults also practicing resistance exercise and so you know it's a small trial that's one thing that's worth saying all of these trials are underpowered for efficacy unfortunately we could talk about that that's a bigger problem in this entire space because the the funding for research around longevity interventions still is pretty small what you see are a lot of underpowered clinical trials where really their safety trials and they're trying to they hope they get a hint of efficacy so that's just important just kind of set people's uh expectations but even still I think there's an opportunity here to to see whether or not rap ay has any negative impact on either strength or muscle mass body composition changes there there will be a clinical trial reporting soon it's the Pearl trial um that looked at body composition with uh people taking rapy and byxa and so that will also be interesting to see how that comes out so that's one area another is around periodontal disease so um my lab at the University of Washington showed that in mice first of all mice as their aging normally develop periodontal disease so they lose bone around the teeth they develop inflammation of the gums G vitis and they show pathogenic remodeling of the oral microbiome just with normal aging and if we give mice uh old mice uh 10 weeks of rapy we can reverse all three of those things okay so now there's a clinical trial by John an who who he was the graduate student who did that work in my lab he's now a professor of oral Health Sciences at the University of Washington he's doing a clinical trial to look at whether or not rapamycin in people with periodon disease can have a positive impact on those those three clinical end points um so that'll be super interesting I think periodontal disease is is underappreciated much like human connection is underappreciated for its role in uh uh total overall health span or oral health in general I should say not just peronal disease underappreciated how big of a role that can have in health and potentially longevity so that'll be interesting to see if rapy has an impact there and then the third area which is which is um very different is looking at reproductive Aging in women and particular premature ovarian inessence so again we know from studies in mice that Romy treatment can delay ovarian syence and at least in some cases partially reverse ovarian inessence so you can actually see a reversal of the atrophy of the ovaries in aged mice so yushin Su and Zev Williams at Columbia University are doing a clinical trial enrolling now um uh to look at whether or not in women with premature ovarian inessence rapamycin treatment can preserve ovarian function and perhaps uh boost fertility in those women that is incredibly fascinating I I'm sure you've seen the videos I mean there's a woman in the UK who was going through what she dubbed menopause but it was just premature ovarian failure at at 18 years old there was another actress or musician I mean in the last year this has really become like a a sensation phenomenon if you will unfortunately um and I think amh levels are dropping and and all these sorts of things so that to me is incredibly uh practical because if you look at fertility rates in both men and women they're declining and it's also I think important to consider like not only what is the connection between ovarian inessence and biological aging which is super important interesting biology uh in fact uh this afternoon I'm going to be interviewing Jennifer Garrison from the buck Institute who's one of the leading people on reproductive Health in in women who does research in this area so I think that's super interesting but also why is it the case that this seems to be happening in more people at an earlier age and what are the environmental or lifestyle factors that are potentially causing earlier ovarian inessence earlier entry into menopause for many women um and related to that it's worth I think just stating explicitly that um I think it's pretty clear that the four pillars we've already talked about influence biological aging and they probably influence onset and progression of menopause in women so lifestyle can play a big role here I certainly wouldn't want to suggest that you know Rapa is going to be the The Cure I think you know for people who are thinking about what can I do in my own life I think it's clear that that a healthy lifestyle can have a big impact not just on your sort of overall biological aging process but if you're a woman on your ovarian aging process I mean it's just amazing to me that these conditions we didn't hear about even 15 10 years ago all of a sudden it seems like in the last several years I mean not only this premature ovarian failure but early onet cancer I mean that was not a term that was in the literature and now in the last few years we're hearing all about that so it seems that something in the environment in the last 15 20 years has significantly changed and you know the the rate of biologic aging which is affecting all these the function of these organs is causing things to just accelerate at a greater level I mean it's yeah I don't know um uh I think you could certainly certainly you can speculate that's the case I'm I'm a little bit more cautious because you always have to wonder like how much of this is more reporting and given you know how how Concepts can go viral without a lot of data on the internet so I I don't know yet in part I haven't done a lot of digging to really try to look carefully at the the rates I certainly know there is a lot of talk of increased cancer rates at least for certain types of cancer in younger people these days I think that's probably real I think it probably is environmentally driven um but I also think that that shouldn't be too surprising in a sense because if you just look at how our environment has impacted Health going back 50 years it's enormous I mean again all you have to do is look at pictures from the 1970s just look at the shapes of people right fundamentally different you did not see obesity or if you did it was extremely extremely rare in the 1970s now I don't know what the statistics are 50 plus% of Americans are obese right that is purely environmental genetics have not changed in 50 years and so it shouldn't be surprising that as our environment continues to change there are going to be impacts on health and I wouldn't want to suggest they're all negative I think there can be some positive impacts on health from environmental changes as well I think the key and what would be great is if we could get ahead of some of these things instead of being reactive like we were with obesity um then maybe we could actually prevent some of the more detrimental effects of these environmental changes yeah I agree 100% uh if we could close the loop on the optimal dosing and I know this is sort of off label as a preventative prophylactic uh for rap amyas where does if there is any research to suggest what a from from a prevention standpoint everyone is working on the four pillars that we talked about fasting exercise connection and all that we didn't talk about fasting well I think it's implied the time shifted feeding I mean what do you think about this research I'm completely unconvinced to be honest with you so here's what I would say I think fasting and Tim restricted uh feeding or eating depending on whether you're a mouse or a human um uh clearly can have benefits if it's in the context of overall caloric consumption I think for a lot of people those are useful strategies for maintaining a healthy body weight and not overeating I think for longevity lifespan the data are almost non-existent that fasting or time-restricted feeding in laboratory animals increases longevity independent of calories so if it's also caloric restriction it will extend lifespan um it's not there's no evidence really that it has an effect on longevity outside of that in people I think it's mixed but people are hard right again trying to really do these studies well in humans is challenging there are certainly biologically plausible mechanisms by which fasting or time-restricted eating could have beneficial effects I think um if done in certainly time-restricted eating if done in a way that matches your circadian rhythm can strengthen circadian rhythms in some people maybe improve Sleep Quality so I think for some individuals but as a pure longevity intervention independent of caloric restriction I just don't think there's any data to back that up it seems like people get really excited about it though on the internet fasting definitely people get excited about it and I think again um I'm not saying that there's no benefits and certainly for some people there are I'm coming from the angle of is it a is it impacting the biology of Aging in a way that will slow aging and impact uh lifespan or health span if it's not also caloric restriction there's no real evidence to support that now you could certainly make the case that if you were let's say fasting I don't know once every 3 days that's pretty extreme but let's say you did that the likelihood that in the two days you're not fasting you're going to make up for that day that you're fasting is pretty low if you did I don't think there's much reason to believe it would be beneficial for you so I think it's more about context right and again I think fasting or time-restricted eating can be a very useful and easy way for some people to also limit their total caloric consumption the last thing I'll say on this though is I think it's a total mistake to think that fasting or time-restricted eating if you don't also pay attention to what you're eating is going to have any big benefits for you I think paying attention to the quality of your diet is probably at least in my view more important than trying things like fasting or time-restricted eating great perspective what do you make of the Latin American and European lifestyle of having dinner at 11:00 p.m. right because you mentioned the Obesity rates here in the US north of 50% in certain parts of the the US um you know you go to like you're going to go to Brazil here in a little bit I was in Latin America you know last year um people start to go out at 10:30 11:00 at night and they eat dinner late and they're not really to my knowledge sleeping into noon you know they're getting up and having breakfast again so for all the talk about compressing your feeding window it seems like there's less obesity the top causes of death are completely different there in terms of heart disease I think is that two or three Alzheimer's is one at least in Colombia I looked at so yeah what do you make of that so again I think it's it's really hard to draw strong conclusions I think you can and in part you also have to look at what is the um sort of distribution of life expectancies right because that's going to have an impact on frequency of different age- related diseases things like that but I would say you know I I think what we can we can probably conclude with some degree of confidence is that these things about like the window that you eat in are not going to be major determinants of population longevity right that and it's going to be the other factors like social connection which is again you could certainly speculate going to be greater in in countries like that or activity level I think also and this is where it's a little bit hard to get really rock solid quantitative data around diet quality my speculation is Diet quality is probably worse in the United States than just about anywhere else in the world how much worse I don't know but it's probably worse and I think diet quality probably is contributing to to all of all of these things sedentary lifestyle in particular though is is probably the big difference I am shocked at how many people in America I mean when we say sedentary I think we probably don't think how sedentary a lot of people really are and I think that has a huge impact yeah I mean we're talking and they don't leave the house everything's being delivered not even getting out of bed or washing themselves yeah wild stuff um what's interesting about Europe in other parts of Latin America the smoking prevalence is yeah much higher so one one thing I I uh I I say sometimes about smoking is I mean they both so smoking and obesity will both shorten lifespan um smoking will kill you fast it has a much lower impact on health span than something like obesity so smoking will kill you fast obesity diabetes will kill you slow they both will negatively impact lifespan yeah so just don't smoke what do you think about vaping a lot of people my my Barbera was telling me how she quits smoking but now she Vapes yeah like I I don't I again I don't have a strong opinion other than it's probably not a great idea is it better than smoking probably but again if your goal is to you know get as close as you can to Optimal quality of life optimal healthspan very likely there are going to be significant negative effects associated with vaping I don't think we know yet exactly how um how big the negative effects are going to be and I think it's probably the case it's not as bad as smoking but you know I um I I totally get that the that that that addiction whether it's behavioral whether it's chemical is real um and and so you know if if people are addicted it's probably a better strategy than smoking but to the extent you can maybe that's the pillar to to work on if that's if that's something you're struggling with yeah what about alcohol where do you sit with that yeah so I mean um personally I've I've dramatically reduced my alcohol consumption in the past three years and I think it's been one of the best things I've done for my health so uh uh mentally uh physically um metabolically uh it's had a huge impact and and I would say you know of the of the the health changes that I sort of have gradually you know gotten more dialed in um that was that was one of the later ones that I made but it's had a huge impact so I think what we know about alcohol is that um it definitely has a negative impact on Sleep Quality I don't think anyone can debate that um the epidemiology is complicated so you can make a reasonably good case from epidemiology that one drink a day uh results in lower all cause mortality so lower risk of death than no drinks a day there are all sorts of confounding factors that could account for that is it the alcohol or is it some other reason I don't think we know but there are lots and lots of studies that show that um I think it's important to appreciate those are like one European drink not one American drink um and it's very hard for a lot of people to stop it at one drink so you know my view is if if you like to have a glass of wine with dinner no problem if you like to go out with friends once in a while and do it in the context of a social sort of environment that can have some some benefits independent of the alcohol I don't think anybody should be drinking alcohol or particularly red wine because they think it's a longevity intervention I think the net risks are are way higher than than potential rewards for most people yeah well I agree with you with regards to alcohol I've I've significantly cut down my alcohol consumption uh and have notice just sleep quality overall energy mental Clarity to be significantly improved and I was one of those people that would r ize consuming red wine to uh say that it's heart healthy or the polyphenol content is good for me or yeah so you probably don't know this but I have a long history with resveratrol so so so Resveratrol of course is the miracle molecule in red wine and and I was um one of the scientists who first debunked that whole longevity piece again not saying there's no benefits to Resveratrol it is not a longevity drug but even then I rationalize drinking red wine so I think there's all sorts of mental tricks we can play with our our El to do do things that we want to do that maybe aren't best for our health but um and you said it's not a longevity supporter all the the research on cin and that from Sinclair's it's it's pretty complicated but I here's what I would say um whether or not Resveratrol can activate cerin in Viva by that I mean in cells in our bodies is unclear um the original report was a test tube artifact so I can't rule out the possibility that some context some specific Target Resveratrol activates cerin but I think the preponderance of evidence and and and certainly an unbiased view would suggest that it probably doesn't to any great extent more than that though um there was a meta analysis published last year I think where they looked at at least as many of the published um longevity experiments with resol across all organisms and asked what was the sort of median effect zero wow zero and that's with a negative publication bias meaning people usually don't publish results that don't work or where there's a negative effect on lifespan so probably if anything in the pre-clinical literature in laboratory animals Resveratrol has zero or a depressing effect on lifespan wow so again there's all sorts of there's all sorts of literature out there suggesting that in certain contexts at very high doses or whatever that Resveratrol may have some positive beneficial effects on a variety of different conditions I I'm not ruling that out but I think again if you want to look at it through the lens of longevity it's very very hard to make a case that Resveratrol um there's any rationale for Resveratrol as a longevity drug now what about spermine that's been really popular of late spermine is pretty interesting so so spermidine you know is a natural component of our diets different people get different amounts of polyamines it's a class of molecule for polyamines um seems to be an autophagy booster that data seem pretty clear at least in cells again the extent to which spermine acts to boost autophagy in tissues and organisms of animals I think the data is a little bit less clear there but it seems to be an autophagy booster in cells I think the lifespan data at least up through invertebrates is pretty convincing and there is some not a huge amount some longevity data in mice and some epidemiology so correlational associations with polyamine intake and longevity in people so I kind of put it in that that class of of sort of second tier longevity interventions that seem interesting there's some smoke there probably some fire you know to what extent just in taking spermine as a supplement not in the context of a normal diet to what extent would that have a positive effect on autophagy or longevity is is unclear at this point but you know it's intriguing and and worth paying attention to for sure are there any other compounds out there that are popular right now I mean it seems like every year there's some new compound that's purportedly some superfood and and so forth uh since R veratrol came on the scene in 2006 anything like that that actually excites you yeah I mean I think there are some things that are that are worth paying attention to right so and again I I kind of put these in two buckets there are Pharmaceuticals right where you would need a prescription or there are natural products that potentially are being sold as supplements you get over the counter um it's harder for me to get excited about a supplement mostly because you rarely if ever get the quality clinical trial data that you will sometimes get with Pharmaceuticals right so I think the the supplements people are excited about that again I might put in that sort of you know second tier group Alpha ketoglutarate interesting um uh did not reproduced the lifespan effect in mice recently that was published by the interventions testing program but I think there's enough Health span data to to still kind of keep it in that that second tier category um uran a is interesting also not yet much human data but a couple of small clinical trials so uran a is thought to be a mitophagy booster so autophagy targeted towards mitochondria probably does other stuff for mitochondrial Health as well um so I think that's pretty interesting to think about NAD precursors are the one that people are really really excited about still um mixed data so uh there's a lot of smoke with the NAD precursors um there's also a lot of really bad science in that space and so it's hard for me to have a ton of confidence at this point my sort of current speculation around NAD precursors is I think that boosting NAD for some people if you have particularly you know a high level of mitochondrial dysfunction or metabolic dysfunction for those people it may be beneficial I I think for the average person is probably not going to move the needle there also may be some specific neurodegenerative diseases like Parkinson's disease where there's some intriguing clinical trial data the other thing to say about NAD precursors again because I know probably a lot of people listening have heard of NAD precursors or maybe taking them yeah so taking NAD won't get into your system orally you can do an NAD drip I don't have an opinion on NAD drips I've never done one but taking it orally won't get into your system you can pay for nicotinoid mononucleotide which technically the people selling it should not be selling it but they still are um and nicotinoid rib as side both of those I think will boost NAD levels in the liver May boost NAD levels and some other tissues and and organs but you could also take nicotinamide or niin and do the same thing and it's pretty pretty clear that much most maybe all of the nmn and NR is broken down by the gut microbiome to nasin or nicotinamide and gets taken up that way and R might also get taken up directly by the gut um I just uh interview Charlie brener who's the person who discovered NR um and he's very much of the opinion that it is bioavailable but most of it is probably being broken down before it gets taken back up and resynthesized into NR and nmn and then if all goes well back to NAD last thing I'll say on this there was a study that just came out actually I'm not sure it's been peer-reviewed yet it's a pre-print um in aged mice where they treated the mice with nmn at doses that had been shown to have positive effects on health and brain and and kidney in that study or sorry brain and and liver not kidney in that study they were actually looking originally at heart function they saw positive effects on heart function in aged mice but then they also looked at the kidney and they saw pathology in the kidney and they make a pretty compelling argument that superphysiological doses of NAD in the liver get metabol ized to to byproducts of NAD and they they listed a few they focused on one called one methyl nicotinamide that the kidney has to clear and in a young kidney that's no problem can handle it just fine in an aged kidney or in a diseased kidney it might actually push things over into the realm of pathology and I don't know if anybody has ever looked at kidney function kidney pathology in the context of aging and NAD precursors I'm not like raising major alarm Bells but I think it's enough it's concerning enough that people should really look at this and get this figured out it could be the case that at least high doses of NAD precursors could cause some problems in at least some people who are prone to kidney dysfunction interesting so those are the ones that I that come immediately to to top of mind um and then on the prescription medication side there's just a couple things to say so there are a few that have come out of the interventions testing program in mice as increasing lifespan um acaros is one that's a anti-diabetic drug that um prevents uh uh breakdown of complex sugars into glucose and so reduces blood glucose by reducing uptake similarly sglt2 Inhibitors canag and in particular increases lifespan in mice that reduces blood glucose sort of at the other end of the Spectrum by preventing re-uptake by the kidney so you pee more of it out um uh and then the other one that that is pretty compelling is um estrogens so both 17 Alpha estradi and estriol have um been been showing to increased lifespan in mice now the reason why I think those in particular are are really interesting um especially the sglt2 Inhibitors and the EST estrogens are in a recent study from UK biobank where the researchers looked at essentially all of the prescriptions that had over I don't know was 500 or a thousand in their data set um and then tried to match them to people of similar health status and look at all cause mortality most prescriptions were associated with higher mortality so increased risk of death that's what you would expect there were 16 I think that were associated with lower all cause mortality like six of those were estrogens which is amazing there's super interesting biology there going back to what we talked about earlier about ovarian failure and menopause really really interesting biology there interestingly in the mice 17 Alpha estradi works better in male mice than in female mice so we could we could spend a whole show on this but I think there's something cool there and then the sglt2 Inhibitors also came out multiple sglt2 Inhibitors came out as being associated with lower all cause mortality when compared to people of similar health status it's mostly going to be probably diabetics who are taking these things interestingly metformin did not come out as having reduced all cause mortality and this kind of fits with you know what some of us have been saying for years which is that the prolongevity evidence for metformin was always pretty weak so the original Mouse study showing lifespan extension from metformin was in a very short-lived strain of mice that all died from a specific type of cancer when it was tested in longer lived strains of mice it either had a tiny tiny effect positive effect on lifespan or had no effect on lifespan and it sort of got a lot of attention for potentially being beneficial for human longevity from a study that initially reported certainly that diabetics taking metformin live longer than diabetics who didn't take Metformin who took other drugs and they they they made a hint that diabetics taking metformin might live longer than non-diabetics not taking metformin if true that's really really compelling turns out that hasn't been reproducible in two subsequent studies so I think the perception of Metformin as a longevity drug has shifted in the last few years not as much enthusiasm there certainly it's a really really solid anti-diabetes drug may have some beneficial effects particularly in diabetics for other age related diseases heart disease dementia some forms of cancer but in non-diabetics I don't think there's a lot of evidence for benefits from metformin at this point and some concerns around um offsetting some of the potential benefits of exercise so again risk reward I personally don't put metform and and the the reward is favoring risk at this point was there enough people on Rapa in that data set no it did not make their cut off for enough people taking it mostly because still it's a pretty rarely prescribed medication mostly in organ transplant patients some rare forms of cancer but not a lot of people on the drug yeah uh going back to urethan and mitophagy um if people are exercising which is arguably one of the best ways would that be a worthwhile supplement or is that kind of I don't know again I don't I don't I don't know of any data I I should be careful because I feel like there might have been one small clinical trial where they looked at muscle function certainly there's some evidence in people of of improved mitochondrial markers they may have looked at muscle function in that trial I can't remember if those people were exercising or not my intuition is that um I mean you're going to get big benefits from exercise particularly if you're not trained right and that if euroian a or NAD precursors or anything else or rapy have positive effect on top of that they're going to be relatively small compared to the benefit you get from just practicing resistance exercise MH and you mentioned the ND precursors to close the loop there so just taking good old nin is probably that's a fraction of the cost I it's like a 10 10 to 50-fold cheaper yeah yeah I mean people have been using that for yeah I mean some people flush on nin so it does have that that side effect but in terms of its ability to boost NAD yes you should be able to get the same effects on NAD from nasin that you get from nicotinate riboside or nicotinate mononucleotide that still leaves the question of is boosting NAD net beneficial for most people which I don't think we know and just for folks that don't understand why would they consider potentially boosting NAD what's the value yeah so there's um some evidence this is this I think is an interesting case much like Resveratrol maybe not quite to the same extent of as Resveratrol where the sort of perception or Dogma in the field got way ahead of the data so there is this sort of perception that NAD levels universally decline with age and that that leads to impaired metabolic function and mitochondrial function because NAD is a co-actor that's required for hundreds if not thousands of metabolic reactions and there is also the sort of uh surrogates of NAD nadp and nadph which are also super important for biosynthesis and all sorts of metabolic reaction so really important molecule but it got popular in the longevity field because cerin which at the time a lot of people thought were potent longevity targets they probably aren't but a lot of people thought they were um because ceru use NAD they consume NAD there was a model that would became popular that that if you could increase Ned levels you could activate cerin and that would be beneficial for Health and Longevity so you had the two sort of of arrows one Ned levels declining with age two boosting NAD activating cerin that suggested that if we could sort of artificially therapeutically increase Ned levels that would have beneficial effects since then we've learned there are other things happening that also deplete NAD like DNA damage or hyperactivation of the immune system so I think it's I think there's good reason to believe that at least in certain tissues or at least in certain contexts like you get exposed to covid-19 you have a severe immune reac ction Ned levels will at least be transiently depleted and that will have an impact on fundamental biology metabolic function so boosting Ned in those contexts probably is a good thing um and so I think there's some reason to to support that but the idea was that if you could turn up n you would slow aging and there were some initial studies that seemed to support that so A study in yeast suggested you could increase lifespan in yeast a study in cagans so it kind of Hit the invertebrate uh Target and then there was a paper published out of Johan A's lab in mice where they started treating mice in middle age and reported a increase in lifespan and improvements in some health span metrics so that result has not been reproducible I'm not saying it's wrong the studies were done a little bit differently but it has not been generally reproducible that you can increase lifespan or I would say even generally increased Health Span in mice from NAD precursors and so at this point I feel like you know there's a body of literature reporting benefits from NAD precursors there's a body of literature reporting no benefits from NAD precursors and there's probably another body of literature that again as we talked about earlier never got published because people don't publish negative results also not showing any benefits in the context they were looking at it from NAD precursors so on the preclinical side it's kind of hard to know where to land um on The Human Side there have been a series of small clinical trials um all of none of which have shown at least to my knowledge any concerning outcomes like you know really bad side effects um also they typically haven't hit their primary end point so they were underpowered but they didn't typically hit their primary end point so I would also put those in the category of maybe so I think we just don't know that's kind of where I'm at with the NAD precursors maybe so not super excited about it you'd focus more on V2 Max or strength or other proxies of Health span yeah well so in terms of what you measure right here here's the way I I think those are two different things I think if you took NAD precursors and you did a study and you showed that you know somebody's body composition went in the right direction or their V2 Max got better you know or their strength got better I'd be like yeah that's a meaningful outcome um if you show that you you take NAD precursors and you raise NAD in your blood I'd be like eh that's what we'd expect does that mean anything I don't know so I think what you measure and what the end points are is is important and I tend to gravitate towards functional outcomes as much as possible because I feel like we don't have a ton of biomarkers we're super confident in at least in the longevity space this might be a good time just to quickly touch on the Aging clocks because I think that's what a lot of people would point to right there are these epigenetic um assay so so they look at uh uh changes on top of the DNA so epigenetics really just means you know changes that control gene expression without modifying your genome so your DNA but they can affect which genes get turned up or turned down and methylation is the one that most people talk about there are a bunch of other types of epigenetic changes but that's the one most people look at and people have developed these signatures of methylation that are correlated with chronological age so these are the chronological age clocks it turns out you can take a blood test and with a pretty high degree of precision based on your epigenome tell how old you are chronologically that's not super useful cuz most of us know how old we are but um but it works and and then kind of the next level is researchers have found you can look at different signatures in the epigenome that are predictive of future health outcomes so future mortality risk 5 years 10 years down the road or future risk of developing age related diseases the hypothesis is that those are monitoring biological age and so that's why you'll hear these things referred to as biological age clocks I think the only thing I'll say about that I'll say two things one is we don't really know that they're measuring biological age I think it's plausible they're measuring part of biological age but there are a bunch of other ways you can measure biological age you can probably do as well with facial Imaging using artificial intelligence as you can with an epigenetic clock in terms of predicting future health outcomes or predicting chronological age so I I think if you have a sufficiently high dimensional data set meaning you have lots and lots of features you can look at and it's for a phenotype that changes characteristically with age you can take a subset of the pieces of that data set or a subset of the dimensions and come up with a signature that will correlate strongly with chronological age you can come up with a different subset that will correlate strongly with health or future health outcomes that's what I think these clocks are measuring so there's two things I would question now about the epigenetic clocks I think they're super powerful research tool TOS I hope we get to a point where either alone or in combination with other biomarkers they can be used as surrogate end points and clinical trials to assess whether an intervention is likely to work without having to do a full longevity study which for obvious reasons is you know not feasible in most clinical trials um I hope we get there we're not there yet I'm I'm I'm not to the point where I think that these things are useful for most consumers even though there are lots and lots of companies selling these epigenetic tests um I I kind of say they for entertainment value only and there's a couple of reasons why I I'm not a big proponent of these tests for consumers one is I like I said I don't think we actually know what they're measuring I don't think we can have a high degree of confidence that they are strongly predictive for future health outcomes these specific tests and we could talk about why I say that or that they're predictive for whether or not an intervention whether it's lifestyle or a drug or a supplement is working at this point that's one reason the other reason is I think there is a um unfortunate lack of transparency around a lot of these companies offering these tests we really have no idea what the accuracy or Precision of these tools are it's probably different for different companies we have no idea what their quality control looks like there's just no regulation in this space and so you kind of have to trust that these companies are doing it right and I don't see a lot of reason to to believe that I'm not saying that they aren't I just don't know and so those two things combined make me very wary of you know how much this has been sort of popularized in and at least the you know the biohacker community and and to some extent beyond that um so last thing I'll say is I'm a little bit wondering to what extent these tests are predictive of future health outcomes today and the reason I say that is because the way these tests have been developed is they looked at bank samples from 10 years 20 years ago so these long-term longitude studies like en Hanes or Baltimore longitudinal study of Aging have biobanked samples from people and they have enough people now who have gone on in the last 10 or 20 years to develop heart disease or cancer or die that you can make correlations by looking at their samples from 20 years ago as to to which signatures are associated with these Health outcomes today as we sort of alluded to earlier the environment is fundamentally different today than it was 20 years ago and so whether or not the same signatures are going to predict future health outcomes 10 years 20 years from now as those that did 20 years ago I think is an open question they probably do to some extent but my guess is that the accuracy is going to be less just because the the human environment is different now than it was 20 years ago so I think we'll have to wait and see super interesting the one that I recently did was based upon the dunaden pace of Aging inflation profile right I know that that Horvath has one LaVine has one and all that but I think that that particular study is quite interesting that 40-year but they also talk about in those data sets the facial age Imaging facial Imaging right do you use that in your clinical practice we don't um we we don't so we we don't use the facial Imaging we do do three different biological age tests from blood so we look at the epigenome so and and it's worth saying so you talked about the denen pace so I should explain that briefly so that is also an epigenetic signature it's different than the sort of Horvath or LaVine clocks in that that signature is thought to predict the rate of Aging that's why it's called pace of Aging right so these epigenetic biological age signatures were first correlated to biological age right and the idea is that your biological age can be different than your chronological age the denan pace is correlated at least in theory to the rate at which your biological age is changing and so it should be the case that that particular signature is more responsive to fluctuations in the rate of Aging interventions and can you move that in the right direction or not and that's how a lot of people are interpreting it um so I do think I do think those kinds of those kinds of signatures um if they work as well as advertised are really powerful because then you can actually use those as surrogate end points for assessing whether or not an intervention is working so to speak for longevity um so uh so that's the that's the the denan pace and again there's no reason why you couldn't create a similar pace of Aging metric using other types of data um it's just a matter of having the right data set to do that okay so what we do at optisan right now is we are looking at three different aspects of biological age epigenetics uh blood glycans which is another sort of a protein measure in blood that changes with age and uh a a non-commercial test that looks at immune resilience and immune aging so it looks at um syence of immune cells t- Cell Activation inhibition and autophagy inhibition um we're using all of those as really sort of exploratory though we don't think that any one of those or even all three of them combined are necessarily more informative or even as informative as the other types of data that we collect so it's really more about getting a an overall picture of each individual from multiple different angles and then trying to synthesize that data um I think over time we're also evaluating them so I think over time we expect that we will be able to start to make some at least for our own purposes conclusions about which tests are useful maybe which aren't as useful amazing personally I really like the immune test I think I like it because the the biochemical marks the are being measured are clearly important for immune function and we know that immune function and immune resilience is really really important as we get older and so it's it's a combination of in my view both a molecular test and an immune functional test and so that that will triangulate degree of ccent cell accumulation amongst other thing as well as immune exhaustion is what we're looking at so it's not a that that test is not a perfect measure of immune scence because we're really only looking at one protein marker of sence p16 but that's kind of the canonical protein marker of syence so we would expect it's at least strongly correlated with total immune syence now it's important to note that you know immune syence in a snapshot in time is really telling you only about the ccent burden at that moment in time and that can change over time it can change if you've recently had a severe covid-19 infection for example so it's in and of itself s only one metric that gives you one piece of information but in general if you look across the population that marker goes up with age and you can create you know predictions of immune Age based on p16 and other markers in the immune system going back to the co infection um that would increase the preponderance of ccent cells within your immon system or the other way um so I think I have to be I have to be careful here I so so here's here's what I would say I think it probably depends on when you look right so anytime your immune system is strongly challenged you're going to go through you know a series of um sort of reactions to that challenge which is going to include sort of massive expansion of the uh immune system to Target that pathogen or that challenge and react to it if it's in the case of something like a severe covid-19 infection what will often happen is you will have a prolonged inflammatory hyperinflammatory respon response right that's the cyto kind storm which is counterproductive to say the least um I don't know for sure but I would be surprised if you don't see a much higher burden of ccent cells in the immune system in that sort of an situation but assuming everything resolves itself you're going to go back to a steady state level and presumably you're going to achieve something close to if not close to your Baseline level of of immune syence I think there are a variety of factors that can influence levels of p16 in this assay um and infection state is only one what we're really trying to get at is is less the sort of acute infection response and more the sort of Baseline over time for an individual how is that changing and then how would you characterize inessence or describe this to a high school biology student what would you say and why should people care about preventing accumulation of these cells yeah so so maybe one place to start is there are a variety of paths that cells in our body can go down when they stop doing their job okay so all of our cells in our body have a job to do but sometimes they stop working the way they're supposed to so One path is apotosis which is just cell death right so the cells die they go away that might seem like it's a problem but it's really not because our stem cells can replenish and regenerate so you can have cells die or you can have cells that refuse to die they just stop doing their job those are ccent cells um and we know that ccent cells are important in a few specific cases so there are cases of program sence like during early fetal development where we need these cells to kind of stick around they give off signals that are important for continued development senescent cells also seem to be important in wound healing for the same reason so right around the site of a wound you will have these cells that stop doing their job and what I mean by that really is they stop dividing they stop functioning metabolically like they normally would they go into this non-dividing arrested State and then they start to give off signals mostly inflammatory signals okay but as we get older we also have ccent cells accumulate and Cellular sence in the context of Aging in particular is really important because it's a potent anti-cancer mechanism because the other thing that can happen the other path cells can go down is they become cancer nobody wants that so dying is probably best in most cases becoming senescent is better than becoming cancer and so um as we get older our bodies accumulate these cells that just kind of hang out our immune system is pretty good at clearing them when we're young but the immune system gets less able to clear the senescent cells as we get older so it wouldn't be a problem if they just hung out but they don't just hang out they kind of they're kind of like rabble rousers so they they're like they're like guys who on the work side who stop working but then they're off getting other people to stop working and start goofing off right so they give off all these chronic inflam fatory signals which then have an impact on the cells around them can promote tumorogenesis in surrounding cells or can promote other cells throughout the body to become senescent or can lead to high-grade chronic inflammation which is what many of us experience as we get older so the thought is if we could get rid of the ccent cells that would be a good thing because we don't want them around the immune system doesn't when we're young but it's not able to do it as we get older and so people have tried to develop these drugs called senolytics or other strategies to kill specifically ccent cells so that's the concept behind this idea of senolytics you have a drug it's going to specifically target senescent cells kill ccent cells not do anything to the surrounding cells in theory that would be great in reality no drug is that clean and I'd say the current crop of ccent cells are mixed at best so they they do kill some fraction of ccent cells they also do bad things to cells that aren't ccent and so people are really trying to work on better and better second generation third generation senolytics at this point um what we know is that if you treat mice with sentics you can increase lifespan you can improve multiple measures of healthspan there are some early indications from again underpowered clinical trials in people that you can get some benefits I think um idiopathic pulmonary fibrosis is a place where a lot of attention has gone there seem to be a lot of ccent cells there so that's one place people are looking um some eye disorders as well uh there's a lot of sence and so people are trying to think about where can we go what disease conditions can we look at where there's a high burden of ccent cells to try to demonstrate some clinical efficacy but my sort of read is that the current crop of senolytics isn't quite there yet um but in theory if you could develop very specific analytics almost certainly there would be some clinical benefit it's also probably worth noting that Ramy is not a true senolytic it is an indirect senolytic in the sense that it can actually aged animals boost the immune system and the immune system's ability to clear ccent cells it it is also called what's called a xenomorphic meaning it is pretty good at turning down the bad signals that senescent cells are giving off so if you look at these inflammatory cyto kindes that ccent cells secrete if you treat ccent cells with rapamycin or if you give mice old mice rapamycin you see that it is pretty potent at turning that down so it does seem to be some overlap between rapy and senolytics in terms of mechanism of action amazing and outside of rapy what other cocktails are you excited about there's cortin datinb there's all these different things is there anything that has more or less efficacy from what you've read yeah I mean um I would say dasatinib plus quarin is probably the one that has the most evidence supporting it at this point in terms of small molecules there are genetic constructs in mice where the mice are engineered in a way that if you feed them a certain drug the senescent cells will commit suicide that works really well in mice that's not relevant for people but I think right now dnq is probably the one where there's the most data there are a bunch of other molecules that people will say have senolytic activity most of those it's it's pretty unclear at the doses that could be achieved by just supplementing with those molecules if they really have any potent cenotic activity or not and what about exercise yeah so exercise is interesting I don't know that exercise itself has a direct senolytic activity I think it's very likely and there's good evidence to support the idea that that regular exercise can have an immune protecting immune boosting effect so you might expect an indirect benefit from exercise in terms of allowing the immune system to be better able to clear senescent cells and that's going to be true for cancer surveillance as well I think this is again something that maybe isn't as well appreciated as it should be um our immune system is probably our most potent anti-an can mechanism directly right we are constantly developing early stage cancers that get cleared by our immune system as a consequence of chronic inflammation that leads to an inability of the immune system to respond to normal pathogens or cancer surveillance so we we see a decline in cancer surveillance we see a decline in senescent cell surveillance that decline in ccent cell surveillance creates this this vicious cycle where there's now more inflammation which is further causing decline so I think things like exercise this is a place where you could make a case for fasting right where fasting um because of its anti-inflammatory effects may have a beneficial effect on immune function and senescent cell clearance things like that again if you were to make up for fasting by overeating you might offset those benefits but it's plausible that fasting could have some benefits through that mechanism interesting so exercise by way of immune enhancement could lead to the favorable changes and getting purging the cells it's not directly cytic again there may be there may be cases where it's directly cytic but I think that it's more plausible just from a mechanistic perspective to speculate about effects on immune system and then senescent cell clearance again it's also probably worth saying I think the way people measure sence is tricky and I still don't know that there is full consensus in the field about how you would actually measure even in a mouse like what is the senent cell burden what is the gold standard way to do that there are a whole bunch of markers that people use so you could probably find a paper that says that exercise is senolytic you'd really have to look at what they measured and did they actually measure senescent cells and how believable is it this is a challenge in general though with the sence field that because there isn't consensus in what people measure oftentimes people will default to the lowest common denominator make claims about analytics but when you actually look at the data it's like eh that probably isn't really a cytic it seems that obesity and the adipocytes themselves are particularly problematic would you agree with that yeah I mean again I think the the preponderance of evidence at this point is that accumulation of senescent cells in uh fat particular visceral atap POS is driving a lot of chronic inflammation age related inflammation that has a big impact on metabolic dysfunction again it's sort of this vicious cycle right you get metabolic dysfunction you get less immune function you get less clearance of ccent cells but yeah I mean I think that that is that is pretty clear that at least um right now probably if you had to pick one tissue that you could clear ccent cells in uh uh fat would be the place that you would start yeah and speaking of another tissue to go I want to go back to rap amiin in the dosing we talked about ovarian sence yeah now people know what sence is and why that could be problematic in the context of the ovaries particularly if one wants to have children but we wanted to kind of close a loop on the dosing of rapin because I think again Allen Green has been recommending I think you mentioned 6 milligrams you know once a week yeah um morning night body weight dependent where do where are people Landing with that yeah so I can tell you what most people are doing I unfortunately can't tell you what's optimal because we just don't know we just don't have the data so from the like double blind randomized Placebo control clinic iCal trials let's start with the gold standard data we know from studies that Joan manik did you know several years ago now with everus which is a derivative of Romy that once weekly dosing around the 5 milligrams per week dose gave positive effects on boosting flu vaccine response in the Aged immune system and had side effects that were really no different than Placebo so most people have gravitated towards that once-weekly dosing around the 6 milligrams per week for off label use of Romy there are some speculative but plausible biochemical reasons why once weekly dosing could make sense um the one most people will point to is that and this gets in the weeds just a little bit but I won't go too far in the weeds um there are two complexes that mtor acts in mtor complex one or M torque one and mtor complex 2 mtor 2 mtor complex one is the rap a sensitive complex so biochemically Romy is a specific inhibitor of mtor complex one if you have chronic inhibition of mtor complex one you will get of Target effects on mtor complex 2 the idea I I was going to say I don't want to say how I'm not completely convinced this is the case but some people are the model that's been put out there is that the positive effects of rapy for longevity and health are predominant if not exclusively due to inhibition of mtor complex one and the side effects are predominantly if not exclusively due to mtor complex 2 the reason why I'm going down this tangent is that Weekly dosing because you don't ever get that chronic inhibition of MTAR complex one probably doesn't lead to the of Target effects on mtor complex 2 so it's probably a more specific mtor complex one inhibitor in that sort of context and so that's one biochemical rationale for this this weekly dosing and that does sort of fit the side effect data I talked about from Joan So most people are doing 6 milligrams once a week but there's a big variation so some people are doing like 1 milligram once a week some people are doing 20 milligrams once a week we don't have any data on efficacy one way or the other again my intuition is that one milligram once a week is probably too low to have any real potent anti-inflammatory effects and again if we look at Jones St which is really the only data I'm aware of to to go on at this point 20 milligrams once a week may not be past the the optimum for efficacy but it's probably getting to the point where you start to uncover more side effects so intuitively somewhere around 6 to 10 milligrams once a week I think is a reasonable place and again that's where most people are landing and and what were you dabbling with when you were you would you do a cycle periodically your an a told a story about your frozen shoulder is pretty impressive yeah so that was at 6 milligrams once a week I've I've gone between six and 10 um I did try 20 once just to see so so to be honest with you I've noticed no differences between six and 10 um uh or even at 20 so no acute uh effects that I would ascribe to dose differences um I do think and again we don't have a lot of data but it it it seems certainly reasonable that um certainly there will be different tissue of it bioavailability no question we know that for Romy um and so at different doses you're going to get different degrees of mtor inhibition in different tissues and so if you're and again this is very speculative because we don't know for certain that mtor is going to prevent Dementia or rap ayon is going to prevent dementia but in mice it does okay so if your goal is you're taking rap ay because you say have two apoe4 alal you're at high risk of dementia you might want to take a dose with the rationale that that rapamycin doesn't get across the blood brain bar barrier very efficiently you want to get higher brain penetration that's reasonable um so I think I think it depends on the context and and what the what the hope for outcome is you can sort of be guided in terms of dosing there the other thing that this is probably just worth saying is because rapamycin is um metabolized by the cytochrome p450 system it is inhibited by grapefruit FR juice so some people will take grapefruit juice with their rap ay and you do get about I think it's like three to sixfold higher Peak levels in the blood from from rapamycin dosing so in real time you do both concommitantly grape grap food juice with rapamycin right interesting right and so you you mentioned the apil we4 I mean I don't some people do some people do sure that makes sense um the genotype having one or two Al of the ae4 would that be the best clinical use case for a prophylactic regime do you think those people are most likely to experience the greatest benefit it's a good question um I don't know if it's the best use case it's a it's a reasonable use case right again I I and this is this is purely my observation right I'm I I I don't have any quantitative data to back it up I it is my perception among all the people who I've talked to who who've used rap and M I've talked to a lot of people who've used rap and M off label there are a subset of people that feel nothing or they get mouth sores some people will get mouth sores that's about the only real side effect that I've I've picked up on um some people will feel nothing I'd say that's most people maybe two-thirds they just don't you know maybe maybe not uh a lot of them keep taking it but they don't really notice anything obvious and then there's a set of people where they're like oh my God I feel so much better and I think those are the people who have very high levels of chronic inflammation so like my case with my frozen shoulder right it was a nightmare I couldn't sleep I couldn't throw a ball with my kid 10 weeks later I was back to normal right so I think the people who have that sort of experience are the people who have very high levels of chronic inflammation and it's influencing a whole bunch it's influencing how they feel right um and so I think there are use cases like that where it's an acute condition like with my frozen shoulder again I wish somebody had done a trial by now right to to actually demonstrate to what it how many people who have frozen shoulder a lot of people do how frequently does it actually have a positive benefit right but for people like that clearly there's a huge Improvement in quality life that's a use case we don't know yet about periodontal disease body composition ovarian failure right we'll wait and see how the data plays out those could all be very reasonable use cases as well and then there are a bunch of people who have clinical autoimmunity right and those are those are the places where there are case reports in the literature for different autoimmune conditions where Ramy seems to be effective um that again makes sense in to some extent chronic inflammation with age is an is an autoimmune disorder aging to some extent is a low-grade autoimmune disorder for many people yeah even obesity I mean it meets four of the five defining criteria of autoimmunity which is really interesting so you know I think people we love to talk about body fat and mental performance but I I think a big theme that you've highlighted here especially when it comes to syence is the health of your immune system really dictates how you will age I mean that's absolutely right so and I do want to say I mean we you know I anytime in I'm in a conversation we tend to go down the rap ayon Trail which is great I love talking about Rapa but you know you can have positive impacts as we've already alluded to on chronic inflammation through diet right through exercise through cutting out alcohol right all of those things are probably more potent than rapamycin or at least equally potent I mean rapamycin again is a very specific drug with one biochemical Target those other interventions are non-specific and they do a lot but they're also potently anti-inflammatory and so I certainly wouldn't want to suggest that people should take rap a and not worry about nutrition or exercise or sleep you know I think for some people it can be a potentially valuable addition to those pillars agree 100% was there any concomittant roll out of the covid-19 vaccines with rapidin that you knew of no and this is sort of a this is sort of a sad story so Joan was um Chief science officer at a company called restore bio uh in in 2019 and they were moving forward so they'd gotten the rights to the mtor Inhibitors from novaris so they were moving forward based on Jan's earlier work with uh phase three clinical trial with an mtor inhibitor was called rtb 101 not a rapamycin derivative we can come back to that in a minute where they were actually testing whether or not rtb 101 this mtor inhibitor could boost flu vaccine response in healthy older people they were doing this in two phases one in the southern hemisphere one in the northern hemisphere because the flu seasons are opposite they'd gotten halfway through um I remember this timing because I was with Joan at the gerontological Society of America meeting which is always in November it's November 2019 gotten halfway through the clinical trial and they did an interim analysis and we're not hitting their end point okay so the end point here is important um we'll come back to that they weren't hitting their endpoint so the board of directors decided to shut the trial down in November 2019 um of course we all know what happened in March April 2020 right Joan went back and did a post talk analysis on the data from that study and it turns out the people who got rtb 101 or looking at the prior studies the people who' got in the Rapa derivative were protected against at least three different fireal viral families I don't remember I don't remember what one of them was one of them was influenza pretty big deal the other one was Corona virus of course it wasn't covid-19 because nobody knew about covid-19 in 2019 when these patients were dosed so I think this is an very unfortunate situation where because of the endpoint which again I'll come back to and because the board of directors you know basically chickened out they cut the trial off too soon if they'd known what was coming I I suspect they might have made a different decision and boy wouldn't it have been nice if we had a drug that older people could take in 20120 to uh to prevent or reduce the severity of covid-19 infection okay I know it's a little bit in the weeds but the end point here is it's important to appreciate why clinical trials fail clinical trials can fail for all sorts of reasons you have to make all sorts of decisions when you're designing a clinical trial some of them are based on science some of them are based on pragmatism how much money do you have um what's your end point so in the first two clinical trials where everus or everus plus rtb 101 this other mtor inhibitor um boosted vaccine response the Endo was clinically validated infections so in other words a test a PCR test for the virus for reasons I don't I don't really understand FDA going into the phase three made them change the endpoint to Patient reported infections which makes no sense from a scientific perspective and people think they're sick all the time when they're not sick or vice versa but that was what the endpoint was and that was the end point they were failing to hit when they got halfway through the clinical trial so I think it was just a combination of of unfortunate timing unfortunate you know luck in the way that the trial was designed I also did say rtb 101 is not a rap ayon derivative they took the rap ayon derivative out of that trial again for reasons that you'll get a different answer depending on who you ask I speculate at least part of it was based on IP they had a longer patent life on the the the rtb 101 um which works by a different mechanism so it still inhibits mtor but it also has offt Target effects and it works by a different mechanism so might it have hit the end point if they had the rap ayon derivative in there we'll never know because because that trial wasn't done but it had in Prior trials maybe suggesting that the whole is greater than the sum of the parts like there's something unique about a rra ofite or sorry yeah ramyon right derivative the yeast isn't it or so so so Rapa Ramy um maybe it's worth just briefly talking about the the way ramyon works so Romy inhibits mtor but it does it through what's called an alisic mechanism meaning it doesn't directly bind to the active site of mtor active site is where the the enzyme does its job that's where the action happens right so rapy binds another protein called fkbp12 that complex then goes and breaks up mtor comp complex one so it's an alisic indirect inhibitor of mtor there are another class of drugs that are called ATP competitive Inhibitors that bind the active site they look something like ATP which gets into the active site and so they get into the active site and basically inhibit the enzyme that way so it's a fundamentally different mechanism of action the thing about the ATP competitive Inhibitors is they also tend to hit other proteins in the same family other kinases because many kinases have a similar structure to their active site and so rtb 101 is a class of drugs called a dual kinas inhibitor because it also hits pi3 kinases which have all sorts of you know implications in cancer and growth so it could be that it's because rtb 101 is a little bit less specific it could be that there's something about the mechanism of action and the way it inhibits mtor complex one and not mtor complex 2 that's certainly different about Romy so I don't I just think we don't know but they do seem to be um potentially different in the effect they have on the Aged immune system and yeah in the phase 2 clinical trial where they combined both ever alus which is the rapy derivative and rtb 101 they did see better effects than than ever alus alone interesting stuff we could go all day with all these different topics Matt really appreciate you coming on the show if folks want to connect with your podcast and your work how do they do so yeah so our podcast is called the op topan podcast where on YouTube and apple and Spotify and um pretty easy to find me uh my handle on X is at mcine and I hope people tune in amazing thank you for coming on yeah thanks a lot