Is Aging Solvable? | Matt Kaeberlein

okay our first speaker is at the Forefront of a really exciting area in medicine called Aging which will apply to all of us sooner or later he has been at the Forefront for a long time he focuses on understanding the biological mechanisms of Aging for health span Improvement there are a number of our entrepreneurs in the audience that are working on Aging so I think you'll get a kick out of this as well he's published over 250 papers on Aging biology and is currently the chief scientific officer at optuspend geroscience so please Welcome Matt caberline [Applause] um so it's uh uh I don't know how I should feel about being introduced to being at the Forefront of Aging for a long time because another interpretation could just be that I'm old um which is ironic considering a study aging so it's uh it's a pleasure to be here um and uh one of the the interesting things about having been in this field for a long time um is that you know 10 years ago if I'd given this talk probably almost nobody in the audience would have heard of Aging or longevity and now I'm guessing many of you have heard of Aging or longevity and depending on where you get your information and the podcast that you listen to I would guess about half of what you've heard is probably accurate so um what I want to do today is give you sort of an introduction to the field some of the questions that I think are important I've been asked to touch on several topics so I'm going to go a little bit fast through the introduction but the slides are available if anybody wants to get them afterwards go to optusband.life coastla2023 you're welcome to use them in any way that you would like um so I want to start by taking a step back and really just talking about the way that we think about health and and I would certainly suggest that what we call modern medicine I would actually say it's 20th century medicine really has approached Health from the perspective of disease so you may hear me use this phrase reactive disease care a few times today there's no question that we have approached medicine from the perspective of individual diseases in silos this is true in healthcare it's true in biomedical research it's true in drug development and um one of the consequences of siloing diseases individually is that we typically wait until people are sick with one or more diseases and then we optimally try to cure those diseases but in reality what we end up doing is treating the symptoms most of the time and so again you'll probably hear me say this a couple more times we have been very successful at keeping sick people alive we have been less successful at keeping people healthy and this I think is the fundamental challenge that we face but also opportunities as we go forward one of the consequences of focusing on diseases in isolation is that we lose track of the site that all of these functional declines and diseases that are the major causes of death and disability in developed countries share at their root a single greatest risk factor and I would argue a single greatest causal risk factor and that is the biological aging process and it's not even close so just to give you a feel your risk of developing heart disease goes up about two to threefold if you have high blood pressure and that's true for other risk factors that are commonly talked about your risk of developing heart disease from four Decades of biological aging is 40-fold your risk of developing Alzheimer's disease over that same time period goes up 300 volts so we're talking orders of magnitude difference in risk and one of the implications of this idea that it's biological aging that underlies all of these diseases is that if we can understand that biology we can actually start to manipulate it in a way that may slow the onset and progression of many maybe all of these functional declines and diseases simultaneously so this is the promise of What I Call 21st century medicine if any of you listen to Peter ortia's podcast he calls medicine 3.0 the idea here is that we are on the cusp I think of having an opportunity to shift Health Care away from reactive disease care more towards keeping people healthier longer and in part that will be through targeting the biology of Aging so that's kind of the big picture that I'm going to present you with today you can ask the question you know what would the impact be again from these two very different approaches reactive disease care is about curing disease in sick people if we could be successful at curing individual age-related diseases you can ask the question at the population level what would the impact be on life expectancy and people have done that this is work from J.L shansky originally simply asking the question if we could cure heart disease or cancer what would the impact be on life expectancy for a typical 50 year old woman it turns out it's about three years for each of those diseases even if you could cure both I'm talking about all forms of Cancer all forms of heart disease it's about seven years and the reason for that when you actually think about it is pretty obvious it's because if you only take one disease at a time out you still have all those other diseases of Aging increasing exponentially and if cancer and heart disease don't get you one of the others will now we can ask the question what would the impact be of slowing aging and admittedly this is a hypothetical at this point I can't tell you that we can do this in humans what I can tell you is we can do this pretty routinely in laboratory animals including small mammals like mice and rats so if we could slow aging by 30 percent which again is pretty routine in laboratory animals what would the impact be on life expectancy for that same 50 year old woman it turns out it's much bigger it's about two to three decades with the added value that those extra years are predicted to be spent in good health free from chronic disease and disability so this leads to the concept of Health span which I think is really important and so I'm not going to define a bunch of terms but I want to I want to give you three terms that I think are important to appreciate life span's easy right birth till death e easy to measure no ambiguity about what lifespan is Health spans a little bit more of a squishy term we don't have a consensus definition for health span and the reason why I'm I'm explicitly saying that is you will hear people talk about we've extended Health span and I get a little bit uncomfortable with claims about extending Health span because it's hard to statistically say you've done something that you can't really measure quantitatively but I think Health span's a really useful concept and I think one way to define healthspan is the period of high functioning life and again recognized health is not binary it's not like you go from being healthy one second to unhealthy the next second okay but I think this is a useful concept and one way to define high functioning would be the absence of chronic disease and disability so so the goal really here is more about pushing the diseases of Aging back as far as possible and maximizing Health span than it is primarily about extending lifespan although the reality is when you target the biology of age you do both and again I'm explicitly calling this out because I want to differentiate from reactive disease care 20th century medicine I think we've been not not too bad at extending life expectancy what we've actually been quite successful at is keeping sick people alive longer we haven't been so good at extending Health span and that's a really important thing to to understand and then I just want to to define the word geroscience for you because I think this will start to permeate the collective Consciousness a bit more that's just referring to the biology that connects aging to functional Decline and disease and again if we can understand that biology we can do something about it okay so I was asked the question is aging solvable and my answer is we're starting to right we've made a lot of progress at solving the biology of aging and there are lots of ways to appreciate that one way to appreciate that is through the lens of the Hallmarks of Aging which again some of you may have heard of this is based on a review paper that's now about a decade old where the authors attempted to kind of synthesize the the consensus factors mechanisms that drive biological aging across the animal kingdom and they came up with Nyan Hallmarks there have been this has been updated depending on who you asked there may be 11 or 12 Hallmarks of Aging today it doesn't really matter what they are for the purposes of this talk what I want you to understand is we understand a lot now about some of the fundamental mechanisms of biological aging that seem to be shared across all animals including humans one of the important implications of that is that each of these Hallmarks potentially even in isolation and can be targeted therapeutically to have a positive impact on the biology of Aging the other point I want to make about the Hallmarks though is that they're not acting independently there is a network underneath these Hallmarks that connects them and that's what the whoops I went forward that's what the the arrows uh in the middle there are meant to illustrate so we don't know everything about that Network at this point okay we're still learning the details of that really complicated system we know some of the nodes in that Network that seem to be useful for targeting the biology of aging and I'm going to talk about one of those in a minute the other point I want to make though is that what we really don't know in the field and you won't hear too many people in the field talk about this what we really don't know is what we don't know and I don't know how much of the biology of Aging we actually understand today but my intuition is it's a lot less than many of the optimistic more optimistic people in the field believe that we know I would guess that our understanding of the biology of Aging is somewhere akin to the understanding of the Known World in 500 BC and so this is a map of the Known World in 500 BC on the right you'll see there's sort of this nebulous shaped Europe which kind of looks like the shape of Europe there's a shape of Asia that looks nothing like Asia and then there's very big Libya and then there's the ocean around it and if you sail too far you're going to fall off the edge of the Earth okay that's my speculation is that there's a lot more we don't know than we do know and the reason why I'm saying this is because I worry a little bit that one of the limitations in the field right now is that the field has become somewhat narrowly focused on what we think we know it's actually become a little bit difficult to study things that are outside of the Hallmarks of Aging because of this construct and I worry a little bit that this is slowing down progress by focusing so much on the little bit that we do know and not very much on what we don't know I would argue that most of the field is looking under the lamp post right now not looking at what we don't understand we're focused on the Hallmarks and you'll see a lot of people also focused on clocks and I'm going to use I'm going to use the word biomarkers maybe more than aging clocks but that's something a lot of people are excited about now and I'm I'm enthusiastic about clocks as well but the clocks can only measure what you know they can't measure what you don't know and again I'm a little bit worried about what we don't know I would also simply note that um while there's been a ton of progress in understanding the biology of Aging there hasn't been as much progress in sort of game-changing new interventions to Target the biology of Aging with large effect size and I think this is an important concept again to appreciate so you'll hear people talk a lot about caloric restriction that's the most effective intervention for slowing aging and increasing lifespan in laboratory animals up to about 60 percent in mice with about a 60 reduction in caloric restriction that's the biggest effect that experiment was done in the 19 80s we've known about caloric restriction as a longevity intervention since the 1930s okay the most effective drug for increasing lifespan and health Span in laboratory animals is rapamycin I'm going to talk about rapamycin in a minute that was first discovered in 2006 in yeast and first shown to extend lifespan in mice in 2009 so I think it's a legitimate question to ask why hasn't the field done better than rapamycin in the last 15 years and I would argue in large part it's because nobody's really looking so I'm personally very interested in finding interventions of large effect size that can really move the needle and I would like to see more people really focused on outside the lamp post rather than looking under the Lamppost and so one of the ways that I'm approaching that is with some technology that we developed in my laboratory we've spun out a company called Aura biomedical really with the goal of trying to to explore the unexplored and we are proposing a 1 million molecule challenge to try to test one million interventions for their effect on lifespan in commonly used laboratory animals and I can guarantee you we're going to find things that are better than rapamycin we're going to find a lot of things that are better than rapamycin and I'm pretty excited to see what those things are okay so what do we know um we know aging biology is real okay we we understand some aspects of Aging biology uh we know it's modifiable so again there are multiple ways in the laboratory we can tweak that biology to increase lifespan and improve several metrics of Health span okay in laboratory animals um we also know it's more effective than targeting individual diseases and I already took you through the math there we know some Keynotes in that Network and among those nodes I think some of them have pretty significant therapeutic value okay and I think that we're likely to be able to have an impact on health Span in people by targeting some of those nodes and I'm going to in a minute do a little bit of a deeper dive on one of them which is called mtor for the mechanistic target of rapamycin and a drug rapamycin which has been shown again in laboratory animals and we're starting to get some hints in people to have positive effects on health span but I was asked to comment on where the hype is ahead of the reality in the field and um that's both a a pretty easy question to answer and a difficult one because I think you can point to a lot of different things in the field where the hype is ahead of reality which is true in many fields um the three that I've chosen to call out specifically here are by no means an extensive list but I think there's some of the ideas that lots of people are thinking about right now and probably many of you in the audience have have thought about as well or heard about I think um oh and also mentioned Rich Miller who's at the University of Michigan and myself just earlier this week did a webinar for genetic engineering and biotechnology news on this topic uh separating the science from the snake oil it's available online if anybody's interested where we do a little bit of a deeper dive on some of these so supplements probably a lot of you maybe not a lot some of you are taking supplements that you've heard about that may affect aging anti-aging supplements longevity supplements um it's really hard to know which of these supplements have value so what I would say is I don't personally have a lot of faith in most of the over-the-counter supplements that are being marketed for their potential effects on the biology of Aging some of them are pure snake oil some of them have some science to support them what I would say though is I don't think any of the natural product supplements that are out there now are really going to move the needle as much as people are hoping certainly I would not suggest that any of them are going to make up for a poor lifestyle for example so while I'm not saying you shouldn't take any of these supplements what I'm saying is I don't think they're going to really have a big effect we'll talk about risk reward in a little bit and I think you could make a rational argument that the potential reward outweighs the risk for taking some of these supplements but it's really hard to point to any of them with a lot of confidence and say yep that's that's what you should be taking that's really going to move the needle the other question that I'll pose is we don't really understand combinatorial interactions for a lot of these supplements or longevity interventions in general okay and that's an area of weakness I think in the field we can say one drug by itself may have a positive effect but we don't really know a lot about what happens when we start to combine things biological aging clocks is another area where I feel like the excitement and enthusiasm has gotten a little bit ahead of the science so the idea here is pretty straightforward biological aging clocks are meant to measure the rate of biological aging using different types of information so you can do that phenotypically we can all look at a person to some extent and develop our own biological aging clock and guess their biological age the the clocks that people are excited about now measure molecular information and one type of molecular information that people are most excited about now are these epigenetic aging clocks okay you've probably heard of those the only point I want to make is how having tools that can measure biological aging is very very important we need those for a bunch of reasons we need those in order to test interventions we need those to do personalized medicine um we need those to predict future health risks and disease outcomes but I think it's important to appreciate we don't have any clocks today right now that there's confidence that they are actually reporting on those things in a actionable meaningful way so you can go online there's a bunch of direct to Consumer companies that will measure your epigenetic age we don't yet have confidence what those things are telling us what their Precision is what their variance is and all of them are only measuring one sliver of biological aging so I just think that's important if you want to use that for entertainment purposes great if you want to use that to actually inform yourself about your future health outcomes or your mortality risk I'm less confident that they're useful in that way an epigenetic reprogramming I don't have time to dive into this probably many of you in this room have heard of epigenetic reprogramming some of you might be actually studying it this is an area of the field that has immense promise the idea here is that we know that the epigenetic epigenome changes with age there are some tools now that that can be used experimentally to reverse that the question is what impact will that have on Health and Longevity and that's a complete unknown you will hear people talk about reversing aging that's in my view um I was going to say nonsense it's it's a poor choice of words I I would say um we don't know at this point how effective epigenetic reprogramming is going to be from a therapeutic perspective to have a positive impact on the biology of Aging at this point there's some evidence in mice that you can improve function in some tissues and organs using epigenetic reprogramming so far there's no evidence that you can even do as good as rapamycin okay so I'm not going to say that you can't there's no data yet demonstrating that epigenetic reprogramming is even as effective as rapamycin in terms of increasing lifespan and health Span in mice so I prefer to be data driven and that data doesn't exist yet so so we don't know so again I think it's fair to say the hype has potentially gotten ahead of the reality so I'm going to talk about rapamycin very quickly rapamycin is a pretty interesting drug I would say it's the current best-in-class longevity drug it's not a miracle drug I certainly wouldn't say that um but we know a lot about rapamycin and has some pretty exciting effects I would say so it's actually been FDA approved for more than 20 years so we know a lot about its use in humans it is the most effective longevity drug to date in animal models up to about 30 percent increase in lifespan in mice one of the important things about rapamycin is it actually works in laboratory animals starting in middle age this is really important because if you think about a translational intervention for health span and Longevity you don't want something that you have to start giving to teenagers right you want something that you can potentially start treating middle-aged people with and that seems to be the case with rapamycin and importantly it doesn't just extend lifespan in pretty much every tissue and organ where people have looked and there are a bunch they're kind some of them are shown on the left uh rapamycin has been shown to delay the declines that go along with aging and in a few cases actually reverse the functional declines within about six to 12 weeks so the four that are shown in red are the the places where there's the best evidence again in mice you can start treatment in middle age and within about six to 12 weeks actually see functional improvements in the Aged tissue or organ that's true in the heart several Labs have reported this and there's some evidence even in pet dogs that this is true it's true in the immune system you can restore the ability of the Aged immune system to respond to a flu vaccine it's true in the female ovary this is quite striking actually you can see morphological Rejuvenation of an atrophied ovary in mice and there are now some clinical trials in people for premature ovarian failure and it's true in the oral cavity we've shown in my lab you can reverse periodontal disease in aged mice so again from a translational perspective that's quite powerful you could imagine clinical trials designed to actually measure some of those endpoints where you actually make things better rather than trying to see a change in the slope of the decline and you can extend lifespan with a transient treatment in middle-aged mice so this is again work from my lab several years ago where we took 20 month old mice that's about the mouse equivalent of the 60 65 year old person we treated them for 12 weeks with vehicle or rapamycin and then we just asked the question what's the effect on survival and in this particular case it was about a 60 increase in remaining life expectancy if you think back to that 50 year old woman that I alluded to earlier again that's about two decades for a typical 50 year old woman so I have no idea whether the magnitude of effect is going to translate and whether it will translate linearly if it does but potentially pretty significant impacts on life expectancy from these kinds of geroscience interventions okay we'll rapamycin work in the real world I am confident it will work to some extent in the real world but I don't know how how well it's going to work or if the magnitude of effect again will be anywhere near what we see in laboratory animals we are in the process of doing a double-blind placebo-controlled randomized clinical trial in pet dogs pet dogs share the human environment live in the real world we should know the answer to that in a few years and there as I alluded to there are now some small clinical trials happening for ovarian failure periodontal disease dementia I think we'll start to get data from those clinical trials and then we've recently wrapped up and the the URL is there for anyone who's interested for the paper a study of people who are using rapamycin off label I suspect they're in fact I know there are some people in the room who are using rapamycin off label right now for its potential effects on health span we collected data from about 330 people who've been using rapamycin off label and some some non-user controls and obviously there are lots of weaknesses in that data but there's some interesting hints for potential benefits from rapamycin and I think the other thing that's that's important is no real evidence for significant side effects um and I just want us to say I think there are tons of good endpoints for papamicin clinical trials I hear a lot and I agree we need clinical trials we need to know the answer to this I completely agree with that we also need somebody to pay for it okay so unless somebody's willing to pay for these clinical trials and there are lots of good endpoints to look at we're not going to get that data and so we're going to be left with small underpowered clinical trials and anecdotal data from people using rapamycin off label until somebody steps up and actually pays for the big clinical trials okay so where will we be in one to two decades now I'm going to speculate a little bit um I don't I don't think there's any evidence yet that aging can be cured in the sense of you will no longer age we can make you age in Reverse you will be immortal I don't think there's any data to support that at this point um I'm not saying it's impossible I'm not saying that shouldn't be the goal but there's no evidence to suggest that that's likely any time in the near future and I and I just think that's important because some people like to make um questionable claims but I will say we already know enough to intervene in biological aging and I put weekly It's weekly in the sense of I've been thinking about this for a long time and I'll tell you what I mean by weekly in just a minute but I will say compared to reactive disease care it's a pretty big Improvement I think we already know enough to do that and I predict that in the next couple of decades we will get to the point where we can move most people to where we think the species maximum lifespan roughly is which is about 115 years so to illustrate this I wanna I wanna uh talk briefly about this concept of the Lost decade I believe almost everybody today 95 of Americans are giving up at least 10 years is probably closer to 15 years of healthy longevity I think we can get that lost decade back from people for people today some of that is going to be through lifestyle changes and some of that will be through the science of the biology of aging and those things are interconnected right again I think that's important to appreciate most of the lifestyle changes that you've heard about that can have a positive impact on health are modulating the biology of Aging that's why I believe they have such a profound impact on health so I think this is doable right now um I think where we want to get to is what I would call the longevity dividend and we're not there yet I'm not going to argue that we know enough today to do this but I think we'll get there and I think the science where it's at today there's enough indications that we can mature to the point where we can push most people's Health span out to match their lifespan and get back close to what we think is the species maximum lifespan so we need second generation geroscience interventions and biomarkers in order to be able to do that and this is where I'm focusing the next phase of my career how do we get the Lost decade back for people and then how do we expand on that to achieve the longevity dividend so what should you do now right then I'm not going to give you the list of the stack of supplements and medications you should take sorry if oh and I will be around all day so if anybody wants to talk to me offline I'm happy to tell you what I think more specifically you should do um I do think you should invest in your health like it's your greatest asset because it by God is okay think of really think about the quality of your life when your health declines getting back this idea of the last decade a life where you develop heart disease kidney disease diabetes in your 50s is a very very different life than if you develop those diseases in your 80s 90s or never so you should really be paying attention to your health I see a lot of young people in the audience you're probably not thinking about this yet but you should be um okay so how do you do that number one don't die that's my rule number one of longevity don't die how do you not die well part of that is making sure that you don't have something that's going to kill you already and I think this is where Advanced Baseline and preventative Diagnostics play a role this isn't geroscience this is some of the tools that we have now to make sure that you're not sick and we've got some pretty good ones and I'm I'm as I've started to get into this world I'm kind of shocked how few people actually take advantage of them and I think there are lots of reasons for that um but I would say you should be thinking about Advanced preventative Baseline Diagnostics today to make sure that you're not going to die tomorrow finding a good Doc is really important and that's really hard and this is where some of my work at optispan I hope will make a difference so at optispan our goal is really to enable providers to practice science-based friction-free preventative longevity medicine and so we're trying to build the tools to allow that this is hard right now there aren't a lot of a lot of doctors especially Primary Care docs that know enough about this space to really do it well so I can't point you to those docs but I hope I can help help make a difference there I also hate to say it but lifestyle matters okay it's not you can't just do whatever you want and expect to live to be 80 90 in good health okay so you got to pay attention to Lifestyle you need to educate yourself and find credible sources this is also easier said than done I will simply say there aren't enough credible sources out there in this field right now but I hope there will be more soon I will say I I've mentioned Peter attia's name once already I'll mention it again I think Peter's one of the better sources in this area right now so I can recommend him and I think as a last concept I want to leave you with because I had just realized I'm out of time I want you to think about risk reward I don't think we spend enough time thinking about risk reward in the in the context of our health and our future health traditional medicine is very risk averse and most doctors are are are not going to consider that doing nothing has risk I can guarantee you doing nothing in in the context of Aging has risk we all know how it's going to end and so we should spend some time thinking about what is the appropriate level of risk if the reward is to push the diseases of Aging back five years ten years 20 years I would argue there is a level of risk that's taller ball if that's the potential reward and I think that many of us in the field are working hard to educate medical providers policy makers FDA to try to rebalance that risk reward ratio and I'll just leave you with I think you should think about that for your own lives okay what level of risk is appropriate for you for the potential reward of many extra years of healthy longevity and so with that I'll stop I don't think I have time for questions so thank you for your attention and again I'll be around all day if anybody wants to talk further thanks [Applause]

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Length: 30min 41sec (1841 seconds)

Published: Wed Jul 12 2023