Brian Kennedy – Undoing Aging
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thank you for inviting me oh okay slides so I’m gonna tell you a little bit about what we’re trying to do now at National University of Singapore I’ve been there for about six to nine months and I’m gonna mix that in a little bit with some talk from data from my own lab mostly from my lab in California which I still have at the buck Institute I I think that well I can tell you a little bit of the reasons that I went to Singapore later in the talk I’m hoping it can be a real sight for testing interventions in human aging that’s really the goal this is sort of it my career trajectory and during research and it’s kind of been where the fields been going to if you look back at AG meetings like three decades ago most of the talks are many of the talks were in these non vertebrate models I guess worms flies that’s where I got my start in yeast and a little bit in worms and they turned out to be great model organisms for trying to identify the range of genes and pathways in an unbiased way that could affect the aging process and that led us with lots of different candidates that might affect aging and a lot of been the last decade has been spent trying to test which of these pathways are functional and regulating aging in mice and surprisingly a lot of them are other people are looking at primates and dogs and I think now we’re at this point where we’re really to start ready to start trying to validate things in humans and the question is how do we take interventions as no matter what kind of intervention they are and test them and some effective way to see if they’re altering human aging I don’t need to tell anybody here that the goal is health span and not just lifespan but how do we measure this what does health spend mean and and in in a world where we don’t want to do trials for 40 years how do we measure lifespans and I think that what strategy that’s emerged really is to try to develop certain targets or biomarkers as Diagnostics to measure whether these interventions are working and I’ll talk a little bit about that the other is to really try to prevent early stage disease progression and things like the tame trial or variants on that I’m not sure which one is right but I think we have to start testing in this area to begin to understand how to design these studies and then eventually the idea is to implement this in a way that we’re actually doing healthcare instead of sick care which is what most of the industry is doing right now now if you look at the lifespan extension agents out there there really is a growing list this is actually woefully outdated at this point there many different behavioral interventions that are thought to affect aging and also many different small molecules and a lot of what my lab has been doing right now is to try to take a harder look at these different interventions and trying to understand mechanistically how they’re impacting the aging process we’ve worked a lot on rapamycin and I’ll just mention that briefly today but the labs also worked on metformin and ibuprofen and acarbose and a range of other things we have a couple other things to put on this list and aren’t published yet that I’m not going to talk about today and I think the the understanding that mechanistically is really important because it’ll give us a better feel for how they might work in humans and it’ll also tell us which ones can be combined together to have synergistic effects and which ones might cancel each other out and we have some evidence for both now when we’re trying different interventions simultaneously of course the behavioral interventions have been tested and much more detailed calorie restriction there’s great data on in a minute and fasting and I thought I would start my talk today in honor of Aubrey by discussing alcohol a little bit more in so there have been many studies on acute toxicity of alcohol and animal models but much less looking at whether you can drop the benefits of alcohol from the with low to moderate consumption and the reason I got interested in this is the National Institute of Alcohol Abuse and Alcoholism invited me to give a talk on the benefits of alcohol and aging and I was a little bit worried about people throwing fruit and vegetables at me but they were actually nice and but I went through the literature and there’s really surprisingly little done in animal models and we really don’t know what the mechanism of the benefit might be and so let me dispel a couple myths well first let me show you that the recent metadata from the human study so this is about 33 different studies put together and we wrote a review on this this is the actual where we took this talk this graph from this and we also wrote a recent review you really have to consume a lot of alcohol before mortality rate goes up beyond zero so this is abstainers here and for men you have to get almost a four drinks a day before your got back to where you weren’t abstainers anywhere in this gap means you have a lower mortality rate women the same is true up to two drinks a day so there really is a striking tolerance for alcohol consumption and it’s not really red wine much to the chagrin of people in Napa Valley it’s if you do look at cumulative hazard here for people that have high wine consumption they have a lower cumulative hazard so it appears that there’s some benefit from wine but if you factor out socioeconomic status there’s really no benefit it turns out that rich people have lower mortality rate and they also like to drink wine now there have been a lot of studies looking at potential benefits of moderate alcohol consumption and there are also problems with mod even moderate alcohol consumption increases risk as well so their benefits in cardiovascular disease surprisingly there’s data out there suggesting lower risk of diabetes metabolic syndrome benefits potential benefits and cognitive disorders even protection against weight gain which is surprising given that their calories in alcohol but there’s also a higher cancer risk for other than just a digestive cancers some lung to type tumors and breast cancers so not everything is good here I think like all aging interventions you’re gonna have many benefits but also some increased risk and as I said I’m gonna go through this fast that ethanol is a source of calories and so it’s really kind of striking that it might provide protection against over nutrition or diabetes because you’re adding extra calories really kind of empty calories into the system when you’re drinking so we’ve done just one pilot experiment but I just wanted to show you the results just to give you a little bit of a feel for where we’re going on this and so we took ten mice and put them on 10% alcohol in the drinking water starting at five months of age I’ll get back to that just relax starting at five months of age and then at ten months of age we did some metabolic analysis and then harvested the mice at 15 months of age now 10% alcohol the drinking water sounds like a lot I agree but I wanted to tell you that it’s not that much when you think about it this is the California advisory panel for how much blood alcohol content you have for alcohol consumption they recommend drinking zero drinks a days not surprisingly but remember when people are drinking alcohol they’re consuming a couple drinks a day in a short period of time their alcohol rate goes up and then goes back down now the mice you we’re not gonna give them two drinks a day it’s too difficult so we’re putting in the drinking water but Mike’s also have very fast metabolism of ethanol and so if you average this out they get about the same overall level of alcohol that humans do except this dispersed throughout the day as opposed to going up and going down so these mice still consume the water that have the alcohol in it they still eat the same amount of food they’re actually eating if anything maybe perhaps a little bit more food their changes in respiratory quotient are almost exactly what we would predict if they’re consuming alcohol because alcohol itself changes their respiratory quotient not going to go into that too much detail and we something that’s true in humans is also true in mice if they drink all night they sleep during the day and so the amount of sleep goes up their exercise goes down their body composition is really not altered at all over time either with raw or as a percentage of body mass but surprisingly they’re protected from weight gain and so we’re still trying to understand what this means we’re trying to figure out where the calories are going but this recapitulate some of the human studies that you can actually protect animals from weight gain by giving them alcohol and I can’t believe I’m gonna say this but their livers are protected to again this is low low level of alcohol consumption high level of alcohol consumption is really bad for the liver don’t don’t get me in trouble but Anna tend not study there’s much less lipid accumulation in the liver with a low level of alcohol consumption so what we’re trying to do now is get back into the real question and I don’t have any data for this yet but what is the mechanism why is this beneficial and one of the studies that’s out there is that alcohol can actually impair the Tor pathway so you can decrease muscle protein synthesis which would be indicative of reduced tor signaling and you can directly effect phosphorylation of m. TOR kinase targets with alcohol this is one of the things that so far our evidence suggests this is true and this is one of the mechanisms we’re looking at for a possible benefit so more on this later but so far at least in a one year as a study we are able to recapitulate some of the benefits of alcohol and so hopefully this will lead to more mechanistic analysis and I just want to touch on the tour and then I’ll get to Singapore so this m. TOR pathway probably all of you have heard about this now this is the one of the major flagship pathways modulating aging the drug rapamycin extends lifespan and and everything from non vertebrate models to different kinds of mouse strains it can be given to mice at early in life late in life for a short period of time in life and an extensive lifespan so there’s a very robust effect on Aging by inhibiting m. TOR signaling and we’ve been working on this for a long time now and our model is this that whatever is happening with normal aging is not necessarily tor tor is the response to that so you get your favorite type of damage perhaps that happens during aging DNA damage protein misfolding in telomere shortening oxidative damage and the cells respond to these accumulation of macro molecular damage by trying to up regulate the tor pathway and in this case though it’s not a compensatory change it’s a maladaptive change and this is further contributing to the pathology that’s associated with aging now it’s striking how similar this is to disease if you have a favorite disease that you study go search on Pub. Med and look at the tor signaling I’d say there’s about a 50% chance you’ll find a paper saying there’s aberrant lis up regulated tor signaling and your favorite disease so I think if we’re looking at this this paradigm here and trying to understand what kind of pathology is emerging I think the disease state and the aging state are both going to contribute to elevated tor and then cut in that all three of them in concert are going to define the type of pathology that’s occurring in a given tissue or organ okay so this is this hypothesis is somewhat bearing out in stem cells there are now four different types of stem cells that have been shown to be number one depleted with aging in terms of the ability to regenerate tissue and to have elevated tor signaling with age we’ve just now shown this in recently with a collaboration with Henry Jasper and Tom Rando and tracheal stem cells and also in muscle stem cells it’s Bream shown previously and about aquatic stem cells and there’s another paper in mesenchymal stem cells so we’re really considering the model now that one of the ways that the Tor pathways driving aging is through impairing regenerative potential and in various adult stem cell populations throughout the body and just to give you an idea how we’re testing this we’re using a lot of genetic mutations in the Tor pathway and now we can turn up tor signaling turn down to our signaling and into simplistic level what we find is you can really kind of ramp up aging or delay aging depending on which way you go in this pathway and I just want to point out that I’ll show you just one slide where we’re looking at a mice that lack TS c2 and these this is an inhibitor of tor so this turns up constitutive tor signaling in the animal now in a young animal this is beneficial and so what we see is that this is a paper by markus rug and might call that if you look at a denervation reinnervation model and muscle that if you have elevated tor signaling the muscle repairs faster and if you have reduced to our signaling it takes longer for the muscle to burn to repair so you need elevated tor activity to drive stem cell differentiation to repair the damaged tissue and that’s also true if you take out myoblast and plate them this is data from Tom Rando showing that these cells that have higher tor activity start proliferating much faster in a dish when you pull them out so these stem cells are poised to add entry place damaged tissue you this is the trachea now and what you see in a normal Mouse is that this is the epithelial lining of the trachea these are the stem cells here in green and they decline quite rapidly with aging and what we can show is that if there’s elevated tor if we impair tor signaling we can rescue that phenomenon so this is you can start rapamycin at different stages you get similar results let’s just look over here this is the loss of stem cells and we can regenerate our we can recover most of the stem cells with rapamycin treatment so this is really where we’re looking a lot now with respect to tor signaling and this is model that we have that you need to our activation for a quiescent stem cell to become activated and differentiate to recover clinician most tissue your many tissues over time though with things that may be happening to these stem cells you’re getting an activation of the Tor pathway it’s getting too high in the stem cell population and then you’re getting too many cells that are going into a differentiated state and that you’re depleting the stem cell population over time because these not enough cells are going back into a quiescent state in the aging animals you can suppress this with rapamycin so that just gives you a flavor of where we’re trying to go let me tell you a little bit about Singapore this is Singapore you come visit it’s a little bit humid but otherwise a nice place to go and what we’re really trying to do there is to establish a clinical approach to human aging we’re still very excited about bringing a preclinical scientist as well but it’s how do we take all this knowledge we’ve accumulated about Aging and interventions and begin to apply it and it’s an interesting challenge when you think about it because there’s really two different ways that people that think about treating aging work so you have the aging researchers who would be you know enriched in this crowd who are really thinking about preventing aging what can we do to people when they’re at risk of chronic disease so again if you imagine this is when you’re born you’re you’re healthy then you start getting sick and eventually gets to be too much and you die the aging researchers are largely looking at interventions here to drag out this period of health span perhaps compress morbidity so lifespan will be extended but health span as well and this is mostly done in animal models if you look at what the geriatricians are doing they’re more about managing aging they’re taking people that come into the hospital in their 70s and 80s they have multiple diseases they have probably pharmacy issues and it’s not a question of stopping aging it’s about how do we manage it in a way to improve quality of life as long as possible and so the question is if you’re going to go into the clinic and try to take this approach who do you work with and so that one of the challenges we have is to try to bring clinicians together with the researchers so that we’re all thinking about things in the way and taking a preventative approach obviously both of these are important and ultimately your this the effective strategy is going to be delay gene as long as possible and then manage it when you have to but right now we have two different groups of people the Ph. Ds and the MDS largely that are talking in different paths and we have to bring them together and so the goal over the long term is to really extend human health spend in Singapore identify indi risk interventions test them and healthy aging people or at least very early stage disease people and then develop implementation plans and one of the benefits about Singapore is it’s a very progressive minded government it can’t think ten years ahead it’s probably still going to be there and they’re very concerned about aging they have about the third longest life span in the world by one measure the birth rate is 1.3 per couple there’s not much room to put more immigrants and right now there’s going to be two point one working people for every retired person 12 years from now so the government is saying what can we do about this and they get the idea that it might be beneficial to really extend health span so this could this island could essentially be a testing ground for interventions to really try to keep people healthy longer so we’re looking at different kinds of strategies right now we’re just getting up and running this is the kinds of things that NIR Barzilai has been doing yeah this is the tame trial where you’re looking at a long intervention trying to prevent many different diseases simultaneously I think this is an interesting trial and it may ultimately be the right one but right now what I want to do is compare multiple interventions to each other and I can’t spend 60 million dollars per intervention to figure out which ones are gonna work in this context so I don’t think we’re gonna look at this we’re more interested in these kinds of things this is what Neer’s doing although we may not doing quite this way where we do short term treatments and really begin to try to look at biomarkers of aging I think that everybody knows that interventions have really become a lot of them have been discovered in the last ten years that might affect human aging but the other thing that you’ll hear about later this afternoon is that the biomarker field is really being revolutionized to aging so there’s a lot of different potential biomarkers now we don’t really know which interventions are going to affect which biomarkers we don’t really know if they can just be slowed down or reversed there’s a lot of questions that remain open but I think we have to begin to test these things in humans we’re going to know the answers there’s a lot of other emerging approaches beyond the ones I mentioned there’s nutritional supplements young serum factors Senna lytx I’m not sure I’m ready for this yet but there’s gene therapy even mindfulness you know there are a lot of studies in Singapore looking at community based mindfulness looking at yoga looking at choral singing I actually told the person if I’m having to do choral singing every week I’m not sure it’s gonna make me live longer it might drive me crazy but anyway I think the issue is there there are lots of people out there thinking of different strategies to affect aging but we have no way to really compare them side by side and figure out which ones are likely to be the most effective and I’m kind of agnostic to the approach right now I think the idea is to develop a strategy for this kind of comparison and there are a lot of potential biomarkers about which you’ll hear some later today at the genetic algorithm you know cell populations metabolomics microbiome senescence I can go down the list I think that probably no one of them is going to be perfect and what we’re looking to do is create a suite or a platform of different interventions that we can apply to a blood sample and a stool sample and then work across all kinds of different clinical trials to try to compare notes on how things are coming out so this is generally the idea you’ve got all kinds of different things you can test you’ve even got like cardiovascular disease trials the primary endpoint doesn’t have to be aging we can layer this platform of integrated biomarkers that we’re trying to develop on any of these different interventions and then really begin to hopefully get some data that’s relevant to human age in a large scale way okay we’re also I just mentioned this establishing long term cohorts in Singapore one of the other advantages of Singapore is it has three different ethnicities that represents 65% of the world population that are basically largely not tested so we do know something about aging in the Han Chinese population but if you look in the Indian and Malay populations we really don’t understand aging at all in those groups and if you look at something like diabetes there are very different kinds of diabetes that are going up in these ethnicities there there’s a non obesity related diabetes in the Chinese and Indian population that’s really accelerating and nobody understands that I would be shocked if we don’t see big differences with aging as well and so I’m gonna just stop there I think that I’m very happy to talk to anyone who’s interested in and more in what we’re doing in Singapore we’re recruiting faculty and postdocs and all kinds of things and I think it hopefully it’ll be a exciting place to test some of these interventions that may affect human aging thanks for your time..
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