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Professor Brian Kennedy on reducing human epigenetic age by more than 8 years – Our Longevity Futures, with Chris Curwen | Ep. 1

26 February 2021

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Over the last 150 years, our life expectancy has grown, from 40 years in 1850 to over 90 years today in some countries. This can be attributed to advances in medical science, improvements in public health, and equitable access to healthcare, especially for maternal and infant care.

What will the future hold for our world? Will we be overwhelmed by a ‘silver tsunami’ of retirees with poor health, or will we use the latest research findings to rejuvenate the elderly and extend their lifespan?

Our Longevity Futures is a show where I, Chris Curwen, speak to scientists, engineers, entrepreneurs, doctors, politicians, and community activists who are giving the world the hope that we can all live longer and better, and improve our health.

In this fascinating first episode of ‘Our Longevity Futures’ we host Dr. Brian Kennedy. Dr. Kennedy is currently a Professor of Biochemistry and Physiology at National University Singapore and Director of the Centre for Healthy Ageing in the National University Health System. He also serves as a Co-Editor-In-Chief at Aging Cell.

Dr. Kennedy discusses his personal long-term health journey, his current work in Singapore and how they’re becoming ‘healthy-ageing’ progressive nation, and how he plans to improve human health and longevity.

Dr. Brian Kennedy is also the Chief Scientific Officer of Ponce De Leon Health. Ponce De Leon Health is a longevity company focused on reversing epigenetic aging. In 2020, they announced the results of pilot research suggesting that their Rejuvant® LifeTabs®, reduced the biological age of customers by an average of 8.5 years. The biological age was assessed by way of a DNA biomarker test that measures DNA methylation. Of the subjects in the analysis, two-thirds showed a statistically significant reduction in biological age. The analysis was based on data from subjects who had taken Rejuvant LifeTabs for a period of four to six months.

LifeTabs® is a formulation containing LifeAKG™, a proprietary form of Calcium Alpha-Ketoglutarate (Ca-AKG), designed to ensure optimal delivery for use by the body’s cells. Rejuvant™ LifeTabs™ is a patent-pending combination of GRAS ingredients developed in collaboration with Dr. Brian Kennedy of the Buck Institute for Research on Aging, to modulate pathways associated with healthy aging, including DNA de-methylation, potentially decreasing biological age.

Dr. Kennedy’s research interests are in the biology of ageing, specifically the role of epigenetic mechanisms in lifespan determination. His lab focuses on dietary and endogenous factors that modulate aging in model organism. Dr. Kennedy’s human work has also focused on the identification of biomarkers of healthy ageing (i.e., biomarkers associated with longer life) and has subsequently developed interventions to slow down aging in humans using regenerative medicine methods including nutrition.

In this episode of Our Longevity Futures, Dr. Kennedy discusses his current work in Singapore, and how they’re becoming ‘healthy-ageing’ progressive nation using regenerative medicine. He also discusses Ponce De Leon’s pilot study in more detail, and updates us about upcoming human longevity clinical trials.

Here are some of the highlights for my conversation with Dr. Brian Kennedy:

Chris: What started off your interest in the longevity field and what has been your journey to lead you to where you are now?

Prof. Kennedy: Growing up as a only child, really the only child in the whole family, and everyone in my family lives forever, so when I was 17 years old I had all of my grandparents and my great-grandmother still alive both grandmothers lived to a hundred. So I was sort of watching people as they get old and some people were having problems and some people were living a long time, but having chronic diseases and my one grandmother was completely healthy really almost 100. I was just fascinated by what was driving that process and I knew I wanted to go into biology. So when I went to graduate school at MIT we talked to Lenny Guarente and he was really open to another graduate student Nick Ostriaco and I doing a unique project in yeast. We decided to try to tackle ageing and I left ageing research a little bit as a postdoc to do some cancer stuff, but came back to it when I was a assistant professor at University of Washington, and haven’t left it since.

Chris: You were president and CEO of the Buck institute for research on ageing which is one of the world’s leading institutes on ageing, could you please elaborate a bit on your time you spent there, what research you did there and your translational agenda?

Prof. Kennedy: I think that my goal in getting there was to really help the Buck and the field go beyond the basic research and try to get more translational, because I feel like that the ageing research had gotten better and better over the last two or three decades leading up to 2010, when I moved to the Buck, and it was time to really see what we could do in humans. Will these interventions that slow ageing and animal models work in humans? That’s been a challenge because at the time there was very little interest from the private sector. That’s changed now for good, but it was hard to get money from companies or investors. So the field has really gone through this dramatic change and at the Buck we were able to start seven different companies, one of them is unity, which went public, and is focused on senescence and several others are still ongoing. I think that that was one of the big drivers, and also just to try to maximise the high quality research. We had a new building open when I was at the Buck, we started a phd program and jointly with University of Southern California so it was really about continuing to build the great academic research that was happening there.

Chris: You are now working in Singapore, can you tell us a bit more about what the aspect of ageing you’re involved in at the moment?

Prof. Kennedy: Well that desire to really get to humans is what brought me to Singapore, because the bBuck institute really doesn’t have a clinic or hospital attached to it, so it’s hard to get into the clinical studies there and in Singapore we have great hospital, we have great clinical research and also the country is very focused on ageing. It’s one of the longest lived countries in the world with a very, very low birth rate and really no room for immigration, so right now, as of 2030, there’s going to be two working people for every retired person. The country’s really worried about what they can do about the ageing population and how can we keep them healthy. So there’s motivation at the government level at the university level and a great clinical research enterprise here and while I’m still doing a lot of pre-clinical, basic and translational research what I’m excited about really is that we’re setting up human intervention studies. Where we can take people in late middle age that are still relatively healthy and look at ageing interventions and try to measure whether we can slow down or reverse the ageing process.

Chris: You are currently the chief scientific officer of Ponce de Leon health and in June last year, you announced that your team had been able to reduce biological ageing in humans, could you just tell us a little bit more about these results?

Prof. Kennedy: This is another company that’s spun out of the Buck institute and the company was interested in finding combinations of natural products that could impact the ageing process. There’s an easier route to market with natural products, and we all know the difficulty of getting drugs approved for ageing right now, and also, finding combinations of natural products can lead you to more defensible IP. Along with Gordon Lithgow’s lab at the Buck, we screened a lot of compounds and then tested them in mice, and so we have combinations now that are on the market from Ponce de Leon. But the molecule that really excited me the most was alpha-ketoglutarate. This is a natural product and your body makes a lot of it every day, but it declines with ageing. What we found is, if we supplemented back in mice starting at 18 months, which is more or less a 60 65 year old human, we have an effect on lifespan, but it’s relatively modest about a 10 extension. But the biggest thing we found is that we could really dramatically reduce frailty. We have about a 50 reduction in frailty and so what the compound is doing is compressing morbidity in the animals and that’s really an ideal goal to try to accomplish in humans keep people alive and healthy as long as possible. So we have a lot of self-reported data from the company looking at biomarkers of ageing, the data looks quite promising, but the clinical study, the double-blinded clinical study, that’s being sponsored by the company got slowed down a bit by COVID-19. So we should have pretty definitive data in the next few months and we’re starting another study here in Singapore with just alpha-ketoglutarate. It’s a time-release version and I think that’s important to get the molecule through the gut, but we’re doing just that and not the other components of the product, because we want to understand more mechanistically what alpha-ketoglutarate is doing.

Chris: What is the sort of normal function of alpha-ketoglutarate?

Prof. Kennedy: It’s a TCA (tricarboxylic acid cycle) cycle component and, in fact, it’s a substrate for several hundred chemical reactions in the cell and that may be why these kinds of molecules can impact ageing, because they influence a lot of different things that may be relevant to aging simultaneously. But it also makes it hard to deduce which of these reactions are important for the ageing process, so it helps drive respiration and mitochondria, but it’s also at the interface between protein catabolism and carbohydrate metabolism. It’s kind of a metabolic flexibility marker and when levels of that molecule go down with ageing it may make it harder for the cell to adjust the energy sources it is providing with to the outcomes it needs. But then we’ve found that alpha-ketogluterate also improves red blood cell function and oxygen delivery to peripheral tissues which could be important for ageing. It preserves adult stem cell function at least in the mice, and also it seems to have interesting impacts on the gut microbiome that we’re just getting into now. So there’s a lot of interesting things going on but, you know, we’re still trying to figure out which ones are most important for ageing. Having said that, you know, we talk about these hallmarks, they are pillars of ageing, and I think that it’s too easy to get focused in on one thing. What we really have there is a network so your body is really good at preserving function in the face of challenges and so as you get older damage is happening but your body compensates for it and and these readouts of the network like adult stem cell function or proteostasis or DNA damage those are telling you how the network’s functioning. So really I think what the interventions are that are slowing ageing is they’re targeting nodes of that network and they’re preserving the network longer so you can read that out with all kinds of different endpoints. But what’s really happening is the network is more robust.

Chris: Are you going to be looking into conducting human clinical trials at some stage?

Prof. Kennedy: Yeah, so it’s taken a little while to get all the infrastructure in place here in Singapore, but we have it now. We have a brand new clinic, and we’re having participants come in starting March 1st, so these will be people 45 to 65 years old, and one of the first things we’re doing is measuring a whole range of biomarkers of ageing. To a large extent, we’re going to use those biomarkers as endpoints. Now we’ll look at physiologic functions as well pulse wave velocity, heart rate variability, various metabolic markers, inflammatory markers etc. but we really believe these AI driven biomarkers are going to be very useful to measure which interventions are working the best. So we’re hoping that we can impact these biomarkers by short-term intervention, something like four to six months, and it’s a bit of a guess right now. It’s still very early days into trying to do these studies, but we think the 45 to 65 year old target range is the ideal place to start, because these people are at risk of getting chronic diseases but most of them are not yet have them. Once people have multi-morbidity or frailty it’s not clear to me that slowing ageing is going to have that much of an impact. It might, we just don’t know, but i’d rather start where I think we’re most likely to see success, and then work out from there. So we’re going to work in that middle middle age range. 

Chris: One of the most challenging sort of aspects of producing longevity products in humans is figuring out whether they actually slow the ageing process. You mentioned that you are look using the biological hallmarks of ageing as end points, could you just sort of be a little bit more specific as to which ones are you using, and how are you sort of measuring those?

Prof. Kennedy: Really what we’re using mostly are these ai driven biomarkers, like the methylation clock, which I guess is an assessment of the epigenetic state of the cells. We’re using another clock based on metabolomics, we’re looking at trying to develop a clock based on microbiome, there’s one proposed, we want to see if it validates, and we’re also excited about using Jackie Hans’ research in china to assess biologic age from 3d facial reconstructions. Really what I want are minimally invasive strategies to measure someone’s age. We’re looking for things we can scale at a reasonable cost so that everyone in Singapore, when they hit 45 or 50, can assess their biologic age and we can identify the people at highest risk. So we can’t have muscle biopsies and things that people don’t want to do and it costs a lot of money, so we’re looking at really things we can assess with nothing more than a blood draw – either non-invasive, or at most, taking blood. Right now, I think one of the main goals is to understand how these different biomarkers interact with each other, so if you score biologically young by the facial pattern analysis, does that mean you’ll be biologically young by the methylation clock? Which methylation clock should we use? There’s a lot of interesting questions around that. But I have enough faith now in these clocks that I think they’re going to be really good endpoints for the interventions, and what excites me is the clocks really came from sort of unbiased AI analysis of deep data sets and the interventions mostly came from animal models, so they came from different places. So if they connect to each other, and the interventions impact the biomarkers, then I think we really know we’re on the right track, so we’re excited about trying to get data like that.

Chris: Do you think that governments, around the world, are doing enough to prevent the so-called silver tsunami from occurring in the near future?

Prof. Kennedy: The answer to that is: no. I mean, the governments have had that have sort of known about this, but had their head in the sand for a long time. But I think we are seeing change, Singapore hasn’t fully decided what has to be done but they’ve recognised the problem, and they’re thinking about it very progressively. I think you’re seeing a lot of movement on the part of China, the UK has some interesting initiatives around healthy ageing. now you know even though a lot of the innovation has been done in the United States, and a lot of the research has been funded by the National Institute of ageing, it’s still not clear how we’re going to instigate some of these longevity interventions, I mean, it’s really a change of mindset that has to happen. We have to be less focused on sick care. Waiting till people come down with something, go get diagnosed and then spending a lot of money trying to treat them, and we need to focus more on prevention, which to me is what true health care really means. I think that governments are waking up to this at different rates, but it’s starting to happen and you couple that with the strong academic research that’s been going on for a while and the emergence of the private sector, and the longevity space and I think we have the right recipe now to really make progress. I’m not saying it’s going to be all smooth easy flowing. It could well be that some of the interventions we developed in animal models don’t work in humans. I think we all have our favourites, but we really don’t know which ones are going to work. There might be some surprises still with the biomarkers, but I feel like we’re on the right track.

Chris: What do you envisage for the future of longevity and you know what other projects are you working on at the moment?

Prof. Kennedy: Well you know it’s funny, because I think that when Aubrey de Gray came in the field in the early 2000s he was way at one end of the spectrum and I think a lot of the people the ageing field were still hesitant to even predict that you could affect human longevity, so they were at the other end of the spectrum. I think we’ve, over the years, sort of met in the middle you know. It’s like I have no idea what the future holds, and I do suspect that there’s not a limit to maximum lifespan and that amazing things can happen. Our focus is more on establishing and validating even small effects or modest effects with the interventions we know today, because I really think that once we can convince the world that we can slow ageing or reverse aspects of ageing, that then we won’t have trouble with resources anymore, people will really be excited and then things will really be possible. You know I don’t know if escape velocity is possible but I am fairly convinced that we can extend maximum lifespan over time you know and I think the exciting thing is that we’re probably going to go from small molecule interventions, which I think are going to have some effect, to more exciting strategies, like stem cell based therapies gene therapy. These things are already starting to happen and there are even more exotic things in people’s minds, so it’s hard to know what direction it’s going in. I’m just happy I can be in a position where we can still do that basic research, address key questions, focus on translational studies and develop new interventions, and at the same time, be able to test them in humans. So we feel like in Singapore, and not just my lab, but the whole ageing program we have here, we’re building a whole pipeline to try to to deal with this ageing problem, and even to the point of trying to bring in the longevity industry into Singapore. So I hope this becomes a hub for interventions targeting ageing in this region anyway.

Chris: In what ways are the Singaporean government actively pursuing the research of longevity?

Prof. Kennedy: I think the government, they’ve set aside money for ageing and they’re trying to wrap their brains around what needs to be done. I mean, because you can approach ageing from lots of different ways: you can make buildings that encourage people to walk more, you can put your money in apps that measure people’s steps, you can build roofs on sidewalks, and in Singapore that’s a big deal because it’s hot and humid, and that encourages people to get outside, and you can do urban planning, you can do society based measures, you can work on helping people with their finances with ageing, and then you can also do biology of ageing. So they’re trying to balance those different kinds of initiatives, but I think they’re coming to the realisation that the best way to tackle this problem is to stop people from getting old as fast and if we can do that it really dramatically improves life quality. But also as an economic boom for the country, and the world as well, so that that’s really my goal. I think there’s a growing awareness on the part of Singapore that’s a goal that can be accomplished if we put our minds to it.

Chris: How do you personally define ageing as a process?

Prof. Kennedy: That’s an interesting question. I think that we used to sit around and argue constantly about what ageing is and, especially if you get into evolutionary arguments, it becomes a really long drawn-out conversation. If you put enough scientists in the room you would eventually distill this down to: you know happens, and then you die, which is not very informative. So I tend to look at it as a sort of a a more operational definition coming back to that network and so I think that the body is really trying to maintain homeostasis and over time it’s not one pathway that’s going wrong, you have a lot of different challenges. You can measure ageing: people don’t run as fast when they’re 30 and 40 as they did when they’re 20, cognitively you can measure decline if you try hard enough by the time they’re 40 and 50. But the body is really maintaining that homeostatic mechanisms to keep you functioning at a high level and it’s really the breakdown of that network that triggers the capacity for disease. Then depending on how things spin out of control you get one chronic disease or another. So I really believe there’s a systemic process in the body that’s aiming to keep you healthy and the breakdown of that process is what’s driving ageing. That’s what biologic ageing clocks are really measuring I think, and then if you couple that with a person’s propensity to get one disease or another based on lifestyle and genetics then maybe you can really predict at a relatively early age when they’re gonna start getting sick and what they’re gonna get. I really think about it in terms of that systems level it’s more of an operational definition than getting involved in semantic arguments.

Chris: What research, outside of your own personal bubble, most excites you in the ageing field at the moment?

Prof. Kennedy: What we’re getting really interested in is what’s going on with stem cell injections right now, because there’s more and more evidence that factors that are secreted by stem cells are beneficial for ageing, and if you look at the studies by Tom Rando, fusing old mice and young mice together, there are factors in the young mice that are protective and the old mice that drive ageing. This really seems like a way to systemically influence the process particularly maybe adult stem cell function. We’re really interested now in trying to find ways to test you, there are clinics all around the world that are injecting various kinds of stem cells, some of which sound scary to me, some of which are probably safe, but what I’d really like to know is how efficacious they are towards maybe biomarkers of ageing, and so that’s something I’m thinking a lot about right now.

At Gowing Life, we appreciated Dr. Kennedy’s willingness to talk with us during his busy schedule. We look forward to future results of the clinical trials going on at Dr. Kennedy’s company Ponce de Leon Health. Also, we want to point out Dr. Kennedy’s Healthy Longevity Webinar Series, which is a collaboration with the Yong Loo Lin School of Medicine at the National University of Singapore. The webinars in this webinar series are not to be missed for anyone interested in how we can make better health decisions and learn about the future of longevity based on the latest scientific research.

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