The meeting ended with a vigorous discussion by a panel of luminaries from academia, industry, and government. Moderator Saul Villeda guided the conversation through his questions, touching on the current state of affairs in aging research, speculations on what the future might hold, and the challenges that must be overcome to get from here to there. Villeda then passed the microphone to the audience, who had provocative questions of their own.
Below is a full transcript of the panel discussion, edited for clarity and length, and separated into sections on a question-by-question basis. I found the conversation fascinating from beginning to end, including the Q&A session involving the audience, and I hope our readers enjoy this insight into the perspectives of some of the most prominent figures in modern biogerontology.
For more coverage of BAAM 2018, see
Saul Villeda: First of all, just a little introduction. Maybe everyone could just say your name and where you're coming from. We'll get the ball rolling. You'll get comfortable in my question-asking skills, and then we'll go from there. I'll start with the young gentlemen over on the end.
Ned David: I'm a co-founder and president of Unity Biotechnology, and we develop drugs to increase human healthspan.
Tony Wyss-Coray: I'm a professor at Stanford University, and we work on the role of systemic factors in the blood on the brain.
Cynthia Kenyon: I was at UCSF for a long time, working on genes that control aging in worms, and then when Calico started, I went to Calico as vice president of aging research. Calico is a Google company that is half basic research and half drug development.
Eric Verdin: Until two years ago I was at the Gladstone and UCSF. For the last two years I've been at the Buck, working as the president and CEO there, and still running a lab working on nutrient sensing and aging.
Lenny Guarente: Lenny Guarente, MIT, and you know about me from my talk this morning.
Max Guo: I’m from NIA. I did my postdoc at UCSF many years ago. It's always great to come back to visit.
Villeda: When I looked at who was on the panel, I thought, well, this is a lot of diversity. We're going from everything from the NIA to industry to academia. I want to start by asking you for a brief history of both how and then why did you did you become interested in aging research?
Verdin: I wish I could tell you a sort of really smart story of how I got into the aging field, and that I was prescient and could tell this was going to be such an amazing field, but actually my story is more a reflection of happenstance of basic research and the ability to move along with the flow. So, my life was working on epigenetic regulation of HIV transcription back in the early eighties and nineties. We ended up cloning HDACs, and we were working on cloning HDAC3 and 7, and we were working on these proteins. And then we noticed a really interesting paper published by my neighbor on the left. Lenny Guarente published a paper saying that Sir2, which had long been suspected to be a histone deacetylase, because the knockout has hyperacetylated histones, and Lenny's group published a beautiful papers showing that was actually an NAD deacetylase. And so I had a graduate student. Actually Brian North, who many of you know, who was in the lab at of the time. He ended up being a postdoc with David Sinclair and he asked me, I want to go look to see if there are mammalian sirtuins, and he ended up cloning seven human sirtuins, and then this is how the story went.
Kenyon: I got into it a different way. I was studying pattern formation in C. elegans— that is, how the parts of the body becomes different. And from our work and other people's work in the field we learned that there are conserved regulatory proteins in all species—the Hox genes, for example—even in animals that look really different from each other, and that they generate patterns that are different, but the mechanisms are the same, the laws of pattern generation are the same in all animals, which is really kind of mind-bending because the patterns are so different. Moreover, other people found that some of the changes that occurred in patterns in evolution like spots or legs in place in certain places and not others have to do with deploying regulatory genes in new places. So you can make big changes all at once by switching a regulatory gene. So in worms you can study anything; all you have to do is look for mutants—and so I started thinking about aging, because different species have really different lifespans, so it seemed to me, okay, this is just like pattern formation — you know, aging might be boring, things just wear out, it's entropy, you could imagine — but since the rate of aging is really different, you can imagine that there are regulatory genes that are the same genes, but the dial is set differently in different animals. So I got kind of obsessed with the idea of whether was something simple behind all this complexity, or just entropy. And so we looked for lifespan mutants in worms. There was already one known; it was a little confusing. But we found that you could change this one gene and double the lifespan. The gene was shown by other people to be part of the insulin/ IGF-I signaling system. So that led to the idea that there really are conserved mechanisms for aging that extend all the way up through mice and bats and possibly to humans as well.
Wyss-Coray: I was interested in the role of the immune system in the brain and neurodegeneration and studied mice for a while, and then felt we have to study humans to learn more about this disease, but because you can't study human brains in living people, at least not at the molecular level, we decided to study their blood. And with my background in immunology, the first idea was to just look at immune-related factors and factors that cells use to signal with each other. And so we started to look initially just at a few dozen proteins or hundreds of proteins or so. And what we found is that rather than finding a clear signature for Alzheimer's disease, we found the biggest change is with age, and that's how I ended up in aging research.
“When you see simplicity that exists on the other side of complexity, it's very hard to turn away. And that's where Unity came from.”
— Ned David
David: I have an unorthodox background. I was finishing my PhD at Berkeley and my PhD advisor and I decided to found a company to automate structural biology. So we built large robots that can do a million experiments a day, which was a lot of the time back in the late nineties. And what happened over the subsequent almost 20 years, is I've been founding biotechnology companies, and now have companies that have three FDA approved drugs.... And the way I got into aging... Well, first, when I was in grad school, I read Cynthia's is paper, the first daf-2 paper, but that did not actually by itself set me on a course. It took another decade and a half. I was sitting around eating french fries in the Calgary airport when five different people emailed me Jan van Deursen's paper in 2012 showing that the elimination of senescent cells—a very simple idea at least on its face—could profoundly impact features of aging. Within 72 hours, Jan and I agreed to found a company. And that was seven plus years ago. And so I came at it because as Cynthia mentioned, I'd often viewed aging as this highly complex entropy-driven process, but when you see simplicity that exists on the other side of complexity, it's very hard to turn away. And that's where Unity came from.
Guo: So I used to work on cancer and oncogenes, but started to work on aging almost seven years ago. The reason was very simple: I was getting old.
Villeda: I want to point out that Max is at NIA and funds most of our research.
Guarente: Max, you're not old. I was working on transcriptional mechanisms in yeast. And I got tenure in 1980 based on that work, and I wanted to do something really different that was high risk, high reward, and spent about five years thinking about this and thinking seriously about learning and memory and aging. And the reason for picking aging was that we'd worked on yeast. So I thought that the entry would be relatively easy. And secondly, that we might be able to identify genes that can affect the lifespan because of the power of yeast genetics. We bashed away at this for years, and got several mutations. And really the one main thing that came out of almost a decade of work was the SIR2 gene in yeast, and it was lucky, because years later, Mike Jazwinski did a systematic study where he crossed a long-lived strain, and a very divergent shorter-lived strain. And looked at all the progeny of that cross, did a QTL analysis for lifespan to identify the most important genes and SIR2 came out as the top hit int that screen. So it was kind of lucky that we got the right thing, but I wasn't looking for aging per se. I was looking for something different.
Villeda: So outside of the aging research you are currently associated with right now, what area of aging research are you most excited about? A follow-up to that would be, what would you say is the most important finding in aging research in the last few years? (Again, outside of the research you're currently associated with.)
Wyss-Coray: To me the most fascinating discovery in aging, besides of course finding the genes that my co-panelists have discovered is the reprogramming of cells. It's absolutely fascinating that you can take a skin fibroblast from a 100-year-old person and reprogram it to basically start life all over again. And I think that that really demonstrates that aging is completely malleable, and that it can be reassembled in any way you want in principal if you figure out how to do that. The other question is what I'm personally most fascinated about?
Villeda: You answered the first one, but what, what would you say is the most exciting or important finding in the last couple of years? Something more recent.
Wyss-Coray: Maybe applying that to an in vivo organism and try to reprogram multiple cells in an organism and see whether or not that has an effect on organ function. It is pretty awesome.
David: Lenny showed a little bit of an area that I believe holds tremendous promise, but it's so difficult to manipulate, and that is the ticking of what I believe will be an epigenetic clock. And so this correlation you showed with the transcriptional and epigenetic ticking and change, I believe (though the experiment's never been done, so it's really flirts with faith rather than science) it should be a system that is regulating — not merely correlated with — aging. And the Horvath clock is some of the first evidence of that, but also Bill Frank's work showing similar correlations with transcription and the ticking clock. I hope and believe that much like your reference to reprogramming, which unfortunately has the side effect of also losing cell identity, were there a way to rewind features of that clock. So I believe that's something which holds tremendous promise in the long term, but there's this missing set of tools. How does one manipulate in a way that isn't as crude as four-factor reprogramming?
Guo: Not speaking for NIA, but in my personal view. I'm very impressed with the work done on NAD, like in Lenny's talk. There was a lot of false hope in past years, but this seems more real.
Guarente: How come you don't fund my grants?
Villeda: Lenny, we're amongst friends....
Guarente: I have to agree with Tony. I've always thought that as we heard in that that last talk, if you understood meiosis, you would learn some very important lessons about what you could do to the soma. And Yamanaka showed that you could essentially do some of the tricks of meiosis and gamete production with his factors by reprogramming and generate these iPS cells and I think that was a major, major breakthrough. And I think the second breakthrough Tony also referred to was the potential for doing this in vivo. And I think there are a lot of hurdles there, not least cancer, but, I think there's potential there, and it's a very, very exciting approach.
“The thing that I think about a lot is how can we take what we know from research now and translate it into humans so that we can slow down our own aging?”
— Cynthia Kenyon
Verdin: So I have to agree with Ned. I think with the epigenetic clock, but not so much just for the clock itself. What it tells us is this idea that aging is a continuum that starts at 18 and that we all go through this progressive linear process that continues for the whole life. It speaks to something that's underlying the aging process. And I think I know that Tony has some other data, for example, plasma proteome, that shows exactly the same things with some really unique transitions that happen at a unique age. I find this fascinating because it highlights the fact that aging is not just what happens when you hit 60 years old, but, what has started at 30, and it's one step after the other. So I think there's a lot of work that needs to be done on all of these clocks, whether they be proteomics or methylomics and so on. So, this is the answer to our first question. The second one is, is more related. I think there's been incredible work in the last 20 years and we've identified all these hallmarks of aging and all these pathways and I think in the next five to 10 years, for me, one of the areas that excites me the most is the idea of trying to integrate all these hallmarks of aging and really understanding how these pathways are not actually independent. There are really closely integrated with each other. And I think we can expect a lot of work where they are trying to understand how they are speaking to each other and how their integration is actually what causes the aging process.
Kenyon: I can think of three things. The first is what everyone else has said about erasing age and we can study that in different ways with Yamanaka factors and iPS cells and yeast, and we're studying it in C. elegans germline. But how can you be immortal — how can a cell really be immortal ? That's a deep and amazing question. I also really am interested in the question of whether there's a program for aging, you know, how does it—the female body goes along, you know, blah blah blah, fifty years, and then menopause. What? How come? How does a cell know that 50 years have gone by on a molecular timescale? That's amazing. And by the way, Leanne Jones did an experiment that I think is just amazing. It still amazes me. She showed several years ago—it was my favorite paper from the recent past. I guess— that during the course of Drosophila lifespan in male, over time, the level of a microRNA goes up and it hits a threshold, and then it triggers a cascade that causes male menopause in the fly. And you can raise or lower the levels of all these switches. You can raise or lower the level of the microRNA or anything in this little cascade and you can delay or accelerate this male menopause. So that is a program if you ask me, and there might be a lot more of that that we don't know about. And the third thing that I really think about a lot—and partly because I'm at Calico, but probably everybody thinks of that—is how can we take what we know from research now and translate it into humans so that we can slow down our own aging?
Villeda: Currently federal funding for aging research has prioritized Alzheimer’s disease related studies. In your opinion, what critical areas of aging research remain underfunded and why do you think that is?
Guarente: Well, you know, even though my interests have really evolved to studies more or less directly relevant to humans, I think the most important thing is that the NIA should be funding for the future, and so it should be looking at basic research. And I always found it very, very frustrating that, first of all, most aging grants get funneled through one study section. I think that's a bottleneck. At NIA, the Biology of Aging program covers everything, and we all know that's not big enough.
Villeda: Maybe give us some examples of the type of research you have in mind—for the newer people to the aging field.
Guarente: I think it's type of research that's going on already, but to have the funding line —
Villeda: Yeast or C. elegans?
Guarente: All of the above. It's not the type that's at fault, it's the funding lines. I think instead of funding 10 percent of grants it should be more like 25 percent because at least that number are meritorious, and the difference between a 10 percent grant and a 25 percent grant, in my opinion is generally nil. So I think that's the problem, and I think that at NIA for historical reasons, half the budget goes to Alzheimer's research, or more [consults with Guo]. More? OK, two thirds. And it seems to me to be a little bit out of proportion. I believe the reason is because when NIA was established in the mid-1960s, Congress insisted on that in order to pass the law. So, I think it has to be revisited and I think we need strong leadership within NIH to make that happen.
Verdin: I could not agree more, especially now being at the head of the Buck and really exposed to this need for basic research funding. I think that's the core of this: everyone talks about translational research, and I think this is extremely important. We need to show the relevance to the taxpayer of what we're doing and I think they have the right to demand that we do this. But on the other hand, I think we also need something to translate, and if we don't, if we don't build and sustain a strong basic research effort, soon there won't be anything to translate. So I think that's really one of the key areas. And I think the beauty of basic research is that no one at NIH or anywhere can actually predict what will be the most translatable. CRISPR is the best, most recent example, but the literature and the history of biotechnology are replete with things that we could not predict would have been translatable, like restriction enzymes are another classic example. So, we all share a collective responsibility. We need to do a better job of speaking to the public to educate them. And so we have to come down from our ivory towers and speak to the public and really educate them about the value of basic research. NIA and NIH have to change to recognize what the needs are, but we share a heavy responsibility in helping them to do this. So write to your congressman, do all the things that you have to do to increase the visibility and go speak to Rotary Club. I know someone is laughing, and it's true, it's funny. We don't think that this part of our job, but I think it is. I always use the argument of the NRA—and don't get me wrong, I'm not against guns, but just look at the amount of popular support they have for their activities, and in comparison how much support we have for what we do. I think that should tell you where some of the emphasis on what we do should go.
“This is a great time to do aging research. I think for young people who are thinking about leaving, don't try to pull out. This is the best time.”
— Max Guo
Kenyon: I think part of it is that people just still don't get it. I think they think aging just happens. It's the way it is...and it's really hard to change that. Working with daf-2 mutants, they make your hair stand up on end. I mean, when you look at them, here, you change one gene, you have a plate of worms that are dying; all of them are dead or moving around really slowly looking horrible, and then you have a plate right next to them where they all look like they're younger. See? My hairs are standing up right now. It's really unbelievable and I think when you see it then you go, oh my god, because something that you would never think is possible is possible. If we were dogs but smarter and we owned humans who live so long, we would have figured out a long time ago that there's something really interesting to study. Butthere aren't animals that live to be 200 that we would like to be (like turtles; we don't want to be turtles—but they have muscles just like we do, and they last 200 years). So, we don't have role models and I think these little worms and other animals are our role models. I get it; it's a burning passion. But people just don't get it and if you talk about it, they think, oh yeah, they, I think of a healthy looking 65-year-old, which is a great goal to be healthy and old chronologically, but I think it's not really what the fabulous discoveries that we've seen in the lab really are. So I don't know how you convey that to people. I've been trying for 20 years, but people just don't get it.
Wyss-Coray: I am more fascinated by the basic questions— they just came up in this panel—why do different organisms have different lifespans? Things that's so fascinating. Or do all the tissues in an organism age at the same speed? Are all the cells aging at the same speed? We don't have answers for that. And this is very basic information that we need to understand because most of the diseases that we're concerned with, they are age-dependent. I mean the vast majority of them. So if we don't understand aging, we will keep on missing the goal of treating any of these age-related diseases efficiently. And these are fundamental questions, and the NIH should really put much more effort into this geroscience approach of getting interest across all the different disease focus institutes, asking, "what is the cause of their diseases?" And age is always the number one. And if people would do that, I think we would have a very different view on aging research.
David: So we don't know as of yet how far our biology can be altered. We don't understand the dynamic range of the system unless you look at the germline, which is basically immortal. And so when I think about what's possible, if you accept the idea, the germline could be your inspiration. There are so many secrets that must be unearthed that we don't even have names for. Well, how do you do that, from a funding mechanism point of view?. My belief, and this is this actually comes from story that I'll share, is that a much more nimble small-scale entrepreneurial funding mechanism could be used to give relatively small grants to junior people just coming into the field. And the story I'll share is Judy Campisi. Judy got her first money to work on cellular senescence from AFAR, this is the American Federation for Aging Research. $50,000, small amount of money, but it allowed her to get just enough data for her to get her first RO1 —and today, a company like ours, Unity, is going to raise $300,000,000, and Calico has—god, I don't know how much, it's functionally infinite. And so the point is, is that it's a small seed, a little money given to someone that you can take a risk on. And if you could take, say in a given year, 50 risks or 100 risks on promising people, only a few have to take root. And I think this would be a powerful tool to allow us to try to unearth some of these secrets that if you stare at the germ line, you just know they're there.
Villeda: Max? And this is not as a representative of the NIA. This is just as Max.
Guo: So this time, you know, I'm speaking for NIA.
Villeda: Let me rephrase that. As the NIA.
Guo: First, the basic research. I think it might be about 15 years ago, 10 years ago, there was emphasis on taking money from basic research to translational research, but now I think we are reversing that trend, I think we'll be putting more emphasis on basic research. Second thing I want to mention is the idea that AD got too much money. So on the surface, they're right, they do get so much money, but I have to say, they’re not taking funding away from basic research. They get more money because Congress gave us more money. The budget at NIA tripled over the past six years.
Villeda: With this knowledge, I want to say every junior faculty in this room should submit their R01 by the next cycle and send "Care of Max."
Guo: This is a great time to do aging research. I think for young people who are thinking about leaving, don't try to pull out. This is the best time.
Villeda: Everyone heard that, right? Keep doing aging research. There's money now, please apply. That's what I heard from him.
Villeda: Members of the panel represent entities including NIA, Buck, Calico, Unity, Elysium, and academia. The number one question I got from people was: Given your expertise, what do you think will be the first of the anti-aging therapies currently showing promise in mice to go mainstream as a human intervention?
Kenyon: It could be senescence drugs. It could be; it's possible. I mean they're in trials. They look good in animals, in many different indications. You just never know. You don't know if humans are wired the same way, number one, and you don't know that there will be side effects. There's a lot of questions. There always are. And mice are often not predictive. But there sure are lots of instances in mice where there are benefits. And rapamycin or rapalogs are also kind of hovering around. They're being tested in dogs now. If they're successful, they could cause a paradigm shift for public perception of the field if it goes well. So those would be obvious because they're happening right now.
Wyss-Coray: Okay. I have a conflict of interest, but I would say, if i look at what is most quickly translatable, I'd go with metformin: it's in clinical trials, it has a very good safety profile, and there's a good rationale that they might actually show some benefits.
David: So I'll answer the question literally and then give you some editorial. So, Tony does have a conflict. He's not quite self-promoting enough, but blood fractions, because they are regulated differently than pharmaceuticals, can have an accelerated path. So my prediction is that the earliest things to hit will be some form of blood fraction and a rapalog, if not just simply rapamycin, dosed in a pulsatile fashion, the way Matt Kaeberlein has shown works in a dog. So, I think those will be some of the earliest. However, I think the more interesting question is what will be a relatively near-term thing that is profoundly impactful. And so I think if the blood fraction thing in a recent report from last week holds up and you can impact Alzheimer’s that would be great, but I think actually an entire wave of senolytic therapy across numerous indications—but it's, you know, we're talking, you know, 8 to 12 years out when these drugs start getting approved. So I think there'll be a series of things which are earlier but smaller-impact. But then, pretty profound things start to happen thereafter.
Guo: For the past several years, we've been pushing the geroscience concept. Aging is a major risk factor for most of the chronic diseases. What are the other factors produced during the aging process? We don't know. What are the factors produced by older cells that are not senescent? So I think the identities of these risk factors for all these kinds of chronic diseases are very important. Are they tissue specific or systemic? Proteins hardly communicate between organs. I think the identity of these risk factors will provide targets for many new therapeutic studies in the future.
“If exercise were a drug, it would be a $30,000,000,000 molecule. It is an intervention that has really an incredibly profound effect on aging, but we don't understand the mechanism.”
— Eric Verdin
Guarente: Obviously I've put my money on natural compounds, because I believe that they're more likely to be safe and they're more likely to be able to have mass distribution in a shorter period of time. But I think they're likely to get there first, so we put our money on what I talked about today. So I would say natural compounds. The other thing I would say and this has happened, but we just don't think about it that way, but it benefits quality of life tremendously, is things like knee replacements, hip replacements, surgical interventions that can really make an enormous difference to quality of life. And we in the aging field are thinking about cells all the time, but these kinds of interventions have made to date by far the biggest impact on what I would call aging. That is to say, maintaining healthspan.
Verdin: I'm fascinated by two areas, exercise and nutrition, and for one specific reason: Recent reports show that there's a linear relationship between the amount of exercise and decreased mortality, decreased cancer, decreased diabetes, decreased cardiovascular diseases. It's been said that if exercise were a drug, it would be a $30,000,000,000 molecule.And so in the case of exercise, it's actually the opposite of what we have. It is an intervention that has really an incredibly profound effect on aging, but we don't understand the mechanism—so, the opposite of the system where we have a mechanism and we try to demonstrate an effect in human. So I think there needs to be an effort made to understand the mechanisms by which exercise is actually influencing the aging pathway. The same thing goes for our nutrition: time restriction, fasting-mimicking diets, all interventions that are likely to have immediate effect on people's longevity and health. And so I'm really a proponent. I'm not disparaging the drugs, in fact I actually work on some of them, but I find that there needs to be more effort on understanding what is it about nutrition (which by the way is called a science, but from I've seen is really not operating as a science and needs to be better understood). What is it about nutrition? The work of Satchinanda Panda down at the Salk institute is really amazing if you haven't read it take a look at it. There needs to be a lot more emphasis on what everybody else needs to do: eating and exercise.
Villeda: The media has been fascinated with the possibility of intervening with the aging process, but this opens the scientific field to sensationalism, unreasonable expectations, and the potential for public abuse. What can we do as scientists to counteract these negative effects?
David: So first and foremost, recognize that history is full of overstatement, overinterpretation, hope, and what tends to prevail in the long run is sober, systematic evaluation of data. And so as pedestrian as it sounds, the FDA-mandated regulatory process even though it is expensive and arduous, has created for us one of the greatest public institutions of modern times, which is a systematic apparatus to determine what is a true pharmaceutical. And so my belief is perhaps best tool at our disposal in addition to being thorough scientists, is leveraging this set of institutions — take things into the clinic, study them, and do so to establish safety and efficacy systematically. What you're referring to, the media sensationalism, tends to fall outside of that system, but that which resides in that system is predictable, it's interpretable, and tends to rise above the sensationalist noise. So that's how we do it. And that's where I personally find comfort. I would say I'm assaulted on a weekly basis with some new sensationalist thing, but it tends to disappear as quickly as it arrives. But the slow-moving process of clinical experiment and the FDA regulatory process, it endures.
Guo: I think these findings need to be reproduced, they need to be confirmed by independent groups before you oversell them. It's very important, because you don't want to give the public false hope. So—I won't mention names, but 15 years ago, they promised that cancer would be cured in 10 years. Now 15 years have passed and we did not cure cancer? So that is very bad for public trust in the research community. We can't be too nearsighted, just thinking about the money now. We have to avoid overselling our results.
Guarente: It's a tough problem because I think the problem occurs at least two levels. One is the level at which a scientist presents their work, and the second is the level at which the media reports it, and distortions can occur at both levels. And I think we have a lot of control over the first level and should be accurate and judicious and humble in the way we report results when we're contacted by a reporter. Unfortunately, that's not good enough because the reporters can take a clause out of one sentence out of an hour interview and decide that this is a big deal and they're going to sensationalize it. So, what I would like to see, is one common site that all of us can access and whenever we do an interview with a reporter, we read the final report and we critique it and give it a grade based on sensationalism, accuracy, and so on and so forth, and we religiously go onto the website and say, here's the reporter, and here's what we graded, and somehow the website should be stratified by the impact that each reporter has. Someone can decide by various criteria and then we look at that occasionally and for someone who may be below a certain cutoff on that list and they call for an interview, you make yourself not available.
Verdin: That sounds great. I haven't had the experience of having a journalist take words out of your mouth and twist them and write something that you did not want to say. I think it sounds like peer review for journalists. So the question you're asking, in a way.... One of the gifts that we have in this field, and I think the audience here is a testament to this, is the fact that what we are studying applies to everyone, and so this is in some way bound to create an enormous amount of interest not only in the field, but in the general public, and Cynthia alluded to this. There's an incredible thirst for understanding, for solutions. There's suffering of people who are looking quite for solutions for themselves or for their parents. So I think in some way it is a tool that we all should feel we you can use, but in the most serious manner. I support what Lenny was saying in a way that as scientists we are really considered the voice of reason and the voice of truth. And this is a status that we have with most of the public, and it's not something that we can play around with without taking it very seriously.The interest in the field is only going to grow as results start emerging. I'm thinking of Unity and the blood trials and metformin and so on. If you think this hot now, wait until it starts with delivering tangible results. I expect it's going to get scorching hot, and the temptation is going to be even more to start riding that train. So I think that that's really how I look at this whole area.
“The FDA-mandated regulatory process even though it is expensive and arduous, has created for us one of the greatest public institutions of modern times, which is a systematic apparatus to determine what is a true pharmaceutical.”
— Ned David
Kenyon: Yeah. I just want to say how much I appreciate Ned's comment. I hadn't thought about that because there are people who will say things like, oh yeah, well the first person who will live to be a thousand is already born, or things like that. And so the problem is if you're just a person and you hear this, you think, oh that's pretty cool, and then you hear something about our worms that look young, and that doesn't sound as interesting, but it's true. And so you don't—It's like fake news; you just don't know. It all sounds so good. But Ned's point is that there is a path to regulatory approval that so far, for the most part, is accepted as ground truth by the population, that is operating in this field and can deliver us from this quagmire that we're in. So I really appreciate it.
David: There's sort of an analogy to use of fake news. We are living in an era in which we're trying as a species to adjust to this supernatural level of bombardment with information, and so what we're experiencing as sensationalism is experienced in all sorts of human endeavor. At least we have a channel that is sober, albeit long and somewhat boring to watch.
Kenyon: Also, I think that Lenny has a real challenge because he is trying to push natural compounds down the road of respectable clinical trials, and there was just a big New York Times article saying every time a company sponsors a trial, or is doing a trial, there's bias. So, it doesn't have to be that way, and hopefully he can create a path where natural compounds can gain real respectability and credibility that's unassailable through this mechanism. That will be a real accomplishment.
Guarente: The way to do that is to have the trial run by the most respected people possible. We already have agreement from the Mayo clinic and Mass General Hospital to do the trial, and that establishes credibility.
Wyss-Coray: I agree with what has been said, and just as an example, I talk to lay people at fundraisers about the work, and that we see that young blood has this amazing effect on brains of mice, and I showed the movie where this mouse gets rejuvenated or whatever you want to call it. And if I then say, we need to understand how this works and we want to be figure out what the mechanisms are, I had people saying, no we don't, we know it works, just give it to us now. And this comes back to what Ned said: we have to keep explaining to the public how the process works, how we can believe something in a clinical setting. And I keep on emphasizing this, that we go through Phase I, Phase II, Phase III. And I explain that every time and only if the person who receives the drug doesn't know what they receive and the doctor who treats them doesn't know who gets the drug, and you still see an effect, then you have a result. And to most people in the public, they don't know how that works. So if they read an article and somebody says, this is like this or that, they don't have the quality of information to judge. And I would really appreciate it if there were a foundation that supported the system that Lenny proposed, where you have high-quality reporting and this is a good source, and if you read something from this source, it is scientifically accepted. Because we've all been exposed to journalists from the best journals who completely twist what we say. And then sometimes your colleagues read it, and they say, is that really what you believe? And then you have to defend yourself, and say, I never said that! I mean, politicians undergo this all the time, sometimes rightfully, but sometimes wrongfully, and there is no system for the public to really figure out where the truth is. And that's a big challenge.
Villeda: Thank you. So before I get to my last question and I open it up to you guys, let's just have a recap. Number one, aging research is super cool. Number two, the NIA is giving money away, so please apply. Number three, we all need to have a sense of responsibility with the public.
Villeda: We'll keep this one brief. I noticed when I looked at the panel that despite the fact that you look incredibly young, the average age was about 30. Right? With age comes wisdom. So let's get a little bit of wisdom from you guys. So the panel is obviously comprised of pioneers in the aging field, right? Both in academia and in industry. Now, what advice can you provide to promote recruitment of young scientists to ensure that the next generation of leaders in the aging field is rising?
Guo: As I already mentioned, the NIA budget is doing very well. So, funding will be improved from 10th percentile to 23rd percentile in the past 7 years. The NIA budget tripled over the past five-six years. And we also gave young investigators a break, a three percentile-point break or even six percent. So in the past fiscal year, you got funded if you got a 29 percent. So that's the best time in the past 15 years at the NIH. So I think for young people we are trying to survive, to succeed. Also, there are some special situations you can talk about with your program officers. We can even give you some special consideration, we are open to helping if you struggle.
Guarente: I certainly agree that probably the main thing is money that's available to young scientists at NIA and perhaps other institutes that could fund aspects of aging research. That's the engine, that's going to drive the thing. The other thing I would say, in addition to that, is I think we can do a better job of...how do I say this. So there are a lot of people in this country with a lot of money, and the number of people and the amount of money keeps growing over time, and I think we should do a better job of trying to get those people to donate. Now, it's very difficult for an individual to do, even scientists like us, on our own. So the way academia at least, is organized, of course the university has thought about this and they want to bring money from those people into the university. And so they have officers, foundation officers, to do this. Now, what determines where that money goes? It's going to be who gets to talk with the rich people and who gets to make their case with these people and get their attention. It's dictated really by the program that the university has in their fundraising plans. They want to target this, that, and the other thing, and on that, faculty members can at least have some influence, at the university, through the foundation office, through the deans, and bring more money to the pool, to be there in addition to money that comes from the government.
Verdin: One thing, on the motivational aspect. I recognize this among postdocs and students: gloom and doom about there'd be no job and grants being difficult and so on. But from my experience, the things that have made everyone I know around me successful are being excited about your work, being passionate, and then being courageous. And I think we all have the tendency to look for the safe areas where recent papers have been published, but quite often the people who make a career are the people who are able to step out from where everybody else is and to dig and find something new. So I think as you're choosing your project in the area in which you're going to be investing your time for the next three or five years as a postdoc, just avoid the temptation to run where everybody else is running, go to something completely different. It will be scary, but also incredibly interesting. So that's one aspect. The second one is, biology is changing in a way from the old system which tended to reward single individuals and their PIs, and we need to reevaluate as a community the way we reward collaborative work, teamwork, because biology is increasingly being conducted by large teams of people right now. We don't have a way to really recognize people who might be contributing key experiments on the paper. So I think as a community, this is something that we should think about.
“When you're trying to do something important, you'll know it because most people think you're crazy, and you'll talk to them and they'll stare at you, and it will feel bad. You'll feel like you want to crawl into a little hole. You have to not fall into that hole. You have to keep going.”
— Cynthia Kenyon
Kenyon: If you can, which I think you always can, you should take some part of your efforts and try to do something that's new, that's really new. And when you're trying to do something important, you'll know it because it hasn't been done, because most people think you're crazy, and you'll talk to them and they'll stare at you, and it will feel bad, you'll feel like you want to crawl into a little hole, and so you have to not fall into that hole, you have to keep going. And as long as you in your own mind know that there's really nothing wrong with your idea, as long as you're not risking everything—because it could be that your idea is terrific but biology is just not that way. So you might not get your result, but as long as you believe it, just push on that, like leaning in. But really, it's a feeling. You feel it. And I think when you feel that, you know you're doing something new. It's intellectual, but it's also a feeling. I think you should recognize that feeling and go for it.
Wyss-Coray: I think you should simply go into it because it has never been more fascinating to do research than it is now. If you look at the history of medicine and biology, a few hundred years ago, we had a very crude understanding of organs and in the blood, and then we went into this phase of getting more and more details and into molecules, and we can look at individual molecules, at just an unprecedented level. But over the past few years, the tools that have been developed really allow us to go from this physiology to molecular resolution to now molecular physiology, and the aging field is really at the core of benefiting from this, because you can really start looking at the whole organism, how it changes, but yet look a molecular level. And I think that that is just so fascinating, and right now is the time to reap the benefits of these technological advances. So I would just say, it's an incredibly exciting time and I would want to be part of it if I was young.
David: I have two very concrete tactical suggestions. So if you want to impact aging, don't necessarily join an aging lab, at least for your PhD. So, Lenny made a comment about if you want to impact aging, understand meiosis. I think that's a great suggestion. There is something mysterious and powerful happening in the germ line, if we only knew what it was, and as opposed to going to some lab that's put out a series of high-impact papers in biology that's validated and doing cleanup work, instead work on fundamental questions that address some aspect of being germline, and work there for a while, and then as a postdoc, flip to an aging lab—take all the tools and fundamental insights deep into a particular biology, and then flip them around and build something that's powerful and real. And that's a powerful combination because if you look at history, many powerful insights exist at the liminal edge between two subject matters. Things happen there. Um, that's suggestion one. Suggestion two is a kind of funny paraphrase of what Cynthia said. When you work on something new, it's OK to look stupid for a while. In fact, I would say that in all the companies I've founded over two decades, there were years—in the case of Unity, there were four years—in which various investors would sort of politely say "Get out," because we lacked some of the data, but we kept pressing on. And Cynthia said, if you can connect in your mind idea a to b to c, and you can see the path to it even though others lack the imagination, that is exactly where you're supposed to be. That's how it's supposed to feel. So, when you're out there in the world and you're getting a bunch of negative energy coming back at you, but you can connect the dots, live that, feel that emotion, because that's where innovation is happening, and that what it's supposed to feel. That that's been my experience.
Villeda: Awesome. Thank you. Okay. With that, I do want to open it up to the audience.
Audience Member 1: Given your tremendous knowledge and expertise, what original insight do you hold in regards to basic philosophical questions like what is the nature of reality, what is the purpose of soul, that has helped you to see reality in a different way, and that will help us to reimagine this human operating system.
Kenyon: My answer would be the diversity that you see in the world and what evolution has done. The fact that we are what we have all these feelings, we respond. Animals, if you look at them and get into their world and their heads, you'll see that we have a lot in common. Dogs have a lot of the emotions that we have. There's a lot of bonding that goes on. If you look in nature, what you see is....The world has great potential. You see it because it's there, and it came from evolution, and I think it gives you an idea of unlimited potential . Not only that, we evolved to have certain abilities that allow us to go beyond. I mean, we can make airplanes that fly. For example, in aging, like I said, turtles have muscles just like our muscles, same proteins, but they can live 200 years. So there, you just think about that—maybe we can live longer. So that's where I get my inspirations.
Guarente: Brief anecdote: A student in my lab who started the work on aging, along Brian Kennedy, Nick Austriaco, he went on and then he became a Catholic priest and adviser to the Pope, and now he's at Providence College where he runs a small lab with undergraduates, still doing research and he was at one point asked about, "resveratrol is really something!" And he said, "Look, I don't need resveratrol to think about immortality."
Audience Member 2: As you know, we can use young blood to rejuvenate mice. Although there is no evidence for humans that it also works in this way, I've heard some rich people who are already using this method to try to rejuvenate themselves. If a clinical trial shows that this does help older people to become younger, would rich people just literally milk young people? This leads to a huge ethical concern; how would you address these kinds of concerns?
Verdin: I'll just jump in with one answer, and I think this is an area of concern for many of us in the field. In parallel to what this field represents which is serious aging research, there's a whole other field which is run by, I would call, mostly unscrupulous doctors, and it's called the 'anti-aging field.' It's actually a huge field which is now unbounded by the FDA, by regulations, and I think this is one area in which the people who actually are willing and who embrace the FDA and its burden, this is where we can play a significant role. I deal a lot in this new job with businessmen, and the refrain that I hear constantly is that we have to go to Bermuda, we have to go to Tijuana to do our clinical trials, and the FDA is an impediment to our progress in the aging field. But I keep saying the same thing: that the FDA is our best guarantor of actually proving what we're doing is truly efficacious and not just enriching a few. Being in this field you will be confronted by those people, and I think it's important that as a group we maintain the distinction between what we do and what a whole group of other people are trying to do.
Wyss-Coray: This addresses to some extent what we have been doing. But I think you could say the same thing with kidney donation or any organ transplant. Of course we have to regulate any discovery that we make and that we could potentially take advantage from. And there is a gray market of a lot of products that are being advertised—stem cells or even platelets that are being injected into people. There are no clinical trials that provide evidence, but a lot of athletes now constantly have these treatments. So, I think we need to have regulation. I don't see a scenario where we would have rich people starting to have farms where they harvest blood and things like that. Like, you can always make utopian stories, but I think we have rules and regulations. A much bigger problem for me is inequality in access to healthcare, and that is not just billionaires wanting blood from young people, but regular people getting access to basic health care. That's a much bigger concern to me than the former one.
“A much bigger problem for me is inequality in access to healthcare, and that is not just billionaires wanting blood from young people, but regular people getting access to basic health care.”
— Tony Wyss-Coray
David: One other approach to dealing with this sort of dystopian vision that you described is find the factors in the blood to do this. Purify them. Make them into products, the way the pharmaceutical businesses done for decades. If you think about it, with the passage of time, bizarre clinics in some remote location that take a credit card will not be the way medical innovation is delivered. Things will be discovered. They'll be understood. They will be developed into reproducible, manufactured-at-scale products to benefit humanity. And so, there might be some chaos in the near term and weird stories about people with their 'transfusion associate.' Do you remember seeing Silicon Valley? But that's going to be a weird transition state that goes away and will be replaced by something that looks much more like pharmaceuticals that doctors give out today. I also want to say one more thing about the dystopian vision as it relates to equal access.Drugs that extend healthspan will not increase healthcare costs. They will decrease them. If you can eliminate the diseases (or blunt in some way) the diseases that come with being old, you remove cost from the healthcare system, you do not increase it.And so my belief is these are drugs, on a GDP basis, will do more than just pay for themselves; they will save money. And so the ability to take existing resources we spend doing things like dialysis and use it instead to prevent kidney disease in the first place, this will be a profound reallocation of resources that can benefit, both people with resources and people who do not have them. So I think that this is not a recipe for a dystopia. I think it's a recipe for equality.
Audience Member 3: To bring it back to the mundane funding question: Basically NIA picks a priority like Alzheimer's or neurodegenerative disease. But technically AD is not the first sign of aging — that is decline of reproductive function. Ovarian aging, testicular aging, that's how the organism becomes aged. As a reproductive biologist myself, I know how NICHD struggles right now. It has between a five to eight percent funding level, which is really hard. So I wondered whether NIA and NICHD could and join priorities to specifically fund reproductive biology research and aging-related research on reproductive function.
Verdin: I'll just put a plug for the Buck Institute, which is starting a new center on female reproductive longevity. Actually, this was something that was triggered by a private donor. NIH and NIA recently organized a workshop on the topic, and I attended this workshop. It was astounding to see that one of the earliest phenotype in terms of aging in women, which is menopause, is relatively unstudied. So I think there good news on that front . And for me this represents the example of what I had discussed: Why isn't anybody studying this? Well, it's not only the funding, it's the lack of curiosity, lack of courage, lack of being in an area which is now being studied. And so I'm pretty optimistic about that that whole specific area, and I keep up with the work you're doing.
Guo: Thanks Eric for mentioning the workshop. This is an important area. So I think we'll be trying to issue an RFA in these areas. And also, to the general question, NIA for these past several years tried to work with other NIH institutes, including NICHD, and find common shared interests related to aging. So it's something we are trying to do. So we do have emphasis on AD, but that emphasis may be replaced by a new one. So, as I mentioned, AD is not taking money away from other research.
Audience Member 4: To Max from NIA: I just had a question about how exactly do you allocate your funding to neurodegenerative disorders when you have other funding agencies like National Institute of Mental Health doing the same. I just don't understand how there's such a high proportion going into those neurodegenerative disorders without other agencies doing that as well.
Guo: Thanks for the question. So in general, other neuro disorders are managed by other institutes who also get their own funding. But most of the AD studies are funded by NIA there is some interaction, co-funding. For example, if a grant is submitted to NINDS, but it's on AD, what we do they do is we transfer some money to fund that, even if it's not in NIA. So all NIH is funded by AD money.
Audience Member 5: Simple technical question for Ned, Cynthia, and Lenny. What's your regulatory strategy for getting a drug approved for a drug that improves healthspan or longevity as opposed to a single age-related indication?
David: We actually go after specific diseases of aging. The drug we have in the clinic now is targeting osteoarthritis of the knee and next year—we're letting the biology pick a little bit, but it might be an ophthalmological indication, say diabetic retinopathy or something like glaucoma. It May be injected straight into the eye, and the first one is injected straight into the knee. We may take a drug into the clinic for indications in the lung. So these are drugs that target a disease that's driven by an aging mechanism, but it's a very specific disease of aging. Now, a side effect of this drug may be an impact on healthspan, but the regulatory path is very conventional.
Guarente: I think our situation is a little more complicated because we are interested in both the supplement side and potentially a pharmaceutical side. With regard to the supplement. Just to give two examples, we have a trial running now on fatty liver, a pretty serious problem, both because it can lead to more severe liver problems that are frank diseases although it's not classified as a disease. And secondly, because it's an absolute marker of metabolic syndrome and prediabetes and diabetes, and a positive result in a fatty liver trial — and it's not a disease, so it's outside of the auspices of the FDA, so you can do a trial—and having a positive result would give scientific evidence that you could resolve one aspect of metabolic syndrome, probably a lot more, but one that you could measure. So that will be one way to address what you've asked. The other way is, you know, if you want to do a disease, you've got to do it as Ned said, in the conventional way. So the ALS example is an FDA-sponsored trial. And there's just no way around that, as it should be.
Kenyon: Two other strategies that are percolating up, one is from the TAME trial, the metformin strategy, that may be implemented pretty soon. Where the idea is that if you can slow down all-cause mortality—because so many diseases are age-related, if you slow down aging, you will have an impact on all diseases. So, that hasn't actually been progressing, but the path for progressing has been laid down like the basic agent, which is great. Hopefully that will work. And then another one, we haven't done it yet, is to get an index from aging—something, some set of phenotypes, that samples different organ systems, grip strength and kidney function, a set of indexes that aren't really related to one another but sample different parts of the body. And get the FDA consider reversing the rate of decline as a criterion for approval. Once you get that, the really hard part is to figure out a way that you'll get insurance companies to pay for this. You know, it's one thing if it's metformin and it's generic and it's cheap, but it's another thing if pharmaceutical companies who spend a lot of money making the drug and then it slows down aging, and then you've got to get somebody to pay for it to recoup your costs. So that's another thing that hasn't been worked out yet.
And with that, everyone went to the bar.