The plasticity of the aging process

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Coming up on Harvard Chan: This Week in Health…

Can we change how we age?

{***Will Mair Soundbite***}
(We are interested in what we think about and we call “the plasticity of the aging process.” So, the ability to modulate the rate at which an organism can age through different manipulations.)

In this week’s episode: An in-depth look at the science of aging.

We’ll speak with Will Mair, who runs a lab that studies how animals age—and how techniques such as dietary restriction can change the aging process itself.

It’s fascinating work that could change how we think about treating aging and age-related diseases.

{***Will Mair Soundbite***}
(When we get past 65 we tend to have multiple chronic conditions at the same time. And this really means that the way we target diseases, one at a time, actually doesn’t potentially have as much benefit as you’d hope. So, what we think about is, if we can target age itself maybe we can increase our bang for our buck—really we can have an effect on healthiness and sort of be more preventative, rather than just trying to cure each one at the same time.)


Hello and welcome to Harvard Chan: This Week in Health…It’s Thursday, March 29, 2018. I’m Amie Montemurro.


And I’m Noah Leavitt.

We often think about aging as an inevitable decline—as we get older our bodies break down and disease multiply.


But what if that wasn’t the case?

What if we could change how we age?


It’s an important question as people around the world live longer and longer—and we’ll be taking an in-depth look at that today with Will Mair, Associate Professor of Molecular Metabolism here at the Harvard Chan School.


And this interview is a natural follow-up to the episode we aired on February 8, “A public health approach to an aging world.”

If you haven’t listened to it yet, we’d encourage you to go back and give it a listen.

In that episode, Lisa Berkman and Albert Hofman explained how public health researchers are grappling with issues surrounding aging and longevity—from rethinking work to preventing Alzheimer’s disease.


And in that episode Lisa Berkman made the point that if the world ages in a healthy way, this shift may go smoothly.


And that’s where our conversation with Will Mair comes in.

His lab explores the basic biology of the aging process—trying to understand why we are more likely to get chronic diseases when we are old than when we are young.


Their work seeks to understand what is actually going wrong in our cells and tissues to increase the risk of age-related disease—and then try to find ways to reverse that.


Much of the Mair Lab’s work focuses on using a process known as dietary restriction to manipulate the aging process.

A key to the lab is running experiments using c. elegans, a nematode worm, which carries about the same total number of genes as humans.

The worms live for about three weeks, but in that time they show clear signs of aging—making them a powerful research tool for scientists like Mair.

We’ll talk more about that later in the podcast, but I began my conversation with Mair by asking him to explain the focus of that lab—and how that fits into public health.

{***Will Mair Interview***}

WILL MAIR: So really, I would say the overriding central question that my lab is focused on is really, why is it that we are more likely to get diseases when we’re old than when we’re young? This is something that is obviously– we’re all very aware of. It sounds very obvious, but what is the biological reason underpinning that, and is there something we can do about it?

So essentially, when you think about public health, we identify risk factors for public health concerns, and then we try to get rid of them. And we think about aging as a risk factor. Can we do something about the extent to which age is a risk factor for different chronic conditions?

NOAH LEAVITT: And so I know one of your main aims is understanding the basic biology of the aging process. So I guess– kind of a two part question– what does that mean, and why is it important that we understand these biological processes?

WILL MAIR: So that’s a great question. So when we think about human life expectancy, one thing that’s really striking is we’ve had amazing success in the last 100 years or so in increasing our life expectancy. So we’ve added, in the US, something like 30 years to the time with which we can expect to live, and that’s true across the globe.

And that’s had nothing to do with the rate at which we age. That’s not really affected the aging process. That’s really been through basic public health successes. So getting rid of things which used to kill us when we were young enabled us all to survive until we’re into advanced stages.

The thing about that is that when we evolved, our ancestors weren’t lucky enough to have that same sort of public health, right. And so evolution is quite a thrifty thing. We only evolve capacity to maintain ourselves and our bodies for the amount of time we can expect to live.

And so because we weren’t surviving as long during the course of human evolution, our bodies haven’t caught up with the successes of public health in some ways. So now, because we’ve added these extra years to our lives, we’ve exposed the frailty of our bodies. We’ve exposed the fact that we haven’t evolved to live this long, which means that we’ve added all these different chronic diseases, at higher levels than we’ve ever seen before, because we’ve been a victim of our own success really.

Because we’re living so much longer, we’re experiencing these diseases. So now the next 100 years or so, or as long as it takes for public health, a real focus is to think, can we make those added years that we’ve added healthy ones, instead of ones where we experience high levels of chronic comorbidities?

NOAH LEAVITT: So in a sense, because the evolutionary times scale is so long, medicine has basically outpaced what our bodies can do.

WILL MAIR: Absolutely. And you can see that if you look at the natural world. If you look at, where do we see aging, you don’t tend to see old animals in the wild. You see old animals when we put them into zoos, when we domesticate them. The longest lived animals tend to live in places where there’s really low levels of hazard, so on island populations, for instance.

And so effectively, that’s what we’ve done to ourselves with the success of public health. We’ve almost domesticated ourselves in some ways. So we’ve stopped lots of things that used to really cause us death and early death in our young lives, and experienced these things, and we’ve exposed this– you’re exactly right. Public health has outpaced evolution, but that doesn’t mean that we can’t do something about that if we can understand the basic biology that’s going wrong in our cells in these extra years we’ve added.

NOAH LEAVITT: And so you mentioned a minute ago this idea of making those added years healthier and better years. And you said something interesting in a 2012 interview with Harvard Public Health magazine, you can’t change how old an animal is, but you can change how it ages. Was there a particular moment that helped you realize that, and I guess, how has that point of view informed your work as you’ve gone throughout your career?

WILL MAIR: Yeah, so that’s absolutely true. So I can’t do anything about how old someone is, but you can change the biological age of a cell and of a model organism in the lab. And this is really a central theme of my lab, is we are interested in what we think about and call the plasticity of the aging process, so the ability to modulate the rate at which an organism can age, through different manipulations. Some of them are dietary, some of them are genetic or pharmacological.

So this is a really powerful observation. And really, for me, one of the things that first exposed me to this was work I did now 17, 18 years ago as a graduate student London, was using Drosophila, which is the fruit fly, which is a tool that’s used in the lab often to study genetics, and asking the links between feeding and the amount of food the animals would eat, and the length of time they would live.

And so this was looking at this process called dietary restriction, which is defined as the reduction of food and food intake without malnutrition. And this process has been shown to increase lifespan in every animal we’ve tested it in, whether it’s a single celled yeast, a fruit fly, a mouse, or actually a rhesus monkey, a non-human primate.

And I was working on Drosophila, on these fruit flies, and asking, well, do you have to give them less food all the way through their life, or is there something you could do very late on in their life? And what I did is– as someone who works in demography at the School of Public Health will tell you, to do studies of acute changes, you need huge sample sizes. And I was the sort of graduate student that would be happily– if it meant counting a lot of animals, I would count lots of animals.

So I did these studies where we put diet restricted– imposed dietary restriction in flies, with thousands of animals, when they were very old. And what we saw was really striking. Within two days, these animals that were already old, were already showing signs of senescence, they didn’t fly anymore, they looked kind of haggard, they rapidly reversed those aging phenotypes. And actually, in 48 hours, you could not tell the difference between flies that had been dietary restricted throughout their lives, and some that had been just eating as much as they wanted to eat, until they were pretty old, and then just diet restricted for two days.

And so that was really an example to me that was very obvious. I was looking down the microscope of, aging is a plastic thing, so that the flies were the same age, but there was a huge difference in their youthfulness. And that had been really acutely reversed.

And so some of the work we do now is to try and understand, well, what are the mechanisms that underlie that at the cellular level? Might we be able to target some of those for therapeutic benefits?

NOAH LEAVITT: So I want to dig in more to the fasting part a minute, but just to follow up there, I mean, that seems like a really good example of what you were talking about, of kind of targeting the aging process itself, and this idea that it is this kind of plastic process. So why is that a valuable public health strategy, to not just target the effects of aging, but the process itself?

WILL MAIR: That’s a great question again. So I think one of the reasons is down to the way you get diseases at different ages. So there are things that used to kill in our youth, infectious diseases, things that we’ve gone a long way– sanitation, education, public health has gone a long way to getting rid of those things. These are acute events which could happen to an individual. If you could get rid of that process, remove that problem, they’d survive and they’d live into adulthood.

Unfortunately, when we get past 65, we tend to have multiple different chronic conditions at the same time. So you don’t just tend to have one public health or health concern when you’re old, you have several. And this really means the way we target diseases one at a time actually doesn’t quite potentially have as much benefit as you’d hope. If our goal is to improve these 30 years we’ve added and make people really live a disease-free, healthy and happy life, actually, at the statistical level, if you get rid of one disease in its entirety, if you’re left with other chronic diseases, all who share a risk factor, which is patient age, but maybe have different proximal causes, you’re still left with them.

So what we think about is, if we can target age itself, or at least the reason that age is a risk factor, what are the central links between age and these different diseases? Maybe we can increase our bang for our buck. Really, we can have effect on healthiness and be more preventative, rather than just trying to cure each one at the same time.

NOAH LEAVITT: I mean, that seems like a pretty good argument, I guess, for the value of this holistic public health approach, because it’s not just in Alzheimer’s research, in heart disease research, et cetera. You’re kind of forced to bring all those different disciplines together, I guess.

WILL MAIR: I think that’s exactly right. And really, it’s not saying that the alternative approach is incorrect. Of course we need medical approaches to target each different disease, but what we really want to think and become a bit more flexible about how we might deal with this public health approach. We’re not really prepared for the burden on the public health system that these diseases of old age are going to put, so we need to think a bit more creatively. And I do think if we can find central biological links that happen in an old patient, and also in an old animal in the lab, for instance, which cause increased risk for different disease phenotypes, if we can modulate some of those centrally, we can have an effect.

One of those that we think about a lot in the lab, in my department, the Molecular Metabolism, thinks about is really the links of metabolism and metabolic dysfunction, so how your body processes the nutrients it gets. And if that goes wrong with age, can that lead to lots of different symptoms, lots of different age related diseases in old age?

NOAH LEAVITT: And so is that where the work in fasting comes in? Because if we know the key, if metabolism is kind of this is key factor in aging, is what has led you to research fasting?

WILL MAIR: Well, the fasting link gets back to this idea of evolution. So there’s a kind of famous quote in science that nothing makes sense in biology except in the light of evolution. And when you think about what work people like me are trying to do, we’re trying to find, are there inherent switches in a person, in an organism, which you can throw, which can alter that aging rate? So what were those flies doing to manage to alter their intrinsic biological aging rate?

And so when you think about evolution and what makes a fitter animal, usually it’s live fast, die young is the best approach. It’s important to become vigorous, grow quickly, reproduce and all these things. There’s no advantage to slowing your aging during normal evolution, because actually, you don’t die of old age, you die of different things.

So what we want to think about is, where would be cases where slowing aging is actually advantageous? And fasting is one of those things. If you think about a situation where there’s reduced food availability, now suddenly, the best approach, the one which would really increase your chances of passing your genes to the next generation, which is effectively all evolution’s trying to do, is actually to think about, well, now is not a good time to reproduce. What if we slow down the aging process of the individual, and try and see out those hard times until the food comes back, and then you can restart again.

So actually, that’s why we’re interested in fasting, because when you impose that into a laboratory setting, that’s what we really see. You see suddenly, an animal up regulates all these different capacities to maintain its stress resistance, its disease resistance, actually.

So if you feed an animal less food and then look at the disease outcomes, it’s amazingly striking. They get cancer at a later age. They get protected against neurological disorders. So multiple different chronic conditions that happen with old age are protected when you reduce food intake, and that’s really replicating that, now live fast and die young is not advantageous. Now it’s better to slow down a bit and wait.

So that’s why we’re interested. That’s one of the most ways to induce this plasticity of aging, is to look at the modulation between nutrient intake and aging risk.

NOAH LEAVITT: And so you’ve mentioned what some of your key findings have been. What I think is interesting is in your lab, you use a C elegans worm. And from everything I understand, that’s, I guess, a really powerful part of research. So why have you chosen to use that worm, and maybe what does that enable you to do as you study something like dietary restriction?

WILL MAIR: We do. We use this nematode worm, which is a very microscopic, two millimeters long animal that lives in the compost in the ground. And it lives everywhere. It’s not a pathological nematode worm that lives inside you. It lives free in the soil.

And the reason we use it is actually because this nematode worm was central in really starting the field of molecular biology of aging. So when you look at discoveries in basic science, a lot of what we know about human biology doesn’t come from studying humans. So we know a lot about biochemistry from studying yeast in the lab. We know a lot about genetics from studying fruit flies.

And for aging, a lot of what we know about how you can modulate the aging rate with one intervention comes from this peculiar little worm, where someone in the ’90s did an experiment where they looked for single genetic manipulations which might slow the aging rate of an animal. And these animals are incredibly easy to manipulate in the lab. The main thing is they age very fast. So they live and they die in about two weeks, and during that time, you can really observe and study aging in real time.

And what was shown was that if you modulate a particular gene in those animals, you change its function, now instead of living and dying in about two weeks, they would really slow the aging rate and live about five weeks. And they didn’t live an extra three weeks in a miserable life in an aged state. They looked much more youthful in old age.

And so that was a really striking conclusion and observation. But of course, no one’s interested in making worms live a long time. What was really important is that in the next 15, 20 years of that field, that same genetic pathway which slowed the aging rate of this little worm was then shown by other scientists, actually in the lab that I did my PhD in in England, to slow the age of a fruit fly, and then in a mouse. And so we go up this chain.

And now, in this era where we can really look at– with the powerful and computational and sequencing capacity we have these days– look at very healthy aging humans, so centenarians, and ask, what changes in the genes of these centenarians are different between mere mortals like myself? What was really striking was we saw changes in the same pathways which modulate aging in that nematode worm.

So this is really what we do in basic science, is we can go backwards and forwards between quick, cheap discovery in a simple system, find something, and then ask, OK, how relevant is this to biology? Because what’s really striking is that a nematode worm that lives two weeks in my lab has about 20,000 genes. You and I have about 22,000 genes. We’re not that different genetically. We’re clearly more complicated, but you can learn basic biology about humans by looking at the basic biology of these simple systems.

NOAH LEAVITT: So when you do find something in the worm, what happens next? What are the next steps in the research process for the lab?

WILL MAIR: So that’s a really good question. So the thing we want to do is ask, if we can use this fast and cheap tool to find new biology, the next key step is ask if that biology is relevant to just those worms or they’re relevant to mammalian health. And so that would be the key next step.

So take an example of our work last year on this RNA splicing machinery. The next step is to use that discovery. You could only have made that discovery in a quick system like the nematode worm. You couldn’t have done those experiments in a mammalian system.

But once we made the basic discovery, then we write the grants, and we luckily just got funded by the American Federation of Aging Research to look at this in mammalian cells and in murine models. So that you do the quick discovery of novel things in a simple system– not that simple but, you know– in a fast system, at least, in a cheap system, and then you take that, so you selective out all the– you can ask so many different questions in a simple system, and then you find one which is really exciting, and then you take that and look in a more complicated mammalian system.

So this is exactly what we’re doing with the splicing project now, but we couldn’t have made that discovery to even ask that question, we would not have known where to look, if we hadn’t started with this nematode worm that lives in your compost.

NOAH LEAVITT: That’s really interesting. So in a sense, like you were saying, you can do it either way. You could find something in the nematode worm and then scale that up, or you could look at successful aging any human being and then work backwards, and try to figure out maybe what’s going on genetically.

WILL MAIR: So that second point is a really exciting one. And so it’s quite an odd position to have a geneticist who works on nematode worms at a school of public health. And so when I applied for faculty positions, this was the only school of public health I applied to. The rest was medical schools, genetics departments. The reason I did is we’re a very unique school of public health and we have this big basic science component.

And what I’d like to do is to do exactly what you’re suggesting. So the previous dean’s mantra was we look at public health and genes to the globe. And that’s a wonderful thing, and we can study aging at the genetic level and at the basic science level, and then that the human and social sciences level.

But what we can kind of spin now is we can really go from the globes, to the genes, and then back again. So now in this huge, exciting time, where we have advances in computational capacity, and machine learning, and human genetics, and in genome engineering, we can take things that we see and we observe in human populations, make those modifications, see what they do mechanistically in the lab setting, and then go back.

So the goal, moving forward, is to really integrate both sides of these data, what we can learn from human studies, what we can learn from nutrition studies in humans, take that back to the lab and go backwards and forwards. And I think this is really a huge strength of our school here and what we’re really trying to do in the next few years and move forward.

NOAH LEAVITT: And here’s is what you found so far. What are, I guess, some of the biggest potential benefits of dietary restriction, and I guess, are there any downsides? And how do you try to balance those two?

WILL MAIR: So I think that’s absolutely true. So dietary restriction is this very powerful approach to increase the length of time an animal might live and its protection against diseases, but there are a lot of downsides to doing dietary restriction.

One of the huge ones is it’s pretty miserable. You’d be pretty hungry a lot of the time. It’s not something I would advocate doing personally. So it’s a tough lifestyle decision if you were to try and do that yourself, but also because there are actual biological, physiological detrimental effects of dietary restriction, so severe weight loss, and in case of humans, lots of different– some problems with suppressed immune capacity and various things.

So what we’re really interested in doing is trying to understand, can we uncouple the beneficial effects of changes to diet on human health, and on health in general, from those negative physiological effects? And to do that, we really need to understand what are the molecular sensors, in the cells and in our bodies, which really translate the changes to the food that’s coming in to the output on aging and disease resistance?

So we’ve begun to do that in the lab, actually, and find particular molecular targets which are selective to the aging effects of dietary restriction. And now we’re beginning to then build those up and ask, well, what are they doing, and can we find ways to manipulate those directly? And so that’s a really key goal

I think for a long time, it was thought that you needed the negative effects to get the beneficial effects. I think that’s really been overturned in the last two or three years, which is an exciting avenue for research.

NOAH LEAVITT: And so looking down the line, what would a potential therapeutic look like, when you are able to figure out the best way to get the benefit without those negative effects?

WILL MAIR: Well, so I think for any sort of therapeutic treatment in the long term, we need to identify targets. That’s ultimately what we want to do. Unless dietary changes really become something that everybody wants for health benefits, I think ultimately, there’s going to be people like me, who still want to have your cake and eat, right.

So then we need to understand, are there therapeutic effects we can use which can harness some of these mechanisms for benefits? And so what we will need to do, and are beginning to do, in the field is identify those molecular switches in cells which really sense energy and then translate that through to disease protection. And then once we’ve identified those targets and we can show the evolutionary chain that these work in mammalian cells and in human cells, and potentially, would have benefit for human health, then we need to cooperate with our pharmaceutical company colleagues and then make drug targets to design those things.

And this is something that we’re beginning to do in the aging field already. We have small molecules which you can feed to lab animals, and recapitulate the beneficial effects of a low diet, without giving them a low diet. The question is, will they translate to human health benefits? And those studies are ongoing. And do they also induce some of those negative side effects? And I think that’s a big question that’s very open at the moment and we are actively trying to work on.

NOAH LEAVITT: So you mentioned, obviously, it would be great if everyone could just make dietary changes. And I think it’s interesting, because intermittent fasting has become this hugely popular trend recently. Is there any evidence that the benefits that you’ve seen in animal studies translate to human health? I mean, and what work still needs to be done to, I guess, get to that point where we could make some statements about intermittent fasting and human health?

WILL MAIR: So I think there’s always a huge interest in different dietary trends, and we spend a lot of our time discussing this at the moment. Intermittent fasting is one, there’s time restricted feeding, there’s dietary restriction, ketogenic diets.

And I think what is clear is that when you think about different cultures in humanity, in lots of different cultures and religions, there have always been some link between a fasting period. And if you see something happen lots of times, it’s probably likely that there’s something really in that. And I think it is clear that some of the effects we see of fasting in model systems in the lab, there are data now looking at kind of human interventional trials, where trying to give a short period of fasting and look at health outcomes, and they see some benefit.

What I think from my work is interesting, and what we’re trying to do in the lab, is that I personally don’t subscribe to the idea that there will be one diet which is the universal health diet for everybody. We know from work in the lab that different genotypes, different sexes respond very differently to different nutritional interventions. And there’s some– as ever, there’s some biology underlying that.

So what my lab is really interested in doing is trying to understand, how can we predict ahead of time what will be the dietary intervention that will benefit a particular genotype, a particular individual, or a particular wild animal. And so we’re working very closely with Jeff Miller in the biostats department here to combine machine learning approaches, where you can make sense of this huge data, and the basic science in the lab, to go backwards and forwards looking at, OK, if we give the same dietary intervention to different genotypes, different individuals, and we see a different response, can we understand the mechanism behind that different response? And then can we either modulate that, using things like CRISPR and genome modification, or more excitingly, take something that we just– all we know is the genome of the animal, and predict what the right dietary intervention, drug intervention might be?

So therefore, that’s really where I see this going, is rather than saying, OK, it’s intermittent fasting you should do, or it’s time restricted feeding, the answer might be different for me and different for you, right. So really, what we need to understand is how can we predict personalized medicine approach to aging? How can we predict the sort of intervention that would benefit different genotypes? And we need to start with work in the lab and build up, as has worked so successfully before.

So one of the other projects in the lab that I find really interesting, when we think about how diet affects disease risk and aging rate, is it really what the animal’s eating, or is it what the animal perceives it’s eating? So we published a paper two years ago now, or three years ago maybe, where effectively, we genetically engineered one of these nematode worms so that the energy sensor, which senses how much food it’s eating, always “thought,” in inverted commas, that it was eating less food, right.

So when you modulate this energy sensor– and this is that same protein which is targeted by metformin, which is targeted if you didn’t eat breakfast or if you ran a lot this morning, this is activated. When we activated that enzyme in every cell in the animal, they lived a long time. Even though they weren’t eating much, they were still eating as much food as they wanted to eat.

And then we wanted to ask, well, what if we changed the nervous system so in fact, the nervous system, what perceives energy intake, thought the animal was fed? And we did that genetically too. So we had this organism, this species in the lab, where the body effectively thought it was fed and the brain thought it was– body thought it was fasted, sorry, and the brain thought it was fed, and we asked, who wins?

And the winner was the brain, actually. So in fact, the perception of food intake over-won the body’s actual energy status. And so we’re really interested now in teasing this out in different systems. And what we do is when we get work in the nematode worm, and this is true for the splicing project too, the next step is then take that to human cells, take that to a more complicated model organism like the mouse, and ask, does that hold true?

And so if that’s true, it really begins to think, well, are the ways we can trick our bodies into thinking they’re eating less, even if they’re not? And this is a really interesting area of research, this balance between perception of food intake and actual food intake, and what that might mean for physiology and disease risk.

NOAH LEAVITT: So just a quick follow up there, so what you’re saying is you’re basically like, you wouldn’t have to be dietary restricted, but you could trick your body into thinking that you’re dietary restricted. How do nutrients play into that?

So I’m wondering is that something that you would explore going forward, like– because I’m guessing dietary restriction is one part of it, but if my diet is all like carbohydrates versus healthy fat, I mean, maybe those aren’t equals. So is that something that you’ve started looking at?

WILL MAIR: Well, I think this gets through to how your body processes the nutrients it takes. Really, it only has two options, it either uses them or it stores them, and that kind of acute regulation of how it uses different nutrients is really what we mean by metabolism. There are many different ways to do it, and as you age, you lose the capacity to regulate that really properly. So as you then to make the wrong choices with your metabolites, you then either store them when you shouldn’t, or you store them in the wrong place, and that leads to disease risk.

What your question is about is, is that really happening in, say, a particular tissue, which is maybe a fat storage tissue? Is it the tissue that’s making the choice, or is the brain having a part of that decision making process?

And what we do know is that there’s actual, what we call, central regulation and metabolism. The brain has huge inputs on how the rest of the body deals with its nutrients. And even different tissues communicate with each other to modulate what they’re doing in response to different nutrient intake. We have work here by the Hotamisligil lab, looking at different lipid kinds going between different tissues that can affect their ability to deal with metabolism and regulate metabolism.

So what our work, if it were true and would hold out would say, that maybe that central regulation, the way the brain is orchestrating the rest of the body, if that goes wrong with time, or if you can bring that back into check, you can actually regenerate the right decisions in an old animal, and then maybe make it have a healthier state. So really, the nutrients would end up being processed in a more youthful manner. You’d regain that homeostasis and metabolism by directing this central conductor.

If you think about the orchestra, it’s really, is it the instruments that are playing the wrong tune, or is it the conductor that’s doing the wrong thing? And our work would suggest maybe it was the conductor. So if you can bring that one person back in check, then you can maybe, again, get back to this idea of, is there a single therapeutic, or a simpler way to bring a very complex system back into check? And so that’s one thing we’re really excited about exploring.

NOAH LEAVITT: That’s really fascinating. I mean, I guess, is it surprising to you that the field has reached this point where that is something that could realistically be possible? I guess, has that been surprising to you? Or when you were doing your PhD 17, 18 years ago, is this something you actually envisioned?

WILL MAIR: I don’t know that I was that prophetic as a PhD student, but I’ll go ahead and say yes. But I mean, I think– so I mean, aging research, it’s a very interesting science to work in, because it’s so personal to everybody. We’re all aging. We all see now, relatives who suffer from these terrible, debilitating chronic disease in old age, which means there’s a lot of interest in this area.

And people, certainly as they get older– I’m turning 40 this year. I’m already beginning to feel the signs of age. So you begin to think about your own mortality. And so there’s a big push to find these interventions.

And I think what is surprising to me is that these initial studies that we used these simple genetic systems like these nematode worms, which were really cool, scientifically, and really striking and went against everything evolutionary biologists would have predicted, that you could do one thing and have such an effect on aging, that that really has translated to this incredible way, to have these shared conserved mechanisms of aging. And I think that dietary restriction is something that is a profound phenotype, for use of a better word, profound effect we see in the lab that’s really striking, and it’s really hard to ignore

If you have almost any disease model, in a mouse, say, in a laboratory, the best way to fix it is usually just to give the mouse less food. And this really couples what we see in society. I mean, when we talk about life expectancy raising across the globe with time, actually, we know that in different states in America that it’s not raising as fast as other places. We know that obesity and metabolic dysfunction can lead to an increased risk of aging related diseases in people who are pretty young, not just diabetes, but also neurological disorders and cancer.

So there’s a clear interest, in the public, in the links between both age and disease, and nutrition and disease risk. And so therefore, this is something that becomes– it pushes the science even further, and I think that’s a great thing.

NOAH LEAVITT: And I think you touched on it there, but I’d be interested in how you look at linking your work to public health in general, whether it’s working with nutrition, or maybe it’s understating social determinants of health. As you mentioned, I mean, life expectancies can vary by geography. So how do you look to take what you’re doing in the lab and then work with others, in different disciplines within public health, going forward?

WILL MAIR: So we’re beginning to do that, as I mentioned. We have some work to try and– what we’d like to do is move in these iterative cycles between work on human populations, on big data, on genetic epidemiology, on nutrition. There’s people at the school that have huge data sets on different patients’ response to metformin, which is a drug that’s used to treat type 2 diabetes. One of the targets– indirectly– but one of the things that metformin does is activate the same gene that we use in our lab to make animals live longer. It’s a gene that’s activated under exercise.

So there’s this shared biology linking all these different things. And what we need to begin to do is to take that and make this cycle where we go backwards and forwards, and really make connections to those people working on nutrition and disease risk, those people working on metformin on aging populations, and go, look, now we can really test causality.

What we really want to do is not just end up with this host of studies of, this gene variant is found more often in one place than another, and go, well, look, we can take that and we can recreate that variant in the lab, explain it, try and understand the biology, and then take that back to maybe effecting change in what we do in social studies. So I think it’s a very exciting time now to bring these disparate fields together, and this is a unique place to do that here.

NOAH LEAVITT: What is your biggest unanswered questions? What are the biggest questions that, I guess, you’re most passionate or excited about answering in the years ahead?

WILL MAIR: So one of them I touched on I think. So we published a paper in Nature last year which was looking at a process called RNA splicing and aging.

And basically, to explain in a fairly simple concept what RNA splicing is, so when the Human Genome Project was going, one of the most surprising things that we found was actually, we didn’t have that many genes. We have about, as I said, 22,000 or so genes. But in fact, in our bodies, those genes then make proteins, and there are hundreds of thousands of proteins. And so we make this diversity by taking these genes and moving them into different combinations so that you make different proteins.

And we published a paper last year showing that this complicated system, which is called splicing, so splicing about the different sequences of genes, can actually– goes wrong in aging and can cause aging phenotypes, is protected when you dietary restrict the animals. And actually, some of the machinery that cause the splicing process are directly responsible for the diet restriction effect, and if you target them, you can make an animal live longer without the dietary restriction.

So that was a cool paper. But buried in the beginning of that paper was a piece of data that was really interesting to me. So one was that we could look at young animals, look at the different splicing combinations of a particular gene, and basically assign a population, of very young– this is nematode worms again– animals into two different populations, one that had de-regulated spicing and one that had a youthful splicing.

And then we could age them out in a blind fashion. And these animals all have the same genome, they’re all eating the same food, they’re all in the incubator at the same temperature. But we could predict which ones would live long and which ones wouldn’t, from this one splicing event in really early animals.

So you could really– one of the most curious things about aging is the variance in individuals. So even in these nematode worms who had the same genome, some live and age and die at 13 days, and some live and age and die at 22 days. That’s a big difference. And using this splicing variant, we could predict it. So this was almost a biomarker of life expectancy.

So that’s cool biology, but again, when we think about– we don’t care about worms. We think about translating this to therapeutics. What would that do, if we could do that for me and you? I mean, for me, if you go, OK, Will, you’re turning 40 this year, but really, you’re turning 50 biologically, or really, you’re turning 30 biologically, I can be happy or sad about that and maybe exercise a little bit more, but really, what do I do with that information?

What I would like to do– and it’s a focus of our lab that we’re beginning to do. We’re looking for funding to really build on– is to take those sorts of readouts and, as we talked about, can we then predict whether you’ll respond to this diet than another, to this drug than another, this genomic intervention.

And so we know we have lots of ways in the lab, not just from our work, from many other labs, to make animals live a long time. However, they work differently in different things. Some ways only work in males, some only work in females, some only work in old age, young age.

So what we really want to do is predict, from some inherent, easy to look at read out, what the intervention should be, so what the personalized anti-aging medicine for a person or an individual would be. And that’s a really exciting opportunity that requires the integration of many disciplines. It requires huge statistical capacity, computational capacity, genome editing, which we’ve suddenly had this revolution recently in the last three or four years of CRISPR genome editing, which is wonderful for doing these sorts of questions.

So that really is where I want the research to go, to really go– so rather than having– at the moment, things we do to make an animal live a long time is the equivalent of treating a 10-year-old for Alzheimer’s, right. None of us want that. We want something which we can translate to a therapeutic in someone who’s old, presenting a diseased phenotype, and can reverse some of the problems in that disease.

And also, we can predict ahead of time whether it will work or not. That’s a big question, but that’s one that really is the exciting opportunity for me, and I think we actually have ways to do that now.


That was our interview with Will Mair on the science of aging.

And if you want to learn more about his lab’s work, we’ll have more information on our website,


And that’s all for this week’s episode.

A reminder that you can always find us on iTunes, Soundcloud, Stitcher, and Spotify.

March 29, 2018 — We often think of aging as an inevitable physical decline; as we get older our bodies break down and diseases begin to multiply. But what if that wasn’t the case? What if we could change how we age and make our later years healthier and fulfilling? That’s the question we explore during our in-depth conversation with Will Mair, associate professor of genetics and complex diseases. Mair’s Lab explores the basic biology of the aging process—trying to understand why we are more likely to get chronic diseases when we are old than when we are young. They seek to understand what is actually going wrong in our cells and tissues to increase the risk of age-related disease, and then work to find ways to reverse that. It’s fascinating research that has the potential to change how we think about aging and age-related diseases.

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Learn more

Why do we age? Surprising revelations from a worm (Harvard Public Health magazine)

Uncovering a ‘smoking gun’ in age-related disease (Harvard Chan School news)

Manipulating mitochondrial networks could promote healthy aging (Harvard Chan School news)