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Geroscience and it's Impact on the Human Healthspan: A podcast with John Newman



Ok, I'll admit it. When I hear the phrase "the biology of aging" I'm mentally preparing myself to only understand about 5% of what the presenter is going to talk about (that's on a good day).  While I have words like telomeres, sirtuins, or senolytics memorized for the boards, I've never been able to see how this applies to my clinical practice as it always feels so theoretical.  Well, today that changed for me thanks to our podcast interview with John Newman, a "geroscientist" and geriatrician here at UCSF and at the Buck Institute for Research on Aging.

In this podcast, John breaks down what geroscience is and how it impacts how we think about many age-related conditions and diseases. For example, rather than thinking about multimorbidity as the random collection of multiple different clinical problems, we can see it as an expression of the fundamental mechanisms of aging. This means, that rather than treating individuals diseases, targeting aging pathways may be a better way to prevent or ameliorate multimorbidity. We talk with John about this, and current trials underway to test this hypothesis, along with so much more!

If you're interested in taking a deeper dive in the subject, take a look at these papers that John co-authored:
by: Eric Widera (@ewidera)



  


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TRANSCRIPT

Eric: Welcome to the GeriPal PodCast. This is Eric Widera.

Alex: This is Alex Smith.

Eric: Alex, we have someone in our studio audience ... our office studio? Our studio-

Alex: Our office studio? We have John Newman, who's a geriatrician and geroscientist-

Eric: A gero-what?

Alex: A geroscientist-

Eric: A gero-what?

Alex: A geroscientist who has held a joint appointment between UCSF and the Buck Institute for Aging Research. Welcome to the GeriPal PodCast, John.

John: Thanks, guys. Thanks, Alex. Thanks, Eric.

Eric: I'm really interested in figuring out what a geroscientist is. But before we do that, can we have a little song request for Alex?

John: Yeah, what should we sing about? Do you know a little song called Who Wants to Live Forever?

Alex: Ah, more Queen.

Eric: Boy, you can never get enough Queen.

Alex: Maybe our audience can. (singing).

Eric: John Newman does, right? John Newman wants all of us to live forever. At least that's why I am currently, those who are watching this on YouTube, can see I am getting fresh stem cells from my baby farm that I get infused every day, so I can live forever.

John: We're transfusing you as we speak.

Eric: As we speak.

John: As we speak.

Eric: Yeah, I give John hefty amounts of money for those baby transfusions.

John: Hey, that deal's just for you, Eric. Don't go advertising me.

Eric: So John, geroscience. What is this field, and is it about living forever?

John: It is not about living forever. It's about living healthier, longer, and staying independent. So what is geroscience?

Eric: That, I have no idea.

Alex: That's, I don't know.

John: I thought I was here, so you guys would tell me.

Alex: Gero ... Gero-

Eric: Gero- so, older.

Alex: Ger, Jerry, Ben and Jerry's.

John: Aging ... aging science.

Alex: Aging science.

John: Aging science with a flavor of people.

Eric: So what is the difference between you and Alex? You're both researchers. Is Alex a geroscientist?

John: Well, geroscience is a, it's a made-up word which was coined for a new field, and a whole new idea, which is now reality. Which is going to sound a little crazy. Taking what we know about the biological mechanisms that drive aging. The biology of aging.

John: And not only understanding that, which itself sounds a little crazy. But actually turning that into therapies, to help to treat or prevent disease, or help to improve the lives, especially of older adults.

John: Geroscience is the idea of translational geriatrics, taking what we know about the basic science of the processes that drive aging. And turning it into therapies and helping to improve people's lives.

Eric: The processes that ... Okay. As I age, I start developing some chronic medical conditions. They start building up. I have more and more medical conditions. If only I could just focus on making sure I don't develop those, or I treat these well; like diabetes, COPD. Would I prevent aging? Is that the goal here?

John: Well, one place this comes from is, what's that common underlying factor that's putting you at risk for COPD and for diabetes and for Alzheimer's disease and for cardiovascular disease and for strokes? And for osteoarthritis and osteoporosis? And for almost everything that we treat.

Eric: Nacho cheese Doritos?

John: That's a big one! That's a big one.

Eric: But there's more.

John: But what's the common variable for all of those? We call these age-related chronic conditions or age-related diseases.

Eric: Yeah.

John: Because they're all driven by aging. The key thing is that's not an accident or it's not just like a probability thing or it's not just time passing. But it's actually the biological mechanisms that change in our bodies as we get older that make us what we perceive as older. There's a biology there. And that biology puts you at risk for all these different chronic diseases.

John: You could try to treat or prevent all of these individually. But, if you're not changing, if you're not affecting the aging that's driving all of them, there's a limit to how far you can go with that, or how effective it's going to be.

John: You prevent diabetes, but you get cancer. You cure Alzheimer's disease, which would be amazing, but then you have a stroke. But if you intervene on the aging that's behind all of this, then maybe you can slow or delay or prevent all of these together. That's the great hope of geroscience.

Alex: Is delay or preventing aging ... Earlier, you said that it's not so much about living longer, as it is improving healthy years of life. And yet, but what you just said was, "delay or prevent aging." I'm a little lost there. Can you help me out?

John: Well, delay or prevent all of the diseases and conditions that are driven by aging. So, targeting aging as the underlying biology that causes or contributes to diabetes, dementia, cancer, heart disease, and all of that.

John: All of that might wind up helping you live longer; who knows. But that's not the goal.

Alex: Ah.

John: The goal is to be healthier for longer.

Alex: Oh.

John: To spend, so we all can spend more years independent and being able to do the things we want to do in a state of better health.

Alex: It's like the principle of the double effect. For those palliative care listeners, right, the primary ... right? We're relating the subject to you.

Alex: The primary intended target in the principle of double effect in palliative care is often opioids for pain relief. And yet, as a secondary effect, if the patient dies sooner, that's acceptable.

Alex: Your primary intended effect is to treat the disease that are associated with aging; the conditions that are associated with aging. As a secondary effect, if people end up living longer, then that's fine too. But it's not the primary target of geroscience?

John: I love that analogy. Living longer may wind up being a side effect of being healthier longer. But when you talk about ... Aging is a weird subject, right? Because it's this, it's not a disease. It's not a bad thing. There are many many positive elements of aging. I am happier now than I was 20 years. Hopefully I'll be even happier 20 years from now, even if I can't jump as high.

John: Aging is not a disease. It's not a bad thing. And yet we're trying to target, almost to treat it. The goal is if we can slow or reduce the bad aspects of aging, the parts of aging that give rise to chronic disease. And you're living healthier longer, you'll probably live longer, too, in good health.

John: When I go to a room and I ask people, "We're talking about aging as a target for therapies. Who wants to live to be 200?"

John: Not a whole lot of people raise their hands, because most of them are thinking, "I'm not sure how I'm going to feel when I'm 95 or 85 or 75. You extrapolate that out, and what am I going to feel like when I'm 200?"

Alex: Right.

John: That doesn't seem like a great choice. But if you ask people, "What if you could have the health that you have now, or the health that you had when you're 60, or the health you had when you're 50? And just keep that for longer?"

Alex: Uh-huh.

John: Most people would volunteer for that.

Alex: Interesting.

Eric: I just want to make sure that when you ... When I hear "aging," I think probably the common definition is, I'm getting older.

Eric: When you hear the word "aging," what do you mean by aging? Especially as we're targeting aging? I can't target the clock; I guess I could target my clock and just turn it around. What do you mean when you say "aging"?

John: Well, here's the geriatrician's perspective. How do we know what "old" is, what an older adult is, for making a clinical decision, for example?

Eric: Yeah.

John: For thinking about prognosis, for example. There's someone I know who's done a lot of work around prognosis and how to estimate someone's life expectancy.

Alex: I don't know who you're talking about [laughter].

John: Yeah, the name, it's right on the tip of my tongue. So how do we know? Of course, we know that someone's birthday doesn't really help a whole lot with that stuff. There's 85-year-olds who are very fit and active and healthy and young. And there are 85-year-olds who are not very young. What makes that difference?

John: In geriatrics, we think of things like functional assessments. Mobility and ADL function, idea function, frailty, trying to get that certain aspect of what does it mean to be older, to have an advanced stage of aging? Geroscience and aging biology is sort of the molecular reflection of that.

John: If we know that you have two 85-year-olds, and one of them needs help with ADLs, they're going to be at risk for complications from surgery. But not necessarily because they need help with ADLs, but because that reflects their biology. The stage of their aging.

Alex: Right.

John: We're learning more and more about what that biology really is.

Alex: Right.

John: Is it their telomeres, for example? Like Eric said earlier. Or how many senescent cells they have in their body. Or what is their NAD reserve? What is the state of their chronic inflammation? How are their proteins folding? What is their proteostatic resilience?

John: We're getting closer to be able to understand what all of these biological aspects are, so we can look at someone who we think, "Is this person an old 85-year-old or a young 85-year-old?" And know what their biology tells us.

Alex: I don't want to ... I mean, I don't want to belabor this point. But I know some of our listeners are probably skeptics. We have one skeptic, a nurse practitioner on our hospice and palliative care service. Patrice Villars. We mentioned we were doing this podcast.

Alex: And she said, "Is it," something along the lines of, "is it morally responsible to focus on helping people to live longer, given the current burden of climate change that humans are placing on the planet currently, much less if we were to live longer lives?"

John: I love that question. I love ... Aging is a really unusual field to study, because it's, again, it's not a disease. It's something universal that happens to all of us. That does make it a little bit different, and opens up these really interesting questions about not only how to study it, and what our goals should be; but also how to ...

John: If we have therapies that effectively target aging, target mechanisms of aging, who gets them? How do we decide how to use them? How do we decide who should have them and who doesn't get them? Is that different from the way that we decide who gets other treatments? These are really interesting questions.

Eric: In the work that you do, I'm guessing ... because I think this is a really fascinating thing to do, like if you extend the life, even 20 years, the ethical issues that come up. Even from a population density standpoint, can our earth even handle that? Then who gets all these treatments? In the field of geroscience, are there ethicists in that field, too, that are looking at these questions?

John: Yeah. This is a brand-new field, an emerging field. There are ethicists who are particularly thinking about these questions. Not very many, in the same way there's not very many clinician scientists who are helping to develop and study these therapies.

John: But there are people who are just starting to really think about, because these questions; even five years ago, this would have felt like a really academic philosophical kind of discussion. Therapies that target aging. Sure, let's maybe 10 years, 20 years down the line.

John: But the crazy thing is the first clinical trial that takes a drug in this case, that targets a cellular mechanism of aging, was given to older adults to treat a chronic syndrome of aging. That clinical trial, that first clinical trial has already been done.

Eric: What are they doing?

John: This was a drug that targets protein quality control. It's a drug called Rapamycin and its related drugs. We can talk about how this fits into the bigger scheme of mechanisms of aging. But it helps to activate pathways in your cells that clean up misfolded proteins and help your cells to make proteins that are more functional.

John: This drug and a related drug were first given to older adults before flu vaccine, to see if it would improve response to the flu vaccine. And it did. Then the next step, they did a clinical trial where they treated people with these drugs for just a month, and then gave them a flu vaccine, and saw that it improved their response to a flu vaccine.

John: But then over the next six months, they saw how often they got respiratory or other infections. What they actually found was that the people who received this treatment just for a month had about a third fewer infections over the next six months. So it had this really interesting long-lasting effect on their immune function in these older adults. It was helping to ameliorate what we call immunosenescence, the decline in function of our immune systems as we get older.

John: It's a really small, limited thing. One drug, some older people, flu vaccine, it was just looking at infections. Doesn't seem like a big deal, and it's not. Except it was the first randomized controlled trial of a drug like this that targets mechanisms of aging in older adults, to improve syndromes of older adults.

Alex: And it's already happened.

John: And it's already happened.

Eric: I guess that's probably the hard part with this is that I would imagine you can't do a randomized controlled trial with this drug for 20-year-olds and wait 90 years to see what happens to them. And then market that drug after a hundred years.

John: Exactly. I mean, hey, the average R01 lasts for five years.

Eric: You need results quick.

John: You need results quick.

Alex: RO1, for our listeners who don't know, that's the big NIH research grant.

John: How do you even, how do you study ... Let me back up a second. Many of your listeners are probably, sounds like crazy that we're even talking about studying aging in the laboratory. Like, is this really a thing we can do?

Alex: Right.

John: The answer is yes. We've been studying aging as a process, as a biological process in the laboratory for decades now. That's using the whole panoply of modern science to do that, from using model organisms where we can manipulate their genes and look for genes that control different processes. And high-throughput drug screening and using pre-clinical models like rodents, even primates.

John: We've been studying aging in the laboratory for a long time. And that's helped to give us a good sense of what is the biology that happens? What are the pathways? What are the genes? And, figuring out in the laboratory leads to how to change these things. How to change the genes. Or how to give drugs that target the pathways, to broadly affect aging.

John: So we're already studying aging as a scientific target. But then the next step is, you have some stuff that looks interesting in the lab. Who cares? We can make mice live twice as long, we can help monkeys and non-human primates to be healthier for longer. We can make worms live four times as long. It's amazing what we can do with worms.

Alex: That's an old worm!

Eric: It's like four days.

John: Worms actually live about, the worms that we used as the laboratory model, which is a little tiny roundworm called C. elegans, lives for about three weeks normally.

Eric: Three weeks.

John: But you can make it live for three months.

Eric: Wow.

Alex: Wow.

John: By just changing one or two of its genes. It's incredible.

John: Even more incredible ... "Hey, what do worms matter? I'm not a ..." Well, I'm sort of a worm, but I'm not entirely a worm.

John: You know what the very first ... A researcher here at UCSF named Cynthia Kenyon, when she was at UCSF a couple of decades ago, was the first person to set out to find genes that regulate aging. She decided to use the worm as a model organism, because you can do very powerful genetics with worms. To look for genes that control worm aging.

John: And what do you think she found? What do you think was the first gene, actually? The first hit? It turns out that this is still the gene that has the biggest impact on a worm's life.

Eric: I'm going to pass this question to Alex.

Alex: I was thinking of something snarky to say. But ... I have no idea.

John: It's the apple sensing gene ... what do worms like to eat?

John: ... But no, so the first gene found in a worm, remember .. that regulates aging is the worm version of the insulin receptor.

Eric: Oh.

John: It turns out that worms have fewer genes than we do. They have the same receptor for their version of insulin and insulin-like growth factor, IGF. But it's the worm insulin receptor that is still the single gene that has the biggest impact on a worm's life span, and a worm's health as it gets older. And it turns out all the genes in the insulin pathway have huge effects on worm health and worm life span.

Eric: I mean, is it just because we're making diabetic worms who just die from ... How do you tease out, like ... If I create something that kills worms because they become ... I don't know if worms become hyperglycemic, but let's just say that. Is that an aging-related issue, or did I just create this new acute to chronic condition that's going to kill them?

John: We have some reasonable idea how this works in worms because you can kind of ... you could-

Alex: Swap genes around in worms. Chop them and stuff.

John: Yeah, chat with them. Talk about their goals in life and that sort of thing. So the way this mostly works has nothing to do with glucose regulation. It's metabolism linked, but it's not about hyperglycemia. It's actually about stress response.

John: Worms with less insulin signaling ... I'm calling it insulin but it's the worm insulin IGF pathway ... with less activity through that pathway. How worms are more resilient to all sorts of stresses. So they turn on all these genes that help them to repair their DNA, repair their protein, and they go through life in better shape from when they're young, all the way up to when they're old.It's not about the glucose control, but it's about this receptor is a trigger for all of these stress response genes.

John: It turns out we have very similar genes. And it's interesting that in worms, this insulin IGF pathway is so important and we can see this in mice, too, in mammals. That if you change how they signal through IGF, especially, with all sorts of insulin pathways, you can affect these stress response genes, these repair genes.

John: And either make mice live longer, or shorter. The analog with humans, so there's a group in New York, at Albert Einstein who studies centenarians; humans who live in reasonably good health into their late 90s and hundreds. They've been looking for the longevity gene; what's the secret?

Alex: Mm-hmm (affirmative).

John: What do these folks have that makes them healthy to 100? We know pretty well now it's not one thing; there's no one gene that controls our life span.

Alex: Right.

John: When they look for patterns, the strongest pattern they see is that these centenarians all have some sort of change in their own insulin IGF signaling pathways, just like the worms did. And probably doing the same thing: affecting ... Oh, talking about dual target effects, Alex. Affecting their glucose metabolism, sure. But also affecting their stress response genes, and how they can keep their proteins repaired and their DNA repaired.

Eric: Do centenarians beget centenarians? Is it a ... If I live to 100, my kids are likely to live to 100? I can imagine there's also all these social determinants of health that also influence that?

Alex: Right, right, right.

John: Yeah. Yeah.

Eric: Is there a connection there?

John: There's a lot of discussion about how much of longevity is genetic. And I think the best answer is some of it, yeah. Probably less than we think, because probably a lot of that is confounded by the social determinants of health, which are huge in determining how you age.

John: But there's definitely a genetic component to it, too; we know that somewhat from twin studies, for example. There's definitely no aging gene. But it does seem like there are patterns in genes that can be inherited, that can help some people ... some people win the genetic lottery and will help them to age in a more healthy way. And other people have different genes.

Alex: You mentioned earlier there are some people ... you mentioned who is going to have access to these treatments and medications. This is a very important question.

Alex: There's some money flowing into this field, right? Isn't Larry Page, didn't he start a company, something about this?

John: There's a; well, for example, there's a company called Calico-

Alex: Calico.

John: ... which is not part of Google, but which is related some of the founders of Google. With which is who are very interested in this idea of therapies that target aging. There's a lot of interest in this field. I mean, it's, aging attracts all sorts of folks.

Alex: Right.

John: It certainly attracts folks who want to live forever, or want to try to find that secret to stay young forever.

Alex: Right.

John: But there's also a lot of folks who are in it to try to help the complex and sometimes intractable problems of aging that we see, and just give us better tools to do that with.

Alex: Right.

John: It attracts all sorts of folks.

Alex: Right. So there is a concern here about who will these treatments go toward, and with many other treatments in medicine, we've seen them go towards the best-off groups; worsening disparities rather than-

Alex: ... addressing them. I imagine there's a similar concern here.

John: Absolutely.

Alex: Yeah. I also wanted to touch on what is not geroscience? And ask you if you could talk, because for years, decades, centuries, there have been people who have been purporting this, that, and the other that treats aging. This anti-aging, that anti-aging.

Alex: Is that all geroscience? Or is there some line you'd like to draw on the field to keep some things out? [laughter]

Eric: Is Dr. Oz a geroscientists? [laughter]

Alex: Right.

John: Oh, no. Don't ask me about Dr. Oz. And don't Google anti-aging, or search for that on Amazon.

John: I mean, geroscience and the community of physicians and researchers and clinician scientists who are trying to create this field, the whole idea of geroscience is evidence-based medicine. We think we have real biology, and we can show this in the laboratory. Real biology that affects fundamentally the processes that drive aging.

John: I'm being careful not to say, we're not trying to cure aging. Aging isn't something we can cure, make go away, or stop. I don't even like to say we're treating aging. But we're treating the mechanisms that drive aging. The mechanisms that create what we see in each other as getting older.

John: But the whole idea of geroscience is turning this into from a really kind of flashy, maybe, but weird philosophical controversial field; and just turning it into another boring area of medicine, where we're just cranking out ideas, we're creating potential therapies and drugs and other things. We're testing them in clinical trials for outcomes that matter to people. And we're finding some things, hopefully in the end, to help to improve people's lives.

John: The whole idea that this is grounded in old-fashioned data-driven RCT-validated medical science. So what do we know right now, for how you can cure your aging?

John: Nothing. Well, I shouldn't say nothing. We know that for example, exercise is amazing. You can even cite plenty of randomized controlled trials for the benefits of exercise. And we know that intersects with the biology we're talking about, the biology of aging. I mean, exercise activity are amazing. If you want to try to improve your autophagy and your telomeres and your senescent cells and everything, exercise is the best evidence-based way we know to do all of that right now.

Alex: How about diet? Mice fed fewer calories live longer than mice fed a regular mouse diet. Right?

John: Yeah. Yeah. This is fascinating. This is the other undergirding pillar of the science of aging. This goes back almost a hundred years now.

John: One of the very first experiments that tried to make animals live longer in the kind of modern age of science, involved feeding rats less food. And seeing that they actually lived longer the less they ate. Up to a certain point where they actually starved; they died. But as long as you don't hit that point-

Alex: Right.

John: ... you feed them less and they live longer. Those experiments were done in the 1930s. A lot of the field of aging biology has been trying to understand why that is. We know a lot about that now.

John: We know it's not actually about eating. It's not about how much you eat or what you eat. These are ways that you or I can influence the biology, but that's not why they have biological effects. It's because of this close relationship in our cells and in all organisms between nutrition and mechanisms of aging and repair.

John: Eating less, or feeding rats less food, or fasting, the idea behind all of this, is that these are sensed in your cells as there's less energy around. There's less stuff around. All of our cells, all the time, have to make this choice between if there's a lot of energy around, a lot of nutrients, I want to grow and I want to divide and I want there to be more of me. I want to reproduce.

John: If there's not a lot of nutrition around, those cells hunker down and they just want to survive. The best way to do that is to turn on repair, to keep what you have in good shape.

John: Fasting, or feeding rats less food or feeding a worm less food, these are ways to activate these repair mechanisms and cells. But now, we know what these mechanisms are. We know the genes, the pathways, the proteins that are actually involved. And we can, for example, design drugs to target these mechanisms directly.

John: That gets back to ... Remember what I talked about the first, what we're going to remember in history as the first geroscience clinical trial?

Alex: Mm-hmm (affirmative).

John: Using a drug called Rapamycin and another drug like it. These are protein sensors. They actually affect the genes in our cells that sense how much protein is around. If there's a lot of protein in food, this protein complex senses there's a ton of protein around. I should build stuff; I should build muscle.

John: If there's not a lot of protein around, then this complex turns off, and it tries to repair what you have instead. Rapamycin short circuits that. It tricks the cell into thinking that there's not a lot of protein around; I need to really focus on preserving what I have.

Alex: Right.

John: So it helps to keep your proteins in good shape. It turns out that's better for aging. There are times when we need to grow, and we need to get bigger.

Alex: Huh.

John: This protein sensor, which is called TOR, Target of Rapamycin, if you want to put on muscle mass after you exercise, or if you want your patient who's rehabbing in a nursing home, to rebuild their muscle strength after a surgery-

Alex: Right.

John: ... they need to eat protein and activate this TOR complex to turn on muscle synthesis. But you don't want that all the time. Most of the time, you want to repair what you have.

Alex: Right.

John: A drug like Rapamycin gets right in there and turns on the repair mechanisms.

Alex: Right.

John: That helps to keep an organism and keep cells healthier as they get older.

Alex: Is there an issue here with developing drugs to help humans deal with issues that we should be ... attending to using lifestyle modification? Exercise, changes in diet, et cetera?

John: I love that question. That's also a question we get often asked. If so much of what we study at the molecular level in the aging field has to do with nutrition and exercise; which much of it does, much of it is linked; so why can't we just have everyone live the perfect life?

Eric: Or, have access to healthy foods in those food deserts throughout the world. Or for those who don't have access to food.

John: I think of this in a couple of angles, right? One is, when's the last time you guys prescribed an anti-hypertensive or Metformin or aspirin or a beta blocker for someone with coronary disease or diabetes?

John: I mean, there are many, this is one of the things that we all have to grapple with in our society. Many of our chronic diseases of aging are at least exacerbated by environmental factors and lifestyle factors related to that.

John: But we generally don't hesitate to ... Sure, we would rather that someone be more active and get the most benefit they can out of these lifestyle changes. But we also use drugs. And we don't generally hesitate to do that, because you certainly don't want to let someone stay hypertensive while they're trying to lose weight. So we do both.

John: But I think that there's always going to be a role for pharmacological therapy to augment lifestyle changes. But then there's the other issues that ... Not everyone gets the same biological response, even, to activity or exercise or fasting.

Alex: Right.

John: It may work for some people, but not others. And then you and I, we all know that this stuff is not determined by willpower or by gumption or whatever. There are real barriers, including many of the things we refer to as social determinants of health, which can prevent people from being able to live a healthier lifestyle.

John: I think that understanding how that affects them biologically can hopefully help us as a society to change things; to make it easier for people to eat real food and to live a more active lifestyle. But still, there's always going to be people that just aren't able to do that, and need some help.

Alex: Right.

Eric: You mentioned Metformin. That's also a drug, right, that-

Alex: I've heard of that one.

Eric: Yeah, that has something to do with ... I don't want to say anti-aging. Geroscience?

John: It does. It does. The perspective of a geroscientist is that Metformin is a drug that affects mechanisms of aging, and lowers blood sugar as a side effect.

Eric: How does it do that? How could it do it?

John: Well, Metformin is ... Believe it or not, even though we've been using Metformin for decades; and millions of people take it, and we have all of this data about how it affects people's health, often in a good way, especially with diabetes. We still don't really know exactly how it works.

John: We have a few ideas. It may be more than one thing. But several of the things we know are that it gets into this whole, the same idea of nutrient sensing. Metformin helps to trick your cells into thinking there is not a lot of energy around and not a lot of sugar around. So it helps to make your cells more sensitive to the energy and sugar that's there.

John: It also probably activates some of the same protein quality control pathways that Rapamycin does. There's some evidence that it works in mitochondria, for the same thing. So kind of optimizing how your cell uses energy, and helping to turn on some of these repair pathways that are affected by energy metabolism.

John: It turns out a side effect of that is that Metformin sensitizes your body to insulin, and lowers blood sugar. That always gets me back thinking to those worms, right?

Alex: Mm-hmm (affirmative).

John: With their insulin IGF receptor and how important we know that insulin signaling is to health and longevity in general. Metformin seems to be one of these drugs that gets at that mysterious root biological problem of diabetes; the idea of insulin resistance and metabolic dysfunction that we still don't entirely understand. But which I think is pretty closely related to mechanisms of aging.

Eric: I guess the question I got is like, we're developing these drugs but it also seems like you have millions and billions of years ... Well, I guess not billions ... but to evolve, and to develop-

John: Yeah.

Eric: ... all these mechanisms that if we take something, there's always going to be a side effect. Even in those worms that you talked about earlier, it sounds like there's got to be a trade-off, right? There's a reason why they only live-

Eric: ... three weeks versus 12 weeks.

John: Yeah.

Eric: Is there a reason? Why didn't evolution build 12-week-living worms instead of three-week-living worms?

John: We should ask the worms.

Eric: I've tried. Birds keep on eating them.

John: Well, one thing we know is that there is no perfect genome, there's no perfect diet, there's no perfect lifestyle. Nothing is always good; everything has its own context, right?

Eric: Yeah.

John: What we're talking about with protein sensing; this is my favorite example of this. Like in general, for most of your life, you would rather be repairing your own proteins than building new ones. In the laboratory in animals, we know that doing that helps to delay, helps to prevent metabolic disease in animals, helps them live longer.

John: But there are times when you actually need to build muscle. There is a time and a context for everything. There's a song about that, isn't there, Alex? There's a right time and a right context for everything.

John: Evolution may have optimized us for a certain environment. But our environments are different now, and what we may need from our bodies at different times may be different now.

Eric: Yeah.

John: And we're starting to learn how we might be able to help our bodies to do that.

Alex: I have two more questions. One is, we talked about a lot of treatments that are effective in rats and mice and worms. And a clinical trial in humans. Are there any treatments out there that are closer to being ready for prime time?

Alex: In humans?

John: There's a bunch of treatments which are in clinical trials now. We should talk a little bit about this: how do you test something that you think affects aging broadly, right? Eric was suggesting that we run an 80-year clinical trial; we start, we enroll-

Eric: Yeah.

John: ... college students.

Eric: 20-year-olds.

John: Randomize them.

Eric: That way they've built up their muscle, we're in repair phase now.

John: Exactly.

Eric: Instead of building phase.

John: Yeah.

Eric: See, I'm learning something, John.

John: There we go.

Eric: Watch them for 80 years.

John: So there's ... How do we ... How would you even design a clinical trial?

Eric: Yeah.

John: There's a lot of folks a lot smarter than me who've been trying to think about this. Many of them are geriatricians, and if you want to test whether something broadly affects aging, then you want to look at outcomes that broadly represent aging.

John: What do we think of as, what are the ... Sorry, I'm a scientist ... what are the phenotypes? What are the conditions or the syndromes that we think of as most representative of-

Alex: Right.

John: ... aging as a whole?

Alex: Frailty.

Eric: Frailty.

Alex: Multi-morbidity.

John: Yeah.

Alex: Cognitive impairment. Disability.

John: Yeah. Functional status, ADLs. Yeah, exactly.

Eric: Hearing, vision.

John: One of the ideas is using these sorts of complex syndromes, complex multi-factorial syndromes, which represent aging; using them as outcomes in clinical trials. If you ... that actually is ... It might be an effective way to run a clinical trial, because you could really see if you affect something like frailty in just a couple of years. Or something like multi-morbidity, as we'll talk about.

John: It also makes sense biologically. What is a geriatric syndrome? Geriatric syndrome, it's a common phenotype; something like a fall or delirium or dementia or cognitive decline. Which has many causes. They're multi-factorial. They're caused by problems or changes in a bunch of different organs, a bunch of different tissues.

John: How do we treat these things as geriatricians? We try to identify all of the underlying contributors we can. Like, how do we prevent delirium in the hospital? We try to treat all of the things we can think of that might be contributing to delirium. So we try to address all of the multi-factorial issues.

John: Maybe we can do that biologically, too. If you have a therapy that targets aging mechanisms, that for example, helps to improve your protein homeostasis. That's not just good for ... So proteins misfold in Alzheimer's disease, right?

Alex: Right.

John: But they also misfold in your heart, and they misfold in your kidneys, they misfold in your pancreas. Something like a fundamental process like protein misfolding affects lots of different tissues.

Alex: Yeah.

John: Maybe if you're trying to help a complex multi-factorial syndrome, maybe you need to use a treatment that could address or help a bunch of those contributors all at once. That's the idea. Use therapies that target aging mechanisms, and then geriatric outcomes. Things like frailty-

Alex: Right.

John: ... ADL function as outcomes in a clinical trial.

Alex: Right. Are there any current treatments or medications that are in testing?

John: One group are these protein sensors; they're Rapamycin and similar drugs. Another drug in testing, if not right now, soon, is actually Metformin. The idea is that if older adults ... This is called the Targeted Aging with Metformin Study, which hopefully will be getting underway soon, if it's not already underway.

John: It's going to use multi-morbidity as an outcome. The idea that Metformin doesn't just affect diabetes, but it might, is what they're going to test. It might slow the onset of other chronic diseases like cardiovascular disease. Which we already have a good hint it does. Or dementia, or cancers.

John: Older adults will take Metformin for several years. Older adults who are already at risk for multi-morbidity, and then they'll follow and test whether Metformin slows the onset of multi-morbidity.

Eric: So the trials; are there some things that we should just be recommending that right now, the targets? It sounds like exercise-

John: Absolutely, exercise. No dose too small, never too old.

Eric: Never too old. Diet? Do we have any firm recommendations on diet? Ketogenic? Intermittent fasting? Just eat healthy?

John: What does "eat healthy" mean?

Eric: Everything in moderation, including moderation. That's my own feeling.

Alex: Mark Twain, one-upping the Buddha.

Eric: Yeah. More greens, less meat, wasn't there a quote from-

Alex: Eat plants.

Eric: ... eat plants-

Alex: No, "Eat food, mostly plants. Not too much."

John: "Eat food, mostly plants. Not too much." Yeah.

Eric: Yeah, that seems, that to me is the epitome of a healthy diet right there.

John: That's good. I think that's good general advice. I mean, diet's not a controversial field at all. It doesn't evoke passions [sarcasm]

Eric: No, no, there's no money in it, either, so.

John: None at all. I've never seen a book suggesting what diet people should eat.

Alex: Never.

Eric: There's a lot of talk about intermittent fasting.

John: There is. There is. This is also a subject, actually, of clinical trials. There is a large randomized controlled trial that's finishing up now that took healthy middle-aged adults; not obese; healthy. And put them on a dietary restriction regimen. Just like some scientists did with the rats 80 years ago, to see what effect it had on the health of already-healthy non-obese middle-aged adults.

John: We're starting to study some of these diet things in clinical trials. There's a few interesting studies about using ketogenic diet in certain dementias. There's some interesting studies about different fasting regimens in metabolic disease; in diabetes especially.

John: Outside of the diabetes world and the weight loss world, there's not a whole lot of data yet on how these might be useful. They might be. But the thing about diets is that everyone responds so differently to different foods and different diets. It's really hard to imagine that a diet intervention; even something like fasting, is going to become the sort of thing that you could just prescribe in the same way that you would prescribe a drug for a condition.

John: But one of the interesting frontiers is if you could figure out who might get certain health benefits from different patterns of eating, which we're really bad at right now. But maybe that could become a useful tool.

Alex: Personalized diets.

John: Personalized diets.

John: Still a ways off.

Alex: ... last question for me. You had a terrific article about much of what we talked about. You were an author on this paper in Nature, which is an amazingly prestigious journal. Congratulations.

John: Thanks.

Alex: You also authored a paper in JAGS, about the need to improve the pipeline of researchers, with an accompanying editorial by Tom [Gell 00:43:58]. Is there anything you want to say to encourage any of our listeners to go into this field? Or to convince others that, "Hey, this is a thing. We need to get people in our group who are working on geroscience."

John: Well, I think geriatrics is the most exciting and fascinating and rewarding field of medicine. If you're a medical student, if you're going to medical school, if you're a resident, hey, talk to some geriatricians. It's amazing work, and I love being able to help people so profoundly, often with such simple things.

John: I guess all I would say is that geriatrics is already an amazing field. But it's getting even better because it's becoming a translational field too. It's becoming a field where we can add our understanding of the biology to our fantastic clinical care programs. And we're going to have better, new tools. Different tools that we can add to the tools we already have, to try to help keep our older adults independent and healthy for longer. That's my goal.

John: What I mostly do in the clinic, I mostly work in the hospital. I spend a lot of time trying to prevent delirium and trying to prevent functional decline, and helping people to get home after the hospitalization and staying independent. We have some amazing tools and care programs to help do that.

John: It's amazing how important getting out of bed is. Just getting out of bed, and figuring out how to do that. And keeping the shades open. And keeping people's circadian patterns in sync while they're in the hospital.

John: But I would love to have better tools, too. Because even when we do the best we possibly can, there are still people who get delirious. There are still people who lose their muscle strength. They can't walk, and wind up having to go to rehab, go to a nursing home and maybe not get home at all. I want better tools to help those people.

John: Those tools are coming. If you think that geriatrics is a cool field, if you think, if you want to do amazing science that uses the biology of aging to try to help people live better lives longer, stay independent longer. I think this is an amazing field to be in for the next couple of decades.

Eric: I'm sold. Sign me up.

Alex: Career change.

Eric: Career change.

Alex: From podcaster/clinician/educator to geroscientist.

Eric: Geroscientist.

John: I will get you guys your Pipetman - we'll do our first rostrum block tomorrow. It's going to be fun.

Eric: Going to find some worms in my garden. John, thank you very much for joining us today. Alex, can you maybe end with a little bit more Queen? We've got a second verse now?

Alex: Yeah.

John: Maybe we should say, not, Who Wants to Live Forever but Who Wants More Health Span? It doesn't have the same ring to it.

Alex: No. We can't do that [laughter].

Eric: Compression of morbidity.

Alex: (singing)

Eric: Well John, very big thank you. And for our listeners, we will have links to the Nature article and the JAGS article and accompanying editorial on our Show Notes on the GeriPal website.

Eric: We are requesting a special request to all of our listeners. Our hundredth episode is coming out, so-

John: Wow.

Eric: ... please call 926-GERIPAL. Yes, we have our own phone number now. And leave a comment of one thing you liked about one of our show episodes. Or, anything about our show episodes, 15 seconds or less. And hopefully, you will be on our hundredth episode podcast. So take that little moment, and really appreciate you joining us today.

John: Thanks, guys.

Alex: Thanks, John.

Eric: Thanks folks. Bye.



Comments

Anonymous said…
I am black...not African American.
Anonymous said…
I am black...not African American.

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