160: Molecular Secrets of Aging Told Through Worms

Dr. Heidi Tissenbaum, a molecular geneticist at UMass Chan Medical School, joins Dr. Buck Joffrey to explore what C. elegans worms have revealed about the biology of aging.

She explains how these simple organisms helped uncover key longevity pathways—like insulin/IGF-1 signaling and sirtuins—that also exist in humans.

The conversation dives into the balance between stress and resilience, the role of IGF-1 in muscle health and lifespan, and why she believes true longevity breakthroughs will require understanding how the body’s systems communicate as a whole.

Learn more about Dr. Heidi Tissenbaum:

https://profiles.umassmed.edu/display/133231

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Transcript

Disclaimer: This transcript was generated by AI and may not be 100% accurate. If you notice any errors or corrections, please email us at phil@longevityroadmap.com.

   60 to 80% of the genes in worms are homologous to us humans, and we don't like to think about that, but that is evolution, I think at its best.

Welcome everybody. This is Buck Joffrey, the Longevity roadmap. Interesting conversation today. Dr. Uh, Heidi Tissenbaum. Uh, she's uh, one of the sort of cutting edge. Uh, researchers, you know, we see elegance, uh, which is a worm that is often worked on in the context of longevity research. She's, uh, one of the pioneers in that space.

Um, a really interesting conversation. We talk a little, we talk a fair amount about, you know, listen, this is for science geeks, right? Like we, to help you understand what. For ex, for example, why we use worms in the first place, what they tell us, some of what those key initial, um, studies showed us regarding IGF one.

Which you may know is, seems to be a major player when it comes to longevity, uh, across species. You know, the role of stress, both cellular stress, uh, and sort of the general stress that we, we kind of deal with on a daily basis. Trying to differentiate between those. We talk about hormesis and, uh, ultimately I try to get a perspective on, uh, Dr.

Tissenbaum's, you know, view on sort of the future of. Of longevity, longevity, science. And what I think is interesting is that what you'll find is that she is, she's not as optimistic as others, but I would like to point out that we've had plenty of people in the same space, literally in the same lab. She's in the.

Same lab. Uh, she did the same, uh, postdoc, mates included, you know, Matt Capline and, and David Sinclair. And she, um, you know, she's come out with different opinions on that. Um, she's not as optimistic as those guys who, you know, Sinclair in particular talks about how, you know, age reversal is already possible.

Um. Whereas, you know, you'll hear Dr. Tissenbaum say, uh, something to the effect that she doesn't think we're there at all yet. Although she has left the door open for various, uh, types of interventions and research that could at some point, uh, lead to those things. At any rate, if you like science, if you like hearing about, uh, the role of some of these.

Key pathways such as IGF one, uh, in the aging process. You're gonna enjoy this interview and we'll have that right after these messages. Hey, longevity enthusiast. It's time to take you to the next level. I've been fine tuning my longevity regimen for years, and I look better and feel better than I did a decade ago.

In fact, my blood work is even better than it was back then, and it's all because of my data-driven regimen. And it's inspired me to create a course and community just for you. It's called the Longevity Roadmap, and I urge you to check it out. If you're tired of your belly fat, tired of being tired, or just wanna optimize yourself for the next 50 years, visit longevity roadmap.com.

That's longevity roadmap.com. Welcome back to the show, and today my guest on Longevity Roadmap is Dr. Heidi Tissenbaum. She's professor of Molecular cell and Cancer Biology at UMass Chan Medical School. She completed her, uh, graduate, uh, uh, work at Harvard Medical School with, uh, Dr. Gary Ruvkun and her postdoctoral training, uh, with Dr.

Leonard Guarente at MIT who you may recognize, uh, these days as kind of. Big name, uh, around the supplement industry, uh, and uh, also where, uh, David Sinclair did his PhD as well. So that must have been an interesting time. Uh, Dr. Tissenbaum is internationally recognized for her work using gon uh, to uncover the genetic and molecular pathways that influence lifespan, particularly those in.

Involving insulin and IGF one signaling diet and stress. Her research is helping, uh, connect the dots between the fundamentals of biology and strategies to promote resilience, metabolic health, and healthy aging. Welcome, Dr. Tissenbaum. Nice to meet you. I'm happy to be here. So, um, why don't we just start out with this, I mean, for our.

Audience who you probably hear about worms and c gon you know, often when they, when you hear about basic science research, especially when it comes to longevity, um, why choose worms? Um, and, and c Elgon in particular is a powerful way to, uh, to look at this kind of biology. That's a great question to begin with, and it seems kind of strange when I tell people I work on worms, they kind of close their eyes, but if I tell 'em I work on longevity, they are very, very interested.

So, so I've had, you know, 30 years of answering this question and the real reason is. The worm c Elgan, um, everything is done under the microscope, but the whole worm is 954 cells. What was the Nobel Prize was awarded to many, several, probably 20 years ago to um, Bob Hobits, um, John Alstein, Anton Brandon, for discovering the worm.

And what they did is they did meticulous. Uh, lineage tracing so they know from one cell what happens to that cell as it divides a two to four all the way to high to 154. And now we can ask questions. How one cell is different from another, which you could never do in a complex system like a human or even a mouse, but with 954 cells, you can actually ask what makes one cell different from another.

And so that is the basic uses of the worm. But for longevity, the worm lives above three weeks. And when you're a graduate student or a post-op or fellow, or even a researcher, that makes a huge difference because you can do many, many experiments, uh, in a short amount of time, which you cannot do. In a more complex system.

Moreover, the average lifespan is very tightly regulated, so you can find modifiers of lifespan as little as 10 to 15% different from the average, and that is not, you know, that makes it very easy to identify modifiers of lifespan. The other thing that is kind of hard to believe, but depending on what you read, 60 to 80% of the genes in worms are homologous to us humans.

And, and that is, we don't like to think about that, but that is evolution, I think, at its best. Yeah. That's great. Well, we'll let you know in terms of these, these, this, this model with Ganza. What, what kinds of things have, you know, we've been able to re reveal about the fundamentals of aging that we might have never discovered if we were just using, uh, you know, mice or tried something silly, like using humans for that.

Okay, so that's a really good question as well. And I think that gets into the insulin IGF one singly pathway. So when I was a graduate student, um, we discovered that several of the GS we were working on we're, when we identified them molecularly, and this was in the laboratory of Gary Ruvkun. Who recently won the of a prize, I might say, but not for this work.

Um. Anyways, so what we discovered was the genes that we were working on in the world, and Cynthia Kenyon had previously identified one that was associated with lifespan as well as Tom Johnson had done the original work of the gene that age one appropriately named, and we discovered when we called them, they were part of an insulin IGF one sly pathway.

And about less. Within a decade, about eight to 10 groups had identified one of the genes to be associated with longevity in humans. So I think that's the, that's sort of what brings. Warm aging to light in the fact that what we were sending in a little crater that only lives three weeks goes to identify, uh, something associated with human longevity across multiple populations within just a decade.

So that's the first thing. The second thing is the whole field of sirtuins, which is sirtuin biology, which I think some of your audience might be knows about. That began with some of my work when I was a postdoc at MIT to show. That, um, basically extending of lifespan of 31 also occurred in worms, not just in yeast as our laboratory, uh, had previously showed.

So those are two major flags that. Are relevant to longevity, to the longevity field. Yeah. Who is that? Uh, do you have a postdoc? Was that Lenny Ante's? Uh, yes. Yes. Le okay. Interesting. Interesting. So he's gone on obviously in a big way in that's longevity space as well. So let's, let's drill down on IGF one.

I mean, it's pretty important, right? So, um, can you walk us through what you found in worms that might be sort of a universal thing that, um, that, that pathways turned up or turned down in worms? So originally we discovered, uh, the genes that we were working on were also important for a process called DPAs, which is sort of like a spore or sustained long, harsh environments.

And these genes also worked on that. And what we found was that. We basically identified all members of a signaling cascade that begin with a receptor that is homologous to both insulin receptor and IGF one receptor. So in mammals we, you have both insulin receptor and IGF one receptor. In wars. It's just one receptor that singles down a canonical single and cascade.

To, uh, ultimately lead to a for transcription factor, if you wanna be detailed, but into some, uh, something that binds DNA and it modulates the, the whole pathway modulates the gene at the end going in other nucleus so it could turn on or turn off genes that are required. For whatever, for, you know, metabolism, longevity is associated with that, but all these other genes.

Yeah. Yeah. So basically the idea is if you can down regulate a ig, uh, IGF one, it basically, you know. It, it creates a cascade of events that, that seem to extend life. Is that right? Exactly. Exactly. Exactly, exactly. So, um, you know, you also studied stress resistance, so, um, why is the ability to handle stress such an uh, central determinant of longevity?

Well, in my opinion, uh, from all my reading, I think that what stress does is it if you lower your stress, you're ultimately modifying an inflammation signal. So ultimately. The, the ability to deal with stress and to deal with it in a way similar to evening, our levels, uh, keeps inflammation at bay and you don't get a spike in any inflammation.

Moreover. Stress is linked to metabolism, and what we don't want is any strong changes in our metabolism. That's why if I could just take a leap, uh, if we think about. Our eating and our diet. People want us to have six meals a day because then I, in my belief, I believe it's keeping our insulin levels constant.

And if we don't, if we're getting back to insulin, if we don't keep these levels constant, it's not good for our. In worms, the reason stress is, is linked to longevity is because it's controlled through insulin and we wanna keep those levels constant, not have these big spikes in our levels 'cause it's not good for our overall system.

You mentioned something about six meals a day. I mean, that's sort of, um, uh, that's different from our, you know, a lot of longevity, uh, people out there talking about intermittent fasting, various fasting. Uh, so how, how, how do you put, how do you, I mean, there's plenty of evidence that there is, at least in the short term.

Um, benefits to, uh, to people, uh, in terms of, of metabolism, in terms of, uh, metabolic syndrome and that kind of thing. So how, how do you. How do you put those together? Because I guess the other question is, when you talk about stress, particularly cellular stress, there's also the concept of of hormesis, right?

So some level of stress, which, uh, we know is, uh, induced, uh, by fasting, uh, can be beneficial to us. And some people think that that may actually trigger some of the longevity. Uh, longevity Gene. So I'm curious on your take on all this. Okay. So there's a lot to tell. Yeah, yeah, yeah, sure. So hormesis, so hormesis is the, as you, you know, it's the fact that if you give a little bit of stress during development or even in early adulthood.

And then you tress the animal the same way. It survives much longer, and it's quite, uh, quite easy for us to do a variety of stresses in the laboratory and see that occurring. Okay. But so to, to me, what all of that does is it, it's like a vaccine, like when you get a little bit of, you know, when you're getting vaccination, that you're able to survive stress better.

But it's all, I think what that does is it modulates your ability later. You are able, and you don't get a sense spike in your stress response. So that's what I think it is. It's all about modulation now, intermittent fasting. I definitely works. It's, it's something many people do and, and I, you know, I, I believe it can work for a lot of people.

Um. But again, I think what intermittent fasting does is it decreases the total amount of food that you eat so you don't get a huge bolus of insulin at one time. And I think that's what's really bad is it's the constant of your body. Uh. Like, I even think of, I live in the war in a cold climate, so I even think about when we're cold outside and then we go through an overheated building in the winter.

You know, that's not good for your system. You know, I, I, I just think constant stress is bad for your overall metabolism and your ability to survive long-term and deal with stress. Yeah. Yeah. Can you just for the audience, kind of just make the distinction between cellular stress and the concept of, you know, again, hormesis being like, you know what the simplest way to say it is, what doesn't kill you makes you stronger.

Right. I mean, that's, that's essentially it. And so students, yeah. It, and, and so, so, you know, uh, a lot of the things that we hear about in this space, um. You mentioned cold. I mean, I, I don't know that there's any evidence that, uh, these ice baths or anything like actually do anything for longevity that may help with dopamine release and that kind of thing.

But certainly saunas, right? Saunas, sauna, there's a tremendous amount of, at least, uh, uh, you know, data from Finland and all that. Who again, the idea being potentially that we are sort of shocking the system a little bit, we're stressing it. You, you actually brought up sort of the change in temperature. Uh, I would think that, um.

From what the sauna data shows us, that that kind of changes in temperature actually might be good for us. No, I I I'm actually unaware of the sauna evidence there. No. Oh, okay. Yeah. Yeah. I, I just have to say that in longevity research, we, whether there is so much data out there, because everybody, especially as we age, everyone thinks about this more and more and more.

And I'm sort of at the other end of the spectrum where I want evidence and I always go to read the primary articles. And so, and it's very hard to keep up in the field. Oh, a hundred percent. It's very, very hard. And so, no, no, and I totally get that, and if it were anecdotal, I wouldn't bring it up. The, the finish that is pretty robust.

It might be something I would be curious to hear about from you at some point if you had a chance to look at it, but, uh, I would be happy to look it up. But I can, sorry, I can comment on cellular stress versus organismal stresses. That's what you were interested in. So just for the audience, when people talk about cellular stress, they're really talking about what happens in our cells directly.

So people will notoriously do experiments in cell culture. So they'll have cells on that plastic Petri dish growing, and sometimes these cells are primary cells from human tissue. And sometimes they're cells like you might have heard of helo cells, uh, helac cells that are transformed. And so they will go on and on and on and on in culture.

Now I don't study that. What I study is organismal aging, let's say not cell aging. And so when I do lifespans or all the experiments that I've never done. Or just like aging, just like you and me. How many days does the animal actually live? Okay, that's organismal aging and there still is some. Uh, some differences between people that study cellular aging or cellular senescence and organismal aging.

So, but something that I think that your audience is interested is what is the difference between lifespan, which I just said that, and healthy aging or health span, and, and we could talk about that as well. Yeah. Sure. Well, let's talk about that. Okay, so about 10 years ago, and I'm talking about myself. I don't, I'm not tuning my own horn here.

Yeah, no. Sure, sure. Okay. So, um. Probably about 15 years ago, I went to a conference and about 10 years ago we published a paper where we were looking at health span in long live worms. Now health span or people acquainted as healthy aging. I, in the laboratory setting, I look at it similar to lifespan. So it's a span.

How healthy is it animal over the course of its life because the. The, the good and the bad is lifespan is a defined measurement. Anyone could go to any laboratory that's studying organismal agent and ask what is the lifespan of that animal? And everybody knows what that means. Okay. It's simply how the long, how long the animal lives.

So for about 30 years, many people successfully did really good work showing chemicals, genes, regimens, that extended lifespan. But the question always became, what is the quality of that long-lived animal? Are they increasing a frail. Segment of their life, or are they actually healthier for a longer period?

Because if you think about it, if we're extending, if we're leaving healthier till 80, but now we have 40 years in a nursing home, that's not good for society, right? I mean, it's unsustainable. So. Uh, many people started speaking about healthy aging or health span. The problem is there is no universal definition of health span, and if you type anyone in your audience types healthy aging into the Google browser, you'll get pictures of gray haired people smiling.

That is what, I'm sorry, but that's what you get. And so how do you define healthy aging or health spa in the laboratory? First? In animal second and in a worm thi Right. So, so you're saying, uh, there's no gray-haired worms out there, doctor, are you? No, no, no, no. And then moreover, I mean, people do things like look at gray haired mice and see a reversal that, but you know, I don't know.

If you just aged a mouse normally, what would it look like? Like. You know exactly what you're saying about a gray hair and worm, like what normally happens, you know, not every human gets gray hair at the same time. Not every human loses their ability to be mobile at the same time. Not every, you know, it's, it's individual, you know, we could assess an overall of the population, but it's individual.

So the good news is that in the longevity field, many people have started to put in measures of health span in their manuscripts. And what people typically look at is mobility and survival of and ability to survive stress. And those are two things I think that are really good to look at. We've looked at it extensively, so I, I believe that those are good.

The ability to, you know, to bounce back from a stress as you age, the ability to move either we, we do both horse movement and force movement. Those are, I think very good. I think for people. They also measured their ability to walk. Ability to stand up, you know, so you're not frail basically. Right. Um, in humans, uh, whenever you talk about IGF one in particular, or you, you're invariably you.

Enter into conversations that involve growth hormone. Um, and, um, also, you know, one of the, one of the ways that you can, in you ultimately increase your igf uh, one most potently is actually by, uh, weightlifting. How do you put together, how do you bring these things together because it's. You know, um, people think about, well, in humans, well, maybe I should be trying actively to decrease my IGF one, uh, and well growth hormones no good.

Uh, so, but the problem is that every time I go and lift weights, uh, I am increasing my IGF one. And, uh, in that case, but I'm supposed to be lifting weights because all, there's an enormous amount of literature that says that is good for me. So how do you put all these things together for like somebody listening.

I think it's very difficult. I think that, you know, my motto is from my reading, and of course I don't study humans, but for my reading, weightlifting. Is the single most important exercise as you age, because you be, you get frail and uh, you know, it kind of goes against a lot of signaling pathways. But I believe that weightlifting is significantly important, and especially now with people like on all these, uh, ozempic like drugs.

Where you lose muscle mass, I think it's gonna become more important. Yeah. Yeah. Well that's, yeah, and that's itself. Big question. There's a trade off of somebody who is 50 pounds overweight, uh, with poor, uh, glucose can control and, and, uh, versus getting that under control and losing weight and, and then losing muscle mass.

So it's all a, all a big trade off, right? Um, yes, yes. I mean, my motto really for Cuban longevity is. Really keep your mind active and your bra Yeah. Keep your mind active and your body moving. And also avoid sugar. That's my, yeah, no, I think that's a, that's a very good place to, that's probably about 80% of it right there.

Right. So, um. You know, other stuff. There's a lot of buzz, uh, these days about various drugs, supplements, uh, that claim to, you know, mimic caloric restriction and therefore, you know, modulate IGF one. Do, do you, do you look at anything that's out there? Any drugs, any, um, any supplements and have any sort.

Feedback. So the problem with most of the supplements is they're not tested in the laboratory. There's no regulation, uh, of supplements. I mean, you know, I personally. And then second of all, personally, I get skeptical when people's personal finances interfere with laboratory findings. So I'm very skeptical about a lot of the things out there.

As I said, I think that. You know what I said in terms of keeping your mind and body active, and so for mental stimulation, even if, let's say you retire whenever 65 or whatever, you know, and you're used to doing crosswords. Don't just do a crossword, throw in a sudo code, throw in another card game, or throw in something else to keep those neurons firing in, making new connections.

That's intrinsically important. Then the other thing is there is something to genetics. Some families can, you know, live into their nineties or even after a hundred. They usually have a brother or a sister that's also long lived, and those people, for some reason seem to be resisted. Two things like diet and smoking.

All the things that we think are bad for us, for the majority of the of us, they are bad, but there are a few in the population who have genetics in their favor that they're long lived within their family. And that's something we don't understand yet. Yeah. Um, from your perspective, is a. Basic science researcher on longevity.

What in the big picture? I guess my question is how far away are we from potential discoveries that will actually, you know, impact health span and lung health span certainly is, is a. Something that we're addressing Al already. But you know, this idea that, uh, you know, most people, uh, are still going to die before they're a hundred years old.

Uh, there are people in, in, in your field, uh, who think that that really is something that we can fundamentally change that, that we can make discoveries that make us live, you know, uh, a material, uh, number of years longer in good health. What's, what's your perspective on that? I'm gonna get into trouble.

So I'm skeptical. You're skeptical? Yeah. I'm skeptical that we can do that. I mean. I don't know. In some ways I feel like these Glip one, you know, the ozempic like drugs are longevity drugs because people would've died of heart disease or diabetes before and now when they lose 50 pounds, all of a sudden their A1C is normal.

And they're no longer needed to go to the cardiologist or the diabetes clinic at the hospital. So in some respects, you know, something like that could be a longevity drug, but. I still, you know, aging involves our whole body, so I think we're not at the point where we understand the fundamental key signal that regulates all our signaling pathways.

All of our body, like if we, if we have something that works on our muscles. Will our brain still be active? If we have something that works on our brain, will our bodies still be active? I mean, most of us, most of us know elderly people whose minds are fine, but their bodies aren't fine. And then, you know, so, so I wonder if we can really do that on such a complex.

Complex problem. And of course that is the ultimate goal, but I don't believe we're understanding it yet. I believe we will, but not yet. But you, but you do believe we will, which is, I guess, kind of the fundamental question. And when you, when you think about the, you know, and I'm just asking you kind of think in a, um, a big sort of big picture way, where do you think the most promising, uh.

Basic science research is, uh, about, you know, fundamental reprogramming. And there's, you know, there's tons of people talking about various things, whether it's, I just talked to somebody who was talking about, uh, who was an expert in, in both, uh, mutations in the genome and epigenetic drift and that kind of thing.

Uh. Sort of similar take as you, uh, in that, like, that alone is not the, you know, the, the golden or isn't the silver bullet, but that there is ultimately something in the genome. That if they're able to figure out how to slow down mutations, you know, DNA methylation and epigenetic drift, that that could do things.

So I'm just giving you that one example. It's a long question I'm asking you, but when you look at all the different things that are out there, like what get, what gets you excited, what makes you think, gosh, that that could, that could do it, or that might do it someday? That's a really difficult question.

I'm sorry. I, that's what I'm here for. That's right, that's right. I, I'm really not sure. I think it's gonna be a combination of things, but ultimately it's so, comes down the question of how do you prove something like that, you know? What are we actually looking for in a drug? Are we looking for something in a cell-based assay that's gonna make the cells survive stress, and that's gonna have a human intervention?

How? How are we gonna do something in anything right now? You know, if we have a problem it takes. Or so for us to figure things out, like what actually are we looking for and how are we actually gonna prove that? That's why, that's where I come from, you know? That's my pessimism is. What is, if we had that answer, how is that gonna look in the laboratory, you know, in the clinic anywhere before we know that that's real.

Yeah, I get it. Fantastic. Well, I do appreciate your time, uh, today, uh, Dr. Tissenbaum. It's been really, uh, great learning from you and, uh, yeah. And, and again, thanks so much for being on the show. Thank you very much. My pleasure. Thanks for listening. A quick reminder that while I am in fact a surgeon, nothing I say should be construed as medical advice.

Now, make sure to include your physician in any medical decisions you make, and also, if you're enjoying the show, please make sure to show your support with the like, share, or scribe.