Why Scientists Can’t Agree on Aging

It's the new year, and with it comes the annual onslaught of New Year's resolutions. Whether you're working on your posture or trying to decrease your screen time or even trying to spend more time with friends, these goals have a way of showing us our priorities. The most popular New Year's resolutions are often centered on money, getting fit, or aging in a healthier way, so let's talk about it. The science of aging isn't just about living longer, but adding more healthy years to our lives. And it's surprisingly complicated, so I'll be speaking to Dr. Paul Robbins to discuss how scientists are currently looking at aging and how we can all use their knowledge to better take care of ourselves, whether we're 25 or 85. But first, I'll dig into what we can learn from a study of a woman who lived to be 117 years old. And then finally, we'll talk about cellular aging and some new research on how mitochondria may be able to slow that process down. The Happy New Year, my name is Dr. Samantha Yimine, and this is Curiosity Weekly from Discovery. Researchers look for the secrets to longevity by studying people who reach extreme ages. One of them was Maria Branias Moreira, who lived to be 117 before her passing on August 19, 2024. She's what's called a super centenarian, someone who lives beyond the age of 110. According to verified records from Guinness World Records and the Gerontology Research Group, Maria is the 8th oldest person ever, with the absolute oldest clocking in at 122. To learn more about how Maria may have lived so long, researchers met with her multiple times to collect urine, blood, and stool samples, and also interview her about her lifestyle. With this data, they were able to build a robust profile of her health, characterizing her genetics, epigenetics, the proteins and metabolites in her blood, and even her gut microbiome. They compared her profile with those of the women living in the same Catalonia region of Spain, and published the results in cell reports medicine. They found something I thought was pretty surprising. Extreme age and poor health don't necessarily go hand in hand. Maria showed the expected signs of advanced age, but she didn't have the major diseases often associated with it, like cancer or neurodegeneration. Her telomeres were short, below the 20th percentile, which is common in older adults, and often linked with disease risk. But in her case, short telomeres didn't reflect any underlying disease. This subtlety suggests that age-related markers aren't automatically indicators of illness, and that living to an extreme age doesn't mean disease is inevitable, which is something I've always wondered about. She had some genetic variants that are known to protect against cardiovascular disease, cognitive loss, and diabetes, but none that increased the risk for conditions like Alzheimer's. She also had some variations in genes where the equivalents and other animals are linked to longer life spans. The researchers believe it wasn't just any single variant that did the trick, but probably the combination. So there was some element of what you might call genetic luck, but her active lifestyle and healthy Mediterranean diet probably played a big role too. If there's one thing to take from Maria, it's this. Her everyday habits line up with what we always hear researchers talking about on this podcast. The things that matter are good sleep, strong social connections, time with pets, reading, gardening, walking, playing piano, all the small grounding moments that rarely make it onto our big annual goal list. And with that, let me just text my mom to make some plans. Longevity seems to be the latest rebrand for anti-aging. Something that, as a woman, I've been pressured to think about from way too young an age. While it used to be about dying gray hairs, now Botox fillers, and avoiding a different food every day, those are all the latest attempts in staying young for longer. And I think it's great to optimize our health and get to spend more years with the high quality of life. But with the conflicting advice and self-experiments by billionaires, I wanted to talk to an actual expert on the biology of aging to learn more about what we actually know so far, so we can better sniff out the hype. We're chatting with Dr. Paul Robbins, a professor and co-director of the Masonic Institute on the Biology of Aging and Metabolism at the University of Minnesota, who also has several clinical trials related to aging based on his discoveries. Welcome to the show, Paul. Great. Thanks for having me, Sam, for pleased to be here. thrilled to talk to you about this very hot topic that we see everywhere, I can't know more than three scrolls away from something some sort of hype about longevity, so very relevant to our everyday lives. I think a lot of people know what aging looks like. We, depending on our age, may start to feel some of its effects, but on a cellular level, what is aging actually? Yeah, it's actually, it sounds like a very simple question, but it's very complicated that there was a paper published where somebody asked a hundred aging researchers, what is aging? We got a hundred different answers, so the definition that I use is really the loss of the ability of tissues to repair itself with time, so as we age, our tissues start to lose the ability to repair the damage that occurs and eventually that damage catches up with us and we go to this period of rapid decline and eventually mortality, but there are many different definitions, including when you look in the mirror, you know what aging looks like. But at the molecular level, it's even more complicated, so what the field is done is broken out aging into what they call the hallmarks of aging. So these are things that can go wrong in the cell over time with aging, and these include things like loss of stem cell function, mitochondria, which are the powerhouses of the cell, start to become dysfunctional. There's an increase in reactive oxygen species, there's DNA damage, your genome is affected. So all of these things contribute to driving aging in loss of the ability of a tissue or organism to repair itself with time over time. How do animals who don't seem to age like certain jellyfish, Hydra, naked mole rats, lobsters, do you look to those to kind of inform an understanding of aging, or are we very focused on mammalian or human biology? Well, I think you gave a lot of examples and I would argue they don't all live forever. Hydra and others have been shown that at least live for an extended period of time, although predators eventually take them out, naked mole rats probably have a finite life span, it's just not something we've defined in the laboratory, but they do age, and it's just intriguing that some organisms, even within the species, so I'll use the example of bats, that's a talk I just heard recently, but some bats live two years and some live 50 years, and the question is why does a species that looks similar among the different strains, why does one live much longer than another, another example, be sea urchins. You might either eat a nice restaurant in Japan that are hundreds of years old, as compared to others that live only one to two years, and so why does something that really looks the same have this huge difference in lifespan, and it's a intriguing question, and so we're looking at different organisms to know why one may live much longer than another. There was a lot of publicity just recently about a study in the bowhead whale, which lives at least 211 years, because they found the harpoonin' one that was 211 years old, they probably live longer, but they identify some pathways in the bowhead whale that may contribute to longevity, so studying different species is, I think, a very fruitful area in the aging research space. It hasn't answered all the questions, but it does provide insight into changes that can allow one organism to live 200 years in the open to live two years. You mentioned different organisms within the same species live for different lengths of time, and that's kind of also true for humans, and so I know you've done some studies in centenarians, people who have lived to 100 or more, I'm curious, are there common genetic or even lifestyle characteristics for people who reach that age or beyond, what's the constraint in humans? It's a great question. The data, which has been slightly controversial, but the data suggests that the maximum lifespan in humans is around 115 years of age at this point, there may be one or two examples living a little bit older, although there are questions about their birth certificates if they're really that old. That's our maximum lifespan, and some people have a genetic, or their genetic makeup, seems to allow them to live longer. They seem to be more resilient, their immune functions better, they don't have these hallmarks of aging, progressing at the same rate as in non-setanarians, but there's not necessarily a lifestyle choice. I mean, obviously a Mediterranean diet has been at least linked to longevity, but many of these centenarians, they smoke, they drink, they do everything that we're not supposed to be doing, but yet they live to be 105 years old. Those are their sister, brother, other relatives, showing there's a genetic component, but not all of us have centenarians in our family, and so many of us are not going to make it to 100 unless we develop ways to intervene, either with lifestyle choices or by developing drugs that may target some of these pathways of aging. And what do we understand about why it's, let's say, 115 years? Is it just that cells have accumulated too much damage in those other hallmarks you described that they can no longer function for everyday activities? Yeah, I think that's the current concept, although what's happens with you, you're still very young, so you have to worry about this yet, but some people, maybe there might a conjury at this start to show defects, other people may be losing stem cell function, other people may have more DNA damage, which may lead to cancer, what drives aging, one person may not be identical to another because of their genetic makeup and their environment. The food they've eaten, what's called now, the buzzwords, the expose zone. What are you exposed to in your environment that may contribute to either you living healthier or not? And these all contribute to our lifespan. But when it comes to satanarians, it's clearly a genetic component. It's not all genetics, but it's a genetic component, and if we can identify those genetic changes and try to mimic them with other therapeutic approaches, such as finding a drug that mimics the effect of that satanarian variant. I think we'll help all of us live a little bit longer, maybe there are going to be satanarians, but we'll help us all live a little bit longer and healthier, which is really the goal. The goal is not to keep us alive for longer, the goal is to keep us alive healthier, because we don't want to live longer than the nursing home. I think it's a good distinction that optimizing quality of life is different than optimizing the length of life outright. And a lot of the people, I think the misconception that those of us in aging research are all focused on living longer, living longer may be a byproduct of living healthier. And so we'll take it. But what you want to do is compress that period of morbidity. There's that period when everything starts to fail, and at least the people going to nursing homes, you like to compress that. So you don't have as much time being set with multiple diseases. It's a very rapid decline at the end when you're hopefully 100 years old or 105, and you can die on the golf course of a heart attack or such, but that's kind of the goal. Is that the goal? I'm not a golfer, but for some people would be maybe it's a tennis court or some other activity, but yes. Yeah, a sleep on a beach would be nice. Exactly. So when it comes to genetics, are there certain pathways that we know are critical and high level, like what are they doing in? So I think both the genetics of centenarians, but going all the way down kind of the model organism scale. I mean, studies done in worms, which see elegans as the model system used in the lab. These worms live two weeks, but we can manipulate them or treat them with certain drugs that will extend their lifespan and health span. In the pathways we've identified in worms are actually conserved in humans. There's just more complicated. We have more genes, more contributors to these pathways. Like the same pathways seem to be popping up across all species. So we have a good idea where to start and their drugs being developed that can mimic the changes we think will allow us to live healthier longer and clinical trials have started. So, but these are pathways that may regulate your blood sugar levels. It seems like many things that treat diabetes actually seem to allow model organisms to live longer. I think there's a number of drugs, such as metformin, SGLT2 inhibitors, all across these species. They've been shown to have positive effects on lifespan. So I think these pathways were identifying them, and we're now identifying interventions, which can mimic the effects of what we're seeing in centenarians or in long-lived species. So I think the future is very optimistic about the ability to keep people healthier for longer. It just doesn't happen overnight. There's going to take a lot of clinical studies, not just phase one, phase two, but lower-scale studies because it may vary. We have to identify the people that will respond to a certain intervention and not another. So I think there's going to be a lot of research, a lot of clinical studies that are needed, but I think eventually we'll identify approaches that will mimic what we're seeing in these different model organisms. You're part of the team that was the first to identify synotherapeutic compounds. These drugs that can slow down aging or increase lifespan, even if that's not their explicit or sole goal. Some work by killing these aging cells or senescent cells and others target cell signaling pathways involved in aging. Can you tell us a little bit more about that concept of these synotherapeutics? So senescence or cellular senescence is one of the hallmarks of aging, and that's what happens to this process of cellular senescence is what happens to a cell when it acquires damage or stress. So an example of stress to a cell would be if you were taking chemotherapy to kill a tumor. Many of these are caused DNA damage. That stress on the cell can drive it to a state of cellular senescence, and we've evolved this system, thought to actually prevent cancer. So another way to induce senescence is if the cell starts to divide in an uncontrolled manner. This pathway of senescence kicks on, the cell stops growing, and it starts to release inflammatory factors that tell the immune system, this cell is damaged, this cell is pre-cancerous, come clear it, and your immune system comes in and kills that cell. So when you're young, like you are saying, your immune system is clearing these damaged cells very efficiently. As you age and you start to accumulate more damage, your immune system is not as effective, these cells aren't cleared, and so they're releasing inflammatory factors that tell the immune system, come clear them, the immune system is not. So they accumulate, they drive chronic inflammation. That inflammation can affect the immune responses, it can affect stem cell function, it can affect a variety of other harm ranks of aging. So it's not the end all to get rid of these senescence cells, but we've shown in at least in model organisms that getting rid of them extends health span. It doesn't necessarily extend life span directly dramatically, but it seems to extend the period of healthy aging. So we've developed drugs as you refer to, which we call senotherapeutics, that either will kill us in senescence cell or suppress the inflammation driven by the senescence cell, and those we call senomorphics. So we have senobivics that kill senescence cells, senomorphics that suppress it. And what's interesting is these drugs, many of them are anti-cancer drugs, because these senescence cells have many of the same hallmarks of a pre-cancerous cell. So many things that will kill a tumor cell, seem to be able to kill these senescence cells. And clinical trials have started, and so there are some positive results coming out, but what we realize is we have to know who has more senescence cells than another. So when we go back and look at some of the redels from the clinical trials, we realize that those that have higher senescence cell burden respond better. So in future trials, we can hopefully identify that subset, that the third or the half of the population that should be getting senolytics. Those are the ones that are enrolled in the trials, and those that do not have an increase in senescence, but may have myoconjual dysfunction, may have other things going wrong, they would need a different class of drugs to suppress those changes. So we are very excited about the future of senotherapeutics, but this is going to require a lot of testing and identifying the right population that needs senotherapeutics. If you don't have an increase in senescence cell burden, senotherapeutics will have no benefit. So we have to identify that right subset. And then that's almost surprising to me that just targeting those senescence cells could have this overall bigger effect, like you're just removing, I guess, the product, but I guess because they're so central in this whole cascade, it slows things down a bit. Is that the logic behind it? Right. So senescence cells with this inflammatory, all the inflammatory factors they release, what it does is it affects adjacent cells. So the example I use when talking to the late public is I show a bushel apples, and you have one bad apple on the bushel, and it releases things, not inflammatory factors, but other factors that lead to kind of all the other apples in the bushel becoming bad. And that's the way, if you're looking to live in an aging person with senescence cells, we see senescence spreading to adjacent cells. So one or two or three bad cells in an area can lead to hundreds of bad cells, which lead to thousands, and that can lead the loss of ability of a tissue, the function appropriately, whether it's the brain or liver or kidney or muscle, et cetera. So this spreads, it's not the only thing that goes wrong with aging, but it's one of the things. And then animal models, clearing these cells has a tremendous benefit. But we'll have to see in humans. We'll have to say, like I said, we have to identify the right patient population. These trials haven't been done for aging, they've been done for diseases. So they're trials for Alzheimer's, they're trials for diabetes, there's a trial for just muscle skeletal health, but they're trials for a variety of different conditions, because we're doing aging that takes years to see changes. But here they can see responses much faster, at least that's the thought. There's a trial down from macular degeneration in the eye, so they actually inject in the back of the eye, these center therapeutics, and the trial just missed its primary endpoint. But if you look at those that have the most senescence in the eye, they respond at the best. So when they redo the trial, I think it's going to be very significant. So we're learning, if you look at what's been done in cancer or in other areas, it took decades to really develop these drugs that are used in cancer studies and identify which patients to be enrolled in those studies. So we're just scratching the surface, but very optimistic about the future. Now long-devity hacking is a very hot topic, some advice that seems reasonable, like getting enough sleep, beating a balanced diet, getting regular exercise, wearing sunscreen, and there are things that are a little more creative, daily sun as avoiding seed oils, intermittent fasting, eating lots of beans, ultra-process foods. The list goes on, and it gets worse, or more fringe, perhaps I should say, what's actually, what actually has scientific evidence behind it? What are the things that you see that are like big no-nose or big yes? Well, I can't say they're big no-nose out there. The question is, does the supplements you're taking or your lifestyle choice actually work? I think the data might suggest that for one person, it does work for another person because of just their whole exposed zone, their genetics, it may not work. So that's what we don't know. If you did intermittent fasting, you may not see the benefit. For example, if you take 100 different strains of mice, some live longer on chloric restriction, other ones do not. So the genetic makeup really influences how you respond to these. So people are trying a variety of things. I do think some of the supplements that people are using do have benefits. The question is, we just don't know which person is going to respond to those supplements. We have shown there's supplements that will kill senescent cells. There's supplements that will improve stress resistance. There's supplements which will have other positive effects. We just don't know which person will respond most effectively to these supplements. So people are taking a handful of supplements every day. It's hard to say is that really providing the benefit to them or not. Once we can sort out who really needs what supplement or drug, then we can see big changes. And then animal model systems, we see that supplements can cancel each other out. I don't know if this is true in humans, but yet maybe one supplement suppresses a pathway that's the target for another supplement. So it's not that the more you take, you see add of effects. We actually have shown in model organisms that some of these have not necessarily adverse effects, but they don't provide the benefit because they cancel each other out. So what supplements, how often, how much these are things we don't know. That's why I don't advise people to take handfuls of supplements because we just don't know. So I think we're just scratching the surface in the next decade. It's going to be an amazing time in aging research. There's going to be a lot of supplements, new FDA approved drugs coming down the market that will have positive effects on your health. That's fantastic. That's Dr. Paul Robbins, professor and co-director of the Masonic Institute on the Biology of Aging and Metabolism at the University of Minnesota. Thank you so much, Paul, for being on our show. Thanks, Sam. It was a pleasure talking with you. Cellular aging. It's that process where our cells slowly lose their normal functions, which can take a toll on tissue health and how well our bodies perform. But what if I told you that there's a way for a cell to recharge its aging parts using the body's own built-in tools? Cellular aging, a team of researchers from Texas A&M University may have found a new method to do just that. At the heart of this research are the mitochondria. They're the kidney bean-shaped structures often called the powerhouses of our cells because they turn energy from our food into fuel that cells can actually use. The fuel is called ATP and it powers everything in our bodies, from muscle contractions to digestion, and even brain cells firing. These tiny structures are so important for energy production that a lot of diseases, like Alzheimer's and heart diseases, are associated with them not working as well. Same thing for aging. As we get older or deal with illnesses or take treatments like hemotherapy, our body takes a toll and the number of mitochondria can drop. That makes it tough for our cells to do their jobs. Enter this new research, published in the Proceedings of the National Academy of Sciences. The researchers developed a new way to swap out worn-out mitochondria with fresh ones to keep our cells energized and functioning at their best. The team's method takes advantage of the fact that some stem cells can naturally transfer their mitochondria, but it's usually pretty inefficient and doesn't necessarily happen when and where you'd want it to. So they mix those stem cells with some pretty cool, tiny, flower-shaped particles called nanoflowers. Think of these nanoflowers as little energy boosters. They turn the stem cells into mitochondria factories, making twice the usual amount of mitochondria. That makes them much faster at replacing worn-out or aging mitochondria in nearby cells. It's like giving aging cells a second chance at youth. Dr. Gahawar led the study. He said in a press release that it's like training healthy cells to share their spare batteries with those that are running low. The nanoflower-boosted stem cells can transfer 2-4 times more mitochondria than untreated ones. This energy hand-off helps revive damaged cells, allowing them to kick into gear and even resist cell death, even when a chemotherapy drug was added to the dish. Given how essential mitochondria are for our cells, there's a big need for ways to improve their function, whether it's in diseases or aging. Other methods to replace damaged mitochondria are out there, but they typically come with some drawbacks, like needing frequent doses. Whereas these nanoflowers stick around inside the stem cells, giving mitochondrial production and replacement a longer-lasting boost, potentially requiring just monthly administration. There's also potential for things beyond aging, too. These stem cells are really mobile and so they're good at getting to a bunch of different tissues, meaning that this approach could also apply to illnesses spanning from muscular dystrophy to heart disease. For Warner Bros. Discovery, Curiosity Weekly is produced by the team at WheelhouseDNA. The senior producer and editorial correspondent is Theresa Carey. Our producer is Kiaranoni. Our audio engineer is Nick Currismy and head of production for WheelhouseDNA is Cassie Berman. And I'm Dr. Samantha Yween, thanks for listening. [BLANK_AUDIO]