Transcription
I think we're going to come up with different drugs and different cocktails of drugs that will show signs of not reducing senescence but actually using transcriptomics, the lipidome, the metabolome, all the different omics to make a cell look younger. So, could you engineer our genome to carry variants that have been shown to lead to extend the lifespan in humans?
Dr. Robins, welcome to the show.
Great. Pleased to be here.
See? Yeah, I'm happy to have you on the podcast. Now, many people might not be aware of you, but uh, you're pretty known in the longevity field. So, maybe you can give a short and brief introduction about your background and um, what is your main area of research?
Yeah, great. Yes. So, I actually started in the gene therapy field. So, my first job as assistant professor was at the University of Pittsburgh, focused on gene therapy for a variety of diseases. I ran a vector core facility in addition to running a molecular medicine institute. Uh, but as we were developing therapies for a number of different diseases, I started to realize that the root cause of many of these diseases were similar and they seem to be things that change with aging. So I very quickly bought into this geroscience concept that the greatest risk factor for most diseases is the aging process. So uh, when I moved to the Scripps Research Institute in Jupiter, Florida, we started to focus on ways to target aging therapeutically, uh, choosing cellular senescence as the hallmark of aging, which we thought was the most druggable at the time, and this was more than a decade ago. Uh, six and a half years ago, I moved to the University of Minnesota where I'm the co-director of the Masonic Institute on the Biology of Aging and Metabolism, and we're very focused on cellular senescence, but a few other hallmarks of aging as targets to try to extend health span, not lifespan.
Gotcha. Yeah. You know, senescence is synonymous to aging, and you mentioned one of the hallmarks of aging is cell senescence. So, um, what is cell senescence in the human body and and other organisms? Like, what kind of a phenomenon is it and how does it relate to aging?
Right question. So, cellular senescence, or it's senescent cells, it's a cell fate. So, this is what happens to almost any cell in your body if it acquires too much damage. So, this could be genotoxic stress, it could be oxidative damage, it could be mechanical stress. Um, and if these cells then are stimulated in a way that they don't like, what they do is they exit the cell cycle and they undergo what's known as cellular senescence. And what your body wants to do is get rid of these cells. So, these senescent cells, in many cases, not all, start to release inflammatory factors. And this stimulates your immune system to come clear them. So, see, somebody of your young age, your immune system is probably clearing thousands or tens of thousands of senescent cells a day, does it very effectively. Uh, but as we age and our immune system starts to fail, and you accumulate more cells, there's a tipping point where the immune system doesn't clear them, and this leads to an increase in inflammation, but other adverse effects that are caused by this chronic accumulation of senescent cells.
But cellular senescence is thought to be an anti-tumor mechanism. So, one of the ways that the cells are induced to enter a senescent cell state is by activation of an oncogene, a mutation in in the gene or protein that drives cells to replicate. So, when cells start to replicate when they're not supposed to, this senescent fate kicks on, cells enter this, exit the cell cycle, enter a state of cellular senescence, secrete these inflammatory cytokines, and the immune system clears them, and that reduces our risk of cancer. Um, so senescence is is a positive thing, but as we age and these cells accumulate, it can drive adverse pathologies and and diseases related to aging.
Mmm. So, there is, every cell has its, I guess, expiration date or lifespan, and one of the outcomes of that journey is cell senescence. I don't know if they all have necessarily a lifespan, if just if a cell, and this can be a fully differentiated, non-dividing cell such as a liver cell or a kidney cell or a brain cell, um, if they acquire so much damage that this fate, this fate then is stimulated and takes over. So, some cells never senesce, other cells, if they have damage, will senesce. The other thing is that a senescent cell can drive neighboring cells or cells at a distance to enter a similar state because of these inflammatory factors that they release. So, one senescent cell can drive additional cells to enter the senescent fate, which then amplifies the adverse effects.
Should also mention that senescence can play a positive role. There are examples where senescent cells come up or arise acutely in cases of wounding, um, during embryogenesis. Um, and so it's thought that some of these kind of transient senescent cells actually release good factors that can stimulate wound healing or facilitate embryogenesis or some other positive effects when we're young and healthy.
Yeah. So, it's like the aging process, you know, aging is characterized by many things, one of them being inflammation and uh, mitochondrial dysfunction. Like, there's other hallmarks of aging and immune cell immune dysfunction as well as you get older. So, your cells become more vulnerable to this, let's say, you know, damage like collateral dermal damage. And then the, uh, damage, the cell can decide, okay, we can either turn cancerous or we can turn this cell senescent. And the, you know, anti-cancer mech, anti-cancer more rational approach would be to turn it senescent. Um, so it's a better outcome than turning it cancerous, but both of them still lead to a decline in health over time because as the cells in essence accumulates, then, uh, you're experiencing, I guess, faster aging, as I understand it correctly, right?
And, and so, as you probably heard from others, you know, these hallmarks of aging which have been identified are all linked. So, senescent cells have dysfunctional mitochondria. There's a lot of evidence that that dysfunction in the mitochondria plays a role in driving cellular senescence. Another example is that stem cells in your body, as they age and acquire their damage, may become senescent. So, you lose stem cell function. And obviously, senescent cells release inflammatory factors. So, they contribute to, to what extent we're not quite clear, but they contribute to inflammation. So, senescent cells have many of the hallmarks of aging in them. They have altered proteostasis, altered autophagy, different changes in epigenetic marks. So, a senescent cell has many of the same features that affect the whole body, in, in our other hallmarks of aging, because they're all linked.
Gotcha. So, it's not like some chicken or egg, right? Problem? It's, or it is a chicken and egg problem. Yeah. And if, you know, so, senescent cells have dysfunctional mitochondria, that leads to increases in reactive oxygen species, which causes more DNA damage. This causes oxidative DNA damage, and then that leads to, uh, the stimulation of more of a senescent state. So, there's this autocrine effect. There's also a paracrine effect, like I said, affects neighboring cells and drives them into a state of cellular senescence.
You mentioned that, that in early life, these senescent cells can be beneficial for wound healing. Um, would the, I guess, the question is like, in older people, if they have good wound healing, would it be somehow pathological or would it somehow be detrimental because it would be like a sign of a higher amount of senescent cells or?
Right. It's, it's a great question. I think the field's still trying to determine what a good senescent cell looks like, how to characterize it versus a, a bad senescent cell. But I think the data is suggesting that in older people, that clearing senescent cells, and that may be predominantly the chronic ones, actually improves wound healing. When you're young, and you get rid of these senescent cells, it seems to inhibit wound healing. But when you're older, getting rid of the bad cells seems to be beneficial.
Gotcha. And, and clinical trials will be determining that. I think trials are currently ongoing. So, we will see if wound healing, whether it's diabetic ulcers, or if it's recovery from surgery, the wounding from surgery, or other types of events, if clearing cells in older people improves those processes. My, my guess is the answer is going to be yes.
Gotcha. What about lifespan in animals? Does clearing them out, uh, improve lifespan?
Yeah, a great question. So, um, there's, I won't say conflicting data, but there's some experiments, and this has mostly been done in transgenic mice where they've been modified so that you can clear with treatment with a drug certain types of senescent cells, and in certain cases, clearing those cells using these genetic models does not lead to a dramatic extension of lifespan. There was a recent paper that said that clearing a subtype of these senescent cells, these are ones that have a marker called P21, extended the lifespan by about 10%. And there's a little bit of evidence with with drugs, which we term senolytics, that will preferentially kill senescent cells, that there may be a slight increase in longevity. But what we're looking for, I'm not a big believer that we're going to extend lifespan by 50 years over the next, uh, generation. Uh, the goal is to try to keep people healthier for longer. So, we really focus on health span, and I think one of the side effects of extending health span is that there is an increased lifespan.
Gotcha. Yeah. What you don't want to do is increase lifespan so that the same decrease in vitality, you know, accumulation of frailty, still happens at the same rate when you're just a little bit older. What we want to do is compress the curve so this period of comorbidity is very short as we age. So, we're healthier for longer and then fall apart quickly, right? Not even have that slow decline that we're seeing that leads to time in nursing homes.
Yeah. You know, people are living longer on average today than in the past. And, uh, that can be a negative thing because if you have a lot of old people who require a lot of help and, uh, medical expenses, etc., then that can overwhelm the system. Um, yeah, the goal is, yeah, to have, uh, people who do live slightly longer, but more importantly, they stay healthier for longer, and they have this longer health span, that they don't, uh, accumulate a lot of these co-morbidities late in life. Yes.
And, you know, there's a lot of discussion, and you may have had guests on your program that may argue that, you know, we're going to see this huge extension of, of lifespan. And I'm not necessarily disagreeing with that, but I think we're a long way off to start seeing those effects, right? Um, again, I see what we, what we're seeing in, in model systems, mice, rats, maybe non-human primates, is we can kind of extend this period of healthy aging. Whether it's going to be a few years or longer, you know, that's, that I think is the, is the initial goal, and we'll talk about longevity in the future.
Yeah. Yeah. And, uh, senescent cells can obviously have an important role in that. Do, does a, I would imagine then a higher amount of these senescent cells correlate to more of these co-morbidities like heart disease, cancer, Alzheimer's, and, uh, other health ailments?
Yes. So, you know, the question is whether all ailments are going to be driven by, or at least have a contribution of, senescent cells. I think in many cases, it appears that in with human disease, whether it's osteoarthritis, or if it's Alzheimer's, or, uh, liver diseases, that there seems to be an increase in cellular senescence. And always the question is, is that the consequence of the disease or the cause of the disease? And I think senescent cells contribute, but it's not the only cause, and not the only target. So, you know, I think we will see benefits in numerous human diseases if we can reduce the senescent cell burden. Um, but it's not going to be the cure for everything. Uh, there's going to have to be other hallmarks of aging targeted, other modifications made to treatment protocols. But clearly, reducing senescence in older people that have an increase in senescence. And that's the other issue, is that we're not a, a, a mouse model that shares identical genomes. Everybody's different. And I think that if you took a, a room of 65-year-olds, there would be a third of those that would have high senescent cell burden and may not be aging as well. And then you're going to have a third that really have not, not much senescence. So, we really have to identify ways of monitoring your senescent cell burden to determine if you're really one where senolytics will work, right? And so I think, you know, biomarker development so we can identify markers of bad senescence, or, you know, maybe there's a certain type of senescent cell that drives heart disease versus liver disease versus, uh, neurodegeneration. So, I think trying to identify the, the senescent cells we need to target for different diseases is also going to be important.
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Are there any ways to eliminate these senescent cells, or is it actually something that you want to do to remove them?
Yeah, it's, it's a great question. I think the data in model systems says clearing senescent cells, kind of across the board, is beneficial, at least in older mice. Younger mice, that's a different question because they're, like I said, these cells may be beneficial. Um, so it appears that if you take older mice and you treat them with drugs, and I'll talk about these drugs in a second, and these are drugs that are termed senolytics, that will kill at least a subset of senescent cells, that there are benefits across the board. Um, and this seems to improve immune function, seems to improve cognitive function, seems to improve liver function, seems to reduce inflammation, improve mitochondrial function, improve stem cell function. Um, and, and so, so the drugs, the class of drugs we're working on are termed senolytics. Um, and we were involved in the identification of the first senolytics with Jim Kirkland and Tamar Jacone at the Mayo Clinic. Um, and so we identified the first generation of drugs, which in most cases turn out to be anti-cancer drugs, and it makes sense because, as I alluded to, senescent fate can be driven by oncogene activation. So, you have cells that are starting to become cancerous, senescent fate turned on, and what appears that there actually are these networks or pathways that block apoptosis or cell death. The tumor cells turn on. That's one of the ways they become, uh, kind of immortal and able to proliferate in your body. And so drugs that target these pathways that keep the cells from dying, tumor cells, also appear to kill many types of senescent cells. So, many of the drugs which have been approved for cancer seem to have effects, at least on certain classes or types of senescent cells. Um, we've also identified natural products that have this ability to kill senescent cells, but many of these also have had the ability to kill tumor cells. So, in some ways, we're kind of killing that early stage precancerous, uh, cell that may lead to a tumor cell, uh, using drugs which have this senolytic activity. So, in theory, if we use our senolytics, it's going to clear these senescent cells that have oncogene activation that if they break through the senescent fate, they eventually lead to cancer. So, senolytics will reduce your risk of most types of cancers as a way of extending health span and potentially lifespan.
Gotcha. Yeah, that's a, that would be like the best-case scenario, that you'll eliminate both the senescent cell and the cancerous cell.
Yeah. Um, which of these senolytics are the best researched?
Right. So, the first generation, and this was the paper we published with Jim Kirkland in 2016, was showing that an anti-cancer drug that targets what are known as, uh, tyrosine kinase receptors, a whole family of them, that this drug, dasatinib, in combination with a flavonoid that's present in many fruits and vegetables called quercetin, that that combination was able to induce what we call senolysis, or death of senescent cells in culture. And there probably have been two dozen or more clinical trials either started or completed at this point with D plus Q, as we call it, the dasatinib plus quercetin. Um, there's evidence, I mean, it's not overwhelming evidence, but in some of the clinical trials that have been finished, there's evidence that in the top 35% that have the senescent cell burden, that they're responding or showing benefits of D plus Q. Uh, I don't think the dasatinib and quercetin is really that, uh, much of an optimal senolytic combination. It was just the first one identified. Um, the dasatinib is an FDA-approved anti-cancer drug. Quercetin, you can buy from Amazon and as a supplement. So, it was easy to move into the clinic. But there are now what we call second-generation senolytics coming, multiple targets identified in different types of senescent cells. Um, so I think there's going to be much better and much safer, uh, senolytics, uh, that are at least in preclinical models, and we'll have to see how they function in, in the clinic. Um, I should point, I keep talking about different types of senescent cells, but it's really becoming clear that if you take a tissue such as the brain or the liver, so for example, the liver, you can see senescent hepatocytes, senescent Kupffer cells, um, senescent infiltrating immune cells, and each one of these senescent cells seems to have a different inflammatory profile. So, the thought is, and we haven't proven it, that they may be having different types of adverse effects. And so, it may be for, uh, certain types of liver diseases, you want to clear senescent, for another type of disease, you may want to clear the infiltrating senescent immune cells. Um, so, you know, so we're still trying to sort out what are the different types of senescent cells that we need to target, and then what's the best drug or drug combination to do that.
And I guess, I guess is the other question you asked, you know, is it, is it beneficial to clear senescent cells, you know, because you're, you're in theory making a hole in a tissue where these senescent cells are. Um, and I think the best example is, you know, if there are senescent neurons that accumulate with Alzheimer's or Parkinson's, and these cells don't replenish because they're fully differentiated. So, killing off a senescent neuron may not be a good thing. Um, but at least in animal models, clearing senescent cells from aged mice or mice with neurodegenerative diseases like Alzheimer's, it's been beneficial. There's better cognition, uh, better behavior, better motor skills. So, we've not seen any adverse effects for eliminating a few senescent cells in the brain or in other tissues, at least at this point. You know, we'll have to see if we continue in the clinic with these clinical studies.
Yeah, I guess, you know, the most important thing is what's the final outcome. You know, there might be some side effects with clearing out senescent cells, but if you live longer and you're healthier, then, uh, it's apparently not that bad, or, you know, there's, uh, the end, end outcomes are something that I think matter sometimes more, right? And, you know, it may be that, um, as we'll find out, that there really are not that many senescent neurons. So, it's only a few that are being cleared. It appears that it's the microglia, which are immune cell types in the brain, they're, they're similar to macrophages, that they develop a senescent-like phenotype. So, clearing those appears to have a benefit. Maybe astrocytes, maybe oligodendrocytes. So, we're still identifying the right senescent cells that are arising, you know, uh, what they are, where, where we see them in the brain, and then, and then what drugs are the most effective at killing them. But again, as I said, animal models, we've seen no adverse effects of clearing senescent cells.
Gotcha. In, at least in older animals. Yeah.
Would it be possible to somehow reverse the senescent cell to back to a normal cell or more youthful cell? Kind of some, uh, gene editing with Yamanaka factors or something to make it more youthful again?
Yeah, that's a great question. So, you know, there's, you could discuss whether taking a cell that's been damaged, that may have acquired, uh, mutations or other changes that might make it detrimental if it started to proliferate again. Uh, there's been discussions that, you know, that's the last thing we want to do is rejuvenate a precancerous cell. Um, but it does appear that with OSKM, which are the Yamanaka factors, that you can take at least certain types of senescent cells and make them look younger. Um, and I think it's going to be something we're going to have to determine clinically, is if these more youthful cells, um, are, you know, if you have ones which are maybe damaged and have mutations that make them more youthful, if that's going to be a bad thing. Um, you know, maybe as we rejuvenate cells in the body, it's going to improve your immune function, and so your immune function might still be able to recognize these precancerous cells and clear them.
Mmm. So, that's the other, the other, uh, kind of unknown is when we treat mice with drugs like senolytics or other targeted hallmarks of aging, if you improve immune function, you're going to reduce your senescent cell burden. So, many of therapies out there might have indirect effects on senescence by improving immune function, which then leads to better clearance of your senescent cell burden. So, there's maybe multiple ways that a drug could function to extend health span and reduce your senescent cell burden.
Mmm. Yeah. You mentioned the immune system, that it's, uh, central to clearing out the senescent cells during youth, and with age, you see a decline in immune system function, which is one of the reasons there's a higher burden of senescent cells. Um, are there any, I guess, therapeutic options, uh, here to, uh, support immunity in elderly people?
Right. So, there obviously a lot of supplements that are being sold because they improve immune function, I think with very little evidence that suggests that's the case. Um, I, I, I, I think there are, and, and so we have a large grant from, uh, the NIH to look at ways of reducing immune senescence because we do know that T-cells, B-cells, macrophages, NK cells show profiles that make them appear senescent. Are they truly senescent, or they're senescent-like? But they're clearly dysfunctional. So, if you get rid of these dysfunctional immune cells, will that improve the function of the remaining cells? And so, we are doing experiments to look at that phenomenon and see if we can identify compounds which may not have to be senolytics, but other classes. Can we improve immune responses to pathogen exposure and to cancer? And so, uh, we and others are, are, are working on that. And I think that at least the animal data looks very promising.
Mmm. Um, and, and there's, you know, there's probably trials in humans too. I think the question always comes is, you know, as I'm alluding to, if you have senescent cells that are releasing inflammatory factors, those inflammatory factors alter immune function because it changes their ability to react to a pathogen or to a tumor. Um, so clearing senescent cells from the liver might improve immune function. Alternatively, if you can target the dysfunctional, potentially senescent immune cells, it will then clear the senescent cells in the liver and make the liver better. So, we're still trying to sort out, you know, do we need to target immune cells or non-immune cells that are senescent? Um, and I think the answer is going to be both. I think, as always, it's going to be a contribution of both. Just the overall senescent cell burden you want to reduce, and you want to try to reduce senescence in different classes of immune cells.
H. What about rapamycin? That's, uh, one of those, uh, pharmaceuticals that has been seen to improve immunity in elderly people, right?
So, it gets back to, you know, what, what cells are being targeted by rapamycin. But clearly, you know, that was the first drug really demonstrated to extend lifespan in mice. It's in a number of clinical trials in humans. Um, I think dosing and when do you start treatment is still a question. Um, but yes, rapamycin has been shown by a variety of groups and ourselves to actually reduce senescence. It doesn't kill senescent cells, but it suppresses the inflammatory factors that senescent cells release. So, drugs like rapamycin that suppress this inflammatory component, we call them senomorphics. So, it doesn't kill the senescent cell, it suppresses that. Um, what we don't know is what the key target is. Well, not target, but which hallmark of aging is, is the target for rapamycin. And clearly, the target is mTOR, that that regulates nutrient signaling, regulates gene expression, regulates this inflammatory component in senescent cells. But is that how rapamycin is working? Is by reducing the inflammatory component of senescent cells? Is it, uh, improving responses to nutrients? Is it affecting metabolism? Is it affecting stem cell function? I think we're still sorting out, as in many cases with drugs, what's the key pathway, uh, but it does reduce senescence, and I think that contributes, and, and through that reduction in senescence, we think improves immune function also. Um, and that was shown by Joan Mannick, where she, uh, treated a number of older patients and showed that they responded to either, um, a tetanus vaccine or the flu vaccine, uh, much more efficiently if they got intermittent rapamycin treatment.
Yeah. Yeah. The, uh, previous belief was that rapamycin is a, well, it is an immunosuppressant drug that is used for, uh, organ transplant patients. But that turns out, yeah, if you dose it intermittently, then it actually increases the immune system function.
Yeah. Yeah. Intermittent treatment is in lower doses. So, the dosing is also important. You know, rapamycin has some side effects at high doses, or continued treatment. There are a number of what are called rapalogs being developed, which may target more the right mTOR complex and not other mTOR complexes that might be beneficial. Um, so we'll have to see. I, I think, uh, you know, a number of these trials have started for different age-related diseases, and we'll see if the rapalogs are, are as or more effective than rapamycin. But, you know, clearly rapamycin has a beneficial effect if dosed correctly, uh, in mice, and appears in people with certain conditions.
Mmm. What would be then more, let's say, practical things people can do to reduce their senescent cell burden? And obviously, it's going to be different between younger individuals and older. So, maybe we can do, let's say, older than, uh, 50 and younger than 50, right?
So, you know, unfortunately, the answer is the same answer you would get when you ask, what can you do to live longer and healthier? And that's diet and exercise. Um, it's been shown that, uh, exercise in mice, and I think in humans, uh, can reduce senescent cell burden, at least with the markers we have that measure senescence in humans. Um, so exercise has, you know, whether it's through stimulating your immune function to clear the senescent cells, or if it's through a different mechanism, still not quite clear. Uh, your diet can affect senescence. We had a review article in Cell Metabolism recently with Dudley Lamming, talking about all the ways you can reduce senescence and a variety of dietary interventions which will do that. I, I think caloric restriction has a benefit there too. Um, but not everybody, as we know, at least in the US, exercises or eats well. So, we still think there's a, a role for developing, uh, pharmaceuticals that can target senescent cells that can be taken intermittently and safely to reduce the burden. Um, and, and in mouse studies, senescence, diet, or a senolytic seem to give similar results with many cases, though the senolytic working slightly better. So, diet, exercise, and hopefully eventually we'll have, uh, have compounds that you can take safely, and, and I think the reason why they'll be safe is because you take them intermittently. You don't have to take them daily to eliminate your senescent cells.
Yeah. What kind of dietary components did you, uh, find were beneficial?
Uh, well, there's numerous studies. It depends on the model system, but, uh, you know, it's been, it's clear they're reducing your caloric intake. Uh, compressed eating, uh, has a benefit. And then there, you know, amino acid, uh, or diets are reduced in certain amino acids that have altered effects on senescence. But it's still not clear what your right mixture of carbohydrates and proteins and then amino acid composition, uh, in humans is going to have the biggest benefit, because we see differences between mouse strains. So, even within mice, different strains respond differently.
Gotcha. I think what we're going to need is, uh, a way of, like I said, really determining your senescent cell burden and determining if you need a certain type of diet or treatment as compared to somebody else. And so, eventually, this will become a personalized treatment regimen. You can either, you know, send your blood in and get your epigenetic clock, or they can measure five senescent or proteins that senescent cells secrete, determine your senescent cell burden, and then make suggestions on either diet, exercise, and/or drugs you could take that target your senescent cells.
Mmm. You mentioned the amino acids. Is it that certain amino acids increase cells in essence, or, uh, or protein restriction or amino acid restriction reduces them, or which way is it?
I think it, it depends on the strain, probably depends on the cell type and the tissue. Um, but, but clearly, you know, I think if you look at mice, drugs that have the biggest effect on lifespan, there's rapamycin, but then there's, there are, uh, metformin, SGLT2 inhibitors, and these are ones that seem to be used or are used to treat diabetes because they normalize metabolism. So, at least in mice, normalizing your metabolism is beneficial. And if you normalize your metabolism, we know metformin treatment, SGLT2 treatment, or inhibitor of SGLT2, that they reduce your senescent cell burden. So, improving metabolism reduces senescence, or maybe these drugs reduce senescence, which affects metabolism. But clearly, drugs that humans are taking for type 2 diabetes, metformin and SGLT2 inhibitors, are having a, a benefit on health span across the board, as well as able to reduce markers of senescence.
Interesting. Yeah. And I guess the other drug I should toss in there, um, and maybe we can discuss this later on, is, uh, is GLP-1 or GLP-1 receptor agonists. That there was a long discussion at the recent, uh, meeting on aging research and drug development in Copenhagen. You know, is GLP-1, or are GLP-1 like drugs our first anti-aging drugs? Because there's data coming out that GLP-1, you know, and related drugs can have effects on Parkinson's, Alzheimer's, heart disease, osteoarthritis, liver disease. Um, and it's still not clear the mechanism. I'm, I'm still surprised, but yeah, every time I pick up a journal, there's an article about a GLP-1 or related compound having a positive effect on an age-related disease.
Mmm. So, they're saying, will GLP-1 agonist, GLP-1 receptor agonists be the first true anti-aging drug? And, and the panel of people from pharma, they all said yes, right? Surprising. So, um, you know, GLP-1 also normalizes your metabolism. Again, we don't understand all the mechanisms. Um, there may be adverse effects on muscle function, which they're trying to develop combinations of drugs that don't reduce muscle mass and function when you take GLP-1 agonists. But I think they're going to eventually overcome that side effect, and these will be drugs that people will take after a certain age to extend their health span.
How big of a, that effect comes from just a calorie restriction or eating less?
It's, it's a question I always ask, and, uh, I think the answer is not quite clear. They think they're actually some disease modification. That, you know, the best example would be osteoarthritis, is a simply losing weight allows your knee joints to feel better. But they say there's actually changes in the joint architecture. It almost looks like a disease-modifying drug that can, that can improve the joint structure. So, and that's thought not to be just through weight loss, but is the caloric restriction, uh, mimicking, you know, caloric restriction mimetics? Yes, that probably is part of it, but they think there's more. And, uh, and what's interesting is that many cells in the brain, chondrocytes in the joint, actually express the receptor for GLP-1. Yeah. Which again, I'm very surprised at why these cells would express a receptor for something that regulates appetite.
Mmm. Still a lot to learn about GLP-1.
Yeah. You know, people have the impression that it just makes you eat less, but, uh, yeah, there's a lot of other systemic effects because, uh, because of the hormonal effects you get from that, uh, increase in GLP-1. So, yeah, it's, um, you know, probably a lot of the effects come from eating less, but, uh, there's additional benefits as well, probably.
Yes, I think that's definitely the case. Yeah.
What about the, um, you know, these over-the-counter supplements, you mentioned fisetin, quercetin, apigenin, etc. Is it something that people should consider already, or like, what, what do you think is the evidence, uh, right now?
Right. It's, it's a great question. I'm asked this one a lot because, uh, again, in collaboration with Jim Kirkland, we were the first group to publish that fisetin had senolytic activity, and this has led to multiple clinical trials with fisetin. Uh, fisetin is not the best senolytic, um, and it takes high doses to see a benefit in mice. Um, we have made analogs of fisetin which we think are much more effective that we hope to take to the clinic soon. We've identified some of the targets of this class of flavonoids that probably bind or interact with 50, 100, you know, hundreds of proteins. So, we don't really know what the key target is of fisetin. Um, I think the problem with taking fisetin, and, and I, I don't think there's a downside. In fact, many people in the aging field are taking fisetin. I, I take it intermittently myself. Um, but we really don't know the dose. So, some people take a certain dose daily, some people take a higher dose once a week. During COVID, when we showed that fisetin actually protects old mice from a virus similar to SARS-CoV-2, we started to take fisetin to protect ourselves from COVID if you were so infected. Um, but again, we, we don't know what the right dose is. So, we were taking two high, uh, you know, for two days, we took high doses, went 14 days, and another two days with a high dose. No evidence that that's the right dosing regimen.
Mmm. Um, so I don't think there's an adverse effect of, at least we've not seen that, but I don't necessarily recommend people taking these huge doses every week or two. Uh, people that take it once a day, I've seen say they feel better. You know, quercetin is probably like fisetin, maybe not quite as effective. Um, but there are a number of flavonoids. And another one that we're working on, it's not a flavonoid, is a drug called fucoidan, which is a complex polysaccharide that comes from brown seaweed that's taken as a health supplement in Asia. And there are dozens of different, uh, types of brown seaweed that you can isolate fucoidan from. But we showed fucoidan actually functions as, we call it a senomorphic. It suppresses the inflammatory components of senescent cells. And we think it does this because it stimulates an enzyme called SIRT6, uh, which is involved in DNA repair. And we have evidence in mice, at least not in humans yet, but in mice, that fucoidan can improve DNA repair, which if you reduce genotoxic stress, there's less senescence, less inflammation. Um, and so they're now starting clinical trials with fucoidan to see if there's benefits in humans. Again, people take this, but there's been really no controlled studies to look at markers of aging, epigenetic clock, mitochondrial function, etc., and senescence.
Mmm. Yeah, SIRT6 is, I think, the only SIRT that's been seen to extend lifespan in, in animal models. The other ones, not so much, but SIRT6. Yes. Yes. So, there are multiple companies now selling fucoidan as a SIRT6 agonist. And, you know, and I'm hopeful that the clinical trials that are being set up, um, that hopefully are going to be set up in a blinded manner, quality control, that will determine if certain sources indeed has a health benefit. Um, but people take fucoidan, they take quercetin, they take fisetin. You know, we could talk about NAD precursors that people take. You know, I think the data is still limited in humans about the benefit, um, because we don't know the right dosing regimen or the subset of people they're going to respond best to these drugs. Not everybody's going to respond the same way across the board.
Gotcha. What about like gene therapies? Um, there's, they become, I guess, more known in the longevity space. And, um, is there any even like a possibility to do some gene therapies to help with senescent cells? Or I mean, I guess you can make gene therapies for immune system function, but what about senescent cells?
Right. So, when you talk about gene therapy in aging, there's, there are different types of gene therapies you could imagine. So, you know, one of them, um, being developed by Scott Lowe and Krina Moore, um, at Cold Spring Harbor. They're making CAR-T cells. So, we can engineer T-cells that will target a tumor cell. They're trying to engineer T-cells that target a senescent cell, and they have shown if you clear senescent cells expressing a protein on their surface using these modified T-cells, that the mice are healthier for longer. I think the issue was going to be is what is the right protein to target on a senescent cell? Is there really something specific for a senescent cell that's not expressed on normal cells? And so their question is going to be about safety moving forward. But I think there will be clinical trials using CAR-T cells that target senescent cells in the future. Um, other people are trying to deliver growth factors, um, using viral vectors, um, that you deliver to different tissues. Uh, for example, you could deliver Klotho, which has been shown that if mice without Klotho live a very short lifespan, if you deliver it back with a gene therapy, you can, you can extend lifespan of those mice. Um, so that's another approach. I think the question there is, is if the protein you're expressing can have adverse effects if you make too much of it? There's going to be a safety consideration. So, it may be certain gene products are going to be safe if you deliver and overexpress them in the body, other ones may not be. You know, if you make GLP-1 at an elevated level constitutively, is there going to be a downside in five years? So, I think there's some safety considerations. Um, the other approach, which has been discussed, um, and George Church, I think, has been a big proponent of this and has talked about it, is using CRISPR-Cas9 or other mod, other forms of gene editing to deliver variants that are found in centenarians into people that are not centenarians. And so, I am part of a large effort with Albert Einstein and Columbia University to do sequencing of centenarian genomes to identify what we call not mutations, but their variants. For example, we identified a variant in SIRT6 that makes it more active, which led us to do the fucoidan studies. So, the thought might be that you could actually deliver or or engineer certain cells and certain tissues to have this rare variant in SIRT6 or IGF-1 receptor, or in other, there's some in genes regulating cholesterol synthesis that may have effects on health span. So, you know, so could you engineer our genome to carry variants that have been shown to lead to extend the lifespan in humans? I think we're a long way off from that, but, you know, it is feasible in theory. Uh, so we can deliver genes. Um, another example of a gene, you know, keep talking about SIRT6, but it's kind of been, uh, something that my lab, in collaboration with Vera Gorbanova and others, that we've been focusing on, but we found variants in SIRT6 in centenarians. Companies have taken that centenarian SIRT6 and delivered it to the liver with an AAV (adeno-associated viral vector), and the mice are healthier if you overexpress this, this variant of SIRT6, or you could engineer using CRISPR-Cas9, the gene edit in the liver to introduce this variant into the SIRT6 gene. So, you could think about ways going forward, and I think we're a long way off because I think there are safety considerations, but it's something we could consider in the future that will allow those of us who are not going to be centenarians, um, to live healthier for longer.
Mmm. The, uh, how many of these rare variants do you need? That takes somebody who's not a centenarian, and I have no centenarians in my family, so I'm not expecting to live to 100. But can I engineer five genes, 10 genes, 50 genes? What, you know, how many do you have to engineer for me now to be a centenarian? You know, what tissues, and how, what percent of the cells in that tissue? Lots of questions. Uh, it is something that companies are working on, and, and, you know, I think eventually we'll be there, whether it's 10 years or 50 years, I think eventually these approaches will be applied to, to the human condition.
Yeah. You know, some, some of the ones we are aware of, things like APOE4 and maybe IGF-1 pathways, maybe, and I would imagine there's something, uh, related to senescent cells as well. Some genes that help them to clear them out more easily, or something like that. You know, there's immune system related genes that are associated with longevity. So, there's a handful of them that we're aware of. I guess there's no one who has, you know, done all of them to actually see what's the effect.
Yeah. I, you know, so that's, it's always the question when you look at rare variants, you talked about, you know, IGF-1 pathway, you know, SIRT6, you know, and then you talk about bad genes like APOE4. You know, the, the beauty of the centenarian studies is there have been, there have been centenarians identified that have high-risk variants in APOE, even people with BRCA1 mutations, that something about these rare variants that they carry that are beneficial can, can block the adverse effects of a bad APOE or BRCA1 or BRCA2. So, you know, I think there's going to be a lot to learn from centenarians, and then, and then obviously modulating IGF signaling, which is one of the first variants identified in centenarians. Uh, there's a transcription factor, FOXO3, that's been shown to be, uh, expressed differently in centenarians. Um, so I think if we can identify the beneficial variants, they can actually suppress these bad variants. So, you may not have to actually gene edit that APOE4. You may have to edit in a SIRT6 variant or an IGF-1 variant, or, uh, some variants that affect the level of a transcription factor, NF-kappaB, maybe downregulate NF-kappaB so it's not as inflammatory late in life. So, but these are things that will be coming as we sequence more centenarian genomes, we validate them in mice, we validate them in cell culture models, and then, you know, eventually, as the gene editing technology gets better and safer, I think these will be applied to trying to make us more of us centenarians.
Yeah. And then, you know, I think this is going to be, you know, one of the big leaps that will, you know, lead to some more breakthroughs in, uh, longevity and, uh, life expectancy, because, uh, genetics is very powerful. I think a lot of people underestimate the power of genetics when it comes to how long you live. Even just by the fact that if you have long-lived parents or grandparents, then your likelihood of reaching that also, like 100 or 110, or something like that, is, you know, huge compared to the average person who doesn't have long-lived parents. So, yeah, longevity runs in families a lot, that it's very genetic, and if you understand those genes, then yeah, maybe we can use these gene editing to actually apply to, uh, more people.
Yeah, I think it's just going to be, you know, the safety issue. Uh, you know, treating a rare disease that has a very poor prognosis with these new methods, I mean, that you can justify, but taking millions of people, you know, across the country and starting to edit.
Their genomes, you know, wait 10 years and see what adverse effects there could be if it turns out there's offtarget effects. Uh, you know, so there's going to have to be a lot of studies done treating more severe diseases with these approaches to really support moving us into treating the masses. And there's also a cost factor too. I mean, the goal for all of us is to develop safe, effective, and affordable ways of extending health span. So again, we're not trying to do this for just people in Silicon Valley and Wall Street. We're trying to do this for, you know, the average American and the average person around around the globe.
Um, and so we have to do this. We have to do studies and characterize people with different ethnic backgrounds, uh, which there, you know, genetics may be a little bit different. There may be different rare variants, and some may have a different ethnic background than another. But we have to come out of a way to make this kind of safe, effective, affordable for everyone. And that's the reason why something like a facet, if we can make a better facet, or make, you know, a natural compound, or come up with a cocktail, um, that's cheap and affordable. I mean, metformin is about the cheapest drug you can get, and if, you know, if it really shows in the TAME trial to extend health span, uh, you know, that's a drug that many people could get access to.
What are you, what are you, um, what is your like next biggest projects you're focusing on? Like, what, obviously, we talked about, uh, the 10-year goal with, uh, a lot of these, uh, therapeutics. What is the your biggest focus right now for you?
Yeah, it's hard to always pick one, but, um, I guess, I guess I, I'll, I'll name three. We'll start with there. But, uh, so, so the first one is that, um, within our institute, we've generated mouse models where we can induce senescence in the cell type or tissue-specific way. So we're making a whole panel of mouse models where you can induce DNA damage and senescence in cells in the liver, the brain, and muscle, and the heart, and pancreas, uh, the intestine, and then trying to look at what pathologies those subsets of senescent cells cause. Again, trying to identify what are the key senescent cell types we should be targeting. We're then trying to optimize our analytics. We've developed in vitro cell culture screens. We have been mouse models that can validate the drugs that score positive as senolytics on certain types of senescent cells, and we're trying to optimize them with doing medicinal chemistry. So we really have a portfolio of new senolytics that we're trying to take forward, as well as identify what the right lead compound is. I mean, that's the problem is we have too many senolytics that look promising. We have to identify the one or two we want to take forward.
Um, and then we've gotten into trying to understand partial rejuvenation. Um, you know, again, you asked about, uh, partial rejuvenation with the Yamanaka factors, which companies like Altos and others are really focused on, um, and whether, you know, these iPSC factors can rejuvenate senescent cells. And it appears in mouse models that they can. Um, so, so we've been screening for senolytics that can take a senescent cell and not kill it, but make it not showing all these markers of senescence. And some of them actually make the cells look younger, healthier at the transcriptional level and the epigenetic level. So we're starting to think that that some of the drugs we're identifying may have partial rejuvenation effects, not only, you know, and and that's how they're affecting senescence is through partial rejuvenation and not by directly targeting senescence. So, so we are now trying to do more assays and more characterization, both in cell culture and in mice, about some of the drugs that we've identified, uh, that may have partial rejuvenation effects.
Uh, you know, I do think that what Altos and others are doing is is very exciting. The question is always going to be safety, uh, of expressing Yamanaka factors. The drive cells into a state of, uh, embryonic, uh, stem cellness, um, is not what we want to be doing. So, and some of the genes could be causing cancer if overexpressed or not turned off. So how do you regulate their levels and control them? So we're trying to look at other approaches, including small molecule approaches, that may have the ability to partially rejuvenate cells. And I think that really is the holy grail. I think in some ways, when we're focused on these different hallmarks, many of the the approaches are actually partially rejuvenating an aged cell. Uh, we just never really look at partial rejuvenation. So I think we're going to come up with different drugs and different cocktails of drugs that will, um, show signs of not reducing senescence, targeting other hallmarks of aging, but actually using the transcriptome, the lipidome, the metabolome, all the different omics to make a cell look younger. And then the question will be, is what's, you know, are there safety risks doing that?
Gotcha. Yeah, it's, uh, unfortunately, it takes a long time to, uh, do these studies. And I mean, that's the problem with aging is that, um, you know, animal models, if you don't work on worms and flies, take a long time. Um, so how I got into the aging space was started to collaborate with somebody that has mouse models of accelerated aging that that mimic human progerias. Um, and so these mice age six to seven times faster. So we're able to do drug treatment studies faster, or assess a genetic change in these mouse models, what effect it has on aging. Um, and then take those, what looks positive, we can take into natural aging, and then hopefully eventually in people. Um, and it may be that picking individuals that have, you know, progerias, whether it's Hutchinson-Gilford or Xeroderma pigmentosum, or Cockayne syndrome, that they might be actually an orphan disease that could be these drugs, these, I can't say anti-aging, but drugs that extend health span might be beneficial in these individuals that are aging faster.
Gotcha. So that would accelerate some of these studies. So we're trying to find ways that we can identify therapeutics faster and then identify the right patient population for for testing them.
Yeah. Well, I'm definitely going to keep an eye out on, uh, your future studies and, uh, work before I ask my last question. Where can people learn more about you and your work?
Yes. So if you look for, uh, the Masonic Institute in the Biology of Aging and Metabolism, it's called MIBAM. If you search for MIBAM at University of Minnesota, um, our institute's website, there's a lot of information, um, about what's going on. Uh, we are starting, um, hopefully a quarterly newsletter that, uh, you'll be able to download from our website. Uh, we've only talked about it for six years. We're finally launching that this fall. So we will have a newsletter that highlights accomplishments, uh, both pre-clinical and clinical, highlights papers, highlights awards, etc., for new grants. Um, so I think between the newsletter and the website, I also have my own website at robins.umn.edu, uh, where again, we have updates on papers and projects. Um, I, I think it's a goal for everybody in aging research to make the public aware of what's happening, uh, both the positive and the negative, uh, based on high-quality science. Um, I think science, we won't talk politics, is under attack in the US at this point. So, uh, it's up for us doing aging research to get the message out about where the field is and what we've shown and what we haven't shown. Uh, you know, we're not out hawking supplements, uh, just for the sake of supplements, but, uh, trying to do well-controlled clinical studies to evaluate whether supplements work either alone or in combination. So, so it's something we're all trying to do is how to determine how to get the word out about, you know, high-level science in the aging space, but from my lab, our institute, but also around the world, how do we get this message out? So we're working on new ways to convey it, whether it's podcasts, newsletters, websites, etc.
Hm. Yeah. Well, I'm happy to help with that. And, um, my last question is, uh, what's this one piece of advice or habit that you wish you adopted sooner?
Oh, it's a great question. Um, you know, again, getting back to nutrition and exercise, uh, it, it took me turning 50 before I started to think about this more. Uh, I always exercised and played sports, but then as your body gets older and your knee starts to hurt a little bit, you're not as active on the squash court. Uh, so I think I finally learned to find exercise routines, um, and diets that I actually can follow, not just imagine, but actually follow, um, that are, you know, appropriate for older people. Uh, and, you know, I, I'm not a big pill taker, but I do take Fisetin. Um, I have taken metformin in the past, but, uh, for whatever reason, didn't continue it. Um, but I think I'll probably be taking a few more supplements as we identify in well-controlled blinded clinical studies that they show a benefit. But I think coming up with a a diet that is manageable, uh, and an exercise routine that's appropriate, uh, that you can actually follow, uh, is a big step forward. You don't have to go out and run marathons or bike 100 miles, but there are things you can do, um, that that can keep you fitter for longer. And I think that all has benefits as we're developing, hopefully, the first generation of, I don't, I hate the word anti-aging, but compounds that will extend health span, slow aging.
Yeah. Yeah. Well, looking forward to it, too. And you, we have to do what, uh, is possible in that time and moment. So, uh, right now, this is the most effective way to slow it down on aging.
Well, you're such a young guy, you have time before you have to start worrying about this. So I think by the time you get older and have to worry about the aging process, there's going to be a number of, uh, pharmaceuticals and biologics that have shown efficacy in well-controlled clinical studies. So I think you, there's going to be a lot of hope for those of us who are older. Uh, we keep talking about how we're running out of time. We have to do this quickly. But, uh, the field is definitely moving forward because the quality of the science has, uh, gotten better, and there are true scientific studies being done, and not just snake oil being sold. So the field is really moving forward. It's a very exciting time to be in aging research.
Yeah, absolutely. Uh, well, thanks for coming to the podcast, and, uh, it was very valuable and informative.
Well, thank you for having me. I enjoyed it. Thank you. I'll see you around.
All right. Take care.