Dr. Andrew’s Perspective On The Current Theories Of Aging In The Context Of Telomere Biology​

Joseph M. Raffaele, M.D.

Well, Bill it’s great to have you back on the Telomere Summit. Last time we covered a lot of great material, your whole history in Telomere biology, talked about mouse models. Why you think telomeres are sort of one of the keys to, reversing aging and preventing aging. At the very end of our discussion though, I think I asked you about whether you had any closing thoughts about things, and we got into a little bit about aging and you made the statement that no one really knows what causes aging. And then I said, well, I thought that there was some agreement on sort of the overall sort of understanding of aging with the 2013 paper, the hallmarks of aging. And then I think Len Hayflick published a paper in 2007 saying that aging is no longer an unsolved problem in biology. Of course, that was back in 2007. And you basically said to me, I think you, you need a little schooling in too. I wanna talk about, where we are with aging and really to understand how to cure aging, you have to, I think have a pretty good idea about what are the mechanisms. So you know what to focus on and obviously you’ve been focusing on telomere biology, but I think getting into a discussion about what are the causes of aging, why aging occurs with your evolutionary background and knowing that aging and cancer are two sides of the same coin, I think it would be great to sort of talk about what you think the current state of the art is of our understanding of aging.

William Andrews, PhD

Okay, well, first let me comment on some of the things you just said. The recent paper hallmarks of aging, that’s actually wasn’t, I mean, it got a lot of press, but it actually didn’t really provide anything new, for instance wasn’t provided in Leonard Hayflick’s book, I figured out what the title of that is, what is aging and there’s other things even back in the 1980s, late seventies, eighties, and things like that when I was attending aging conferences, all those things were discussed before. So it was just kinda review of where we stand. So it’s nothing new, but the bottom line is aging is still just a guess. I mean, we know what aging is. Everybody knows what aging is, but also nobody knows what aging is, okay? 

It’s I mean, we just all saw William Shatner go up in his space, but when we look at a picture of him side by side, from when he was in Star Trek enterprise or the Star Trek series, nobody’s gonna not know which photo of William Shatner was taken first, okay? So we do know what agent is. If we could turn William Shatner today into the William Shatner, he was 30 years ago, nobody’s gonna say, prove to me that you actually reverse aging, okay? So we do know what it is. We just don’t have any way of defining it, okay? And that’s one of the reasons why we can’t really do clinical studies just on aging, ’cause I agree with the FDA and Don Fink last night, I was trying to remember who it was at the FDA that I’m talking about. I said it was Don Fink, but I wasn’t sure it was Donald Fink that I’ve had lots of discussions with.

And the bottom line is, we don’t have any way of measuring aging We have these markers, including then DNA methylation and glycosolation, IGG glycosylation, but are those symptoms of aging? Are they causes of aging or what is really going on there? I mean, I think we come back to telomeres lately, I think I can distinguish between Telomeres and the other ones if I didn’t last time. But the fact is is, that if we let’s say that many of these markers of aging are symptoms of aging not actually because of the aging. If we reverse those markers, have we reversed aging? And the bottom line is no. I mean, we, well, we don’t know. I mean, it’s like in order to actually prove that we have reversed aging, we need to show that William Shatner, or oftentimes I use Betty White as an example, people that have aged very well, we have to show that everybody looks at their picture and say, hey, they look like they did when they were young, okay, or they act like they were young or they behave like they were young or feel like they were young, it’s all that kind of stuff. 

So, we don’t have a good marker of aging, but we all know what aging is. So I always talk about to prove we’ve cured aging, we have to have somebody to pass the Betty White test, or now I am gonna be calling it the William Shatner test also. Now, a lot of people are doing things where they’re saying they’re slowing down aging, but there’s no way to measure a slowing down of aging, unless you’re gonna do it in fruit flies, where you have a thousand, each different group, and show a statistically significant difference. In humans you can’t say you’ve slowed somebodies aging down, unless you have a negative control to show that, let’s say an identical twin, okay, that wasn’t on the treatment, and they didn’t slow down like the twin that was treated. Okay, so, but even one twin wouldn’t be sufficient because of an effective environment. 

It would be very difficult to control that. So you’d have to do thousands of identical twins and you’d have to first pick thousands of identical twins that were absolutely identical at the time the study started. And that just happens. I’m an identical twin and my brother and I look extremely different right now, but it’s, we do have 100% identical DNA is shown by 23 and me. So what is aging is something that is very complex, but I think we can still do clinical studies by measuring diseases of aging, okay? So let’s say we do a clinical study to cure Alzheimer’s or as we talked about the last time, several other diseases too. And so we get an FDA clinical approved study to do this, and then during the study, we have this surprising result that the people got younger, they passed the Betty White test, or that William Shatner test, when that really wasn’t something we were looking at. Okay so that’s the only way I think we’re actually gonna get an FDA approved clinical study to actually look at aging by looking at diseases of aging, ’cause we don’t really know what aging is. But again, we all know what aging is.

Joseph M. Raffaele, M.D.

Well, I mean, it’s sort of like a Potter Stewart quote from about the famous Supreme court case, talking about pornography. And we all know what pornography is, we just can’t define it. It’s sort of one of those things where, yeah if you have, and I was thinking about this when you said it last time, because as I mentioned to you, I’m I guess very interested in, and invested because I spent a lot of time looking at biomarkers of aging. But if you have a truly amazing age reversal technology or therapy, it’ll be pretty obvious, right? It’ll be obvious that the person is gone back to their previous self instead of, I have people that run, you’re a runner, they’re running nine minute miles whereas when they were 25, they were running six-minute miles. If they’re back to running six minute miles again, then we know that they’ve had their aging reversed. 

You don’t even necessarily need to look at a lot of biomarkers of aging. And we may have a therapy like that at some point, but I’m gonna assume that it’s probably gonna be a little bit more incremental progress, and so perhaps if you look at many different biomarkers of aging, including the ones we’ve talked about, the molecular ones, epigenetic DNA, methylation, telomeres, glycosylation, and you look at organ system ones as well, and you see arteries becoming less stiff, lungs, becoming more capable of blowing out air faster, cognitive function, being faster, and those are all measurable, with good low variability, over the course of three or four years. I measure with my patients, you might be able to see a signal at that point. It’s just would have to be a, I think, a multi-point approach to it. 

So, that’s my view, but what I kinda wanted to do today was also sort of look at aging from the standpoint of sort of theories of age, ’cause there are, after our conversation, I went and looked out there and while, I think you’re right, the hallmarks of aging paper was, widely cited and got a lot of press. And I think it was a good laying out a sort of major factors that impact aging, but it wasn’t anything earth shatteringly new, there’s two questions really that maybe the audience might be interested in sort of, what is aging, but also why does aging occur? 

Which has been something that I think, George Williams talked about in his, the antagonistic pleiotropy theory of aging, and particularly with regard to telomeres, if there’s such great things, to keep long, why have we not had to select the pressures to keep them long? And I think getting into that a little bit might be helpful and then finally, I read some other people that are looking at this, like Mikhail Lygus Kalani, who talks about other things being more important, like this quasi program, hyper function of, cells and mTOR has a lot of talk about mTOR and rapamycin and I’d like to get your thoughts about rapamycin vis-a-vis, your approach from telomere biology standpoint as well. So I know that’s a lot, but I think those are the kinds of things that I kinda like to get your thoughts on it. I really, it’s an open question for me.

William Andrews, PhD

Okay, well first let me say just one thing on markers I believe biomarkers of aging are extremely important to test. I think it gets a really good measure of health and showing that you are actually have symptoms that are similar to a younger person. And I think that’s really important, but all I’m saying there is from the scientist in me, that’s the study of aging, that doesn’t really mean we have reversed aging or reversed those biomarkers, but it’s still good to reverse those biomarkers. And I think more biomarkers reversed it better. Okay, antagonistic pleiotropy. That’s becoming a really popular subject lately as to why we cure aging. And I kinda wonder why it’s become so popular, but it is kinda fun to say, okay, antagonistic pleiotropy. And I think it’s gotten caught up in, but if you ever studied poetry which I was had to do extensively in my high school, you’d know that it’s actually only one syllable short of Iambic pentameter, okay? Which is kind of like a poem antagonistic pleiotropy, so it’s gotten really popular, but I don’t understand really why, because and I think there’s, let me say a lot of theories about why we age are based a lot on some possibly misunderstandings about evolution or biology, the biology of particular traits they’re looking at. 

And again, nobody knows it’s all best guesses, but the question is we’ve been evolving for so many millions of years, why haven’t we evolved to get rid of aging, okay? Why do we age when that seems like, wouldn’t that be an evolutionary great thing to have, change to us that make humans better? But the fact is that’s the exact opposite of the truth, okay? And so that’s why understanding evolution, is really important to really understanding the evolution of aging. And the evolution is, really comes down to the ability of a species to survive a rapidly changing environment. And sometimes that environment is humans, okay? So animals on the planet are disappearing and stuff like that because of humans. And really let me go on a tangent here, just five days ago, Science magazine published a great little study on tusk less elephants, okay? So elephants with no tusks, they’ve shown that the percentage of elephants that don’t have tusks have gone from 2% to something like 40%, in the last 30 years.

Joseph M. Raffaele, M.D.

Makes great sense.

William Andrews, PhD

It’s ’cause of poachers. So, all of a sudden, when you talk about different gene combinations, variations, you have your alleles, different types of genes that occur at the same locus in the chromosomes, so different alleles and some are called risk alleles, okay? Doesn’t mean that they’re a mutation, it means they’re probably the maybe they were the original gene, and we evolved a different mutation, that’s not that there’s not a risk and that’s the mutation, okay? But, sorry, I got confusing there. But the fact is that tusks, the genes to produce tusks in the last 30 years or 40 years or whatever it has suddenly become a risk allele, okay? So an elephant that has a gene to produce tusk is more likely to survive and that may, in fact, in this study, they say one in five, they have a five times better chance of dying from a poacher than an elephant that doesn’t have any tusks. 

So now all of a sudden elephants have evolved partially to where they don’t have tusks. And if we keep it up, they’re gonna be, you’re never gonna see any elephants with tusks. Okay so evolution, that’s the ability to survive a rapidly changing environment. The onset of humans was a rapidly changing environment for the elephants. Okay, so how do you, what’s the best way to survive for a species? And remember evolution is not something that’s geared to make the individual better, it’s to make the species better. 

Okay, what is the best way for a species to survive changes, rapidly changing environment? And that is shuffling its genes, okay? So by creating as many variations of the species as possible increases the chances that at least one or more of those variants are gonna survive a rapidly changing environment. And an example is the elephants with the tusks. So, before I end there was no evolutionary advantage to having tusks or not having tusks, or maybe there was evolutionary advantage to having tusks, but suddenly it got changed. Well, we, in aging, we wanna survive a rapidly changing environment by shuffling our genes. But if you do the math on shuffling of genes, you actually get a lot more shuffling by letting the offspring interbreed with each other, than by allowing the parents to re breed. 

Okay, so if you just, let’s say, go to the extreme, let’s say you have a population where the parents keep re breeding and producing offspring, but the offspring aren’t allowed to breed, okay? Where the shuffling doesn’t get very extensive. It gets more expensive by allowing the offspring to have whole variations of genetic genes than the parents do. So if you have two species and one is encouraging the offspring to interbreed and the other one isn’t the species that is allowing the offspring to interbreed is gonna be more likely to survive that rapidly changing environment. And what’s the best way to ensure that the offspring interbreed and that’s eliminate the old, okay? There is no evolutionary advantage to living longer than it takes to raise your young. After that, you’re just in the way, and that’s why we age in my opinion. I mean, but that’s based on a lot of understanding of evolution and biology and stuff, so if you have two species, again, one that doesn’t have an aging process, and one that does have an aging process, that species that has the aging process is more likely to survive than the one that has no aging processes.

Joseph M. Raffaele, M.D.

So, I mean, that is, the set of facts that you put forth there can also be consistent with the idea that it’s the hostility of the environment that a species is in, that is the major factor. So you take the example that’s given of the field mouse and why they have a life expectancy of under a year, because the owl of the Hawk is gonna come down and take them out. And Tom Kirkwood’s, I don’t know he was the originator of it, but popularized around the idea of the disposable Soma, that aging comes in through the back door, not because it’s programmed, but because it’s not programmed for, the mouse is gonna be as fit as it can be for the time that it’s likely to make it to reproductive maturity and then after that, to invest in keeping the Soma healthy and not aging is energetically, it doesn’t make sense for selection for evolution and therefore you don’t have to invoke necessarily that you wanna get rid of the older generation, is just is gotten rid of, because you’ve reached that peak where this environment is such that that species, doesn’t wanna invest more because they’re gonna be dead of unnatural causes before then. 

So that’s where antagonistic pleiotropy comes in. If you take the mouse into the laboratory, then you keep breeding them, like they have, then they start getting longer telomeres. We all know that, mice in the laboratory, live longer than mice in the field, then you get a sort of a different thing. And I don’t know, I mean, I’m almost asking, does your theory necessarily, out-compete not to use an analogy, the one of, sort of a disposable soma where, it’s just not invested in those repair and maintenance or the longer telomeres to maintain the Soma after peak reproductive age. That’s the kind of thing, classically what I’ve read, in a lot of books and what you’re talking a little bit is about group selection, I guess, on a species level.

William Andrews, PhD

What selection?

Joseph M. Raffaele, M.D.

Group selection, I guess you’re kind of talking about, and you and I have talked about this before, whether I guess that that’s back on the table I mean, I think it had been sort of not thought to be, what’s happy with aging, but you think that is to a certain extent. And if that is, does that change though? The understanding of aging and the understanding of how to alter it?

William Andrews, PhD

Oh, well first let me start off by saying, I think aging is actually a very recent evolutionary event, okay? And I think that a lot of, especially when there’s more and more animals on the planet and more possible, so predators are changing environments, different species have evolved different mechanisms of aging, okay? And then they also have evolved different mechanisms of getting rid of the old to increase the shelf life of the genes. But I personally don’t believe that mice age in the same way humans do, and we haven’t gotten into telomeres but telomeres is a big key there. And, Richard Color for instance, I wanna say 30 years ago, published a really great study on antioxidants, natural anti-oxidants in the body. And humans have, like a hundred times better antioxidants than mice do. 

So mice actually, I think suffer tremendously from oxidative stress and mitochondria dysfunction, whereas humans really don’t. I mean, we would, if we get overcome our other, which I think is telomeres, if we overcame our other aging processes, I think we might become victims of oxidative stress and mitochondria dysfunction at a much higher rate than we already are. Let’s see and you said something that I wanted to come back to? Oh yeah. Okay. So in terms of different species, I mean, there’s our strategists and case strategists for some reason, I think we discussed that at our last.

Joseph M. Raffaele, M.D.

No we didn’t get into what you and I have discussed but I just listened to it, and we didn’t talk about our species in case species, which we should.

William Andrews, PhD

Yeah, I get the R and the K mixed up sometime, but humans are either K I think–

Joseph M. Raffaele, M.D.

I think R is rapid, maybe. So I think that might be, but I’m not 100% sure.

William Andrews, PhD

So we’re good, we’re good. But, the point is, is that some species breed, young produced lots of offspring, some breed, some species breed old and produce a few offspring, okay? And so they have to have the depth to evolve, different mechanisms to surviving, whereas the species that breed young and produce lots of offsprings, they can afford to lose 99% of their offspring and the species will still survive, whereas organisms like humans, we can’t do that. We have to evolve mechanisms to keep us alive, long enough to raise our young, okay? Now, and that’s all. After we’ve raised our young, as I said before, there’s no evolutionary advantage to staying around, we’re only in the way. And what I wanna say was, so the key strategy, our strategists, we wanna, oh, shoot. There was something else I wanted to say.

Joseph M. Raffaele, M.D.

For longer life of the Soma, because they need to be around, could be around longer. So, I mean, I think that that is, that’s a key distinction, when you’re looking at animal models and a lot of people and you included, I think mice are not a great model for studying aging, just because they’re, they had that, they are in on our species, and a lot of things that might work in mice, nevermind C elegans or some of these other ones that are around for nine weeks, that’s a different aging model. So, and I hear about growth hormone and people talking about how growth hormone is pro aging and IGF one is pro aging because knockout models, the mice live a little bit longer, but those mice aren’t gonna survive very well. 

So, we’re talking about optimum function as well as we get older, and I think there’s a little bit of a trade off there and to use a mouse model for that, is I think it’s not a great, I mean, Stephen Awestat talked about that. We need to be studying naked mole, rats, or bats long lived mammals that are more akin to humans. The other thing I wanted to bring up just briefly was also, you talked about getting out of the way, there are some species like whales and particularly any species that doesn’t reach a fixed body size, it just keeps on getting larger that don’t have sort of any kind of major aging going on and what’s in play there in your evolutionary theory.

William Andrews, PhD

Evolution is just probabilities and statistics, okay? So even though there’s a selection, I hate to use the word selection when I talk about evolution ’cause I don’t like to use it. Evolution is not a force, it’s a result okay? And the result is that some of us, some of the species have evolved aging, but that doesn’t mean all of them. It’s just a probability kind of thing. Some let’s say whales and other animals like that, haven’t been through a environmental, a rapidly changing environmental phenomenon that had caused them to need to have an aging process. But of course we still don’t know if they have aging process, we just know that so far aging is undetectable or at least it’s very negligible, relative to other things. Before I was saying, there was something else I wanted to say is , I do wanna say, I do strongly believe in antagonistic pleiotropy okay? I do believe that there’s a lot of roles that that has played in evolution. But when we come back to the idea of telomeres and cancer, I’m gonna give an argument that that really has nothing to do with it. But I do believe in all that, I do believe that’s a very strong factor in evolution. I just sounded maybe I might’ve misrepresented myself there.

Joseph M. Raffaele, M.D.

No, I mean, I wasn’t sure whether, so I’m glad you made that clear and I think there are good examples of it. But I mean, getting back to Telomeres then if the idea is to, aging is there to get rid of older members of the species that have already passed their genes along, is that, I mean, I thought that the reason telomeres any hypothesize this telomerase is suppressed at birth is to prevent early cancers, retinoblastoma and things like that then occur before peak reproductive age and that because it’s continued, then it causes aging later, not necessarily the cause aging to get rid of older adults.

William Andrews, PhD

Let me ask you a question. How does turning off to telomerase prevent a young person who’s younger than, been able to raise their young? How does that prevent them from dying from a cancer?

Joseph M. Raffaele, M.D.

Well, I mean, for retinoblastoma, I guess, I mean maybe they just lose their eyesight and they can’t look around and take care of themselves, but anything that if a cancer doesn’t actually kill you, if it makes you dysfunctional or like a Wilms’ tumor or something like that then, you’re not gonna make it into the next generation. If you can prevent that, then you’re likely to then pass your genes on to the next generation. But again, I’ve always been I’m agnostic, I still don’t quite know that I understand, whether, because if it has this, I mean, how did it evolve? That’s really my question. If you don’t mind me asking, how do you think it evolved that it was turned off? If it would be such a great idea to keep our telomeres long?

William Andrews, PhD

Yeah. Well, here’s the thing. So, maybe you you misunderstood my question, is how does turning off telomerase prevent the, of course I said, dying from cancer, but how does it prevent the symptoms of cancer? And the problem is, the problem is, is that when you’re young, let’s say under 30 years old or under 25 years old, your telomeres are so long, that if you got cancer, that cancer is gonna get so enormous before telomeres can shut it off, you’re gonna die from it regardless. Okay, so it’s the only time shutting off telomerase or allowing telomeres to shorten, it’s gonna prevent a cancer is in older people. And as I was saying before, there’s no evolutionary advantage to keeping older people around. So, that’s why I don’t believe in antagonistic pleiotropy when it comes to telomeres and cancer, I don’t believe we shut off telomerase, to keep us from getting cancer.

Joseph M. Raffaele, M.D.

So the widely discussed, and I’m sure our listeners will have read papers or heard or read in lay, press lay books that, the reason telomerase is repressed is as a tumor suppressor mechanism, you don’t believe that’s true. I think you’re probably right. But these things get said and they just keep getting said, and I think it’s good to sort of maybe challenge that.

William Andrews, PhD

Yeah, well, or my way is instead of debating all that kind of stuff, of course, I’m doing an interview with you. I didn’t get down here to debate but I’m just telling you my personal views. But to really address that question, we just got to do the science. So, I was saying, so early on, I meant to say, we will never able be able to show that we have control of aging by showing that it can slow down aging because slowing down aging, it’s so hard to measure. Reversing aging is easy to measure. Okay, so my research is geared towards finding a way to reverse aging, partially, I don’t wanna say totally partially to answer that question or be able to ask the question so that we can answer, does telomere shortening have anything to do with aging? And the only way to show it is to show that lengthening, actually reverses aging, not just in engineered mice, but in humans too. So we wanna do that, but at the same time, when we lengthened telomeres, we wanna find out, does it increase the risk of cancer, okay? 

So in all of our clinical studies and ones that you have been actively involved in too, we haven’t done any clinical studies, I mean, the ones that have been involved or you’ve been involved in helping us with some of our clinical protocols, we’re asking all those questions. When we start to study, we’re gonna be looking for cancer in patients like doing pet scans and stuff like that before they get treated, and then again, after they get treated. But we’re also gonna be looking at every bio mark of aging, including DNA methylation, and glycosolation and telomere length. But we’re gonna be doing all that kind of stuff, just to answer the question. So we don’t know the answers, and nobody knows the answers, but there’s social mysterious, but instead of debating, what’s true and what’s not, when everything is really just best guesses right now, I would rather just do the study and get the answer. And so that’s my focus. And that’s why you don’t find that getting up on stage, debating a lot of these things or writing books to debate them on, I call them my best guesses usually when I get on stage.

Joseph M. Raffaele, M.D.

No, I think, look that makes perfect sense if you can show that it’s obvious through the biomarkers and through just the Betty White, with William Shatner tests, now that you have reversed aging, then you don’t have to know the cause of aging at that point. You’ve already fixed it in some ways, and then you can reverse engineer what you actually did, to sort of come up with more credible theories of aging, that had been because I mean, that is, I think the proof is in the pudding as they say, but that kind of thing, but to know what to spend your time on, there are people that talk about telomeres being passe in terms of aging, which is kind of, I think it’s been a bit of a trope lately, in that, they don’t have that much to do with aging, and I point to them, the examples of telomere biology disorders. I mean, those people don’t make it in the first generation, past 50 and the second generation, past 30, And then after that, they don’t make it out of the womb. So clearly telomeres are important for the aging process. 

And I don’t know why, it’s not thought that that telomeres still are, one of the major aspects of it. But yeah, I mentioned earlier that there is a lot of interest in rapid Mycenae and turning down mTOR, and the theory that aging and senescence is all about a program that makes you go from a single cell to a fully grown adult, a growth program that then doesn’t get turned off completely and then causes these, which is, will be a classic example of an antagonistic pleiotropy in some ways, turns on these hyper functioning programs with increase in lipogenesis and increase in cytokine production and senescence, what’s your thoughts about that and what role mTOR might have in aging and whether there’s any mechanistic links to telomere biology, ’cause I know a lot of people are talking about there’s I’m sure hundreds if not thousands of people that are taking intermittent rapamycin now, and I was thinking that perhaps we’re gonna do that, you might wanna do that, after taking something to help your telomeres and telomerase activator too, but maybe you could address that.

William Andrews, PhD

Well, mTOR is like central station firstly, I kinda think of it like a central station where everything comes in and everything go different directions. The mTOR plays a tremendous multiple roles in health and aging. And I do believe rapid myosin is an extremely important thing to take. I’m only concerned, the only reason I’m not taking rapamycin myself is because of the side effects of rapamycin But there are some rapamycin kinda analogs, it’s not really an analog, you tell me what this is, there’s now rapamycin packaged inside of nano particles, that would target specific cells that would make rapamycin in analog, but it does make it the drug kind of an analog of rapamycin. It delivers, rapamycin to the correct cells, not the incorrect cells ’cause rapamycin targets, it goes through a lot of different cells. What’s the company name, select o bio-sciences I think it is. They have this and you and I have talked about this a lot, SVP Rappa, which is SVPstands for, small something particle I can’t remember what it was, it’s not viral particles, small vaccine particle and it packages rapamycin in it, and the results that they’ve had is that there’s no side effects, okay? It just does all the good things and none of the bad things, they’re still in clinical studies, but only when that comes out, I think that’s gonna be a blockbuster. And I think personally I would start taking it, I think everybody will start taking it, but it’s biggest claim to fame is gonna be to actually prevent tissue versus grafts disorder. When you do a transplant–

Joseph M. Raffaele, M.D.

Graft versus.

William Andrews, PhD

Yeah graft versus. Tissue transplant, that person often develops an immune response against it, but if you treat with SVP Rappa, they’ve changed the name to immTOR, I-M-M-T-O-R, still in clinical studies. But when they apply that to the patient at the same time, putting the tissue on, the patient never gets any responses to the tissue. So all the good things about rapamycin and not the bad things. But yeah, I’m a big, big fan of the whole mTOR, mechanisms of controlling health and aging.

Joseph M. Raffaele, M.D.

But they talk about mTOR inhibition being a puzzle tile thing as the best. You don’t wanna do it all the time because you do need to repair wounds and have healing take place. And I think, the low dose protocols, at least that I hear about.

William Andrews, PhD

Yeah, the low dose I was gonna say.

Joseph M. Raffaele, M.D.

Five milligrams once a week, six milligrams, seven milligrams, whatever once a week, there really are very low to quite minimal side effects with it. And the question is how effective is it at that dose? And that’s being studied actively right now. And it’s also being looked at, and I have a few patients that are starting it on their own, and we’re looking at their biomarkers with a lot of curiosity about what’s going to happen with them. Do you think that there is a tie in with telomeres of some sort and how telomerase activation might work with that?

William Andrews, PhD

I think, there’s a chance, but I can’t prove it. I think there’s a chance that if we prevent telomere shortening, there won’t be any need to take rapamycin. But I don’t think that all the pathways involved in mTOR have anything to do with telomere shortening. Telomere, I said, I’d come back to this later, methylation DNA, methylation, glycosylation, those might be symptoms of aging, but also causes of aging. But they are more symptoms of aging. Telomere shortening is not a symptom, is not a symptom of aging, okay? There’s nothing that aging does that causes telomere shortening except at a lower level of increasing inflammation and increasing oxidative stress that will have some effect on telomere shortening. 

But if you did away with all that, you still have the telomere shortening because the main cause of telomere shortening, is just the basic process of cell division. When the cell divides, the new chromosome is made shorter because the cell lacks the ability to replicate all the way to the end. Okay, so that kind of thing, mTOR is not gonna have anything to do with the basal level to rate of telomere shortening, which is just from cell division, but the accelerated rate of telomere shortening, caused by oxidative stress and inflammation, is really cell division just increasing cell division, is also gonna cause telomere shortening, so in that way, I take that back, mTOR. So solving the mTOR problem would decrease inflammation, okay, and therefore decreased rate of telomere shortening. So thinking out loud, I’m glad I just put that together. Yes, so I definitely believe that that should have some benefits whether or not it’s gonna be as significant as the basal level telomere shortening just from cell division. I mean, we have cells that divide all the time. That’s our skin cells or immune cells, our gut cells, line in the gut, they’re called.

Joseph M. Raffaele, M.D.

Intro slides,

William Andrews, PhD

Assistant, I forget what they’re, there’s intermittent replicators, non replicators in terms of types of cells, and there’s the other one, which are cells that constant. Those are one type, yes in the guts line in the guts they’re the actual stem cells that actually produce all the other cells. Then the same as the bottom of your re ridges in your skin are the stem cells that produce all the other cells. So, yeah, so now I forgot what I was going, but it’s what was.

Joseph M. Raffaele, M.D.

Telomeres are involved in that obviously, because if they can’t continue to telomeres get too short they can’t do. So if rapamycin helps that by reducing inflammation, and perhaps if there would be a synergistic action, which I think that makes a lot of sense as well.

William Andrews, PhD

Where I was going was that, cells divide all the time, they’re still gonna divide even in working with rapamycin.

Joseph M. Raffaele, M.D.

Oh, right that’s true right. Rapamycin doesn’t do anything about telomerase activity or anything like that and the cells continue to divide. So, you have this sort of a mTOR inhibitor, rapamycin side of things, you have the telomere side of things. A lot of people are looking at the role of so-called senolytics in aging and how to treat aging because accumulation of senescent cells in tissues not only reduces the ability of those tissues to regenerate, but also secretes a lot of inflammatory cytokines that then cause tissue dysfunction and potentially cancer due to the campesius done a lot of work in that area. 

And so there’s quite a few biotechs now looking at senolytic therapy, but Michael Fossel has written a paper kind of criticizing that approach, saying that if you get rid of these cells, then they’re just gonna have to be replaced by other cells, which will cause the remaining cells to have shortened telomeres, which will then further accelerate the process. And so he thought that particularly in probably your camp, but I’m curious to hear that the better way would be to increase telomere length by turning off telomeres so that those cells potentially get reverted back from senescent cells back into normal, healthy cells. Do you think that’s a possibility and what do you think of Michael’s potential, criticism of senolytic therapy?

William Andrews, PhD

I agree 100% with Mike Fossel, he knows that he and I have talked a lot about that. I’ve been talking about the idea that getting rid of near senescent or senescent cells, you are gonna have to have other cells to replace those, and that’s just going to accelerate telomere shortening. Okay, because of the induced cell division. So senolytics, I mean is a temporary solution worked really well in mice, but again, mice I don’t believe age by telomere shortening, their telomeres are fairly long, but the bottom line that really worries me about snenolytics is that I haven’t really seen any studies yet that show in a 95 year old person, what percent of their skin cells are senescent, okay? And if you were to kill all the senescent cells in a 95 old, is that gonna kill the person? 

So I think we gotta come up with a better solution, I think senescent cells are bad, but I believe that what, the latter thing, you said, turning a senescent cell into a non senescent cell would be the better thing to do. And Woody Wright and Jerry Shay did do that in vitro, okay? They were able to put inducible telomerase gene, into cells, let the cells get to senescence, then induce the telomerase gene to turn on and lengthen its telomeres and the cells came back again. They published that, I wanna say 15 years ago. So it’s, why nobody’s gone and reproduced that, I think is because those experiments are expensive and things like that, but it was a pretty good study. So, I think that’s the better solution, but here’s the thing is that it is true, that cells do accumulate damage, okay? And so senescent cells, especially when telomeres get short, the damage increases a lot because short telomeres accelerate mutation rates. 

But the bottom line is that 99.9% of the time a cell gets mutated into an unhealthy state, it can be replaced if you take let’s pretend now our skin and our other organs are cells in a Petri dish. If you mix healthy cells with unhealthy cells, 50 50, and let them grow after a few passages, the healthy cells are gonna far outnumber the unhealthy cells because they’re going to overgrow. And so by allowing senescence only allows for us to collect these damaged cells by preventing senescence, is going to allow us to replace those damaged cells. The only exception is cancer of course. Cancer is gonna be a case of when cells mutate to become cancer, they’re gonna probably outgrow the non-cancer cells. So if we were simply looking at cancer cells in a Petri dish, yes, cancer is gonna win, but when we look at cells in a human, we also have our immune cells and our immune cells are one of our best defenses and best ways of fighting cancer. And by keeping the telomeres long in our immune cells, increases our ability to fight cancer, but still they could lose too. I mean, the cancers evolve, let’s say evolve mutate to, find ways to actually overcome the immune system. 

So we’re in a situation where there’s no win win perfect win situation, keeping telomeres long does have ways that you can imagine to allow the cancer to kill you better, but also keeping telomeres keeping telomeres long just as keeping telomeres short, actually has a better chance of allowing that cancer to kill you because of the fact that your immune system gets weak and other defensive mechanisms decrease. So, it’s a kind of a balance is, are more people gonna die from turning telomerase on, are more people gonna die from cancer by turning telomerase on or more people are gonna die from telomerase by turning telomerase off. And that’s still a testable thing that we have to test. 

But my best guess is that the idea of keeping telomeres long is gonna traumatically decrease, the death rates and side-effects rates of having cancer. So, it’s just a guess and we have to test it, and I think it’s a really good guess based on everything I know about cancer. I have a strong, very strong cancer background, understand cancer very well, and I also understand aging very well. So when I look at this, I actually see that, there’s still always gonna be people getting cancer, but people are gonna be getting a lot less cancer if we keep telomeres long.

Joseph M. Raffaele, M.D.

Yeah. I mean, I think that right now, the fondants of evidence that we’re not have enough of it, but is certainly in agreement with that. As we went from theoretical thought, the theories of aging and talking about curing aging, as a practical matter, right now, people are doing things like taking some senolytics and potentially taking small molecule, activators like TA 65, what would you say to them in terms of what is something you think would be a good idea, bad idea. I was thinking, you’re gonna take a senolytic, like a less potent one, like ficotin or corsetin, that you would probably given what you and Michael had talked about, and this idea that you wanna be able to replace those cells are gonna be more of a need to replace those cells that you would wanna take telomeres activator at the same time, is there anything you would avoid, like dasatinib or some of these other ones that maybe are a little bit more potent senolytic therapies? And I know you’re not a clinician, but just theoretically, I’m wondering how you think that.

William Andrews, PhD

Oh, no, I know a lot about and ficotin and the third one is you just said corsetin and I take corsetin every day, but that’s funny. That’s what I couldn’t remember just now, but I do strongly encourage it right now, okay. I just think that we, medical research has to come up with better ways, but in the meantime, those are the best things to be doing, okay? As I said, I just worry about the 95 year old, but again, that’s something that, we have to just test or the doctors just have to test and maybe low doses might be better than no doses or zero doses. So, it’s right now, I’m very in favor of senolytics, all kinds of the natural ones and the new synthetic ones that are being developed. I don’t think we need to do it in combination with a telomerase inducer. When we get a telomerase inducer I believe that that will replace the need for senolytics.

Joseph M. Raffaele, M.D.

Ah, okay but we don’t have a really potent one, a milder one could get around the problem that.

William Andrews, PhD

Oh, good, combination of TA 65 and a senolytic is a really good thing.

Joseph M. Raffaele, M.D.

Yeah, that’s what I’m thinking about. And then as a last thing, I know we just have a little bit more time, reversing aging would be fantastic. I’m 62, I’d like to get back to my 25 year old self, but if telomeres are sort of the most upstream thing, would it make sense, and would you expect that aging could be slowed, if say a 25 year old started taking something like a small molecule telomerase activator, could you expect that if they got enough telomerase activity into enough tissues that their aging process would just stop?

William Andrews, PhD

Well, there’s nothing yet, except for gene therapy that could potentially stop it, but there’s a lot of them that can slow it down and I strongly believe that they can, but there’s no way to measure it, that’s the problem. It’s like yeah, I would, I just on faith, just on scientific studies and stuff like that, I’d be taking every telomerase inducer I could get my hands on right now, just to slow down the aging process, but there’s nothing to compare to, there’s nothing to measure. And I mean you could say you measure telomere lengths every year for 10 years and then go on a telomerase inducer and then measure your telomeres length for another 10 years, every year and you can say, well, look, there was a difference, but you still have to have a negative control to show that that difference wouldn’t have happened anyway.

Joseph M. Raffaele, M.D.

Well, to make it scientifically completely credible, yes but in and of one medicine, if the patient sees that, their multiple markers are staying flat and not declining of organ system function like lung function, arterial, stiffness, brain function and their telomeres and or DNA methylation age and their glycols and their glycan age has stayed steady for the last five years, I mean, I think that’s probably a pretty good for where we are right now.

William Andrews, PhD

Oh, excellent, that’s exactly what everybody wants to do right now. That’s the best thing they can be doing is looking at all their markers and stuff. And which the question is, which is the best marker, we talked about that last time.

Joseph M. Raffaele, M.D.

I mean, I think if anything, I probably the answer is it’s a whole panel, as many as you can afford at this point.

William Andrews, PhD

All the markers, yes.

Joseph M. Raffaele, M.D.

Well, Bill, I mean, I think we, did cover that question that came up at the end of the last interview in terms of, the theory of aging, where we stand right now, it’s been very educational for me as always talking with you. And I really appreciate your taking the time to, talk to me and listeners about this fascinating subject and look forward to seeing you again soon, in one of the conferences we’re out in reno.

William Andrews, PhD

All right, well, thank you, thank you. All right, talk to you later.

Joseph M. Raffaele, M.D.

All right. Take care, Bill.