Richard Miller
Appearances
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
Those are interesting. But you don't have to assign a number, a healthspan digit.
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
Yeah, I kind of like the term...
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
So I have a question for you, Steve. What is my health span?
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
that NIH will wake up and start to pay attention to aging research the way they should. It's near zero. It's been near zero for 30 years now.
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
Well, it's gone up. I mean, they funded the ITP, the Interventionist Testing Program, 20 years ago, and they liked it, and they doubled our budget about 15 years ago. So that's something, and I'm very, very grateful to them for that. But there's still an enormous untapped potential for making progress in the basic biology of aging. And the reason is, again, a matter of defending TERF.
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
If you are a cardiologist researcher or an oncologist researcher or an AIDS researcher or an Alzheimer's researcher, anytime somebody says the smart play is to reduce your budget by 10% or your institute's budget by 10%, we're going to go there faster if we spend money on aging and its relationship to the disease you care about. You get the porcupine defense.
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
You don't take any of my money because Alzheimer's is important. Little kids with leukemia are important. Breast cancer is important. You go away. And that is the predominant feeling. Most of the people making those decisions were not trained in aging research. They view it as something interesting. I read something about that in Time Magazine the other day.
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
But they don't understand that to actually conquer or slow down or affect aging, or protect against the disease they care about, the smart play is to do aging research. And so they view your suggestion, which I, of course, agree with 100%, as an imposition, an invasion to be repelled at any cost. No one in a position of power has had whatever it takes to reverse that.
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
And if he or she tried to do that, Congress would, even a good Congress, would smack them down. The Alzheimer's Group has 100 lobbyists. The cancer group has 100 lobbyists. The AIDS group has 100 lobbyists. The aging group has two lobbyists, one who's a lawyer and one who takes the calls. And it's not enough to do it. Can I just add something real quick?
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
Let me give you an example of what the sort of point that Matthew and you have been making. About once every five years, I give a talk, an invited talk at the University of Michigan Cancer Center, and I point out that we have drugs now, anti-aging drugs. in mice and they extend mouse lifespan and they do it mostly by postponing cancer because most of our mice die of cancer.
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
And if you look at age-adjusted cancer incidence rates, our drugs reduce these by a factor of 10. Wouldn't they like to know why, as cancer scientists, we now have a batch of drugs that postpone cancer? Wouldn't they like to study them? Invariably, I get one callback from somebody who says, that's interesting. Maybe we should talk about that. And then it dies.
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
And then five years later, I'm asked to give the same talk or a related talk. So they know how to do cancer research. They are cancer scientists. That's how they know how to do cancer research. And you certainly don't do it by diverting your lab's attention to aging. That's insane. But that insanity is how medical research is organized. And breaking that
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
addiction to the kinds of models you grew up on because they're a better idea, it's not an easy thing. It may not even be a possible thing to do. That's a major hassle.
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
I guarantee these people or mice will get cancer. They'll just have... 10 extra years of life if they're a person or 10 extra months of life. They'll get cancer. They'll need specialists. It'll be all right.
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
Is that even a relevant question? Call me, call me, call me, call me. Yes, Mr. Miller. It's important to use words optimally and to distinguish causes from effects. One of the bad things about aging is it's a risk factor for many diseases. Some things, other risk factors for diseases, aging is a risk factor for disease. And so saying that aging is a disease confuses that discussion.
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
It makes it impossible to see that relationship. So calling aging a disease is a fundamental error. The question itself is incorrect.
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
You're right. It's a marketing ploy. And if you think you can convince people of the importance of aging research only by crossing your fingers and saying, oh, well, it's kind of a disease, isn't it? You think you can fool them? Yes, that's what marketing is. And it's probably good for that. I just don't like lying to people.
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
I got a good result. He's 13, 13 years old.
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
Let me agree with Steve, but just put it in slightly different terminology. It's a matter of taking a very rich, complex data set and trying to collapse it to a number. So if someone wants to know how healthy I am, he or she would need information. How good is my eyesight?
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
how good is my hearing, how good is various kinds of cognitive activities, my aerobic endurance, my joints, all of that is pertinent to how my health is and also about projected future health. Then there's no need, once you've got that information, which is very rich, to say, ah, there's a number, a single number, a real number, a point on the number line that condenses that in any useful way.
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
notion 40, 50 years ago that biological age was not the same as chronological age for a little while was useful. It emphasized that there might well be 60-year-old people who were unusually like youthful people and 60-year-old people who were unusually like 70-year-old people. Would my drug or my genetic mutant or whatever help to discriminate those people or change them in some way?
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
I can slow your biological aging process. That's a discussion that was maybe of interest 40 years ago, it's now time to drop the notion, let alone the silly notion that you can count that biological age, that number which some people, too many people, still think is a value. You can figure out what it is by measuring something, transcriptions or epigenetic markers or something.
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
I can do it and give you personally your personal biological age. That's a waste of everyone's time. And it also distracts attention from things that actually are important and need to be thought about.
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
Oh, yes. Absolutely. Okay.
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
You didn't think it was a real thing. I agree with that completely. You can agree with that and not like the idea of a number that constitutes your biological age. Okay.
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
No, I agree entirely, yeah.
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
The answer to the question is obvious and very well known. You can tell if you have your 40-year-old patient and he or she is fat, doesn't exercise, eats mostly cheeseburgers, you know that their life expectancy is probably not as good as the 40-year-old patient in your next waiting room. that has extremely healthful habits and whose parents live to be 100. And there's tons of published data.
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
Right, but I don't need a biologic age to tell me that. Right, right, that's what I'm saying. There are tons of things you can measure on individuals, four or five of them are all you really need to ask of a 70-year-old.
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
Because their buddies on the line there, they're writing life insurance policies. So it's not at all hard to figure out a very small set of tests that tell you how long a seven-year-old is likely to live. There's nothing to do with methylation clocks or things like that.
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
There are a lot of things that change with age. The literature has 25,000 things that change with age. Average amount of methylation at these 10 spots is number 11,407 of those. So great, you've got another thing that changes with age.
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
But that's not enough.
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
So you made three statements there. broad, general statements. And I think each of the three deserves careful amendment. Let's do it. To be polite about it. The first has to do with hallmarks of aging, which I think set the field back dramatically.
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
I think when you are officially branded a hallmark of aging by two people sitting alone at their computers and writing a review article, a hallmark of aging... I thought they were walking around a pond when they came up with this.
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
All right, okay, okay. means that somebody once said, I'm interested in aging. That's kind of important, isn't it? Let's put it on our list. You can't tell if something is a hallmark of aging. Does that mean it goes up with age? It goes down with age? You can change it in a way that will extend lifespan. You can kill a mouse or a worm by removing it.
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
Basically, it's something that somebody once thought might be of interest to aging. And the downside of that is once you're officially branded as a hallmark of aging, anyone who wants to write a grant on that doesn't have to prove that their fundamental cause and effect model has any merit because it's a hallmark of aging. I don't have to prove it anymore.
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
Someone, I don't know who or on what grounds, has decided it's important. My reviewers know it's important because they've read the hallmark of aging paper. So I don't have to think about whether it's important. The negative side of that coin is that there are lots of things that didn't make it into the hallmark list. I really think it's premature to close thought off on some of those.
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
It's easy to come up with a dozen. things that ought to be investigated, but if you want to investigate it and it's not on the hallmarks list, what are you wasting? So deciding which of the hallmarks is the big daddy hallmark or whatever strikes me as not the correct thing to talk about in the hallmarks arena.
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
So maybe we should talk about that before we go through all of these, because I think there's a lot to unpack there. You'll remember the other ones too, man. If you guys could afford to give me a little piece of paper and a pen, then I'd be able to write down my... I think of the hallmarks as a list, a kind of arbitrary list.
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
I can usefully concretize this discussion. I imagine that one of this, I don't read these papers because they upset me, but I imagine inflammation is on one or more of these. Sure is. I'll bet. Chronic inflammation. Okay, good. Chronic inflammation. So what that does is you say, I'm interested in chronic inflammation, so I'm doing good stuff, huh?
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
But what could be happening is this particular set of cytokines might be overexpressed by some glial cells and that leads to loss of cognitive function. Whereas this other overlapping set of cytokines produced by the macrophages in your fat may make you more prone to diabetes or metabolic syndrome.
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
Whereas this particular set of lymphocytes are necessary to repel COVID, and that's why you are more susceptible to COVID. So learning what changes within the extremely broad, generic idea of inflammation, what changes in what cell types, in what people, under what pharmacological or genetic changes, how they are interacting with other aspects of pathology, that's marvelous to do.
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
But to say, oh, inflammation, that gets bad when you're old, is a way of avoiding the labor of thinking. And that's why I'm against it.
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
Well, I think there are two aspects that I would want to emphasize in response both to your question and to what Steve said. In response to the question, I think people have always been fascinated for millennia on things they could do to stay alive and healthy as long as possible. But there were actually scientific discoveries in the 90s that showed that it could be done.
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
The second of your multi-partite question was, does epigenetic change, what are the results of? Is it causal? Causal effect. And the third, which we may get to, is can you reverse it and would that be a good thing? So let's talk about the second element here, is it causal? The problem is what it means. There are...
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
some changes that occur in this particular set of 40 cells in the pineal, and there are other changes that occur in these cells in the bone marrow, and there are other cells that change in the gut and villus lining cells and the crypt cells. So they are all epigenetic in some. They are caused by some things, and we don't really know which, if any of these count for aging.
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
If someone says, I'm going to prove that an epigenetic change is responsible for aging, they haven't begun to come to grips with the nitty-gritty. People always ask, just as you hinted, does your drug change epigenetic things. And unfortunately, that's where they stop thinking.
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
We're always willing to give people tissues from our drug-treated mice if they are keen on epigenetic changes that affect neuron regeneration. Excellent. Their experts will send them the brains and they can do that stuff. It's important. I'm not making fun of it.
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
But the general notion that it's aging vaguely thought of is due to epigenetic change more vaguely thought of doesn't really get you anywhere. That's my skeptical view.
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
No, it's just that the concept of epigenetic change encompasses thousands of changes in hundreds of cell types under hundreds of influences. Of course, some of that causes other stuff. Agreeing to that, assenting to that notion that epigenetic change is causal for all sorts of age-related pathologies is
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
Everyone can agree to that, but it's meaningless because what counts is to say this specific change is really important in this disease. Here's an epigenetic alteration or this specific broad spectrum change in multiple tissues causes something good or bad. You have to define what it is before you can test it.
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
And then in the last 20 years, there's evidence that it can be done, at least in mice, with pills. So that naturally should lead to speculation that there could be pills you could give to people that would postpone poor health for a substantial amount of time. 20 to 30% is what we're seeing in mice, and 20 to 30% would be very important for people. So I think that is a part of it.
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
My last exposure to the causes of type 1 diabetes was when I was in medical school, which was more than five years ago. But if I vaguely remember, it was an autoimmune disease, right? So if your poor little helpless beta cells are being attacked by antibodies and macrophages and things, those stressors reactions are going to cause epigenetic change.
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
And whether those epigenetic changes contribute to some extent to the ill fate of the beta cells, it's possible. And if I were an expert on diabetes pathogenesis, I'd really want to know that. It doesn't have anything to do with aging, but it's an interesting question.
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
They're a hallmark of diabetes.
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
You can formulate these questions because a lot is known about type 1 diabetes. And I understand 0.05% of the biology of aging. 0.05, yeah.
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
I'm tenfold up. He was raising you by a log. Yeah, I thought, you're one log off. Formulating the questions in exactly the way Steve did makes it clear how difficult it is to evaluate the concept that epigenetic change contributes to pathogenesis and type 1 diabetes. And we know more or less what is going on. We don't know what's going on in aging.
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
We don't even know what part of the body is going on or parts more likely of the body.
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
Or decides that it can't be formulated because it's too complicated. It gives up.
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
If you think osteoarthritis of the knee requires a knee joint replacement and that's going to help your patient, you are not rejuvenating. It's perfectly possible to do great things with technology, including chondrocyte regeneration, without having to decide that that's related to aging. People don't age because they fail to have titanium knee joints or something.
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
The other part is that there are now people who are making a lot of money by selling stuff that is untested to be polite about it or is useless to be less polite about it to gullible customers. And so people who want to make a lot of money have finally found that there's an impetus
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
He's very good. You should listen to him.
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
that will allow them to sell stuff even if there's no evidence that it works, that they control an enormous amount of advertising dollars, both formal and informal. That's a big part of the difference. The one comment I wanted to make with regard to something Steve said has to do with the alleged balance between healthspan and lifespan.
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
Well, we would, but of course, the zero-sum game is a pretty good analogy for what's actually going on. The amount of research dollars at least available to NIH is not infinitely expansible. It's set by a complex political process, and then there's a separate downstream process that allocates it amongst institutions.
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
So saying that it would be a good idea to have more funds, I agree with you, and I'll bet these two guys do as well. But it's not easy to do.
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
I think we generally agree with you that having a greater proportion of available research dollars, both private and public, going into the biology of aging and its impact on late life health would be a good thing. I don't think you're going to get an argument here.
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
I was on the council for the National Aging Institute for three years. And if at any point, I can swear to this from personal testimony, somebody would say something like, I wonder if maybe a few percent of the Alzheimer's budget might instead go to studying how slow aging models would have an impact on late-life neurodegenerative disease. The next day, the director of the Aging Institute
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
would get a call from two or three congresspeople who were on the Appropriations Committee stating that this will not be happening because there was an Alzheimer's Association person who got the call from the NIA staff member in charge of Alzheimer's saying, tell the congressman to call the director and let's put a stop to that reckless idea.
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
They're tied in to the political process in ways that... Well, we just need to go maybe one step further because those congresspeople have a boss.
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
It's become fashionable for the last 20 or 30 years to imagine that you get one or the other, that you have to make a choice, it's a decision, and that if you give up on lifespan, that allows you to extend healthspan. I think that's ridiculous and controverted by all the available evidence. That is, all of the drugs at least that extend lifespan
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
in mice and could potentially do so in people, do so by postponing diseases, both the diseases that will kill you, that's why they extend lifespan, and the diseases that won't kill you, but which will annoy you and make you very unhappy to be old.
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
Just to follow this up, if magically you become in charge and you're able to double the amount of research being done on the biology of aging fundamentally, then we can afford to do, let's give some mice, to start with, a batch of anti-aging drugs and see if it makes them more resistant to infectious illnesses, including pneumonias, but viral infections as well, and many others.
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
I'd love to know the answer to that. And no one has actually really looked in a serious way because the ITP has enough money to just measure lifespan. And then we're hoping that everybody else is now going to look at the brain and the lungs and the infection, the sensory systems. That really ought to be done and it's not being done because of a lack of money.
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
They're strong commercial motivations. You know you're going to sell a lot of the obesity drugs. They're very strong commercial motivations to do those studies over and over and over again until you find one that works better. And they're good preclinical models that you can use so that you're not wasting too much of your time on clinical trials.
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
That could be done for anti-aging drugs as well, although testing anti-aging drugs in people is a whole separate set of tangle of difficulties. I don't want to talk about that right now, but I'm saying it won't be quite as easy as it was for anti-obesity medications. But no one's doing even the first level of research to find the optimal compounds for efficacy without side effects or even
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
to begin to see if they have desirable effects on aging rate indicators in people. That's kind of a cheap and easy study, and no one has really tackled that yet.
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
No, I meant anti-aging drugs. It's a joke. It's a joke. It's a joke. It's a joke.
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
I mean, that's true of exercise. Yeah, absolutely. That's a good point. Not being insulin resistant. I agree with you. So the notion, it's time to put behind us and to make fun of the notion that I'm not interested in lifespan. Don't put me on that boat. I am interested in healthspan because they are linked together and they go up and down together.
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
I know what I want to talk about, and it's the second of those two. Okay. I don't want to spend the next three or four hours explaining why senescence is silly and anti-senolytics are untested at best. There's no way we're not talking about that. Let's go on to item number two. And I think the most important thing is to make a clear distinction between biomarkers and aging rate indicators.
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
Please explain the difference to people, please. Okay, I'll do my best. So a biomarker, allegedly, and in real life, is something that changes with age. So if you have some drug that slows aging, the biomarkers, many of them in the different cell types and in the blood, will change more slowly. They are a good way of looking at whether you're slowing, it'll work in the dog's
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
Long-lived dogs and short-lived dogs will have differences in the rate of change of biomarkers. Very established part of the literature and valuable. But you have to wait till somebody's old, whether it's a dog or a mouse or a person, because only when they're old has the biomarker of aging, the surrogate marker for biological aging, changed very much.
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
So in a clinical trial, certainly in a human situation, no one wants to wait 20 years to see whether the biomarkers have changed. And a one year is such a tiny fraction of a human lifespan that you don't really anticipate detectable change with an appropriately powered study.
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
It's like aging rate indicators, which are much less well studied and much less well established in principle, are things you can measure that tell you whether you're in a slow aging state or a normal state.
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
A biomarker, generically, is something that's easy to measure that is informative about something that's hard to measure. A classical example, famous example, is you want to know how many cigarettes somebody smokes a day. They'll lie to you. But if you measure cotinine in their blood, that's a byproduct of nicotine. You don't have to ask them.
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
Getting people disabused of that false metaphor, the seesaw metaphor, is probably an important goal for the public interface between longevity scientists, aging scientists.
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
You can find out how many cigarettes they had in the last couple of days by measuring blood. That's a biomarker of cigarette consumption.
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
I don't know the answer to that. I wasn't sure. In principle, a biomarker of aging is, there are many of them, and they are measuring biological aging processes, and they're useful in that regard. But they don't tell you how fast you're aging. The analogy I love to use is an odometer is like a biomarker of aging of your car.
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
It tells you how many miles your car has gone, but it doesn't tell you how fast the car is going. The speedometer tells you how fast your car is going. And so what we need and what I think we're just beginning now to document is things like the speedometer, aging rate indicators that reliably discriminate slow aging mice or people from regular old mice or people.
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
We have now a dozen or so things that change in the fat, in the blood, in the liver, in the brain, and in the muscle that are always changed in any slow aging mouse, whether it's drug A, drug B, drug C, calorie restriction diet, or single gene mutations. We've looked now at five different single gene mutations.
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
And this whole set of 12 or roughly 12 aging rate indicators always changes in every slow aging mouse. And it does so in youth, which is the key point. So, if it does so quickly after an anti-aging drug is administered, that's the transition, that's the bridge you need for clinical studies in people.
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
If you want to know whether metformin or canagliflozin or something slows aging in people and you don't want to wait 20 years, but you've got things that tell you whether they're in a slow aging state, how fast they are aging versus normal, and that's a big if. We don't yet have evidence we can do that. We just have hope we can do that.
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
then that allows you quickly, quickly being within six months to a year, to know whether your alleged anti-aging manipulation has moved them to a physiological status which is associated with slower aging. A lot of that can be done in mice, with drugs, with mutants. And are these all proteins, Rich? No. No. Some of them are changes in the fat of different classes of macrophages.
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
The pro-inflammatory macrophages, the bad ones, go away. The anti-inflammatory macrophages, the good ones, go up. UCP1, I recall from our discussion. UCP1 goes up in every one of our 10 different kinds, 11 now, of slow aging mice.
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
Well, we compare them to controls. And the question you're asking is really important. That's what we're doing in the next five years. We just got a grant to do that. We're going to take mice and give them either a good drug or a different drug that doesn't work. and then make those comparisons, a really important thing to prove. So far, our only control has been untreated mice.
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
Not to pay too much attention to Steve's pessimism on this point, although he's completely right. Of course, most things that do have an important effect in mice fail in human clinical trials. And it's for a variety of reasons. Sometimes humans are different from mice. Sometimes the drug has side effects. that are tolerable in mice, not tolerable in people, etc.
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
But I always like to look at the other side of the coin. That is, if your goal is to develop a drug that blunts pain in people and you screen 40 or 50 drugs and you find a couple that inhibit pain in mice, that's a really good start. It doesn't guarantee they're going to work in people, but it gives you this category of snail-based neurotoxins Let's make 40 of those from 40 different snails.
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
We'll find one that actually in people works, can be made by a scalable process and doesn't produce serious side effects. So the mice, it's not a one-to-one mapping. It works in mice, it doesn't, it works in people, but it's an important critical first step which usually succeeds in finding a set of drugs of related families or with related targets at least. that are efficacious in people.
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
Most drugs that are used in people had useful rodent-based research somewhere in their pedigree.
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
That's not a biomarker. My reply to your question is that you've merged two different difficult problems. Problem A, can we find drugs that slow aging in people? Problem B, can we surmount the legal and political barriers to getting them to work? That's not what I was asking. I was asking how do we get to the point- I know you weren't. That's what I'm-
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
What I'm saying is that you are focused on something I don't have any answers to, basically, which is how do we get the FDA to develop and approve clinical trials? I was more interested in a step before that. It'd be nice to have some drugs that actually do work to slow aging in people.
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
Let me answer your question first. Why the lag? I think there's a whole batch of reasons, and they're important, and they're easy to spell out. One is the prevailing attitude is that aging is there. There's nothing you can do about it. I'm going to not be able to outwit aging, though I may be able to be maybe healthier in my older years.
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
What do you think, Rich? Well, I wanted to go back to the example you gave, where you took a lot of people and gave them intense exercises and dietary changes to improve their likely health outcomes. And that's a good place to start a discussion, because you said every sensible person would see the treated group as aging more slowly.
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
And I would want to ask before I agreed to that, do they also have improved cognition? How are they doing in cataracts? How are they doing in hearing? What happens when you give them a flu shot? Do they have a great flu shot? So the things you've pointed to are really important for both overall health and for cardiovascular risk and the things linked to that. So it's nice to know.
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
But to convince me that you now have a slow aging group of people... You need to go beyond the risk factors for specific common human diseases. If you could show that, then for the first time, I would be convinced you had an effective anti-aging manipulation in people. Currently, I don't know that there is any effective anti-aging manipulation in people.
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
If your approach got there, that would be a terrific research model.
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
It's easy to produce a longer life. If you happen to have a clinical condition where you're tied to a railroad track and there's a train coming, you can extend that woman's life enormously by simply giving her a knife and cutting the bonds and letting her walk away from the track. Longevity promoting interventions are not anti-aging.
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
The notion that aging is not malleable, though wrong and provably wrong, is still the overwhelming opinion even of reasonably educated scientists and certainly of the lay public. Then commercially, there are companies that make a ton of money selling stuff that doesn't work by pretending with a wink and a nod and a lawyer that it might slow the aging process down.
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
Yes, yes, yes. That's a good thing, and I'm glad that people are doing that. No question about it. Now, talking about the biology of aging, there are all sorts of things that also happen when you get older that are not part of those chronic diseases. And to make a case that you've got an anti-aging manipulation, you need to show that those are changed too.
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
The nice thing about like the dog examples where you've got well-known, famous, long and slow aging dog breeds, and it's true for horses too, it's certainly true for mice. is that more or less everything slows down together.
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
The tiny dogs that are very long-lived, it's not just that they have a delay of cancer, they have a delay in neurodegenerative diseases, a delay in digestive diseases, in joint diseases. Aging has been slowed in those dogs.
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
Now, fortunately, we can move past the semantic discussions because there's now molecular ways of checking this. Exercise, as I'll bet all of you know, increases an enzyme called GPLD1 in the blood of exercise people and in mice. And Sol Vieda's lab has shown that if you elevate GPLD-1, it does great things to your brain.
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
More neurogenesis and more brain-derived protective factors, brain-derived neurotropic factors. Iresin also goes up in humans and in mice. After exercise, it does great things for your fat. As does cloth, though? Let's leave that for a moment. Oh, boy. Oh, boy. I'm striking all the nerves here today. All right. You may be quite right.
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
I wanted to stick with the GPLD1 and iresin to make the point that they also go up in all of the slow aging mice. That is all the anti-aging drugs, the calorie-restricted diet, the isoleucine-restricted diet, and five different single gene mutants that extend lifespan in mice. They all elevate GPLD1. 17-alpha estradiol? Yes. Can agaflozin? Both sexes? Well, this is the key question.
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
And since they can make a lot of money, they don't actually have to spend valuable marketing dollars on doing research and stuff to prove that it works. Some of the drugs that at least in the hands of our mouse group, the ITP interventions testing program, some of the drugs are the patent is owned by another company or they're out of patent or it's a natural product.
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
Iresin is sex-specific. GPLD1 is in both sexes. This is how one begins to answer that question. This is the exact kind of question one has to ask. So if you are... interested in the idea that exercise regimes have a benefit beyond the obvious exercise-linked physiological declines with age. Do they improve cognition? And if so, how?
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
These molecular changes are the things you need to begin to investigate. The anti-aging studies in mice show that the anti-aging drugs, at least the ones we've looked at so far, increase the same things that exercise does.
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
Well, you're going to ask if we exercise our mice. Yes. Yeah, we've never done that.
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
We have not done that.
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
We never use obesogenic diets. It's worth doing it. The IDP doesn't do it. We don't have the resources. We have enough resources to test about five drugs a year, but if we wanted to test them in exercise versus non-exercise.
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
You wouldn't rule it out. Right. So they're testable molecular hypotheses that link the biology of aging to anti-aging drugs and to exercise and teasing out how those are interrelated and which of your exercise regimes increase iris and increase GPLD1 and increase neurogenesis. That's a research agenda that could be very valuable.
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
And then if you want to screen drugs in people to see which ones deserve expensive long-term testing, the ones that raise GPLD1, irisin, and some aspect of neurological function in addition to the good stuff they're doing for the muscles. That's an approach.
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
None of that says take me to whoever owns a big pharmaceutical firm. And also, even if you do it right and you really want to do it and you've got a very large budget, it's not an overnight kind of thing. Any one drug, a leading agent that, like rapamycin, which you mentioned, and the half a dozen others that we've shown work, at least in mice,
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
Yes.
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
Why? Because it's enormously laborious to do weekly injections.
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
And also you need a separate control group. That sounds like an I need more money problem. Because you get sham injections and are, yes, if you increase our budget dramatically, I think it's a worthwhile experiment, but what we're waiting for is oral drugs that work, that you don't have to do injections of drugs.
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
It was submitted to us this year. The detailed protocol, however, is, again, technically very laborious. Each mouse has to be food deprived for six hours, then the material is administered, and then they have to have a change in their water balance for the next two hours. It is technically not an injection, but it is not any less laborious.
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
And in addition, you have to have your own separate control group that gets all of those different manipulations with a sham injection.
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
Well, I'm not in charge. It's a heavy lift. I'd vote against it. I would vote for waiting about a year until somebody comes up with a pill that you can just mix into mouse food or water and give it to the mice and it'll work.
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
Yeah, that's why the control group is necessary. But the companies are putting so much money into this. They understand why people don't like to inject themselves. I'm reasonably sure. I mean, I know nothing about it. But I'm reasonably sure that in a year or two, there'll be some agent that works when you put it in the food of a mouse or pop it as a pill as a person.
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
Those would be enormously important to test.
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
finding something in that same family that works really well, that is safe for people, that's the member of the 20 congeners of that drug that's best and most potent and safest, that's not at all trivial. That takes a long time and it takes a commitment of money and time and effort and intellectual resources. We're at the place where we can start to make an argument that that's a good idea
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
What do you mean? Do you want me to talk about senescent cells? Okay, yes, I'll be glad to do that. It's a terrible historical accident. Leonard Hayflick, way back, found that human cells would only divide 50 times and stop. One of his colleagues, a guy named Vittorio Defendi, made a joke at lunch and said to him, hey, Len, maybe they're getting old. Ha, ha, ha, ha, ha.
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
and then did not understand it was a joke. He thought it was a serious scientific hypothesis. It's clearly nuts because we don't get old in a way that is modeled by having embryonic lung fibroblasts stop growing. But at the time, the hottest technique in modern medicine was you could grow cells in culture. That was really so cool. You could do stuff with them.
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
So all the cell biologists who really wanted to use the coolest new toys wanted to have a way of studying aging without all these messy mice and rats and having to wait and stuff, they could do it in vitro because this was in vitro aging, this is in vitro senescence. And the field, to skip 30 or 40 years, the field went ahead with this metaphor without ever questioning it.
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
It's now such an industry that the people who review these grants and papers and advise billionaires and advise startup companies They all were trained in labs that just do senescence for a living, so they never stopped to question. One of the most famous and best scientists in this area is a woman named Judy Campisi. She recently passed away. She died last year.
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
She and I were assistant professors together at Boston University. She and I were going to send in a program project with a third person, Barbara Gilchrist. I was going to study immunity and aging. Barbara was going to study skin cells. We talked, Judy, you want to study cell senescence. So she read the literature. She came back to us and she said, it has nothing to do with aging.
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
I mean, it's good cell biology. It's good about cancer biology. But of course, it has nothing to do with aging. And we told Judy, of course, it has nothing to do with aging. We understand that. But the reviewers think it is aging. So if you can just keep a straight face for the three hours of the site visit, pretend you think it has to do with aging. you'll get a great score.
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
And that's what happened. She got a great score. We got the program project when she moved to Berkeley. She took her grant with her. And after a year or two, she had apparently convinced herself that it was aging. It was close enough to aging. So the notion that aging is due to senescent cell accumulation is bad for two reasons. It's a grotesque oversimplification. The evidence for this is awful.
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
But even worse, it, again, cuts off productive thinking. There almost certainly are changes that occur in some glial cells in the brain so that as you get older, they start making bad cytokines as bad for your brain. There probably are changes in some bone marrow cells or some cells in the lineage that leads to the beta cells in the pancreas that lose the ability to divide.
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
And that's bad for you. And finding out how it happens is really important. But once you've convinced yourself that's all the same thing, this cytokine, this loss of proliferation, this change in ability to make specific fibrous connective tissue, let's call that senescence. It's the same thing.
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
but make a good argument that that's a good idea to people who actually have the resources to carry it out has not so far been enormously successful, unfortunately.
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
you've lost what you need to think of good, careful, well-defined experiments with well-defined endpoints. If you say that senescence, there is a thing called a senescent cell, the thing that's happening in this glia and in this marrow cell and this pancreas, it's due to the senescent cell. accumulating, you've blocked off productive generation of research hypotheses.
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
The last point I'll mention in this rant has to do with senolytic drugs. So the ITP was asked to test an allegedly senolytic drug called fisetin. It was given to us by someone who is using this now for clinical trials and who has a company that's interested in senolytic drugs. So we gave it to mice. It had no beneficial effect whatsoever.
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
Oh, it has no action.
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
It had no effect. What is it supposed to do? It's supposed to kill senescent cells or something. So we told this guy, sorry, it had no effect. He said, well, let's prove whether it had any change in senescent cells. So we gave him blind tissues from each of the treated and untreated mice. And he tried a test and there were no changes in senescent cells by his marker. He tried six different markers.
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
There were no changes in senescent cells. So then he said, well, send the brain and the liver and the muscle. Maybe the senescent cells have been changed in the brain. So he sent blind samples to a colleague of his. There were no changes in senescent cells by any of the markers that these folks looked at. So this drug, which is now being marketed in clinical trials, and you can buy it, I'm sure,
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
Yeah, it's a supplement. There's no evidence, as far as I know, that it either has an anti-aging effect or removes senescent cells.
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#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
But once you've got a commercial company pushing this stuff, and your whole brand, your whole lab, your whole program project, and all the people who are reviewing you are convinced senescent cells exist, they're bad, and drugs can kill them, it's a snowball rolling downhill, and a rant of the sort I've just delivered has no impact on the field.
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
Is the Van Dersen paper you're talking about in which they were allegedly depleted?
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#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
Let me tell you about that because I was on the program Project. Two papers. Okay. One was with the short live mice.
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#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
So talk about the one that is not the short live mice. There's a paper, a famous paper by Van Der Sen, Kirkland and several other colleagues, Darren Baker.
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#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
Okay. I remember this. Yep. They've left. Two of them have left. But yes, they alleged that they could remove senescent cells by taking genetically modified mice, giving them a drug. All the senescent cells would go away, and the mice lived longer, according to the paper. This was on the cover of Nature. It was on the cover of Nature. I remember this one. I was a part of the program project.
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#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
So was Judy Campisi. And my job was to do the lifespan experiment. We got the mice from Kirkland and Van Dersen. We got Campisi's mice. We got the drugs from them. And we gave the drugs to the mice at 18 months. And you know, they had no effect on senescent cells. Not one. We tried seven times to show depletion of senescent cells in their mice using their drug and went zero for seven.
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#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
We then took the tissues, blinded, and sent them to Judy's lab, Judy Campisi's lab, so she could measure P16 cells. But she didn't know which ones were from treated and which ones were untreated. When we undid the code, there was no effect on senescent cells whatsoever. So I remain somewhat skeptical. I asked Van Dersen, had he measured the number of senescent cells in his treated mice?
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#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
No, we're planning to do that.
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
Oh, when I, I didn't want to do an expensive lifespan experiment. with an alleged anti-senolytic drug until I knew that it was depleting senescent cells. So how long did you treat for? I used their protocol, and I asked them. I asked Darren Baker, what is the dose, how long do you treat the mice, and how long after you add the drug should you wait before you detect the removal of senescent cells?
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#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
And his answer, astonishingly, was, we don't know. We've never looked at that.
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
That's what I was saying, that there is no satisfactory definition. Satisfactory to you.
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#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
You can't think about it clearly if you imagine that these many, many different kinds of cell intrinsic changes with potential pathological impacts are all aspects of the same phenomenon.
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#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
That's the problem, of course. You referred to it, as almost anyone would, as the SASP, the set of senescence-associated proteins, secretory proteins. And once you think of it as the SASP, you've lost. Because the key point is not to do that. The key point is, here's a set of cytokines that this cell has begun to make. That's really interesting. Here's another set, overlapping probably.
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
They make it when you've made them stop dividing for a separate reason. That's interesting. We should study that. But to think you've proven something about this cell type when you've actually been looking at this cell type because the SASP has been changed.
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#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
I think it's very likely that rapamycin changes cytokine production by many different cell types and that some of those changes would probably have health benefits. I would like to know what it does to the cytokine production from the macrophages in the fat and the glial cells in the brain and cells that are in charge of protecting you from viral infections.
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#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
But the mistake is to say, yes, it's affecting the SAS. It's easy to see an analogy if I said, here's a drug and it helps you because it affects neurons. You'd laugh at me because what you really want to know is, is it motor neurons, sympathetic neurons, parasympathetic neurons, neurons in your hypothalamus? What part of the hypothalamus, the ones that control appetite?
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#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
And I said, no, no, no, it affects neurons. I've got a drug that affects neurons.
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#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
It's thinking that I object to. The terminology is problematic because it makes people stop thinking about the important details and start imagining that they've had a thought when they say, I have a drug that removes senescent cells. The problem is that the words trap you into patterns of thought that are, in this case, nonproductive and misleading.
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
I think the evidence is uncertain. There's a famous paper from Bannister that alleged that diabetics on metformin had lower mortality risks. You don't listen to my podcast, do you? I do occasionally.
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
That's exactly what I was going to say. As a matter of fact, Keyes Christensen, who's a senior member of the group, and I have just written a review article which says exactly that. That's the title of my paper. Is it out yet? It's under review. Okay. Yes, so you know exactly what I was going to say, and I agree completely.
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
The question as to whether metformin would be geroprotective... In a non-diabetic. In a non-diabetic, in humans, I think is interesting, unanswered. It's not the drug I would have looked at myself if I had a big set of dogs, for instance, and I wanted to give them a drug that modified their glucose homeostasis. I would probably start with something like canagliflozin,
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
that actually does work in mice, and which is known to be safe over the long term in people. Metformin is safe over the long term in people, but I don't think there's much evidence that it's anti-aging, leaving aside how great it is for diabetics and pre-diabetics. What do you think, Steve?
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
I'll send you the Keys review article, and then you can rethink that. Okay.
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
Let me agree with the emphasis you were just putting on organ-specific and tissue-specific changes. And I think it's about time to get away from what does metformin do to the body, or any of these drugs for that matter, and start to think what does it do to each of the interesting players and how they talk to one another.
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
Someone in my lab has been looking at the enzymes related to de novo lipogenesis, and she's been looking at a couple of different kinds of slow aging mice, and it has major effects in the liver, and it has major effects on white and brown adipose tissue, and they go in different directions.
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#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
and which is primary, which is reactive, whether any of these are related to the effects of the mutations on the muscle or the brain is now an open question. So, having a diagram of hallmarks which are changed by a drug is much less useful than asking what specific changes in what cell types of which organs that talk to each other
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#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
are being changed by this drug as a primary or as a secondary or as a compensatory effect. That's how you'll start to get into first mechanisms, but also start to be able to think clearly about ways of targeting therapy so that it has a benefit with fewer and fewer side effects.
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
They actually lost weight. Males and females lost weight on canagliflozin.
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
The mice treated with the drug were lighter in weight than controls, and that's true of both sexes.
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#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
They actually lost more weight in females than in males. So the question is very valid, and we do not know the answer. SGLT2 is on many other cell types, and it's quite possible, very plausible, that canagliflozin had an effect principally through controlling peak daily blood glucose, not average but peak, And it's also possible that it had effects on cells of unknown origin in the brain.
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
And all of these are very valid, and I don't think anyone knows the answer. It's well worth evaluating. There are other inhibitors of SGLT2 and SGLT1 that have differential cell specificities and differential effects on different cell types. And looking at those would help give you glimpses into this question. We guessed it had to do with glucose, but we might be wrong.
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#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
I guess I don't understand the question.
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
I don't know enough to say. Many of our slow aging mice, actually mTOR complex 1 function is down in all of them, but mTOR complex 2 is often up. And it's up in an interesting way. Mice eat mostly at night, and they more or less fast during the day. In our slow-aging mice, mTOR complex 2 is elevated, but it no longer responds in the fasting period, but it doesn't respond to food in the same way.
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#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
So they're complex changes. in both its baseline state and its response to food. Whether these would happen in people, would happen in people taking it every other day, every fifth day, whether they are beneficial or harmful or a mixture, I really don't know. The mTOR complex 2 story is trickier.
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
The other thing that is, I think, important but not really appreciated is that not all mTOR complex 1 drugs, like rapamycin, not only lower the overall effect, but it also changes the substrate specificity. so that the kinase that is susceptible to TORC inhibition that looks at a ribosomal protein S6, that goes down. It doesn't work nearly as well as inhibited. For how long? I don't know.
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#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
But the other aspect of TOR downstream is on a protein called 4-ABP1 that's involved in translation. it does not change that kinase. What it does is it changes the total amount of the protein. So the proportion of the protein that's phosphorylated drops down, but the actual kinase that adds the phosphate to that substrate is unchanged.
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
So whether that's important, that it's having at least two different pathways that are being influenced in one case by changing the substrate and in the other case by changing the kinase, no one's really looked at that. They say it's a drug that blocks mTOR kinase 1 function. And downstream is where a lot of the action is. I know your lab at one point was interested in
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#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
cell type specific inhibitors of the TOR complex one. I don't know whether you- Everything you just said, Rich, occurs in what cell?
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#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
Well, the overall decline in the ratio of phosphorylated versus substrate, we also published that, I think, in muscle and kidney. I would have to go back to the papers and see whether we also found the elevation of the substrate before EBP1 in both of those tissues.
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#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
I vaguely recall that it was the substrate that changed, not the kinase in those tissues as well, but I'd rather look it up before I sign my name to it.
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
I agree completely. Let me give you an example. So Linda Partridge just published in BioArchive, at least a nice paper, rapamycin increased lifespan of her mice. If she added an inhibitor of a different kinase called ERK, it did better. The inhibition by ERK worked by itself, but it actually improved on rapamycin.
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#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
So two people in my lab are looking at that, and it turns out that the ERK kinase inhibitor is working in an entirely different pathway. It's affecting the proteome by increasing the degradation through a chavron-mediated autophagy mechanism, which is not affected by rapamycin.
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#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
At least at the dose they used.
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#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
No, we never used black six. No, no, not you. I'm talking about the Partridge paper. No, it was an F1 hybrid, actually. So it's agreeing with and amplifying the question.
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
There may well be multiple cell intrinsic pathways, some of which are TOR-dependent, some of which are MAP kinase, ERK-dependent, which can synergize, as in the Partridge case for lifespan, but also potentially synergize for health impact.
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#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
It has a good PR team.
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
I have no idea.
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
Yeah, the famous experiment which was published as resveratrol, the first drug ever found to extend mouse lifespan. It turns out that the mice die because they were on a 60% coconut oil diet. It's poisonous to the extent that it causes the liver to fill with fat and compresses the thorax so that they cannot inhale.
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#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
Three or four papers later, they published as an obscure paragraph in a discussion section on a paper, Pearson was the first author of the second paper, that, oh, by the way, all these mice on the coconut oil diet, finally, we've looked at them, they're all dying because of lung compaction due to expansion of the liver.
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
So the notion that their drug had slowed aging because on the 60% coconut oil diet, it temporarily extended lifespan was due to the prevention of this extremely bizarre phenomenon. I just cannot get enough of that story. Well, it's all documented in the literature. No, no, no. I believe I know it well. Two separate papers.
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#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
And there was- Strongest negative evidence.
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
I find myself frustrated by the question rather than by the answer because... You've got a horrible question asker here, Rich, is the problem. I think you are well above average, but this particular one I think is illustrative because the reason people like parabiosis is that they've seen it in a sci-fi movie.
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
It sounds exactly like what you do in sci-fi and they're flashing lights and it's so sexy and it's just so great and you can take the blood of young virgins and give it to old people and they stand up and they can... I didn't realize they had to be virgins. They have to be, yeah. But none of that is pertinent.
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
Pertinent is, is there something that is in the blood of old people that it would be good to remove? And if so, what is it? And is there something, a cell, a molecule, a set of three molecules that's in the blood of young people or mice that would be good for you? The only virtue of this parabiosis circus is... to suggest that, you know, the answer might be yes.
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#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
There might be something you could remove from old blood, a cell or some plasma molecule, and there might be something good in the blood of young individuals. So the challenge now is to find out what those things are, and then you can do real-life science. Real-life science is not done by taking blood from young people and putting it into old people. That's medieval science, where
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
But there are two different issues that are being confused here in the discussion. One is the issue of whether you can help middle-aged people live longer. And everybody's agreed that we're getting better at that. We're pretty good at it. And that certainly contributes to whatever you think healthspan might mean.
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#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
is a complex mixture of dozens of hundreds of potentially- Right, but that could be the proof of principle.
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
The issue is what experiments would be worth- You have a limited amount of volunteers, doctors, and money. What experiments are most informative? And in my view, by far the most informative experiments are, what is in the blood of young mice that is so good? And what is in the blood of young mice?
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#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
Yes, that's the only way you can turn your idea into science.
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
It's a scientific question. If you have a choice, the ITP loves to test individual chemical compounds, even sometimes ones where the mechanism of action is not known. And that's very sensible. We are very dubious about, let's take a little of this and a little of that, a little of that. And we're really dubious about taking, let's grind up the asparagus.
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#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
No, I'm not saying we have to know the mechanism exactly of each drug. What I'm saying is that if you have a very complex mixture of hundreds of molecules and something happens, you don't know what to do next because it could be any one or two or eight or ten of those, and you haven't really...
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#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
have trouble then with standardization, with mechanistic tests, and with transferring to a key species like simulants.
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#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
That's an issue, however, that is quite different from a concoction that slows aging do so by extending healthspan. Those both have the word healthspan in them. but they're different and shouldn't ever be confused with one another. The other point in this question you asked was what is healthspan? My own personal answer to that is it's a useless term. That is because no one can define it.
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#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
Gentlemen, thank you for making the- I'll send my nominee committee onto this and I'll get back to you.
The Peter Attia Drive
#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
It's not because no one is smart. It's because the term itself is vacuous and nebulous. If you have somebody that gets a certain chronic disease here and then another one, and then they fall down and bump their head, and by the way, they go to the hospital with COVID, etc., etc.,
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#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
defining when in that 20 to 30-year period they flicked the switch, now they have gotten to the end of the healthspan is impossible and of no interest. The general notion that people are interested in is whether you can do stuff to keep people healthy for a long time, either without changing their life expectancy or by changing their life with changing their life expectancy.