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The Science of Slowing Aging: Rapamycin, Genes, and the Quest for a Longer Health Span · The Science of Skin

• 0:08
  SPEAKER_01: Hello and welcome to the Science of Skin Podcast.
• 0:10
  SPEAKER_01: My name is Dr.
• 0:11
  SPEAKER_01: Ted Lane.
• 0:11
  SPEAKER_01: I'm a board certified dermatologist and your host for today.
• 0:15
  SPEAKER_01: Uh before we get started, if you have any questions, comments, or ideas for additional episodes, please shoot us an email at inquiry at science of skinsummit.com.
• 0:23
  SPEAKER_01: That's inquiry at science of skinsummit.com.
• 0:27
  SPEAKER_01: Today we have a true worldwide expert on the uh topic of aging.
• 0:33
  SPEAKER_01: This is Dr.
• 0:34
  SPEAKER_01: Rich Miller.
• 0:34
  SPEAKER_01: Dr.
• 0:35
  SPEAKER_01: Miller, how are you, sir?
• 0:36
  SPEAKER_01: I'm just fine.
• 0:37
  SPEAKER_01: Thank you.
• 0:38
  SPEAKER_01: Great.
• 0:38
  SPEAKER_01: Dr.
• 0:39
  SPEAKER_01: Miller is a professor of pathology at the University of Michigan.
• 0:42
  SPEAKER_01: He's an MD PhD.
• 0:44
  SPEAKER_01: He is also the director of the Paul F.
• 0:46
  SPEAKER_01: Glenn Center for Aging Research and has been for 30 plus years, Dr.
• 0:52
  SPEAKER_01: Miller.
• 0:52
  SPEAKER_01: Is that right?
• 0:54
  SPEAKER_00: I've been in Michigan since 1990, and our Glenn Center is uh enjoying its 12th annual uh anniversary.
• 1:02
  SPEAKER_01: Okay.
• 1:02
  SPEAKER_01: So for 12 years then uh in the Aging Center for Aging Research.
• 1:06
  SPEAKER_01: And your your research really centers on a few different things.
• 1:10
  SPEAKER_01: Uh and and I just, you know, we talk a lot about how do we match health span with lifespan.
• 1:17
  SPEAKER_01: And what it sounds like to me, Dr.
• 1:18
  SPEAKER_01: Millon, please correct me if I'm wrong, but your research really is focusing on in mammals, so using animal models, how do we really extend lifespan uh more than health span, or do you are you really focused on both?
• 1:32
  SPEAKER_00: Yeah, well, that's a common source of confusion.
• 1:36
  SPEAKER_00: That people imagine, and I think this is wrong, that you can either have lifespan or health span.
• 1:42
  SPEAKER_00: They have a kind of a seesaw model.
• 1:43
  SPEAKER_00: You get one or the other.
• 1:45
  SPEAKER_00: But that's all wrong.
• 1:46
  SPEAKER_00: It turns out that the drugs that slow aging, or the diets, or the genes in mice, elevate both.
• 1:52
  SPEAKER_00: You have more lifespan and you have more health span.
• 1:55
  SPEAKER_00: And if you think about it, that's um entirely what you would expect.
• 1:59
  SPEAKER_00: The reason these animals are not dead is that they're healthy.
• 2:02
  SPEAKER_00: And by extending their period of being in good health, that automatically, or more or less automatically, extends their lifespan too.
• 2:11
  SPEAKER_00: It's not a matter of doing one or the other.
• 2:13
  SPEAKER_00: All of our drugs do both.
• 2:16
  SPEAKER_01: That's amazing.
• 2:16
  SPEAKER_01: And I should say from the beginning here, Dr.
• 2:18
  SPEAKER_01: Miller, we are not offering any medical advice between the two of us.
• 2:21
  SPEAKER_01: We are merely talking about your research, much of which is based on animal models.
• 2:26
  SPEAKER_01: And so I certainly wouldn't want any listener to take take away that that they should be taking or using any of the medications, uh, or or perhaps we might even get into nutrient supplements because that is not the purpose of this podcast and certainly not what you and I are talking about.
• 2:42
  SPEAKER_01: So wanted to get that out of the way.
• 2:44
  SPEAKER_01: But in terms of your research then, Dr.
• 2:46
  SPEAKER_01: Miller, new approaches, so one topic, new approaches to slow aging and disease through drugs and targeted mutations.
• 2:53
  SPEAKER_01: The drugs I understand, can you explain the targeted mutations?
• 2:57
  SPEAKER_00: Yeah, in 1996, a scientist in Illinois, a man named Andre Bartke, discovered that if you made a single gene change in a mouse, the Ames Dwarf mouse, they lived 40% longer.
• 3:09
  SPEAKER_00: And uh that was sort of the opening uh salvo in now a larger literature.
• 3:17
  SPEAKER_00: We worked with five different kinds of mutants.
• 3:19
  SPEAKER_00: Uh, at least those five mutants, uh, you change one gene and you get a much longer-lived mouse, like a 30% or 40% longer-lived mouse.
• 3:28
  SPEAKER_00: So a lot of the work we were doing and still are doing has to do with why those genetic changes slow down aging and increase healthy lifespan in the mice.
• 3:39
  SPEAKER_00: Since no one will want to uh uh change the genes of their babies, it'll be much simpler to develop pills.
• 3:47
  SPEAKER_00: And so uh nearly all of the work we're working on in the last 10 or 20 years has been to try to use the insights from the mutant mice and from other kinds of animals to uh find pills that will work, find drugs that will slow aging.
• 4:02
  SPEAKER_01: How applicable is this animal data to humans?
• 4:06
  SPEAKER_01: Because from my understanding, uh you know, 70% of mouse deaths is due to the development of cancer, which happens very quickly.
• 4:14
  SPEAKER_01: So there's some genetic instability in mice that we don't necessarily have in humans.
• 4:18
  SPEAKER_01: And so does that play into whether we can take the findings from the mouse experiments, from these mice models, and apply them to humans?
• 4:27
  SPEAKER_01: Or how do you think about that?
• 4:30
  SPEAKER_00: Right.
• 4:30
  SPEAKER_00: So those are two very good questions.
• 4:32
  SPEAKER_00: Let's let's take them one at a time.
• 4:34
  SPEAKER_00: Um of course, drugs that do something useful in mice sometimes do it in humans and sometimes don't.
• 4:43
  SPEAKER_00: And often a drug that looks really very promising in a mouse study, like an anti-pain drug or an anti-diabetes drug or a cosmetic or something, doesn't work in people.
• 4:54
  SPEAKER_00: Um often it does, but often it doesn't.
• 4:57
  SPEAKER_00: And there's really no way to guess without actually picking a few of these and seeing if they work in people.
• 5:04
  SPEAKER_00: But nearly everything that is useful to prevent uh diseases in people came originally from some sort of a mouse or rat study.
• 5:14
  SPEAKER_00: So it's not a one-to-one match, but it's a really good first step in coming up with good ideas for drugs that are worth testing in people.
• 5:23
  SPEAKER_00: The other part of your question had to do with cancer.
• 5:26
  SPEAKER_00: Um, about you're right, 70 or 80% of laboratory mice die of some form of cancer, although it's sometimes lung cancer, sometimes liver cancer, sometimes breast cancer, or sometimes lymphoid tumors.
• 5:39
  SPEAKER_00: It varies quite a lot.
• 5:41
  SPEAKER_00: Um, so when we have a drug like raphamycin, which is now, I think, the most famous of the drugs that we we worked on, that extends lifespan, we have to think about two models.
• 5:52
  SPEAKER_00: Maybe, as you were hinting, it's just an anti-cancer drug.
• 5:57
  SPEAKER_00: Of course, that just is ironic.
• 5:59
  SPEAKER_00: A really great anti-cancer drug would be useful.
• 6:02
  SPEAKER_00: But let's we're really interested in drugs that slow aging and not just cancer.
• 6:07
  SPEAKER_00: So what we do is we do another study, as we did for rapamycin, um, we take another batch of mice, we give them the drug, and instead of letting them live their whole lives, we uh look at them when they're middle-aged to see does the liver look old, does the brain look old?
• 6:22
  SPEAKER_00: Does the skin look old?
• 6:23
  SPEAKER_00: Does the kidney look old?
• 6:25
  SPEAKER_00: And in fact, uh in the published paper there, we looked at ten different organs that show aging changes, and nine of those ten were changing more slowly when rapamycin was added.
• 6:36
  SPEAKER_00: These are not cancers, these are not things that kill the mice, actually, they're just ways of looking at aging effects on a variety of tissues.
• 6:44
  SPEAKER_00: So rapamycin slowed aging down in most of the tissues we looked at, and so that's the basic grounds for concluding that it's really an anti-aging drug as a side effect, a really pleasant one, it also slows down cancer.
• 6:59
  SPEAKER_00: So that's probably why, or a big part of the answer why these mice live so long.
• 7:05
  SPEAKER_01: Where uh I'm not sure if you know this is just because of your focus on research is is more in the animal models, but but where are we in terms of testing rapamycin in humans for for slowing down the aging process?
• 7:16
  SPEAKER_00: Yeah, that's a very interesting question.
• 7:20
  SPEAKER_00: Um and the answer has to be a nuanced one.
• 7:24
  SPEAKER_00: The ideal experiment, which essentially can't be done, is to take a lot of 50-year-olds, like 5,000 of them, put them on a safe dose of rapamycin, come back in 30 years and see if they've lived a long time.
• 7:36
  SPEAKER_00: There's a batch of problems with that.
• 7:37
  SPEAKER_00: It's hopelessly expensive.
• 7:38
  SPEAKER_00: No one wants to wait 30 years.
• 7:40
  SPEAKER_00: Drug companies don't want to wait 30 years to see what's going to happen to their stock price, for example.
• 7:46
  SPEAKER_00: Um, and in addition, you don't know what a safe dose is.
• 7:50
  SPEAKER_00: Even if hypothetically, and this is certainly one has to be very cautious, we don't know if rapamycin at any dose can safely extend human lifespan.
• 7:58
  SPEAKER_00: But hypothetically, if there was a dose, we wouldn't know whether it would produce serious side effects or not.
• 8:04
  SPEAKER_00: We can tell, of course, whether rapamycin at a given dose is bad for you over the first few weeks or months.
• 8:12
  SPEAKER_00: But if you're going to give something to people for decades, you want to be really careful and really sure that you're not creating uh problems.
• 8:21
  SPEAKER_00: So for all of those reasons, test the obvious test for does a drug slow aging in people is extremely difficult and impractical.
• 8:31
  SPEAKER_00: My lab has spent the last five years trying to find a trick for getting around that.
• 8:35
  SPEAKER_00: We think we're onto something, but uh it hasn't really been proven yet.
• 8:39
  SPEAKER_00: We we have found a whole series of changes in the fat, in the blood, in the brain, and in the uh in the liver that always change whenever you have a slow aging mouse.
• 8:49
  SPEAKER_00: We have, as I mentioned, five mutants, we also have four drugs, and we have a couple of diets.
• 8:54
  SPEAKER_00: And however you make your slow-aging mouse, all of these changes always occur together.
• 8:59
  SPEAKER_00: So we're calling those aging rate indicators because we think they discriminate normal mice from the slow aging kind, regardless of how you made the mouse slow aging.
• 9:09
  SPEAKER_00: If that's true, and if it worked in people, and there's no reason to think it wouldn't, you could take people, give them a drug you thought might work, not for 30 years, but for like one year.
• 9:21
  SPEAKER_00: And if the changes in their, let's say their blood mimicked those that are always seen in the mouse when you give the mouse a real live anti-aging drug, that would be a really good sign.
• 9:32
  SPEAKER_00: If you had a drug that in people recreated the same metabolic or protein pattern in the blood that you see in slow-aging mice, that would be a hint that that drug really might be working in people or at least deserves more careful and comprehensive testing.
• 9:48
  SPEAKER_01: Well, if you take that to the next level, that that is a doable clinical trial.
• 9:53
  SPEAKER_01: You know, and at the same point you can have multiple multiple cohorts of different, for example, if we took a rapamycl, multiple cohorts of different dosing, you could check for the safety as well, and it becomes uh something that the drug companies very much could do.
• 10:08
  SPEAKER_01: Um so that's that's very exciting.
• 10:11
  SPEAKER_01: How how far away are we from from testing that in humans, the ARI?
• 10:16
  SPEAKER_00: Well, the key step uh was getting it to work in blood.
• 10:20
  SPEAKER_00: Most of our original data came from skin and uh sorry, not skin, uh, but uh brain and liver and uh fat and kidneys.
• 10:29
  SPEAKER_00: So those are not practical, of course, for human trials.
• 10:32
  SPEAKER_00: So what we've done in the last couple of years is we've begun to look at either small molecules, metabolites in plasma, or proteins in plasma.
• 10:40
  SPEAKER_00: And so far it looks good.
• 10:43
  SPEAKER_00: That is, we have a set of metabolites in mouse plasma that are uh consistently changed with each of four different anti-aging drugs, plus the famous calorie restriction diet, which also slows aging in mice.
• 10:58
  SPEAKER_00: So we now want to uh start collaborations with people who are doing human research where they say, I've got a drug, I think it's gonna slow aging in people, I'm gonna give it to some people.
• 11:10
  SPEAKER_00: What we would love to do is get a blood sample from those people just before they start the exercise routine or the drug or the nutritional change, and then say one year later, and what we would do is we would look at the metabolites in those plasma samples and say, oh, wait, for this drug or this diet, the changes strongly resemble those which we see in all the slow-aging mice.
• 11:34
  SPEAKER_00: That would be a sign of success.
• 11:36
  SPEAKER_00: So what we're hoping to do soon is initiate some research collaborations with physician scientists who are interested in drug tests in people.
• 11:48
  SPEAKER_00: Healthy people, not people who are sick, but healthy volunteers who want to try um uh a drug that they think might they and their doctors think might be good for them.
• 11:58
  SPEAKER_01: Yeah, so interesting.
• 11:59
  SPEAKER_01: I hope that happens quickly.
• 12:01
  SPEAKER_01: Uh if anybody's listening, Dr.
• 12:03
  SPEAKER_01: Miller's at University of Michigan.
• 12:06
  SPEAKER_01: Uh in terms of the uh organs that you tested, you said nine out of ten.
• 12:10
  SPEAKER_01: Was skin one of those organs that was tested?
• 12:13
  unknown: No.
• 12:14
  SPEAKER_00: No, it's very, very frustrating.
• 12:16
  SPEAKER_00: I would be desperate to have a skilled experimental dermatologist look at the skin from our slow-aging mice, the ones that have mutations, the ones that have the calastriction or isolution-retricted diet, or the ones that are on drugs and determine whether the pace of aging in the skin was delayed by these drugs.
• 12:38
  SPEAKER_00: Uh, so far, I have not been able to link up with a dermatologist who wants to make this a part of his or her research portfolio.
• 12:46
  SPEAKER_01: Yeah.
• 12:46
  SPEAKER_00: You can also come to the dermatology aging meeting this year.
• 12:51
  SPEAKER_01: That's great.
• 12:51
  SPEAKER_01: Well, we're excited to have you.
• 12:52
  SPEAKER_01: Dr.
• 12:53
  SPEAKER_01: Miller will be speaking at the Science of Skin Summit, and we're hoping to get him at the Science of Skin Longevity Summit as well.
• 12:58
  SPEAKER_01: So uh definitely introducing Dr.
• 13:01
  SPEAKER_01: Miller's work to the dermatology community as much as we possibly can, hence this podcast as well as to amplify what you're doing so that we can hopefully um extend this to skin health span or skin span uh as much as we can.
• 13:16
  SPEAKER_01: Uh, and that may be a requirement of a biopsy that needs to be performed uh on these patients on this kind of clinical trial that we are hoping can be done one day in healthy volunteers.
• 13:27
  SPEAKER_01: Perhaps we do not only blood samples before and after, but also skin biopsies before and after, so there's tissue involved and not just skin scraping or something like that.
• 13:35
  SPEAKER_00: The first step would be to do it in mice, in which you could see whether aging effects on mouse skin was also uh were also blunted by these anti-aging drugs.
• 13:48
  SPEAKER_01: Uh you you mentioned diet as well, Dr.
• 13:51
  SPEAKER_01: Miller.
• 13:52
  SPEAKER_01: What are the diets that you have been testing?
• 13:55
  SPEAKER_00: Well, the famous one is the low-calorie diet, caloribriction diet, actually first discovered in 1935.
• 14:01
  SPEAKER_00: It extends lifespan in uh you know 95% of all the different strains of mice and rats on which it's ever been tested, um, and extends lifespan by 30 to 40 percent.
• 14:11
  SPEAKER_00: To give you a sense of whether that's a big number, um, if you had a drug, a hypothetical drug that stopped all cancer in adult people, no one over the age of 50 ever got cancer again, the average human lifespan in a country like ours, which is well off, goes up by 3%.
• 14:30
  SPEAKER_00: So the calorie restricted diet in all mice and rats extends lifespan by 30 to 40 percent, that is about 10 times more than you would expect from a human drug that slows all human cancers.
• 14:46
  SPEAKER_00: Similarly, if you have a drug that stops all heart attacks, you're on average increasing lifespan only by uh 2.7%.
• 14:53
  SPEAKER_00: So the 30% increase is really a big deal.
• 14:58
  SPEAKER_00: It's worth paying attention to.
• 15:00
  SPEAKER_00: So the calorie friction diet is the first one that was discovered, and we use it a lot.
• 15:06
  SPEAKER_00: Recently, there have been two other special kinds of diets.
• 15:10
  SPEAKER_00: None of these are practical for humans.
• 15:12
  SPEAKER_00: These are experimental tools, they're not really uh diets that any person could stick to.
• 15:18
  SPEAKER_00: But the two that we are studying, one of them has to do with you make a diet that is low in the amino acid methionine.
• 15:25
  SPEAKER_00: In 1993, uh uh Orentrike showed that extended rat lifespan by 20 or 30 percent.
• 15:33
  SPEAKER_00: And my lab, maybe a decade later, found that it also extends mouse lifespan.
• 15:38
  SPEAKER_00: Um, the third has been a pet project of Dudley Lamming.
• 15:42
  SPEAKER_00: Dudley makes diets where the amino acid isoleucine is very low, and Dudley has shown that isoleucine restricted diets also extend mouse lifespan.
• 15:52
  SPEAKER_01: Now, why methionine and isoleucine?
• 15:55
  SPEAKER_01: What about those two?
• 15:57
  SPEAKER_00: Yeah, it's a good question.
• 15:58
  SPEAKER_00: Um, and it has a slightly complex history.
• 16:01
  SPEAKER_00: The people in the Orentreich Institute were really excited by methionine because they thought it would modify glutathione, which is important for oxidation damage.
• 16:10
  SPEAKER_00: So they did all their work with met with with methionine restriction.
• 16:15
  SPEAKER_00: But when Dr.
• 16:17
  SPEAKER_00: Lamming looked at this, he said, well, I'll bet maybe what's really going on is that if you restrict an amino acid, protein translation will slow down.
• 16:27
  SPEAKER_00: Maybe that's the secret, the thing that makes the mice live longer.
• 16:31
  SPEAKER_00: And he found that with isoleucine restriction, you can also get extended longevity.
• 16:37
  SPEAKER_00: So although there's still a lot more that would need to be done to really sort of nail this, the current picture is that those two amino acids are working by slowing protein translation.
• 16:51
  SPEAKER_00: If you have very low levels of either of those amino acids, um new protein translation is going to be dependent upon uh the limited levels of those amino acids.
• 17:03
  SPEAKER_00: Maybe, this needs to be proven, maybe that's why the mice live a long time.
• 17:09
  SPEAKER_01: Okay.
• 17:10
  SPEAKER_01: And lower levels of protein, can we take that to the next step?
• 17:14
  SPEAKER_01: Why would we think lower protein production would extend life's wife?
• 17:18
  SPEAKER_00: Well, that's a misunderstanding.
• 17:20
  SPEAKER_00: Um it is not the case that diets low in protein are proven to be good for you, either in mice or in people.
• 17:30
  SPEAKER_00: The diets that work in the mice lack single amino acids.
• 17:35
  SPEAKER_00: And the way in which the body translates that signal, my God, there's not enough methionine or there's not enough isoleucine into the set of changes which slow aging is really uncertain.
• 17:46
  SPEAKER_00: It's not true.
• 17:47
  SPEAKER_00: Many of the drugs like rapamycin and acarbose and cananglofosin, many of those drugs also modulate the the control inside cells of protein.
• 17:58
  SPEAKER_00: There's an enzyme called mTOR.
• 18:01
  SPEAKER_00: Tor stands for target of rapamycin, so it's not surprising that rapamycin alters it.
• 18:06
  SPEAKER_00: That's that has a very strong regulatory effect on protein translation and production of new proteins.
• 18:13
  SPEAKER_00: All of the drugs that we've studied that slow aging diminish mTOR action.
• 18:18
  SPEAKER_00: So there's a lot of sort of circumstantial evidence that if you slow down the process of making new proteins, that's good for you.
• 18:28
  SPEAKER_00: But why it's good for you and how it produces healthful effects is uncertain.
• 18:33
  SPEAKER_00: We have some ideas we're testing, but it's no one knows for sure, basically.
• 18:39
  SPEAKER_01: Now, protein production is one thing, Dr.
• 18:41
  SPEAKER_01: Miller, and then the removal of proteins, especially proteins that have been damaged, is is a whole nother target of kind of life extension, isn't it?
• 18:51
  SPEAKER_01: And and are you is your lab working on protease activity or uh on that the flip side?
• 18:59
  SPEAKER_00: So there's a this is a really important point where you have to make a distinction that's easy but is not an obvious one.
• 19:09
  SPEAKER_00: There are an awful lot of things that go wrong when you get old.
• 19:12
  SPEAKER_00: And uh some of them are due to damaged protein, for instance, oxidized protein.
• 19:18
  SPEAKER_00: But some of them are due to damaged DNA or cross-linking of molecules or cell death or maybe transformation of cells into cancer cells, um, loss of uh your your hearing gets worse partly because your inner hair the hair cells in the inner ear go bad.
• 19:35
  SPEAKER_00: An awful lot of bad stuff happens when you get old.
• 19:39
  SPEAKER_00: But it's not at all obvious, and probably is wrong, that this change causes aging, or this change causes aging, or this change causes aging.
• 19:48
  SPEAKER_00: What my lab is like is mostly interested in is not what causes aging.
• 19:53
  SPEAKER_00: I don't think there is any single thing that causes aging.
• 19:56
  SPEAKER_00: I think there are dozens at least of things that lead to aging of the eye or aging of the ear or the skin or the brain, whatever.
• 20:04
  SPEAKER_00: We are interested in a quite a different problem.
• 20:07
  SPEAKER_00: What things are cause are changing the rate at which aging occurs.
• 20:12
  SPEAKER_00: So the factors that change the rate of aging throughout life need not be in any way related to the factors that cause bad things to happen to you when you get old.
• 20:25
  SPEAKER_00: They sound kind of almost the same thing in a mushy way, but it's critical to recognize the difference.
• 20:32
  SPEAKER_00: Um is the cause or the timing mechanism, the other is the consequence.
• 20:38
  SPEAKER_00: And you want to be sure you're studying, or at least I want to be sure I'm studying, the things that regulate the pace at which aging occurs and not get distracted by questions about what causes damage in old people or old mice for that matter.
• 20:57
  SPEAKER_01: And is your lab unique in that respect in terms of focusing on the rate of aging versus the causes of aging, or are others in the same pool with you?
• 21:06
  SPEAKER_00: Yeah, well, it's a new idea.
• 21:07
  SPEAKER_00: Um labs for that have been you know playing a big role in this in the last 20 or 30 years have tried to answer the question, which I think is a distraction actually, what causes aging?
• 21:21
  SPEAKER_00: The DNA mutation lab, the guy says it's DNA mutations.
• 21:25
  SPEAKER_00: Mitochondrial lab says, nope, nope, it's immune, it's mitochondria, or no, it's immune system, or whatever.
• 21:30
  SPEAKER_00: Um I think the notion that what you really need to do is study something utterly different, that is, what times the aging rate is slowly catching on, far too slowly catching on.
• 21:46
  SPEAKER_00: Uh, the person who's actually done the best job of making this distinction is a scientist at Columbia, a man named Dan Belski.
• 21:55
  SPEAKER_00: Dr.
• 21:55
  SPEAKER_00: Belski is interested in DNA methylation patterns, and unlike most.
• 22:00
  SPEAKER_00: Most people, he's interested in DNA methylation patterns that don't tell you how old you are, but tell you how fast you're aging.
• 22:06
  SPEAKER_00: And his that that's what we're trying to do.
• 22:08
  SPEAKER_00: We're trying to think find metabolites or proteins or changes in macrophage properties that tell you how fast you're aging, regardless of how old you are.
• 22:21
  SPEAKER_00: The analogy that is very helpful here is from a car, from your odometer or your speedometer.
• 22:27
  SPEAKER_00: If you want to know how old your car is, you look at the odometer, and you can tell whether you've got a brand new car or a really old car somewhere in the middle.
• 22:33
  SPEAKER_00: But the odometer is useless if you want to know how fast you're moving.
• 22:37
  SPEAKER_00: Those are the biomarkers of aging, the things that change with age.
• 22:41
  SPEAKER_00: We're interested instead in what the speedometer is showing you.
• 22:44
  SPEAKER_00: The speedometer is telling you how fast you're aging or how fast your car is going at the moment you look at it.
• 22:52
  SPEAKER_00: It could be that your car is moving fast when it's young or middle-aged or old.
• 22:58
  SPEAKER_00: Doesn't matter.
• 22:58
  SPEAKER_00: We want to know what is the speed.
• 23:00
  SPEAKER_00: And Belski is, I think, among the people who are prominent in this area.
• 23:05
  SPEAKER_00: The first one really to catch on to why that's an important distinction to make, and the first one to sort of hitch his wagon to this current fad for methylation patterns and document that the methylation patterns related to the rate of aging are different from the ones that tell you how old you are.
• 23:27
  SPEAKER_01: Dr.
• 23:27
  SPEAKER_01: Miller, based on your research, you know, I think there's let me back up.
• 23:31
  SPEAKER_01: I think that many people believe that once they hit a certain age, their ability to slow their rate of aging diminishes.
• 23:38
  SPEAKER_01: They just think, oh, it's too late.
• 23:39
  SPEAKER_01: I should have started this when I was much younger.
• 23:42
  SPEAKER_01: Does your research show that there's an age at which the ability to slow the speed of aging or the rate of aging is diminished?
• 23:50
  SPEAKER_01: Or or can we at any age, based on your models, not saying this necessarily applies to humans, but is it is it your research that shows that based on any age, we we possibly could slow the rate of aging?
• 24:03
  SPEAKER_00: Well, first let me agree with you and emphasize that I don't know more than any average reader as to what aspects of improvement decline with age.
• 24:17
  SPEAKER_00: Uh you know, we've all read stories in AARP magazine saying, oh, when you get above 80, it's harder to boost your strength by doing push-ups, or but you can save your mind by listening to a lot of Mozart and doing the Wordle puzzle.
• 24:30
  SPEAKER_00: I know nothing about that.
• 24:32
  SPEAKER_00: Okay.
• 24:33
  SPEAKER_00: The cool thing that we have discovered, and it was a huge surprise, was that we found four drugs that extend mouse lifespan dramatically.
• 24:42
  SPEAKER_00: I've told you already the names of those drugs.
• 24:45
  SPEAKER_00: We imagined that to get a big effect, you'd have to start them in young adults.
• 24:49
  SPEAKER_00: And we were wrong.
• 24:50
  SPEAKER_00: If Brabamycin, for instance, if you start it in middle-aged mice, like 20-month-old mice, which is roughly the equivalent of a 60-year-old person, it still works great.
• 25:01
  SPEAKER_00: It works just as well in a middle-aged mouse as it does in a young mouse.
• 25:06
  SPEAKER_00: The same is true of canagloflosin, and the same is true of 17 hour festradiol.
• 25:11
  SPEAKER_00: The only exception to that rule was a carbose.
• 25:14
  SPEAKER_00: Acarbose does work when you give it to old mice, but it only works half as well.
• 25:19
  SPEAKER_00: That is, we get three out of the four where you get a full effect starting in middle age, and the fourth you get a half effect.
• 25:26
  SPEAKER_00: That was, at least to me, a big surprise.
• 25:28
  SPEAKER_00: I thought the longer you exposed an animal to a drug, the bigger the drug effect would be if you're looking at aging as your as your output.
• 25:36
  SPEAKER_00: But that was wrong.
• 25:37
  SPEAKER_00: It's clear that something is still going on in middle age where these anti-aging drugs can slow it down in an important way and extend the lifespan.
• 25:44
  SPEAKER_00: That is to say, by slowing the rate of health decline, that's what extends the lifespan.
• 25:52
  SPEAKER_00: Why that works is unclear, but it's certainly a good sign for those of us who would like to have drugs that work in people and who want those drugs to be given to middle-aged people.
• 26:03
  SPEAKER_00: It seemed silly before, but now it's kind of consistent with the mouse data, which is good news.
• 26:10
  SPEAKER_01: Very good news.
• 26:11
  SPEAKER_01: I'm just thinking about the the term anti-aging, and it doesn't seem to encompass your research or or what your data is showing.
• 26:18
  SPEAKER_01: It's really we're not anti-aging because it sounds like, as you said, aging is is a process that we could not stop, but but perhaps we could slow it.
• 26:28
  SPEAKER_01: And so anti-aging doesn't necessarily encompass that idea, does it?
• 26:32
  SPEAKER_01: And perhaps we need to start thinking about it.
• 26:34
  SPEAKER_00: I disagree with you on that.
• 26:36
  SPEAKER_00: Um aging, I I the definition I like, and I think it makes sense to most people, aging is the process that turns a healthy uh teenager or college sophomore into someone like me who has more medical problems and looks different and uh has uh some functional declines.
• 26:55
  SPEAKER_00: Um that's what aging is.
• 26:57
  SPEAKER_00: You put in a young person, you get out an old person.
• 27:00
  SPEAKER_00: Um so a drug that slows that, I think it's entirely legit to call it an anti-aging drug.
• 27:09
  SPEAKER_00: Okay.
• 27:10
  SPEAKER_00: I don't I think it's not complicated, it's that simple.
• 27:13
  SPEAKER_00: Our drugs are anti-aging drugs once we've proven that they slow down age-associated changes in many things, and as a very pleasant consequence, they also slow down your risk of death so you live longer.
• 27:28
  SPEAKER_01: Yeah.
• 27:28
  SPEAKER_01: I guess I think of anti as a binary, you know, anti-neoplastic, something like that.
• 27:33
  SPEAKER_01: It just stops it.
• 27:34
  SPEAKER_01: And this is more slowing it.
• 27:35
  SPEAKER_01: But there's nuance to it.
• 27:37
  SPEAKER_01: So so, and and you're much more into this than I am.
• 27:41
  SPEAKER_01: Uh that's that was the genesis of the question.
• 27:44
  SPEAKER_01: But I I also I wanted to move on to the drugs that you were just talking about, the rapamycin, acarbose, 17-alpha estradiol, and the and the flosins that you as you said.
• 27:55
  SPEAKER_01: Sounds to me like the flosins, rapamycin, acarbos work through the mTOR pathway.
• 28:01
  SPEAKER_01: Uh, but the 17 alpha estradiol, uh, in males only I noted that that there were some uh anti-aging benefits of that.
• 28:09
  SPEAKER_01: And and what is the mechanism of that?
• 28:13
  SPEAKER_00: Well, first let's back up a bit because it's important to recognize uh that canagoflosin and carbose probably work not by direct effect on the tor enzyme, they probably work by keeping your blood glucose from going up.
• 28:32
  SPEAKER_00: Um Normally, blood glucose is is you know fairly stable through the day until you have a big meal and then it goes up.
• 28:40
  SPEAKER_00: And in most people, if if I eat three donuts for breakfast and I'm not taking any of these drugs, my blood glucose will shoot way up, and then as I digest the meal, it'll go back down to normal.
• 28:51
  SPEAKER_00: But if someone who's on acarbose or someone who's on a canangophlosin or one of these SGLT2 inhibitors, their blood glucose never goes way, way, way up.
• 29:01
  SPEAKER_00: It goes up a little, and then it stays up for several hours, but it takes much longer to get the blood glucose out of the GI tract for acarbose, and you you use a lot of it in the urine in the SGLT2-treated patients.
• 29:18
  SPEAKER_00: So you're actually modifying glucose biology a lot.
• 29:23
  SPEAKER_00: Uh as everybody knows, GLP1, the one of the drugs that's having the biggest effect on people's health uh uh and diseases now, is also intimately involved in glucose regulation.
• 29:35
  SPEAKER_00: So we don't know how any of these drugs, uh a carbose or uh canangloflosin, or who knows, maybe even uh a GLP1 uh agonist, we don't know how they're slow aging.
• 29:48
  SPEAKER_00: That's a critical unknown question, and one of the main things that my lab is is sort of focused on over the last uh five years and hopefully in the future, how those changes in glucose biology lead to altered aging rates.
• 30:07
  SPEAKER_00: The last drug you mentioned, 17-alpha-estradiol, is a steroid, and we we have no clue at this point, even as to what cell it affects or what receptor it affects.
• 30:16
  SPEAKER_00: It's related to the a famous molecule, 17 beta estradiol.
• 30:21
  SPEAKER_00: 17 beta estradiol is called estrogen.
• 30:24
  SPEAKER_00: So everybody knows what estrogen is.
• 30:25
  SPEAKER_00: Uh, 17-alpha-estradiol is a lot like estrogen, except for one chemical group that points in, quote, the wrong direction.
• 30:34
  SPEAKER_00: For that reason, it's non-feminizing.
• 30:36
  SPEAKER_00: You can give high dose, reasonably high doses of 17 alpha-estradiol to uh males, and it doesn't turn them into females.
• 30:45
  SPEAKER_00: So that's why we're trying it.
• 30:46
  SPEAKER_00: We wanted to see if it would slow aging, and it does in the males only.
• 30:50
  SPEAKER_00: It has no effect on the female mice at all.
• 30:54
  SPEAKER_00: But we don't know the answer.
• 30:55
  SPEAKER_00: We would love to know whether 17 alpha estradiol is affecting some cell in the brain, or some cells in the kidney, or some cells in the in the blood vessels, or and we don't know what what the receptor is, all of that is mysterious.
• 31:09
  SPEAKER_01: It's interesting because rapamycin, for example, we see a greater effect in females versus males uh in terms of the anti-aging uh and Solventine alpha-esterdiol in the males only.
• 31:21
  SPEAKER_01: But but if we go back to rapamycin, why why is it that we I'm not sure if it's known, but why why do we see a greater effect in females than males?
• 31:28
  SPEAKER_00: Yeah, we have a very good guess.
• 31:30
  SPEAKER_00: It's not exactly known, but we have an excellent hypothesis.
• 31:34
  SPEAKER_00: If you give a certain amount of rapamycin in the food to male and female mice, the blood levels in the female are much higher than the blood levels in males.
• 31:44
  SPEAKER_00: So the males are better at getting rid of it, metabolizing it or breaking it down or getting rid of it in the urine.
• 31:50
  SPEAKER_00: The females are less good, and so the the rapamycin concentration in the blood of females is always higher, a lot higher, than it is in the male mice.
• 32:01
  SPEAKER_00: So it it it's quite likely that the higher lifespan benefits you see in females at a given food dose represents the higher blood levels in the females.
• 32:13
  SPEAKER_00: I think if you compare males and females at the same blood level, you would probably find little or no difference in the uh extent of the benefit you see from rapamycin.
• 32:24
  SPEAKER_00: You just have to adjust the blood concentration by putting different doses into the mouse food for males and females, higher doses for the males.
• 32:34
  SPEAKER_01: We don't have much time left.
• 32:36
  SPEAKER_01: In fact, we've gone over time, Dr.
• 32:37
  SPEAKER_01: Mill, and I really appreciate your time today.
• 32:39
  SPEAKER_01: Um but I just wanted to end up with this, and hopefully this isn't our last conversation because you're such an expert.
• 32:44
  SPEAKER_01: I really enjoyed today.
• 32:45
  SPEAKER_01: And and I apologize for some of my ignorance in the questions that I asked, but thank you for being kind to me and reversing some of my thoughts.
• 32:53
  SPEAKER_01: Um as we as we talk about anti-aging right now in terms of lifestyle intervention, not the drugs, which as we know need testing, but in terms of lifestyle intervention, exercise, diet, stress.
• 33:06
  SPEAKER_01: What at the the cutting edge that that you know of, what what do you recommend to your friends and family now to slow aging, extend health span?
• 33:17
  SPEAKER_00: It's very tough because um the the everyone, let me start like this.
• 33:21
  SPEAKER_00: Almost everyone knows the answer, and you do too.
• 33:24
  SPEAKER_00: Um you want to wear seatbelts, you don't want to smoke, you want to get all the right vaccines, uh, you don't want to eat cheeseburgers for breakfast, lunch, and dinner, you want to keep your weight with within uh uh plausible sets of limits.
• 33:36
  SPEAKER_00: Uh make sure you eat some green vegetables every and get some exercise right.
• 33:39
  SPEAKER_00: Don't sit in front of your TV on the everybody knows the answer to that.
• 33:44
  SPEAKER_00: Um and I recommend people do exactly the same thing that their mom told them to do.
• 33:50
  SPEAKER_00: So the the reason this actually becomes a problem is the internet culture and uh bad faith commercial actors want to sell you glop that doesn't work.
• 34:02
  SPEAKER_00: They're called nutraceuticals or they're called nutritional supplements.
• 34:05
  SPEAKER_00: They're not allowed legally, at least in the United States, to say this will slow their aging process, but they are allowed, unfortunately, to make false claims to give you that impression as long as they stay just on this side of the false claims and we can sue them limit.
• 34:22
  SPEAKER_00: So people are nowadays very susceptible to claims, oh, I hear it's creatamine or it's this uh resveratrol or some other unproven untested junk.
• 34:34
  SPEAKER_00: Companies make billions of dollars selling the slop without the slightest evidence because they're not required by our government to uh actually find evidence that the stuff is good for you.
• 34:46
  SPEAKER_00: Um that's the sort of cutting edge.
• 34:48
  SPEAKER_00: When people come to me and say, Oh, I I heard on the TV the other day that this stuff will keep my mind young forever, mostly I have to tell them, no, I'm sorry, gosh, I wish that were true, but there's zero evidence for that at all.
• 35:03
  SPEAKER_00: So um the evidence for what actually is good for you is already well known.
• 35:07
  SPEAKER_00: The last point I'll make is that uh if people have a serious, serious interest in finding real live drugs that will slow the aging process in people, what they really need to do is lobby for more support for this research.
• 35:22
  SPEAKER_00: Real research is now making great progress in that area, but it is still uh astonishingly underfunded compared to what it deserves to be, since anti-aging drugs, even the ones we have in mice, do like 10 times better than a complete cure for cancer.
• 35:41
  SPEAKER_00: There's a lot of value there that is not being really looked at, uh not not being explored enough.
• 35:48
  SPEAKER_01: Perfect.
• 35:48
  SPEAKER_01: There you go, everybody.
• 35:49
  SPEAKER_01: Dr.
• 35:50
  SPEAKER_01: Miller laying it down for us, keeping it real in terms of be careful with all the snake oil salespeople out there.
• 35:57
  SPEAKER_01: It's been since time immemorial that people have been trying to give us the fountain of youth.
• 36:02
  SPEAKER_01: And while it's an exciting time, we have to be careful.
• 36:04
  SPEAKER_01: It's buyer-beware in the United States, isn't it?
• 36:06
  SPEAKER_01: Because our government doesn't really regulate these supplements uh to the extent that it, in my view, it should.
• 36:12
  SPEAKER_01: So uh Dr.
• 36:13
  SPEAKER_01: Miller, thank you again.
• 36:14
  SPEAKER_01: Really appreciate your time today.
• 36:16
  SPEAKER_01: You're sharing your expertise and knowledge with us.
• 36:18
  SPEAKER_01: I think the audience here will all have learned so much from these last 35 minutes.
• 36:23
  SPEAKER_01: So really appreciate it.
• 36:24
  SPEAKER_01: Hopefully we can get you on again.
• 36:26
  SPEAKER_01: It's been fun.
• 36:27
  SPEAKER_01: Thanks for inviting me.
• 36:28
  SPEAKER_01: You bet.
• 36:29
  SPEAKER_01: Thank you for listening, everybody.
• 36:30
  SPEAKER_01: This is a Science of Skin Podcast.
• 36:31
  SPEAKER_01: If you enjoyed today's episode, please give us a five-star rating, subscribe, and of course tell your colleagues we found that the growth of the podcast really occurs by word of mouth, and and we're trying to deliver education that is right at the tip of the spear in dermatology and and healthcare writ large.
• 36:46
  SPEAKER_01: So thank you so much for listening.
• 36:47
  SPEAKER_01: My name is Dr.
• 36:48
  SPEAKER_01: Ted Lane for Dr.
• 36:49
  SPEAKER_01: Uh Rich Miller at at the University of Michigan.
• 36:51
  SPEAKER_01: Thank you again.