Longevity Treatments – Snake Oil or Breakthrough? John Newman & Mahtab Jafari

Eric 00:13

Welcome to the GeriPal Podcast. This is Eric Widera.

Alex 00:17

This is Alex Smith.

Eric 00:18

And Alex, we’re going to be talking about longevity. I can’t pronounce it.

Alex 00:22

Longevity.

Eric 00:23

Longevity science. I don’t know what’s wrong with my tongue today. Miracles or snake oils? That’s going to be the topic. Who do we have with us?

Alex 00:31

We’re delighted to welcome Mahtab Jafari, who’s a professor of pharmaceutical sciences and director of the UC Irvine Center for Healthspan Sciences. We met at the UCSF alumni reunion and, you know, she was talking to me about how she, she had been approached by several media outlets about this or that longevity medication. And I thought, oh boy, this would make a great podcast. So thank you so much for joining us, Mahtab.

Mahtab 00:56

Thank you for having me.

Eric 00:58

Zot, zot, zot. Go anteaters. That’s my alumni right there.

Alex 01:04

Anteaters. I didn’t know that.

Eric 01:06

Anteaters. Zot zot zot.

Alex 01:10

Is that the sound an anteater makes?

Eric 01:12

That is.

Alex 01:12

I’m learning a lot on this podcast.

Eric 01:13

Yeah, you go, you watch an anteater.

John 01:15

They’re just constantly zotting.

Alex 01:16

And we have John Newman, who has been a frequent guest on this podcast, and is a geriatrician and geroscientist who works at the Buck Institute in Marin, as well as UCSF. John, welcome back to the GeriPal Podcast.

John 01:32

Yeah, thanks for having me again. And so much has changed since the last time we talked about this stuff.

Eric 01:36

So much. I’m excited to learn how to live forever.

Alex 01:39

Yeah, I think that was the song request the first time John was on. Who wants to live forever? Not easy to sing that Queen stuff, by the way.

Eric 01:47

So we got, we’re going to talk about, we’ll be talking about why you guys got interested in this and what’s the goalposts and what meds are promising and which ones potentially are snake oils. But before we talk about all of that, song request. Who has the song request today?

John 02:02

I had a song request, although we had, we had a mind meld on the song.

Eric 02:05

Yeah. What is the song?

John 02:08

Wake Me Up by Avicii, which I love because to me it’s, it’s a song about aging. It’s a song about the tension between like, you want to, you want to keep this like vibrancy and the open horizons of youth, but, but also there’s a lot of stress of not knowing what’s going to happen and how you’re going to get through it. when you’re older, you have this self-assurance, you know who you are, you’ve like, you’ve done the journey. And what if you could just meld the best parts together? And that’s kind of what we’re going to talk about.

Eric 02:36

That’s great.

Alex 02:38

And Mahtab, you have a connection to this song too. You want to share that with our listeners?

Mahtab 02:42

Sure. I was so excited when John suggested this song because I happen to know the songwriter and the artist, Aloe Blacc, who is one of my absolute favorite people on this planet, not because he’s an amazing artist, because he’s also a great human being. So I almost listen to this song, believe it or not, every day. I feel like I need to listen to it. It just calms me down. And, uh, with John’s description of the song, now I have new insights. Now I’m going to listen to it a little bit more carefully because he’s right.

Alex 03:16

Yeah.

John 03:16

Well, what is, what is it actually about according to the person who wrote it?

Mahtab 03:20

You know, everybody interprets it differently, and that’s a good question. I should, I should ask Alo that question. I’ve never asked him that question. He just knows that I — this is one of my — I would say this is my favorite song. I don’t want to say one of my favorites. It’s like number one, and then —

Alex 03:37

Okay, before we raise the bar too high, let me play a little interpretation of the first verse and chorus. Here’s a little bit.

Alex 03:44

(singing)

Eric 04:46

Great song.

Alex 04:47

Yeah, I love that song.

Mahtab 04:49

Yeah.

Eric 04:50

Avicii, great artist too. Sad that he died so young. And we’re going to be talking about living longer or living healthier or — well, before we get even into that topic, maybe I could just turn to you. How did you get interested in this topic of longevity? Hey, I actually pronounced it correct this time.

Mahtab 05:10

You did.

Eric 05:11

Uh, Mahtab.

Mahtab 05:13

How did I get interested in longevity? So I run a basic science lab at UC Irvine, and I work with mainly model systems, fruit flies and mice. And for the past 20 years, I’ve been trying to extend the lifespan of my flies and also improve their healthspan. Because until probably 2 or 3 decades ago, the aging research focused mainly on lifespan. So, we extended the lifespan of C. elegans and nematodes, and they were just not moving. So, obviously, their healthspan was not so great.

But now a lot of focus is on healthspan because we want to add healthy years to human life. But prior to starting this lab, I was mainly doing research in diseases of aging, such as, you know, from cardio — mainly cardiovascular disease. When I was at UCSF, that’s pretty much what I did. I was the clinical pharmacist in CCU dealing with patients with coronary artery disease and cardiac issues. But when I came back to UCI to, you know, start another field of research, I decided to develop a basic science lab that focused mainly on aging.

And 20 years ago, I was very naive thinking that I am going to find the fountain of youth, and maybe it’s just one molecule or one botanical extract, and we are going to extend human lifespan. And I think 21 years later, I have, I have a different perspective when it comes to aging. But the idea was that all these diseases of aging fall under this big umbrella of aging. And if we can slow the aging process, and if we can improve the function of the organs or slow the aging of different organs in our bodies, we will have healthier years to our lives.

So we can improve not just the lifespan and healthspan. And, and I have tested 100 different compounds, mainly botanical extracts, for the past 20-plus years. And I’ve had some success stories in, in my fruit flies. Mm-hmm.

Eric 07:17

I love that. We’ll be talking about some of those maybe success stories and kind of which ones you think were most promising. Can I ask you one other follow-up question before I go to John? It just feels like at least here in Northern California, Silicon Valley, in the last 5 or 10 years, especially with just the sheer amount of money that’s flowing into these people with a lot of wealth, there is a lot of focus on it feels like living longer and living healthier. Are you feeling a difference over the last 20 years, or is that just kind of a reporter bias?

Mahtab 07:52

No, I, I definitely feel the difference, and I want to hear John’s opinion. I think probably the, the best example of that is Altos Labs. That is this, you know, I think it was founded in 2022 with a a very modest startup of $3 billion, and now I think they have $5 billion of, uh, worth of funding. And of course, they’re very, they are secretive. They’re not publishing a lot. And, and I want to hear again what John has to say, but I have a feeling that from this lab is developing obviously drugs that they want to eventually test in humans and see clinical applications.

Alex 08:38

Right.

Mahtab 08:39

But they are taking the traditional route of FDA approval. Yeah. I don’t, they’re not into like developing a snake oil. And at least this is my understanding without knowing too much about what’s going on behind the closed doors.

Eric 08:54

Is this Sam Bankman-Fried’s ChatGPT, OpenAI?

Mahtab 08:58

I forget. So Jeff Bezos, I believe, is one of the biggest.

Eric 09:02

It’s hard to keep track of the billionaires nowadays.

Mahtab 09:03

I can’t keep track of them.

Alex 09:06

And I don’t think it’s just —

Mahtab 09:07

One example.

Speaker 5 09:08

I think each one of them has their own.

Alex 09:09

I’m sure they do, but, and I don’t think it’s just a Northern California phenomenon or a Southern California. I mean, certainly there is a lot of obsession with healthy aging or in Southern California. It’s also just around the country and probably around the world based on the influencers I see.

Eric 09:29

And John, you’ve been like —

Mahtab 09:31

Northern California gets the first place.

Eric 09:34

Yeah.

Alex 09:34

A lot of narcissists up here too.

Eric 09:38

So, John, you’ve been doing this for a while too, right? What got you interested in this?

John 09:45

Well, I’m a, I’m a clinician scientist, but I was a scientist first. And I’m, I’m the kind of science geek as a kid where like, I thought when I first learned about like the, our genomes are made up of 4 bases that you could like read the letters of life. And then the first time I, I’m just old enough, I’ve like sequenced a gene and read the sequence on a piece of film that I put up against the window where you can like read, that’s an A, that’s a T.

But the coolest thing I ever learned in science was that aging is biology. And I ran into that the first time in grad school where I accidentally started working on this gene that did some cool like RNA molecular thing in the cell, but was a gene that caused a premature aging syndrome in kids. And like, what? That’s a thing. Like you could one base pair change in a gene and you can have this like multi-system aging kind of thing going on.

Like you can control aging with genes. And that was right about the time that aging biology was really starting to kick off about 20 years ago with labs all over the country. And that’s still the coolest thing I’ve ever learned. And then, and then, you know, I fell in love with geriatrics when I was in third and fourth year of medical school. And that set me on a path of, I want to figure out how to apply this biological understanding of aging mechanisms to meaningfully improve the health and lives of older adults. And 20 years later, I’m still doing that and I’m actually getting closer and closer to hopefully like fulfilling the dream of really changing things with that.

Eric 11:14

And do you think about the same thing? Are you thinking more about healthspan, improving the health for the time people have, or lifespan too?

John 11:22

Oh, in — boy. So in the circles you’re talking about, I am the most boring person in the world because I’m a geriatrician. And so I think about the geriatric problems. I want to fix frailty and delirium and Yeah, that’s going to hopefully keep people functional longer and healthier, longer, better able to do the things they want to do. And probably live longer as a side effect. But yeah, I think it’s, I think it’s about, it’s a lot of people in the field these days are talking about healthspan and healthy longevity.

And it’s more the idea of trying to stay healthier longer so we can do things we want to do longer and not necessarily living longer. Some people use the idea of centenarians as an example of like people who actually live lives like this, like, you know, into your late 90s and you’re living on your own, you’re doing things you love. And then relatively suddenly, you know, you reach the end, but you don’t have this long period of decline and you have a long, healthy life of doing things that you love. And that’s a, that’s something that people actually live and maybe an attainable goal for many of us.

Mahtab 12:22

Yeah.

Alex 12:23

And I think, you know, speaking to our geriatricians, our palliative care clinicians, like they recognize that many, most people want to live long lives, as functional as they can be, as independent as they can be. And I think there’s also this other side, which, you know, this is where it can run into problems is when we exclusively focus on that, we can take away from the focus on supporting those people who are living with disability.

Mahtab 12:52

Yeah.

Alex 12:53

who also have the potential to have high-quality lives. People who are living with cognitive impairment, who also have the ability to live rich, full lives. People who are nearing the end of their life, who still can grow in important ways near the end of their lives. So I think both can be true at the same time. And one of the issues with the longevity focus and the relentless focus on, you know, being youthful as long as possible is that the flip side of that coin is that there can be a stigma. There’s a lot of ableism around, you know, living with cognitive impairment, for example. So I just wanted to say that it’s not necessarily a question unless you have reflections on that as well.

John 13:38

Well, this, this plays right into how does this become, how does longevity science, aging biology become a normal part of medicine? Like, what do you prescribe something for? Like, what do you get a drug approved for? And There is this kind of ongoing debate about, is aging a disease? Uh, are we treating aging? Are we trying to like stop aging? And I, and I have strong feelings about that for exactly what you’re saying, Al, that like there’s so much ageism in the world. And like my interpretation of, of Wake Me Up, aging is not bad. Like I, I would not trade places with my 22-year-old self because I like it better right now. And, uh, but you know, but yeah, but there are some things that might have to be 22,

John 14:26

but there, there are some effects of aging that we like multiple chronic diseases or disability that we wish we could generally put off or try to treat or fix.

Alex 14:35

Yeah. To be sure.

John 14:36

How do you, how do you, how do you square that circle? What’s like, what’s the drug indication? And we have some ideas.

Mahtab 14:42

Right. Okay.

Eric 14:43

So, um, I, I want to make sure we have time to talk about kind of some of the things that people are using, some of the things that you’re most, uh, most promising to you, maybe some of the things you do for yourself. But before we do that, before we say like what works and what doesn’t, I wonder if we can talk about how do we define what works when it comes to this? Because I’m guessing we’re not going to do like a 50-year-long trial to see if it actually extends people’s healthspan or lifespan. And so we’re going to have to use some surrogate markers, I think. I don’t know. How do you define what, what’s the goalpost here?

John 15:15

What works? Well, if you’re, if you’re in the laboratory, if you’re studying flies and worms, even mice, absolutely you can use lifespan. And the fun thing is, so we’ll talk about people in a sec, but as I’m sure you can, you can measure function and healthy lifespan even in worms and flies.

Mahtab 15:36

Yeah. So, that’s, that’s pretty much what I’ve been doing for the past 21 years in my lab. When I decided to shift the focus of my research from pharmacotherapy and, you know, drugs in cardiovascular diseases to aging, I was looking for a model system. And I look at yeast, I look at C. elegans, and I settled on fruit flies because Because they’re great. They are — fruit fly is a great model system to study aging. We share 75% of our disease genes with fruit flies, and it’s very easy to work with them. They don’t have long, you know, lives.

Well, except for the population that I developed in my lab a few years ago, they can live for much longer periods of time. And it’s easy to measure healthspan in fruit flies. So when I started my research 21 years ago, I developed this algorithm, and the first thing that I did was I measured mortality. What is the impact of this, you know, dietary supplement or pharmaceutical on the mortality of the flies? And then after that, I did a lifespan study. And then if the compound increased the lifespan, then I started a series of healthspan assays. And again, it’s not difficult to measure healthspan in fruit flies. Probably the best biomarker would be reproduction. fecundity in female flies and mating behavior and reproduction in males.

You can look at their movement, locomotion, sleep, you know, eating behaviors. And then we started also looking at how, uh, we started looking at memory, but it was a very, very complicated, you know, biomarker to measure. So I stopped doing that. You can look at metabolic rates. And one thing that we have to remember is that, yes, I have been able to extend the lifespan and improve the healthspan of my fruit flies. But then I publish a paper and, you know, I showed that, for instance, curcumin, Rhodiola rosea, Rosa damascena, they, they did great. They increased lifespan, improved healthspan. And then people ask me, should I take it because I want to increase my lifespan and healthspan? I say, if you are a fruit fly, absolutely go for it. But that’s that. And then I’m going to stop there. And of course, we tested one of our botanicals, Rhodiola rosea, in a mouse model…

Alex 17:59

Yeah.

Mahtab 18:00

…leptin-deficient mice and we showed that, oh, it improved biomarkers of diabetes, but I stopped there. So I tell people, yes, if you are a mouse and if you are a fruit fly, but then again, there are clinical studies with these botanicals. And how do you extrapolate the data from a fly to mouse, to a mouse to humans? That’s a whole, that, that could be a different podcast, but.

Eric 18:25

Yeah.

Mahtab 18:26

But I think model systems, studies in model systems are promising.

Eric 18:32

And John, you’re doing a little of that, right? You’re, you’re doing some testing in humans. Is that right?

John 18:38

Yeah.

Eric 18:38

Yeah.

John 18:38

Doing a lot of clinical research with humans now with the goal of answering exactly the question you just asked. How do we know if something works targeting the biology of aging? How do we know that it’s meaningfully improving someone’s life?

Alex 18:51

Do you observe people for, you know, 40 years from the initiation of the trial and then monitor their health

Alex 19:01

I wish that, I wish there was an NIH mechanism for that.

John 19:05

But, but no, so, so you don’t, you don’t have to. And a lot of smart people, people smarter than me have been thinking about this for a while now because the, you know, the single biggest barrier to, you know, why don’t we have medicines that we can prescribe right now that target aging is, is figuring out how to run a clinical trial like that to show a broad effect on aging.

Eric 19:25

Yeah.

John 19:25

But a lot more people have been thinking about it. One of the biggest ideas that is now 10 or 15 years old is using multimorbidity as a target for, for a drug that targets aging. So the idea that you’re not — there are already drugs out there that you can prescribe to prevent one disease. There are also some drugs out there that you can prescribe to prevent or treat several different diseases individually. But what if you could prescribe a drug to prevent or treat 4 or 5 or 6 diseases?

All of which are driven by aging, but are not directly related to each other, but you could prevent all of them together, then, you know, that’s a good sign that a drug is really targeting aging. And, and so that was the design of the Targeting Aging with Metformin study, which was going to be the first big, you know, 3,000-person, 3-year randomized controlled trial testing a drug, which was going to be metformin, to see if it broadly affected aging by delaying the onset of one of a basket of major chronic diseases.

Eric 20:19

So that’s not just one, but multiple, like not just affecting diabetes, but —

John 20:24

Yeah, but dementia, cardiovascular disease, osteoporosis, you know, a bunch of things all in the same basket. That’s still a good idea. And that’s probably still a good path to getting FDA approval for a drug. But nowadays, just in the last few years, this concept of intrinsic capacity —

Eric 20:41

We talked about that in Brazil.

Alex 20:42

We talked about that in Brazil with Eduardo Ferrioli. People can listen to that podcast. We’ll have a link in the show notes here. Yeah. John, do you, but many people won’t have listened to it. So please let us, what’s your understanding of intrinsic capacity?

John 20:58

I’ll give you the thumbnail sketch, but then, but then why is it important for aging? And if you’re a clinician listening to this, you probably should learn a bit about intrinsic capacity because it’s a concept that’s more popular elsewhere in the world right now, but is coming to the US. It’s a World Health Organization framework, which to me is basically a way of doing a quantitative comprehensive geriatric assessment of someone’s whole health across 5 domains.

So it encompasses cognitive function, physical function, mobility, psychological health, sensory health, and vitality, which John Beer, the guy who came up with intrinsic capacity, describes as the ability to maintain all the other abilities. So you measure someone’s health across these 5 domains and you have a, you have a comprehensive picture of their overall state of health, which is a really cool geriatric concept. And so it’s being used around the world to help to guide, you know, multi-component geriatric interventions. But it’s also a kind of holistic measurement of someone’s health in aging that you could use to help guide therapies that target mechanisms of aging. And there is an ICD-11 code for age-related decline in intrinsic capacity.

Eric 22:10

Oh, really?

John 22:11

Based on that, like it’s a real diagnosis.

Mahtab 22:14

Yeah.

Speaker 5 22:14

Yeah.

John 22:14

Maybe that diagnosis could be the reason you prescribe a drug. So this is a big idea. Could you, could you measure intrinsic capacity in a really sensitive way so that you could detect changes in someone’s aging trajectory just over a couple of years? And maybe not even when they’re that old, maybe even earlier in life, in middle age or younger. And use that like a blood pressure or like a growth chart for aging to guide prescribing drugs and getting drugs approved to target declines in intrinsic capacity.

Eric 22:46

Marta, what do you think about intrinsic capacity?

Mahtab 22:48

I think that it’s, it’s a great idea, but I just want to make one quick comment about metformin because I agree with you, John. This TAME study is very interesting. And I really hope that we will get some results because it’s not, it’s not completed yet. But from what I have seen, at least in model systems, metformin doesn’t extend the lifespan universally. It’s very sex-specific. I agree with you, it has pleiotropic effects, and that’s why it makes it a, you know, a promising, a promising drug. But I think we have a long way to go before we say that metformin, this is it. This is the drug that is going to help us with longevity.

But as far as intrinsic capacity, I really like that. That’s why when people talk about biological age clock, I, my favorite, and I know I’m going to be burned and getting some comments on that, is still the KDM age that looks at functional biomarkers when, when we develop studies and we try to have outcomes to measure if this intervention worked. Because this age clock really looks at the functions of different organs in our bodies. And I think this is, this is probably the only way that we can evaluate if the intervention had any impact on aging. And as John said, there are different categories. Cognitive function is one, and then you have all these different organ systems, cardiovascular, renal. So yeah, I agree 100%. But as far as clinical studies goes, Something else, I’m just going to throw it out there.

Alex 24:30

Please.

Mahtab 24:30

That metformin and rapamycin are generic, you know, drugs. Whoever comes up with, like, the best study for these drugs, they’re not going to file an IND application and have, like, a new drug on the market. And I think this is why the funding has been challenging for both studies. I mean, John, I think for the TAME, we still need another like $20 million to complete that study, or I, I could be wrong.

Eric 24:59

This is the metformin study.

Mahtab 25:01

This is the met — yeah.

John 25:03

TAME hasn’t really started yet because, because of challenges with funding. TAME, um, and it, and it’s in describing, so TAME was, TAME was about how to run a clinical trial and it, it wasn’t about metformin really.

Alex 25:17

Yeah.

John 25:17

But metformin at the time was probably the best bet based on the data that existed Almost 15 years ago now. Um, but things have changed since then. But yeah, TAME is not about metformin per se, but about how you would design a clinical trial to get FDA approval. I think it’s going to be the most influential clinical trial that may never happen because it’s so deeply influenced how companies, for example, look at designing clinical trials to get other drugs approved.

Eric 25:46

How so? Give me like an example.

Mahtab 25:47

But TAME is testing metformin. If it’s targeting aging with metformin, is that —

John 25:54

If, if TAME had launched 10 years ago, right, it would, yes, it would be testing metformin for multimorbidity. But the clinical trial design wasn’t designed for metformin. It was designed as this is how you would test a drug that targets aging. And then what drug that’s currently widely used would make the most sense to use in the, what might be the first example of a clinical trial like this? And At the time, metformin was a good choice, but probably we would choose something different now.

Alex 26:20

Oh, we should get into what we would choose now. I think this is really interesting. Just to summarize what I’m hearing for our listeners who may not be familiar with this whole FDA approval process, like we have really promising therapeutics that work in model systems like fruit flies. How do we translate that into medications that humans can use? Well, we do a clinical trial, but you have to have an outcome of that clinical trial and you can’t wait 4 decades to get your results.

There’s no NIH mechanism for that. So you have to have some sort of intermediary marker, and there may be disagreement in the field around exactly what that marker would be or measure, whether it’s intrinsic capacity or something else. But we need some sort of measure that we can say, this is an effective medication in order for the FDA to say, okay, this is something we’d want to improve. We agree this is reasonable drug.

Mahtab 27:13

Yeah.

Alex 27:13

to test and an outcome to test. And boy, if it’s generic, then no pharmaceutical company’s going to fund that study.

Eric 27:20

So let me, unfortunately, let me ask you this. Are there any current interventions that you think have really good evidence already that they extend either lifespan or healthspan?

Mahtab 27:32

In humans?

Eric 27:33

In humans.

Alex 27:33

In humans.

Mahtab 27:34

Pharmacological, non-pharmacological, anything, anything, anything that you do that you think, hey, Yes, but I’m going to sound boring if I say, you know, good lifestyle, exercise, sound nutrition, you know, focused on your mental health and sleep, um, and have friendships and relationships.

Alex 27:54

That’s great. I think it’s important we say that. Yes. Thank you.

Mahtab 27:57

So, so, so I, so some, I was asked actually last week this question.

Eric 28:01

But those are so hard. Can I just take a pill?

Alex 28:04

They are actually harder than you think. Yeah, you’re right.

Mahtab 28:07

But somebody asked me, they said, what is your absolute biohack for aging? What do you, what do you recommend as a biohack so that we can slow the aging process? I said exercise. And this reporter said, but that’s really boring. I said, okay, I’m sorry. There is no other biohack that —

Eric 28:28

Any particular type of exercise?

Mahtab 28:32

Well, I think you have, we have to do a combination of cardio, mainly zone 2 and some zone 3, and also weight training. I mean, we used to think that it’s all about cardio pulmonary health, but as we age, our muscle mass, you know, decreases. And that’s why we need to pay more attention to, um, weight training and strength training.

Eric 28:52

And any particular diet?

Mahtab 28:54

I’m sorry?

Eric 28:55

Any particular diet that you would recommend?

Mahtab 28:57

I am, I’m still a big fan of Mediterranean diet because I think that’s the one with the best Uh, with the best studies. And when I teach my students, um, about nutrition and scientific wellness, I have to really summarize and make it simple. So I tell them, stay away from sugar and processed food. Let’s just start there. I mean, that’s a good place to start. And then we add, you know, we add vegetables and fruits and lean proteins and everything else.

Eric 29:28

John, anything else?

John 29:29

All the same things. But it’s interesting that we all, so we assume that these lifestyle things would affect aging and would help, help you have more healthy longevity. That’s actually never been shown in a randomized controlled trial. It’s interesting. Like that’s the frontier of, of this field actually. So there’s more and more of these large multi-component randomized controlled trials, uh, like, like the FINGER studies and in Europe and just recently in Latin America, the US POINTER study. There was a SMART study out of Kaiser in collaboration with UCSF. More and more —

Alex 30:01

Podcast, forthcoming podcast.

John 30:03

Fantastic. But all of which focus on one domain and haven’t shown yet, you know, broad effects on aging across multiple domains or this idea of like preventing chronic diseases.

Eric 30:16

Yeah.

John 30:16

We’re going to do that. We’re going to hopefully for the first time show that a multi-component lifestyle intervention in collaboration with YMCA can broadly change an overall metric of aging based on intrinsic capacity, which is part of, and just one part of, believe it or not, a large national consortium that’s funded by ARPA-H, the Advanced Research Projects Agency for Healthcare, to create the frameworks for approving drugs based on intrinsic capacity.

So do everything that you would need to do for a drug company or an academic group to be able to just go to the FDA and say, I’d like to run this clinical trial. Here’s an outcome measure that the FDA already has qualified that’s based on intrinsic capacity and represents aging. And I can just plug my drug into that framework. There’s so much work that you have to do to get to that world. And we’re actually starting to do it.

Alex 31:09

Great. Great.

Eric 31:10

Mahtab, you were going to say something?

Mahtab 31:11

I was going to say that that is great. I can’t wait for this study to start and see the results. One of the reasons that, when I started my lab, I stayed away from humans, although I am studying a couple of clinical studies myself, was that humans, we live too long. So, I thought that if I start my lifespan study today, I will be dead by the time that —

Alex 31:34

Right, right.

Mahtab 31:35

–there are any results. But the good news is that we do have smaller studies. I mean, they all have their limitations. I talked about KDM age, and a few months ago, a study was published from some Australian researchers showing that nutritional changes as short as 4 weeks impacted this biological age clock.

Alex 32:00

Hmm.

Mahtab 32:00

Meaning that only after 4 weeks of adding more fruits and vegetables to somebody’s diet, they could see that the functional biomarkers, which was, which KDM measures, were improved. So yes, the study had limitations. It was small. They didn’t do a good job controlling who is eating what. But to me, smaller studies like this, when it comes to aging and slowing the aging process, are still promising. So, but, but I can’t wait for this, you know.

Eric 32:31

So at multi-component exercise, nutrition, sleep, Loneliness, we’re addressing all of that. Do you take anything that’s, let’s say a supplement or anything else that you think, hey, you know, that maybe the benefits are not yet fully formed out, but the risks are small, so I’m taking it. Do you, do you take any supplements or any other things?

Mahtab 32:54

I do.

Eric 32:55

What do you take?

Mahtab 32:56

I come from this framework that you have to do some testing. You can’t just go to the store and buy a bunch of dietary supplements. Yeah. So I have done testing and I know that I’m vitamin D deficient. And if I don’t take D supplement, I am deficient. So I tried to correct my vitamin D deficiency with food and it just didn’t work. So right now I take D. I take 1,000 units of vitamin D every day. And sometimes I have to increase it because one thing that we don’t know is how much sun we need to produce vitamin D. We really don’t know that.

Eric 33:33

Yeah.

Mahtab 33:33

So sometimes I take 2,000 units a day.

John 33:35

Yeah.

Mahtab 33:36

So vitamin D for sure. I think if you’re deficient, you have to take it and you can check really magnesium levels, but based on intake data, we know that more than 50% of, uh, US adults are, you know, magnesium deficient. So I also take magnesium. And then recently I became interested in creatine. I used to be a skeptic until a few years ago, but The studies are overwhelmingly positive with a high-quality creatine. So I also take 5 grams of creatine monohydrate every morning.

Eric 34:12

Alex, you take creatine, right?

Alex 34:15

I do. Yeah, I take creatine. I take it because as many of our listeners know, I like to do triathlons like Ironman triathlons, and I find that it helps me recover faster so that I can exercise sooner.

Eric 34:31

Is the next time, is there any evidence around longevity in creatine or is it just, uh, regaining muscle strength after exercise?

Mahtab 34:39

There’s no data. No data on longevity lifespan. So I think, uh, creatine is more of a healthspan intervention. Okay. Uh, that it definitely improves muscle recovery. Yeah. There are some, you know, smaller studies on its impact on cognition. Yeah. Yeah. But I would say muscle, muscle health is the first, um, John, do you take anything?

John 35:01

I think like a geriatrician, so I tend to be very like, oh, I wanna see the evidence. And yeah, once, once we have a clinical trial that shows something works and like, I know it’s actually, it’s not helping, cuz if you don’t know for sure something is helping, it’s perfect.

Mahtab 35:15

Okay, John, I, I, but I have to ask you a question.

Eric 35:19

He’s got a but. He’s got a but. That means there’s something coming.

Mahtab 35:22

So you said clinical trials, and I agree with you. I wish we had the most amazing clinical trial on vitamin D.

John 35:29

Let’s talk about clinical trials though.

Mahtab 35:31

But the ones we have, they don’t show benefit. I agree with you. But the problem is also with the way we designed those studies. Nobody measured baseline vitamin D levels in those studies. And then we fin — they finished the study and said, oh, no impact on fractures, no impact on this. So, so to me, it’s really hard to design a very high-quality, double-blind, randomized controlled study with with dietary supplements because nutrition is complex and everybody’s different. We all have a different, different omic background, genetic background. So it’s really complicated. So I try to err on the safe side with vitamin D and the supplements that I take.

John 36:12

Yeah. Well, I guess one of my confessions is because I live in San Francisco, I take vitamin D and I am, when I, when I didn’t, I was deficient.

Eric 36:21

And I’ll, and I’ll admit to, you’re also in the sunny side of San Francisco, I believe so.

John 36:27

Sunny, sunny-ish. I’m kind of on the, on the border of the fog line. But creatine is interesting. I admit to experimenting with creatine for the purpose of trying to recover better with my volleyball habit as I get older. And I’ll, I’ll let you know. But we should talk about clinical trials ’cause I think a lot of your listeners may think that this is a data-free area. Yeah.

And They’d probably be surprised to learn, and maybe you guys don’t know this, that there is a national NIH-funded clinical trial network for geroscience. It’s called the Translational Geroscience Network. It’s been in existence for about 8 years or so, and it’s a national network of centers, of major academic centers. And its goal is to facilitate, to provide kind of structure and commonality of data elements and laboratory tests for clinical trials that target aging.

Eric 37:14

Do we have any results yet from that?

John 37:16

Uh, yeah. So last time they counted, there were more than 100 clinical trials that are either completed or underway that use drugs or compound supplements that target biology of aging for, you know, broad neuroscience applications. And some examples of those are using drugs that target senescent cells in studies of Alzheimer’s disease. There’s a couple of examples of using mesenchymal stem cells for Alzheimer’s disease. The NIH has funded 29 randomized controlled trials, mostly drugs and some supplements and some lifestyle interventions to target aging biology. Good. Yeah.

Eric 37:54

For example, yeah, go ahead.

John 37:57

Well, like metformin. So Clara Espinoza at, um, uh, now at Cedars-Sinai is just finishing up a reasonable-sized randomized controlled trial of metformin and frailty. Adam Konopka at University of Wisconsin is running the, what will be the biggest so far randomized controlled trial of rapamycin or TOR inhibitors in middle-aged and older adults. There’s a couple —

Eric 38:21

Can we do like a lightning round based on this? I’m wondering if you guys are open to this. Let’s actually dive into for our listeners, ’cause we only got a couple minutes left. Maybe I can just mention some and we can put it into buckets like snake oil. Yeah. So very promising, eh, or snake oil.

Alex 38:41

Those are your buckets. Yeah. Very promising, eh, or snake oil.

Eric 38:47

Or you think, oh man, we got a lot of promising without data.

John 38:50

Or, cause you can be promising, go like, that’s a cool approach. And we know this is hard towards human studies that might pan out or it might not.

Eric 38:58

And then there’s promising, like maybe some, we have some with a little bit of data too. So. And we gotta be quick. We gotta be quick. People love this one. Jennifer Anderson loves this one. Uh, nicotinamide adenine dinucleotide boosters, or was it NAD+? NAD? NAD? I don’t know how you’re — NAD+. What do you say?

Mahtab 39:20

As of right now, there are no clinical studies.

John 39:24

I say neutral, that the marketing has, has outpaced the clinical studies. All right. Marketing is down. Small ones, but Yeah.

Eric 39:31

So no evidence. This is not, and I think there may also be some potential harms maybe with these drugs. So maybe, Meha?

Mahtab 39:41

Well, I, I’d like to add something because the, the other side of the story is that yes, you know, it’s really hard to increase NAD+ levels in your system, even with IV infusions, because nobody knows how it gets into the cells. But then how about precursors? How about NR, how about NMN? And again, we have some way to go.

Eric 40:03

Yeah. I should not start my infusions of NAD yet. Oh no, I would wait for more data.

Mahtab 40:11

No. All right.

Eric 40:12

Okay. One, I mean, if we’re thinking about intrinsic capacity hitting a lot of different things, GLP-1, should I just, yeah, should I just start some GLP-1s? Where are you with the 3 buckets for GLP-1s?

Mahtab 40:24

If you need it.

Eric 40:26

If I need it.

Alex 40:26

And there are many indications now, right? Like obesity, diabetes. We recorded a podcast about this yesterday. There’s a new cardiovascular bridging indication for Medicare coverage. So they got cardiovascular, renal. There are a lot of potential indications. So sleep apnea, promising.

John 40:44

It’s, it’s among the top 3 classes of existing widely prescribed drugs that might be gerotherapeutic.

Alex 40:51

Can I guess the next one?

John 40:53

Yeah, yeah, yeah, yeah. Pharma companies are really interested in this. Yeah. The big gaps, one sentence, effects on people who are not overweight and don’t have diabetes. There hasn’t yet been a big study showing clear benefit in people who don’t have one of those 2 conditions and safety in older adults. We need more large studies to show that.

Eric 41:13

Which we will have a podcast on talking about the sarcopenia associated with GLP-1s.

Alex 41:17

Yeah. Risk to bone health as well. Wait for that.

Eric 41:20

Alex is going to mention number 2.

Alex 41:21

SGLT2 inhibitors.

Mahtab 41:23

That’s a maybe.

Alex 41:26

That’s a maybe. Okay.

Mahtab 41:27

Because, because we do have good clinical studies, and, and if you listen to the scientists who go for the evidence, I, I would say that this is something that looks promising. This is a drug, I mean, a group of drugs that look —

Alex 41:44

John?

John 41:45

If I were to run a study like TAME today, I’d probably pick an SGLT2 inhibitor. Because they’re the only drugs so far that have multiple indications for multiple major age-related diseases, which don’t require you to have the original indication. So chronic kidney disease, whether even whether or not you have diabetes, heart failure, whether or not you have diabetes, plus diabetes, plus other stuff. Yeah. And the only drugs so far that clearly are a benefit in heart failure with preserved ejection fraction.

Eric 42:12

Yeah.

John 42:13

Is, which is a multi-system geriatric syndrome. It’s not a heart problem. And the fact that these, this class works is the only thing so far clearly shown to work in that to me is highly promising. That the only caveat is that in large studies they have a clearly a big effect on cardiovascular mortality, not as clear of an effect on non-cardiovascular mortality. So maybe their, maybe their effect is mostly about cardio, but still promising.

Eric 42:38

Okay. Number 3, Alex.

Alex 42:40

Well, I, I’d probably say it’s the metformin.

Eric 42:42

Class, whatever that is. What was number 3, John?

John 42:46

You said there were top 3. Metformin.

Eric 42:48

Metformin. Okay. Yeah. Where does that fall for you? Promising?

John 42:52

Still promising, but falling a bit down the list because it just doesn’t have, it doesn’t have drug companies putting out more big studies the way that they are for SGLTs and GLP-1s. And because it’s generic. Yeah. Yeah. So not, not its own fault. Right. And there’s some data that it may blunt exercise effects and exercise is really, really important.

Alex 43:12

Yeah. As Matto pointed out, it’s generic. So what drug company’s going to pay for this.

Eric 43:16

Okay. I, I got to ask another one. Uh, it was a hot topic, I think not too long ago, maybe 5, 10 years ago. Uh, reveratrol, resveratrol. What was the name of it again? Resveratrol. Uh, where is that now?

Mahtab 43:29

Um, I, I would say it’s pretty much gone.

Eric 43:32

Dead in the water. John?

John 43:35

Yeah. Yeah.

Eric 43:37

Was that the red wine one?

John 43:38

That’s the red wine one.

Alex 43:39

Oh, that’s the red wine one.

Eric 43:41

Rapamycin. Now we’re going into other real, real drugs. Like, man, we got some potential risks with these. Rapamycin.

Mahtab 43:49

Rapamycin is the, is one compound that has had really promising lifespan extension in different model systems. Even, um, I mean, in different model systems, I’m just going to leave it at that. But, um, the human study again is facing funding issues.

Alex 44:07

Oh.

Mahtab 44:08

So it hasn’t been completed. But the other issue with rapamycin is like the side effect profile. So, um, you take it with a grain of salt.

John 44:17

Yeah. Rapamycin, high ceiling, low floor. We don’t really — super promising in model organisms. We don’t really know in people, but there are several large, several medium-sized clinical trials. Keep an eye out for the results. Mentioned the ones from Wisconsin, which is in people with metabolic disease. Really interesting one at Columbia, which is pre- and perimenopausal women to look at rapamycin’s effect on ovarian aging.

Mahtab 44:37

Huh.

John 44:38

Which should be really cool. Um, and another study in Texas in, um, Alzheimer’s disease. So we’ll know a lot more in a couple of years, but I’m not sure about rapamycin.

Mahtab 44:45

And the dog studies on rapamycin, the results will be interesting.

Eric 44:49

What about testosterone or estrogen? Is, are they in the, the, the play here? Or are they —

Mahtab 44:56

If you need it and you don’t have any contraindications. So having a hormonal balance is always a good thing. Testosterone is different. But just don’t do it on your own. Talk to your physician because you want to make sure that you need it and you’re being monitored.

John 45:10

John, you were gonna say testosterone is definitely not an anti-aging drug. Not in the right context. It might help with rehab, with building muscle, but it is not an anti-aging.

Eric 45:20

I see a lot of those red light masks and like people are charging like full body red light. Is that a thing? Any, any thoughts on that?

Mahtab 45:29

I think maybe more just about skin aging, but yeah, there are some promising results with really small studies, mainly funded by companies that made those devices that are promising, but I think that’s still, we have some way to go before we say, yeah, this is a miracle.

Eric 45:49

And you look pretty lame with that mask on. Uh, John, thoughts?

John 45:53

I have no idea.

Alex 45:54

I’d never heard of that before this moment.

Eric 45:56

Okay. I got another one. There’s a company coming out trying to get FDA approval to extend the life and healthspan of large dogs using IGF inhibitors. I believe. John, thoughts on that?

John 46:10

This is so cool. This is probably going to be the first drug with an FDA approval around aging, and it’s going to be for our dogs because of course it’s going to be for our dogs.

Eric 46:19

We love our dogs.

John 46:20

There is such a, there’s such a close link between IGF signaling and aging that goes all the way back to worms and flies. Less IGF signaling, longer lifespan. This is why big dogs don’t live as long as little dogs. It’s because the amount of IGF that makes them big dogs, but affects their lifespan. So like biologically, it makes a ton of sense. And we’ll help our dogs live longer. I can’t wait for that to come out. I have little dogs though.

Eric 46:42

I gotta say, as a big dog lover, um, I’m actually excited about this ’cause I don’t really like little dogs. So sorry, John.

Alex 46:50

Mahtab, any thoughts on that before we end?

Mahtab 46:53

Um, no, I’m actually learning about this, but anything that inhibits IGF, I think is, is a good thing. In, in my flies, we have done studies looking at transgenic flies with different doses of IGF, and we see lifespan extension. So, yeah.

Eric 47:10

Any botanicals that we didn’t mention that you think are —

Mahtab 47:14

Well, for the main botanical extract that I’ve been working with in my lab for, you know, the past 20 years is Rhodiola rosea, which is not a very well-known botanical, but the first time we published a paper on its impact on lifespan, everybody was like, what? What is this? What does it do? And then other labs, the beauty of rhodiola is that other labs replicated our work in worms, in silkworms, and in other model species. So, so this botanical extract, if you can get ahold of like a good quality one, so far it has shown a lot of promise in my lab. And there are clinical studies on its use because it’s a botanical extract used in traditional medical practices. I’m talking fast because you kept saying that.

Eric 48:02

Yeah, I know. Thank you. So I’m guessing this is similar to yours, if I was a fruit fly, you’d recommend it for me?

Mahtab 48:08

I definitely recommend it to you if you were a fruit fly, but also I have to say that in, in Europe, European Medicine Agency recognizes rhodiola rosea. They have an indication for it for fatigue. Oh, okay. And the clinical trial that I’m designing right now is going to be an NIH grant, is to test its impact on fatigue. Okay. So there are clinical studies, but not on lifespan.

Eric 48:35

John, you get the last one. Anything else that we didn’t mention?

John 48:38

Uh, well, Kurt, some more about the drugs. Zolendronic acid is actually up on the list. Oh, because it has a surprising reduction in mortality that’s not obviously explained by differences in fracture rates. So some interest in zolendronic acid too.

Eric 48:50

Oh, interesting. Wow. Huh. Oh, that, that was fascinating. I think we could keep all this going for a while.

Alex 48:56

Right, right, right. We learned so much today. That’s why we love doing this podcast. Thank you.

Eric 49:00

A little bit more Avicii.

Alex 49:06

(singing)

Eric 50:04

Mahtab, John, thank you for joining us on this podcast. Thank you for having me. Gonna have to have you come back in a couple years because the field is changing so fast. So thank you.

Mahtab 50:13

Yeah, some of the statements being made today It may not even be accurate in like 6 months. We’ll see. The field is moving at the speed of light.

Eric 50:22

Yeah. Well, thank you very much and thank you to the listeners for all your support.

This episode is not CME eligible.

For more info on the CME credit, go to https://geripal.org/cme/