168: Best of 2025

Over the past year, we covered a wide range of ground—from clinicians working directly with patients to top scientists studying the underlying biology of aging. This episode is a chance to look back at some of the more interesting conversations we had on Longevity Roadmap in 2025.

Looking ahead, there’s no sign that the pace is slowing. In longevity, it often feels like every year brings another set of breakthroughs, and 2026 is shaping up to be a big one. One of the most important trends to watch is the increasing role of artificial intelligence in medicine, particularly in pharmaceuticals. AI-driven, network-based drug repurposing efforts are starting to identify compounds that may influence aging biology and move more efficiently toward clinically relevant interventions. By the end of 2026, it’s reasonable to expect early readouts or expanded trials that begin to meaningfully target the hallmarks of aging.

Before wrapping up this year, I just want to say thanks to everyone who’s been listening this year. Your interest, your feedback, and your willingness to think critically about this space are what make the show worth doing.

See you in 2026!

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Transcript

Disclaimer: This transcript was generated by AI and may not be 100% accurate. If you notice any errors or corrections, please email us at phil@longevityroadmap.com.

  Welcome everybody. This is Buck Joffrey with the Longevity Roadmap and what a year it's been. Uh, that's what everybody says after every year, right? Well, in the world of longevity, it seems that every year we have these, uh, tremendous breakthroughs and, um, you know, we're gonna continue to have them into 2026.

I think it's gonna be a big year for longevity. Um, I think you're gonna see a lot more use of artificial intelligence in the world of, of medicine, particularly in pharmaceuticals. And I think that's gonna be one of the things that I think you should be looking out for. I think there will be a significant progress toward translational aging therapies.

Um. You know, closer to clinically relevant anti-aging interventions. I think that AI and network-based drug repurposing efforts are starting to identify compounds that could modulate, you know, aging biology that could enable faster clinical translation pathways as well. And I think we may, by the end of 2026 C, the first readouts or expanded trials of interventions that meaningfully.

Influence biomarkers, uh, of aging, uh, or the hallmarks of aging rather. Anyway, I think it's gonna be a big year, 2026. Uh, but in the meantime, uh, let's look back at some of the more interesting snippets from 2025 from this show, because we obviously learned a lot, whether that was from the clinicians, uh, in the world of longevity, or as you know, we have a bunch of basic scientists on as well.

So when we come back, uh, you're in, uh, longevity Roadmap Review. Hey, longevity enthusiast. It's time to take it to the next level. I've been fine tuning my longevity regimen for years, and I look better and feel better than I did a decade ago. In fact, my blood work is even better than it was back then, and it's all because of my data-driven regimen.

And it's inspired me to create a course and community just for you. It's called the Longevity Roadmap, and I urge you to check it out. If you're tired of your belly fat, tired of being tired, or just wanna optimize yourself for the next 50 years, visit longevity roadmap.com. That's longevity roadmap.com.

Metabolic dysfunction for. All intents and purposes mean defective or dysfunctional mitochondria, and so the mitochondria are designed to take energy from the outside world and turn it into a TP that your cell can use. So your cell can't use a protein for energy. Your cell can't use a fat for energy.

Your cell can't use a carbohydrate for energy unless it is turned into a TP first. It is estimated that each of us turn over 68 million pounds of a TP every single day.

Hmm.

How's that? Wow. Okay. Because it is just going on constantly. So you're making it, you're breaking it down, you're releasing the energy, the energy gets captured and powers various, um, uh, phenomena within each cell, which ultimately allows you to be alive.

So this is a pretty goddamn important phenomenon, turning food energy into a TP. Well, you have to do it at peak efficiency. You have to do it at a hundred percent efficiency. If you burn energy, if your mitochondria are only at 99% efficiency, that means that 1% of all of the energy that comes into your body is not being utilized properly.

If you just go from a hundred percent to 99%, you're already exhibiting metabolic dysfunction. Well, that energy has to go somewhere and it ends up being turned into fat. And so the obesity epidemic, the diabetes epidemic. The, uh, cancer epidemic, the dementia epidemic are all manifestations of mitochondrial dysfunction.

So the question is, of the various NOVA classes, which ones predict disease, and the answer is only the Nova Class four. It predicts every chronic metabolic disease. It predicts obesity. It predicts diabetes. It predicts hypertension. It predicts cardiovascular disease. It predicts cancer. It predicts dementia.

It predicts depression. It predicts polycystic ovarian disease. It predicts, uh, fatty liver disease. It predicts early mortality in numerous data sets taken from around the world. The question is what? Did we find? Mm-hmm. What is it that we identified as being the problem in ultra processed food? And I can say that there were four things.

Four things that ultimately determined whether or not their products were healthy or unhealthy. Here are the four. Too much sugar, too little fiber, too little Omega-3 fatty acids, and too many emulsifiers. Those were the four things that conferred metabolic dysfunction across the board. What are some examples of emulsifiers if people are looking for, you know, signs of that and emulsifiers are what?

Hold fat and water together. Okay, so the most commonplace you find in emulsifier in your house is in your clothes washer. It's tied. Okay. Yeah. It lifts stains out of your clothes, and the reason is because it holds the fat and water together. So it allows the fat in the stain, you know, to basically be extricated from the fabric and go out with the water.

That's what an emulsifier is. It's a detergent, okay? That's what emulsifiers are. They are detergents, so. What happens when you swallow a detergent, you burn a hole in your intestine, is what happens. Now, obviously these are weak detergents that are in food as opposed to strong detergents that are in, you know, tide.

But they ultimately do the same thing. And what they do is they strip the mucin layer right off the intestinal epithelial surface, exposing those enterocytes in the, uh, you know, the, the intestinal cells to the, the junk in your. Intestinal lumen. And that ultimately leads to gut inflammation, which leads to systemic inflammation, which leads to insulin resistance and chronic metabolic disease, IE mitochondrial dysfunction.

If you have a good functioning thymus, you can actually program that thymus to accept anything that you want as self, which means that, uh, for example, if you, uh, program. The thymus of a given animal to accept a kidney transplant from a different animal itself, and you can transplant that kidney and it will, it will stay in that recipient indefinitely without any need for immunosuppression for the life of that recipient, no matter what else you do, no matter how successful it is.

Let's say for example, you could use reprogramming to take yourself back to the age of 12, you're still gonna die because. You're gonna die of Immunosenescence because at the age of 12, your thymus is programmed to die. And so just going back to, you know, youth doesn't prevent you from death. You have to go back to the aging clock.

That starts the whole thing in the first place. But suppose you can program yourself back to 12 and regenerate your thymus, then you have a pretty fantastic combination. So that's the way that, that I look at it. Everything is good, uh, out there that people are doing, but you can't ignore the primacy of, of the thymus because without that, everything else becomes futile at some point.

Growth hormone, regrows, the thymus, but it has side effects. One of the side effects that was most prominent to me at the time. Is that it blocks insulin effectiveness. So as we get older, our insulin becomes less and less effective. In other words, we suffer from insulin insensitivity and uh, as insulin sensitivity goes down, we become fat and then we become atherosclerotic.

And then you have heart disease and everything else sort of follows from that. You know, you become susceptible to hypertension and stroke and so on and so forth. And if you put animals on calorie restriction. Insulin sensitivity increases, and that may be a significant reason why calorie restriction helps.

So here we have a situation in which we know that if we apply growth hormone to a human or to an animal, we can regrow the thymus, but we also block insulin sensitivity, which is a pro aging effect. So it would be kind of silly to try to counteract one aspect of aging by increasing another aspect of aging.

One of the things that occurred to me is that, uh, if you give growth hormone to an older person, they become sort of diabetic. Like

there's been this big movement to plant-based milks that have no C 15 in it. So population wide, really since the late 1970s, our C 15 levels have been declining. Um, where you have things like, uh, pediatric, uh, recommendations that, you know, are still saying that in fact.

In the 19, it was as late as the 1990s. That's when really the movement away from whole fat milks hit infants where the recommendation was once a child turns two years old, they should move away from whole fat milks and head to, you know, go onto low fat or 1% milks. And then, you know, just us as a population continue to, uh, avoid whole fats.

From the industry's perspective, we now know that cows fed grass have twice as much C 15 than cows fed corn. So even if you're eating whole butter, um, and whole fat milk, it may not have the C 15 levels that it had. Industry-wide. 50 years ago, the presence of a C 15 deficiency syndrome called cellular fragility syndrome, so just like we were talking about the cells being stronger, it needs at least 0.2% of total fatty acids in our cell to have enough bricks in our cell membrane to keep it strong when we have less than.

That amount of C 15 in our cell membranes, our cells weaken and they're susceptible to lipid peroxidation and a whole pathophysiology that leads to iron deposition, um, iron overload, um, onset of fatty liver disease and nash, and then subsequent, um, iron overload throughout the body. Interestingly, when we found this phenotype and pathophysiology that occurred in the dolphins.

The same year, which was 2012, multiple scientists at the University of Columbia published a paper on, uh, the discovery of an entirely new way that our cells were dying called fer Proptosis and fer proptosis. Since that discovery has had 10,000 papers published on Osis, we know all kinds of things about this new form of cell death, except for.

Why did it show up out of nowhere? So what we now know is that C 15 deficiencies cause this new form of cell death.

The greatest correlation in humans with longevity of any physiological parameter that's been measured is muscle size and strength. And so if you're in the top third of the population, in strength in your middle ages, in, in your mid forties.

You're two and a half times more likely to make it to a hundred years of age than if you're in the weakest. Third, we know that if you're in the top third in strength, you're a quarter is likely to die from cancer between the ages of 40 and 60. If I want to get a bigger muscle, I can use any weight that I want.

As long as I keep lifting until I can't lift it anymore. So I get to what's called positive failure. So as long as I get to positive failure, that's gonna be a stimulus. 'cause what happens is if I go to lift the weight the first time I lift it, I don't have to use every single muscle fiber say within my shoulder.

So if I'm gonna do a lateral raise and and raise my hand out to the side, every time I do that, I need to use muscle fibers within that muscle. 'cause there's lots and thousands and thousands of muscle fibers within that. Muscle, but I only use exactly the number that I need in order to lift that weight.

As I lift more and more the the first ones I use get a little bit tired. And so what now has to happen is I have to get more and more of those muscle fibers. So when I reach failure, and what that means is I go to lift the weight and I can't quite lift it by myself. That means that at that point I'm recruiting every single muscle fiber within the muscle I'm trying to use.

When I do that, I've given the stimulus necessary to the all of those muscle fibers that they need to grow,

eat, inject, repeat, curing, obesity worldwide. That was the title page that everybody saw in The Economist, and what they had was a hot dog. So essentially what that tells people is don't worry about exercise, don't worry about what you eat, eat whatever crap you want.

Take this ozempic and it's gonna help you. That is the worst message I think, from a public health perspective. But again, it's what the drug companies want, right? They don't want exercise 'cause it's gonna take away market share. They don't want good diet 'cause it takes away market share. So they love that, um, you know, message to go out.

But I think it's completely misleading, much like. Proving a tree in the springtime, if you can't cleave off those bad areas, the mitochondria become abnormal in terms of their function related to the structural alterations. That impairment of autophagy or slash autophagy is part of what we see with aging, which then leads to decreased in the function.

And in addition to supplying energy, they have many other consequences for the cell. They're involved in apoptosis, art telomeres. They're involved. Inflammation, oxidative stress, so many of those buzzwords that people associate with aging can ultimately be related to mitochondria. The proximate cause of so many of the other factors that are associated with, uh, human aging.

How do mitochondrial structure and function change with age?

So, uh, mitochondria is, uh, you're, I'm sure familiar with, are present in every cell in our body, with the exception of mature red butt cells. And they're particularly enriched in tissues that require a lot of energy. So we have them in, uh, hearts, we have them in.

Muscle. We have them in brain, uh, in a fairly high abundance. In fact, uh, almost 20% of, uh, of heart tissue is actually made up of mitochondria 'cause it's constantly working. Um, so as we get older, um, mitochondria have a very, um, uh, sort of intimate relationship from a structural functional perspective in our tissues.

And, uh, they, uh, come together. That's a process called fusion. They break apart. That's a process called fision. And when those processes are impaired, as they are in some of our patients, we see massive alterations in the structure of mitochondria, which then is very well correlated to the functional consequences.

So with aging, uh, we do have a reduction in the total mitochondrial mass. Um, again, it takes a while before we really start to see that decline, uh, but uh, we start to see alterations in their ability to come together and to break apart.

Can you walk us through how vitamin D. Is synthesized in the skin upon UVB exposure and subsequently activated in the liver and kidneys.

And, and why is it considered a hormone rather than a typical vitamin?

Sure. So by definition, right, a vitamin means that you can't make it. And, uh, and whereas a hormone, you make it, uh, and use it. So as you just asked me, right, how do you make vitamin D in your skin? So by definition, it's a hormone, and the way you make it is that when you're exposed to ultraviolet B radiation, the precursor of cholesterol, 70 hydro cholesterol absorbs that energy and it opens up its ring, actually not the vitamin D, but the previtt d.

Previtt D is thermally unstable, and over a period of several hours, it almost a hundred percent converts to vitamin D. Now, you may ask the question, um, why think about it as UVB and why is that so important? And the reason is that just because you're exposed to sunlight doesn't mean you make vitamin D.

Right. The xenith angle has to be at least 35 degrees because otherwise the vitamin D producing Ray, the UVB is absorbed by the ozone layer, and this is the reason why you make no vitamin D before 9:00 AM in the morning, even if you live at the equator and you don't very much vitamin D after three o'clock in the afternoon, even if the sun is shining brightly, taking vitamin

D orally.

Is it? Just the same. I mean, is there any difference between taking a 5,000, 10,000 IU vitamin D versus making it yourself? Is there some superior value to, to, you know, making it yourself from the sun?

Well, there are two reasons to think about. The first is what's curious, and we had published this over four decades ago, is that it had been argued.

Melanin pigmentation evolved to prevent Vitamin D intoxication because if you're exposed to too much sunlight, you make too much Vitamin D, no, no, no. Mother Nature cleverly designed our system so when you're exposed to sunlight, the maximum you can convert is 15% of the precursor 70 hydro cholesterol. So number one is you can never become vitamin D intoxicated from sun exposure.

The second is that we showed, and others have shown that a variety of photo products are being made separate from vitamin D, and some of them we've shown and others have shown may regulate cell growth and maybe even reduce risk for skin cancer. And we published a, a recent review on this to show how the local production of active Vitamin D in your skin, we think plays a fundamental role in helping to keep your skin healthy.

One of the things I guess people might be wondering right now is how do you, I know you mentioned there was an app, but maybe a little bit more explanation of sort of getting the sun exposure that is helpful here, but at the same time, avoiding. Something that's gonna give you melanoma,

right? So first of all, in my opinion, at least, and based on the literature, right, most melanomas occur on the least sun exposed areas.

And occupational sun exposure decreases risk for melanoma, right? And so. As a result, it's not just exposure to sunlight. Mm-hmm. Right. UVB, which causes squamous cell, um, and basal cell carcinoma. Right. Excessive, excessive exposure to sunlight, well documented to increase risk for both of those type of skin cancers easy to detect, easy to treat.

Okay. Melanoma obviously is a deadly cancer, but we believe that it's the exposure of UVA that may be actually playing an equally important role in increasing that risk. Not so much UVV. And also we know that having sunburning experiences as a child, a young adult, having bad genetics, having a lot of, of nevi on your body.

These are, are some of the major risk factors for developing melanoma.

There is a difference between a couple of the complexes for mTOR, torse one, torse two. Mm-hmm. Um, for those who are kind of interested in, in sort of the, the, uh. Details of that, could you explain the importance of that distinction? Um, 'cause Sure.

I think as far as therapeutics, that becomes pretty important.

You know, you're exactly right. So mTOR signals in cells in two MultiPro complexes. One is called torque one and one is called torque two, the rapamycin. This drug that has these lifespan extending effects, mainly inhibits mTOR NAC torque one complex.

With chronic use, it can start inhibiting mTOR also in that Torque two complex, and it turns out all the anti-aging effects of mTOR inhibitors and rapamycin and the genetic inhi inhibition seems to be mediated by inhibiting mTOR in the Torque one complex. When you inhibit mTOR in the Torque two complex, you actually get hyperlipidemia, hyperglycemia, and some evidence you actually.

Decrease lifespan. So an ideal mTOR inhibitor for extending lifespan is predicted to be one that selectively inhibits mTOR in that torque one complex.

I guess one question I have, and looking back at med school, obviously you talk about rapamycin. I mean, usually my first exposure to that was on the transplant units, anti-rejection drugs.

I think a lot of people have that perception of these types of. mTOR inhibitors in general. And so at higher dose, why, what are they doing to the immune system that we use them, uh, for, for anti-rejection? Basically you suppress the immune system in the first place.

Yeah, it's a great question. There are two things, main things that they do, they stop proliferation induced by a cytokine called IL two, and they also induce regulatory T cells.

That induce tolerance to the graft. But it's really interesting because it, it's also been shown they suppress the immune response to allo antigens, which are the antigens in a foreign tissue that you engraft when you do it organ transplant, but they don't suppress the response to infectious pathogens.

Oh really? You know,

that's been shown in monkeys. It's a very different. It's like a selective immunosuppression to some antigens and not others. So it's complicated. I don't think there's so many effects of mTOR inhibition on different immune cells, and it depends on the dose and the immune cell. So it's more complicated than just T cells, but that T Reg.

Upregulation and then mm-hmm Effector T-cell downregulation is part of the efficacy.

Thanks for listening. A quick reminder that while I am in fact a surgeon, nothing I say should be construed as medical advice. Now, make sure to include your physician and. Any medical decisions you make, and also, if you're enjoying the show, please make sure to show your support with a, like, share or subscribe.