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Joe Baur: Aging, Metabolism, Caloric Restriction, NAD, Resveratrol, Rapamycin, Sirtuins, Longer Life

Full episode transcript below. Beware of typos!

Nick Jikomes

Professor Joe Bauer, thank you for joining me.

Joe Baur 6:43

Pleasure to be here.

Nick Jikomes 6:44

Can you start off by just telling everyone a little bit about yourself what your lab studies and what your scientific background is?

Joe Baur 6:51

Sure, I am a professor of physiology at the University of Pennsylvania. And my major interest is in aging. So my lab really mostly studies mice, and looks at different interventions that might extend lifespan or improve health over the course of the lifespan.

Nick Jikomes 7:07

interest interesting. So we're gonna be talking a lot about the biology of aging today. And I thought I'd start out with a pretty broad question that I think speaks to the the way that the average person probably thinks about aging, I feel like most people, and certainly myself up until pretty recently, the thought of aging the same way that I would probably think about the way that you know, a car just gets old and starts to break down, right, it's just sort of a consequence of entropy, little nicks and dings build up over time, the nuts and bolts start to get rusty. And there's just a sort of slow, incremental accumulation of damage, and that is aging. And so to what extent is aging, this kind of passive process, where we're at the mercy of entropy, versus a more regulated process, where different components of it are actually sort of happening on purpose, so to speak?

Joe Baur 8:03

Well, yeah, there's certainly is a repair component to it. But many of the things that sort of happened by entropy, we have enzymes to go in and reverse. And so we're certainly constantly fighting against the entropy. And so there's, you know, much more than just a car with it, unless you bring in the the analogy of a mechanic or something coming in and occasionally trying to do some maintenance. So there's that aspect to it. But I think, you know, to really get an idea of what's possible, it's interesting to look, you know, around the rest of nature. And when you do that, we find examples of animals where you don't really see this entropy creeping in things like lobsters and giant tortoises, and bowhead whales, for instance, where we there's not really much evidence that they're any worse off year to year, right, they do die at some rate, they have a mortality rate, and they don't live forever. But there's not much chance in many of those species that we can measure that an older individual's going to die compared to a younger individual and say, the next year. We also look at things like, you know, the cells in your body, right? We think all the cells are breaking down, and you're getting older, but it sometimes is eye opening to you. So there have this revelation that if you think about the germ cells, right, the reproductive cells, the sperm and egg that made, you know, they go back to coming from a continuous line of cells through your parents did that sperm and egg and that and that goes back, you know, to sort of the origin to the first cell, right, there has been a continuous line of cells that has not died, you know, that is perfectly healthy and capable of producing the next generation every time. You know. And so I think there's aspects of, of the intuitive view of aging that we can we can say, you know, don't have to be that.

Nick Jikomes 9:38

Interesting. So, if you take, if you start sampling people from the population, you sample a 20 year old, a 40 year old, a 60 year old, a 100 year old, you can say with with pretty good confidence that the 100 year old has a much higher chance of dying in the next year than the people that are younger, but you're saying There's other species where that basically isn't true. So you can take a tortoise that's twice as old as another tortoise, and they've got about the same probability of death year to year.

Joe Baur 10:08

Yeah, that's exactly I mean, in some cases, some of the studies that even looked like the older individuals that were larger, you know, it'd be more successful at laying eggs and actually maybe less likely to diet at a, you know, in certain periods of the lifespan, but that there's, you know, we don't have this familiar sort of human like mortality curve, where there's an exponential increase as you get older, if you, if you graph it out, there's like a shoulder at the curve, where all of a sudden, this exponential drop off occurs, and you have a much greater chance of dying every year, and that that's just not seen in some species.

Nick Jikomes 10:35

Interesting. And so how do we start to think about and dissect that? Do they have better and more aggressive, you know, DNA repair enzymes? Do they have mechanisms inside of their cells that we simply don't have? Do we know at all? What accounts for that that kind of discrepancy between different species?

Joe Baur 10:53

I mean, we don't There are a lot of people working on these types of questions. And in particular, looking at things like like rock fish, where there's one genus where they're very long lived in very short lived members, and really trying to draw these contrasts, but it's not, it hasn't been completely straightforward. I mean, one thing we do see is that there's better cancer defenses in these long lived animals. So, for instance, naked mole rats are kind of famous for being kind of the size of a mouse, but living 30 years where a mouse lives two or three, and they basically don't get cancer. It much better mechanisms to suppress the cell, but that turns, cancers.

Nick Jikomes 11:31

Interesting. And so that's, that's still largely mysterious, we really don't know why are there even any hints as to what might be going on there?

Joe Baur 11:40

There are better I can do them justice, and that there's still, you know, different competing theories about sort of the extracellular matrix, and whether it actually is able to prevent cells from acquiring this growth phenotype, or just the specific enzymes involved with the DNA repair is more efficient, or they're more prone to uniform, a state called senescence, which is one of our cancer suppression mechanisms, right? I mean, you hopefully can kill a tumor cell. But another thing that happens is, if the body detects that a lot of these cells are sort of programmed to go into a non dividing state called senescence on their own, and that's one of the responses you get to toxic insults to cells. And so having more active senescence, engaging mechanisms can also suppress tumors.

Nick Jikomes 12:21

I see. And most of you are familiar with the term senile, we talk about, you know, people going senile at some point, which basically means, you know, they're not, they're not quite their old self. And they're clearly at an advanced age where, where things just aren't running as smoothly as they used to in their brain and in their body. Can you talk a little bit more about cellular senescence, define it for us and and just give people a clear sense of exactly what that is? And why, why has evolution baked that into animals?

Joe Baur 12:54

Right, so it's, it's kind of become a catch all term, you know, it's a button topic, even among researchers exactly how you define senescence. So it's been observed for a long time that under certain circumstances, that particularly if you express an oncogene that you know, is going to drive tumor genesis as one cause if you get severe DNA damage that the cell sort of concludes, is too much for it to overcome. Or if you let the human cell divide enough times, it will reach a point where the the telomeres, which are the ends of chromosomes get too short. And that triggers a DNA damage response. And in all these cases, you get a change in the shape of the cell, it kind of enlarges and flattens out the nucleus, change the shape a little bit, and it stops dividing. And it stains positive. One of the earlier ways the cells were characterized as this enzyme called beta galactosidase, gets upregulated. And so you can stain them blue in a tissue section. And for a long time, that's kind of the way people defined it. If you could get these blue cells, they were senescence cells. But as time has gone on, we've realized all these different ways to cause them to get senescent may have a little bit different features of those senescence cells that are produced. And sometimes you get what looks like a senescence cell that was actually had repairable DNA damage and recovers and keeps going. And so it's, it is a little bit contentious to exactly define it, but in general, it is entering a non permanent non dividing state.

Nick Jikomes 14:16

I see I see. And, you know, a big, I think a big area of discussion for us, generally speaking, will be just certain aspects of normal cell physiology and how that ties into, you know, the different nutrients and dietary components that we encounter throughout life and how all of these things intermix something that I know that you've studied that, you know, quite a number of people are talking about now. And there's, you know, companies with products focused on this molecule, there's this thing called N A D. And I know it's it's sort of a key player in the whole field of aging biology. So can you tell us what na d is and what its sort of normal biological role is in our body?

Joe Baur 14:57

Sure. So I mean, so it's a key player in biochemistry, just the aging application is sort of what's what's become a hot topic now. But this has been something that's, you know, in all the biochemistry textbooks, it's nicotinamide adenine dinucleotide. And so it is a cofactor that can accept and donate electrons. And so for a lot of the biochemical transformations, that you need to get food, all the way processed into ATP, which is the chemical energy that your cells used, in a lot of those transformations, you need an ad to actually accept the electrons and then donate them at the next step or to another process. And so it's one of these molecules you can't live without, it's the product of vitamin d3. So it's sort of as people were back in the day going through what it took to to be able to survive this. This is one of the things vitamin B three, and you need it just just to make any day.

Nick Jikomes 15:46

I see Yeah, no, I remember distinctly learning about an ad, you know, all the way back in middle school in high school biology and how it tied into cellular respiration. So it's this like, very, very core component of just the basic biology that runs all of our cells. You said that, that it has this critical role, and it comes from vitamin B, three, I suppose that nowadays, there aren't many people that are vitamin d3 deficient, but what what would start to happen to a human body, say if you became deficient or severely deficient in something like vitamin d3, and your NAD levels weren't where they're supposed to be?

Joe Baur 16:23

Right? So so if it's severe, you get the disease peligro. And this is actually curing this disease is sort of intertwined with the discovery of na d in the first place. So this was a disease that was endemic in the southern US. It was characterized by the four DS, which are dermatitis dementia. And I of course, missed one and death. Sorry, let me

Nick Jikomes 16:47

but but yeah, but basically, yeah, it's really bad. It's brother.

Joe Baur 16:51

But take another shot of saying that, but it's characterized by the four DS, which are dermatitis, diarrhea, dementia and death.

Nick Jikomes 16:58

Yeah, so it sounds it sounds like it's not fun.

Joe Baur 17:01

No, and you know, and obviously, it demonstrates, you know, in a very graphic and real way that you can't live without an ad. And so, you know, originally this was thought to potentially be an infectious disease. And I named Joseph Goldberger spent the better part of his career demonstrating that you could cure it nutritionally, and that it really was a nutritional disorder. And he intersected with a couple of other folks who were had discovered that there was a redox active factor that they could purify from yeast extracts, and moving toward chemically identifying it and sort of had this convergence of the two fields where it was discovered that nicotine amide and nicotinic acid, which are the two forms of vitamin d3, were curative for pellagra. And we're also producing this redox active nucleotide, which turns out to be Na, D.

Nick Jikomes 17:48

Interesting, and then, you know, so ne D has this core core role in some very, very basic, important physiological processes. If you don't have it, you will die, you'll get very sick, and then you'll eventually die. What happens throughout development and the lifespan to na d do levels go up and down in different phases of life? does it tend to decrease? As we age? What do we know there?

Joe Baur 18:11

It tends to decrease as we age. And so this has been a little bit controversial at times, it's been hard to measure. And then some tissues, it's not so clear, it's going down. But we're getting better data now in humans to show that, as we've already seen in mice that in general, it is going down with age. In fact, there was a study that just came out very recently showing pretty convincingly that in human muscle tissue, there's a drop off of energy levels with age, and that that correlates with functional status.

Nick Jikomes 18:40

Hmm. So So there's obviously this correlation there. And if it's going down with age, it would be very convenient that if you could replenish na D levels, perhaps that would cause aging to at least slow down or perhaps even reverse it is is that the case or is any decline, just sort of a marker of other things is is is replenishing energy levels actually able to causally give an animal any improvements.

Joe Baur 19:07

So in an animal it can. So this is kind of where we are right now. And so in rodent models, were giving large amounts of energy precursors, and in many cases, that does turn out to be beneficial. So there's a whole range of examples, but some of the common themes are in heart failure models, you get an improvement in heart function by boosting energy levels in rodents. In Alzheimer's disease models, you get improved cognition. And in diabetes, you can improve glucose handling and insulin sensitivity. The question is, you know, right at this moment, you know, how well is this really going to translate to humans? So far, there are for some of the indications like insulin sensitivity, it's not been that clear that it's going to translate. Some of the human studies have looked much less impressive than the rodent studies, which has raised questions including whether you know whether the dose translation is working because when you have these masks doses and rodents, you're not really willing to, you know, give such enormous doses of scaling by body weight to humans. And that's, I think, one of the questions if these lower doses that people have sort of deemed safe, you know, just just might not be sufficient, because the same change in biology that you see

Nick Jikomes 20:17

it. So I'm hearing you correctly, when they're doing these experiments in mice, they're, they're, they're being pretty liberal, they're giving them quite high doses of an ad or some precursor to an ad. And then just, you know, for ethical reasons, and for safety and and just for being conservative in a human clinical trial, you're probably going to tend to start at those lower doses. And so what you're saying is, we're maybe not seeing quite the same effects in humans, but that could perhaps mean we just need to use a higher dose.

Joe Baur 20:46

Yeah, but that's one interpretation. But and, you know, the concern there is that they, you know, that that the safety limitations might be real as well, right? Yeah. may not be able to go to a mouse like dose without doing something to your liver, for instance. So, Nick, and I've been vitamin B, three forms, you know, about three grams a day, you start to see how toxicity. And so there is a concern that if you do these massive doses, maybe you'll see the improvements and insulin sensitivity or whatever you were looking for, but you might have liver problems at the same time.

Nick Jikomes 21:12

So I see, we see that in humans, is that what we see in mice the hepatic toxicity

Joe Baur 21:16

in humans without but three grams a day? I see

Nick Jikomes 21:20

I see. Now, what about the mice when you're giving them the ultra high doses? In these experiments? Are they are they also seeing hepatic toxicity? And you know, it's a mouse experiment? So we just sort of note that, or are they? Is it actually not happening in mice?

Joe Baur 21:35

In general, it's it doesn't seem to be happening. Not every mouse experiment measures that, but but we've really seen it. And it it certainly in general, that mice can take much higher doses of things before their livers get in trouble.

Nick Jikomes 21:46

I see. And that might just be a natural consequence of them being small animals with a different metabolic rate or something like that. Yeah. Yeah. Interesting. So what's, um, so So just on the basic topic of NID, how would one boost na D levels, at least a little bit, if it's a vitamin d3 precursor, is there a straight line you can draw between the amount of d3 you're consuming in your diet and the amount of energy that will actually be present in your cells?

Joe Baur 22:17

Not quite a straight line. So and this is, again, you know, one of the things that sort of being worked out in real time. So this is the conventional recurses, nicotinamide and nicotinic acid that we're getting a lot of in our diet, you're making it from tryptophan through what's been termed the de novo pathway that was sort of recognized afterwards that there was this third entry point. Very recently, it was discovered that there's also nicotinamide riboside kinase, which allows a partially formed version, nicotinamide Rob aside, to go into the entity synthesis pathway, kind of bypassing the early steps. So that was discovered by again and Charles Brenner in 2004, I believe. And that was sort of the the first sort of revision to these pathways that had happened in decades and decades, and generated a lot of the excitement that we're seeing now. But supplementing because you've demonstrated, you can use this use this form nicotinamide riboside, that hadn't really been considered before. And so that's what is in most of the popular supplements right now. And what's going into a lot of these rodent studies. And at the same time, some groups have started using nicotine divide mononucleotide, which is an intermediate and synthesis pathway. That's what gets made inside the cell from nicotinamide riboside. And again, bypasses those early steps, which can be energetically problematic and can be rate limiting. And so with both of these compounds, in rodents, you can get much more effective boosting of na D levels.

Nick Jikomes 23:37

And when they, when they boost an ad in rodents, how long as like a percentage of lifespan, you know, are they giving it for a few weeks or months? Like a good a good solid chunk of the mouse lifespan? And what kind of effects do you see on longevity and some of these experiments to do with an ad in rodents?

Joe Baur 23:56

Right, so so there's there's only been two longevity experiments done. Right. So the vast majority in rodents is on different measures of health and disease models where there's lots of positive data. The first study that was done for lifespan was a really small study starting late in life and showed a couple of weeks extension, which was statistically significant and sort of created the dogma that this was going to work.

Nick Jikomes 24:19

I suppose for a mouse right there only living what 1218 months or something like that.

Joe Baur 24:24

Yeah, I mean, typically two to three years, okay. So a little longer than that, if their hell if it's, you know, under optimal conditions. So these guys were two years old, I believe at the time they started that extended mind herbicide and live a few weeks longer. And so it was maybe a few percent of the lifespan but statistically significant. But then the NIH intervention testing program recently did this. This is a a large program that was created by the NIH to test people's suggestions for things that might extend lifespan. So evicted microbicide was one of those suggestions and this multicenter group did it, and they didn't see any any improvement in lifespan. For me younger age and with a larger number of animals and so it's that's at the moment that that's where it stands, it's unlikely that these are extending lifespan overall.

Nick Jikomes 25:09

And, and I suppose you know, when you get in, you know, there's so many like supplements and new products coming out tied to this, this and other stuff, all of the all of the hot molecules in the Asian world, I suppose it just very, very fundamentally difficult to get human, human clinical trial data on this because it would require you to run an extremely, extremely long and and difficult trial. With that being said, like, what is there anyone attempting to do long term trials in humans that might measure these types of things to do with longevity?

Joe Baur 25:43

No, there aren't at the moment, I mean, there are many trials starting up and and so not all of them are registered publicly. So there may be some some longer term ones intended, or sometimes people sort of envisioned extending their trial, if it looks positive, and you're trying to drag it out for these longer term measures. But this is a real problem for you know, for things that are like this, that are sort of nutraceuticals and aren't, you know, developed by a big pharma company, you know, there's probably, I think the office of dietary supplements is estimated something like 4000 different supplements available. And you can imagine, it's just impossible to test all of those in a rigorous way. And so it's easy for people to sort of keep pointing out again, and again, there's not sufficient evidence to recommend this supplement or that supplement. But there never will be unless something changes about the system, we'd basically have to switch the military budget and the NIH budget to even start to approach this.

Nick Jikomes 26:31

I see. What about this, this other group of molecules that I've heard about called sirtuins? What are these things? And how do these tie in to aging?

Joe Baur 26:43

So sirtuins are well maybe, just to get into that topic, I should say the other aspect of energy metabolism we haven't really talked about is its, it has this redox function that's it's sort of primary core function. It's also a co substrate for some different classes of enzymes. So there, there are enzymes that actually break it down. Don't just give it electrons, but break down the backbone as part of their activity. And sirtuins are one of those classes of enzymes. There's a couple others called purpose and CD 38 That people study for their for their own activities. But there's some question about whether when you change energy levels is part of the reason it's beneficial or harmful, because you're changing the activity of these enzymes as well.

Nick Jikomes 27:21

Interesting. And so why have these become like so famous in aging biology?

Joe Baur 27:27

So the sirtuins became famous? Because they were one of the first classes of genes shown to regulate lifespan at all right? So in the 90s, you know, or I think 1988 was the first case where there was an individual longevity gene described by by Tom Johnson, the gene called age one and worms. And so that was sort of the moment when people realize that changing one single gene really could control lifespan, it wasn't that you needed to have hundreds of 1000s of years, not under 1000s of 1000s of genes interacting, you know, to get a change in overall longevity, just one gene could do it. And so Cynthia Kenyon discovered def two a little bit after that, and sort of reinforced this idea. And then Lenny garante is loud, some that Caitlin and Brian Kennedy were in that lab at the time, and came up with sirtuins as something that could control the lifespan of yeast. So that's, that's done by looking at the replicative lifespan by sort of trapping one use cell, which is budding, and taking away the buds and asking how long it can go. How many buds can it produce as a lifespan? And sirtuins could improve that lifespan? And so they were probably the third set of genes that are shown to control lifespan and in any organism.

Nick Jikomes 28:35

And I mean, East flies, worms, mice, what are in any model organisms that people work with? What what to this, to date have been some of the most dramatic life extension results? Like are you Is anyone able to tweak one of these things and improve lifespan by 10%? Or are people you know, doubling the lifespan of worms and yeast and things like this?

Joe Baur 29:01

Well, with this, I think the most dramatic one is a worm lifespan where this age one meeting, the time Johnson discovered was a partial loss of function. And it was thought that if you knocked out the gene completely, it was lethal that the worms couldn't develop from their juvenile stage. And it was shown a couple of years ago, probably five or 10 years ago now. That if you take those complete loss of function worms and wait long enough, they do develop into adults, and they live 10 times longer than normal. Wow. So you live almost half a year.

Nick Jikomes 29:29

But and so what what, what was that gene doing?

Joe Baur 29:35

It's in the insulin signaling pathway. And so that's a general theme, especially in model organisms that that disrupting insulin signaling seems to extend lifespan. Interesting in terms of mammals that tends to carry over so the insulin and IGF one insulin like growth factor one pathways overlap a lot that they can activate each other's receptors at a certain level and A lot of the downstream signaling components are the same. And so in mice, and in humans, it looks like there's more evidence probably that IGF one pathway disruption is maybe beneficial for longevity. But organism? Yeah, insulin signaling in general seems to be

Nick Jikomes 30:15

I see. And could you just could you just give us a sort of insulin 101? Here? What is the basic biology of insulin? What is its normal physiological role? And how does you know from there, we can probably build on some some of it further.

Joe Baur 30:30

Right, I mean, so So insolence the the primary hormone regulating glucose metabolism, right. So if you if your glucose levels go up, you have a corresponding rise in insulin and that sort of instruct cells to start taking up glucose and restores normal normal blood sugar levels. And so diabetics, you know, either have become terribly resistant to insulin, so it's not functioning well enough in their blood sugar gets out of control, or type one diabetics can't produce the insulin in the first place, and, and so have the same effect. IGF one is in the growth hormone signaling axis. And so So growth hormone causes the liver to release IGF one. And that tends to you can have an anabolic effect overall. But inside this episode, like I said, both of them kind of interact on the same receptors and inside the cell, they tend to activate the same signaling cascades. And so it's, it's still kind of a mystery in biology of you know, why how, how these things are partitioned? Why? Why does it seem like these two hormones can have slightly different effects through the same receptors in some cases, or similar looking receptors and then hitting the same downstream pathways?

Nick Jikomes 31:34

Interesting, so yeah, so I mean, insulins obviously involved in diabetes. And, and, and other other other metabolic stuff. I've also heard more in different ways about this thing called mTOR. And I know that's really important for metabolism, but how does that start to tie into this?

Joe Baur 31:56

Right, so so that is one of the direct downstream effectors of both of those pathways. So there's a direct sort of kinase cascade that goes through a bunch of steps, but but mTOR is directly downstream. So when you when you stimulate insulin, you'll activate mTOR or IGF one. And so that whole axis I think, is probably the you know, the thematically the the area where there's been the most sort of success and consistency in regulating lifespan is this new growth hormone, IGF one to mTOR axis, which lineup a lot of the interventions and

Nick Jikomes 32:28

I see I see. Yep, so these things are sort of all tied together in some of these key molecular pathways that have to do with metabolism. And obviously, metabolism and aging are going to kind of go hand in hand in many ways. mTOR, right. I'm not gonna remember the full name, but it's something like target of rapamycin, this other drug,

Joe Baur 32:46

mechanistic target of rapamycin. So it's changed names a few times because it was violating some naming conventions, but that's the current standard.

Nick Jikomes 32:53

I see. And what is what is rapamycin? This drug that can affect mTOR? Because I know that there's been some interesting results to do with rapamycin fairly recently.

Joe Baur 33:05

Yeah, so So rapamycin has been the drug that's been the most consistent for lifespan extension. And it is an inhibitor of so mTOR is actually in two different complexes. So the history of it was that rapamycin was known first, you know, and it was having it was actually discovered as an antifungal but then realized to sort of suppress growth in all kinds of cells. And through you know, the pathway just wasn't known for a long time. And again, a Michael Hall discovered in yeast what the target was and named a target of rapamycin. And then David Sabatini and others discovered the mammalian version and named it originally mammalian target of rapamycin, which is how it became mTOR. But because of the naming conventions, the it was changed to mechanistic target of rapamycin later on. And afterwards, it was discovered that there's another protein complex that uses the same catalytic subunit. So mTOR is actually in two different complexes that have different functions. mTOR complex one is the one that's sensitive to rapamycin that people had been studying for a while, and mTOR complex to his net was named for being insensitive to rapamycin. There's a component of it that actually has insensitive in its name. But it turns out mTOR complex also gets inhibited when you treat chronically with rapamycin. And so actually, both of them are probably playing a role in the in the effects of rapamycin when you treat long term.

Nick Jikomes 34:26

So when you activate this mTOR pathway, versus when you suppress it, like high, high level, what are the overall effects? Is one of them sort of growth, promoting metabolism, promoting an example?

Joe Baur 34:41

Gotcha. Yeah, in terms of mTOR is kind of the decision point of the cell. It's a node that decides whether the conditions are right for growth. And so missing a lot of different things. If you're missing amino acids or you're missing the growth factor signaling or glucose is low. Lots of those things you can dominantly cut off mTOR signaling and shut it down. You have to have all of them on simultaneously to get them toward it to turn on and to start activating your synthesis of proteins and amino acids and, and lipids, it's everything you need for growth, essentially.

Nick Jikomes 35:14

I see. And so the the very simple way that you often learn to think about things like I mean, when you think about something like cancer and cell growth, right, cancers, just sort of runaway cell growth, when you think about growth hormone are anabolic processes that are building up building up tissue and using more metabolic energy to cause more growth. That that tends to be associated with growth on the one hand, which can be good, but also, you know, bad stuff like cancer and aging. And then, of course, I think people hear a lot about these days, the effects of things like dietary restriction, so if you just simply consume lower calories, this seems, to my understanding to have certain beneficial effects. How does when we're thinking about rapamycin and mTOR, and the sort of really key metabolic molecular machinery here is, is that sort of a very simple but intuitive way to think about these things, that things that are generally going to be growth promoting will tend to have pro aging consequences just because you're going to get more oxidative stress and sub stuff happening? And then the reverse being true if you sort of slow down those pathways.

Joe Baur 36:27

So yeah, in a general correlative sense, those that way of thinking tends to hold up, you know, sensors, for instance, when it was discovered that rapamycin extends lifespan and calorie restriction, you know, extends lifespan and model organisms, the thought was okay to calorie restriction shuts down poor signaling, and this is all one pathway that hasn't really proven to be true. As far as we can see, we there's a few observations that contradicted I mean, things like if you just do gene expression profiles and things, just look at how the tissues are behaving at a calorie restriction, rapamycin, several attempts to show that they were the same, you know, ended up proving the opposite that they were they just look completely different. And there's observations like the fact that with rapamycin, you can start very late in life. So the first study that really showed rapamycin would extend lifespan of mice started at about 20 months of age. And you get nearly the full effect on lifespan extension starting at that age where with calorie restriction, the earlier you start, the better it works. And by 20 months, it's just about too late to get any lifespan extension from calorie restriction.

Nick Jikomes 37:25

I see. So in rodents calorie restriction the earlier the better, or the earlier that that you restrict the calories the mice are ingesting, the longer they're going to live. And then at some point, it becomes too late. But you're saying with rapamycin, no matter when you start giving the mice rapamycin, you get this increase in longevity? What kind of increase were you talking about here?

Joe Baur 37:46

So generally, it's been around 15% For most of the studies and rapamycin. If you look at the ones where they optimize the doses, and it tends to have a better effect in females, you can get up around 40%. That's sort of the maximum tolerated dose and in the right gender,

Nick Jikomes 38:02

so 15 to 40% of the lifespan. But if if one could somehow translate that kind of effect to humans, you're talking about decades. Yep. Interesting. And so what what else do we know about rep myosin? I Begley remember learning that it's also immunosuppressant? Does it have any other uses, like clinically for other things.

Joe Baur 38:24

So the two things that it's been used for, I mean, one is an immunosuppressant. And it's still used sometimes for particular, for transplants to prevent rejection. It's also been used as an anti cancer drug. And in most cases, the tumors have developed resistance pretty quickly. And so it's kind of been abandoned as the frontline for a lot of tumor types. But there is a disease called tuberous sclerosis, where the primary defect is hyper activation of the mTOR pathway, and that leads to lots of little tumors. And so in that case, it seems pretty effective to target employer directly. And so it's kind of in rare tumor types still being used as an anti cancer drug.

Nick Jikomes 39:02

I see So, so if rapamycin has immunosuppressant effects, you know, under controlled conditions, you can probably you can probably prevent mice from getting sick pretty easily. But could there be could there be consequences to do with that immune suppression to using something like rapamycin where you know, on the one hand, you're you're seeing this, this good aging effect, but are you more susceptible to to infection

Joe Baur 39:31

potentially, so that the may seem to be in your ear? That's one of the consequences you see is but as more and more infections, there's also mucous membrane defects that patients on rapamycin get. And so the big discussion among people interested in rapamycin for longevity right now is whether you can lower the dose whether you can change the timing of the dosing regimen to kind of eliminate some of the side effects and still have some potential benefits. And there are studies references at the Mayo Clinic they've had an ongoing study with low dose rapamycin and healthy volunteers. The one major paper that they published that was positive out of that was showing that there was an improved response to vaccination among those people compared to elderly people who were not on rapamycin, you got a more robust vaccination response for the flu vaccine. Interesting. And so it's actually not uniformly immunosuppressive, it's more people tend to use the term immunomodulatory now, and I see, I see maybe bacterial infections, you know, are more of a risk, but maybe, particularly if you have an older immune system that's a little bit senescent, that the rapamycin treatment actually makes it function better.

Nick Jikomes 40:33

Hmm. Interesting. I wonder, you know, what, what the general, what some of the general connections between immune system activity overall and aging might be? Naively you know, I might, I might think, to myself that, you know, every time every time there's an inflammatory event, every time you get an infection, or whatever the immune system has to respond and turn on. And you know, all of these inflammatory processes get instigated. And on the one hand, that's good, because it can handle something like a, like an infection, or help heal some kind of tissue damage. On the other hand, whenever this happens, right, you know, too much information from too long can be bad. And there's there's pretty much always some kind of collateral damage, right. So their immune system very much its anthropomorphize, it wants to be turned on when it's needed, but but not, but not when, but but not beyond when and where it's needed. So is there some sort of trade off between the immune system and the aging side of this where more and more immune system activity would actually promote or accelerate aging, just as a natural consequence of, you know, all of the collateral damage that would come from inflammatory stuff happening?

Joe Baur 41:49

Yeah, I mean, there's a lot of interest in that idea right now. And there's certainly good evidence that the immune system does age that you have sort of senescent and defective immune cells circulating when you're older. There's also this idea of clonal, hematopoiesis, right, where the immune cells can apparently acquire mutations that give them a little bit of a growth advantage, whether or not they're functionally doing, okay. And they can essentially take over a large part of your whole immune system, right, the white all the white blood cells in your body, it can be generated from a few clones, at some point as you get older, and that really decreases your your sort of immune repertoire and your ability to respond to different things.

Nick Jikomes 42:29

Wow. So those cells can take over and your immune system is sort of less diverse. I would also imagine, right, if there's this growth advantage, you know, in some sense of if your immune system becomes populated by just the fastest growing and or most aggressive immune cells, that could also be problematic. I mean, even just thinking about, you know, recent COVID events, you know, we know that when people get into trouble, it's often because of this thing called the cytokine storm, which is just your immune system is behaving too aggressively. And as it is, are there any trends like that, where as as it sounds, like almost what you're saying is that throughout the aging process, there's at least the possibility that your immune system is going to become dysfunctional in the sense that it's going to become inappropriately aggressive? Is that known or characterized at all?

Joe Baur 43:17

Yeah, I mean, I think the general feeling is that it becomes active at a low level chronically, I submitted the two things and sort of incapable of mounting the more aggressive response needed, you know, in an actual challenge, but it's sort of that that juxtaposition of you have little inflammatory cytokines sort of drifting up in the background just at your in your basal state, and that's been termed inflammation. It's one of the one of the key markers people look for is these things like il six and TNF alpha, that are immune markers that are that are drifting up as you age, even in the absence of any challenge. But then when you do have something like COVID, your immune response is much less robust.

Nick Jikomes 43:56

And so when we study, when we study these sort of chronic inflammation processes, especially in animals, where we can really dig into it more, I'm curious about how things like chronic inflammation and aging generally, are affected by things like physical activity, to what extent can you prevent these things from happening by engaging in certain types of physical activity? And to what extent can they actually be reversed?

Joe Baur 44:23

It's a great question. I mean, and certainly physical activity is one of the best things we know you can do from human studies. And quite often, you know, if you find these differences that you can show between young and old animals or or people if you have an exercise to elderly group, you can show that they're actually much closer to the young than to the sedentary. In fact, that's that was just shown for mid levels in skeletal muscle recently in this in this study that just came out that they actually did that division and they had they were comparing young, active, elderly and inactive elderly and showed that the decline in NA D was almost mitigated by the exercise.

Nick Jikomes 45:02

Interesting? And is there anything known about, you know, when we talk about these links between physical activity and exercise? And any D or any of these kinds of things, we might be interested in the context of aging and metabolic function? Are there differences? Is it should we think about physical activity purely in the sense of intensity, like how many calories you're burning? Or are there interesting differences that might exist, say, between, you know, aerobic exercise versus weightlifting or something

Joe Baur 45:33

like that. I mean, it's all of the above. But I think that, you know, the bottom line that comes out of most of the studies where people look at this kind of stuff, intensity data over time is that just that first little bit of exercise makes such a difference compared to doing nothing. And there's sort of a, you know, possibility to get more and more benefit as you exercise more and more, but the incremental return on more exercise gets less than less as you go. So I think the most important lesson is to do something, rather than behavior is by far, you know, the biggest problem you can run into here. But there is evidence that, you know, for instance, weightlifting can actually change the fiber type composition of your muscles, right, and give you more more glycolytic fibers that tend to be less efficient, and so can be a little better, actually long term for controlling weight. And so that point gets made sometimes that endurance exercise, you know, well, it causes you to burn calories, while you're doing it fairly effectively. It's also training your muscles to be very efficient. And so there's this discussion, sometimes whether the real strict, the better strategy is designed to generate, you know, powerful, inefficient muscles.

Nick Jikomes 46:39

So if you're doing heavier weightlifting, when you say that you're building inefficient muscles, you mean that they are just burning energy faster to maintain themselves, and therefore the same amount of calories ingested would, would, would lead to less of a buildup of

Joe Baur 46:56

fat storage. Yeah, and those muscles emit fast twitch fibers are the most powerful muscles are generally glycolytic. Great. So there's a lot more glucose that's just being converted to lactate and spit out by those muscles. Compared to slow twitch for endurance. It's typically the mitochondria that so you're completely burning the fuel inside the muscle and generate a lot more ATP for us, because

Nick Jikomes 47:16

interesting. So So one of the key takeaways that I just heard from you as one of the single best things one can do here in terms of physical activity is not be sedentary. So just work out somewhat and doesn't matter. Not that it doesn't matter how hard or how much you're working out, but just not being sedentary is is the first key step. But I wonder, you know, if we could define for people, what exactly does that mean? You know, it's probably not, most of you, most people that are sedentary aren't literally sitting and not moving all hours of the day. And you know, what, what counts is sort of that threshold of exercise? Is it really breaking a sweat? Is it just getting up and casually walking around the block? Where do we start to think about where that line is?

Joe Baur 48:01

Yeah, I mean, I think, you know, so that I mean, this is not really my clinical areas. I'm not stepping on anyone's toes. But you know, from from the studies that I've read, typically, yeah, as much as sort of 15 minutes of a brisk walk in a week, you know, you may have a resolvable difference in terms of overall health compared to someone who just never does any deliberate exercise.

Nick Jikomes 48:21

Interesting. Okay, so it can it can really be that simple. Yeah.

Joe Baur 48:26

Yeah, and any, any amount of deliberate exercise, I think, is going to produce a benefit compared to just trusting that the amount you naturally walk around the house or something like that, is enough. There's that little bit of extra effort.

Nick Jikomes 48:38

Interesting. Um, I want to dwell on coke diet stuff for a little while. So I want to talk about specific things that that are in different items we consume that have at least been talked about as being connected to aging. But maybe let's just start with caloric restriction. So at a very basic level, I mean, everyone understands what caloric restriction means It means you're just ingesting fewer calories. But what are some of the basic metabolic consequences of doing that? And how does that tie into some of the aging related observations to do with caloric restriction?

Joe Baur 49:13

Yeah, well, so yeah, keeps your blood sugar down. I mean, it definitely shifts your body composition. So that mass, I mean, as a percentage of body weight is always much lower in people that are calorie restricted. And it was lowers cholesterol, triglycerides, circulating lipid levels are much lower. And so that's what has been done in humans. I mean, we don't have long term controlled studies of calorie restriction for lifespan. But we do have all these biomarkers that predict cardiovascular health and and certainly diabetes, or tendency towards diabetes that resolve dramatically when people are on a calorie restriction regimen for a couple of years. And that's it. Humans generally about 25% reduction in the calories required to maintain body weight initially

Nick Jikomes 50:00

I see so so when we talk about that, that was basically gonna be my next question like, What? What is calorie restriction? Is it a is a 25%? Decrease one day per week? Is this something that you that we think about persistently when people do these experiments in animals, what is sort of the spectrum of restrictions that get used, where you see some kind of effect on aging.

Joe Baur 50:21

So what's what's been accepted as sort of the standard protocol for animals in the field is a 40% reduction in calories, maintaining adequate vitamins and minerals. And so you would, and that's done daily, so that you have a control group where you're measuring their food intake, and the next day, the calorie restricted group gets 60% of what that control group ate. Again, do knowing approximately what that's going to be typically would have supplemented the vitamins and minerals. So they're getting a full 100% dose of those, but the calorie content of the diet is 60%, lower are sorry, 40% Lower, to make to get you at 60% of normal.

Nick Jikomes 50:58

And I'm going to do my best here to try and connect like animal studies to what a human might expect here. But, you know, I think if you're talking to the average person, eating the average, we'll just call American western diet, certainly working on a lot of calories. And I can imagine that a 40% reduction in calories is still perfectly manageable amount of food that one is getting. Are the when people do the mouse experiments, would you say that the mice that are eating the full diet are having just enough of what they need as a mouse to stay alive? Are they are they having quite large diets? Is that 40% reduction, taking you down to something where it's like, oh, wow, I'm really eating a lot less than I'm constantly going to feel hungry and wish I had more? Or is it what you might call a manageable amount of calories?

Joe Baur 51:51

No. So for the most, it's definitely taking them into a range where they constantly wish they had more. And so in fact, I see them that percent of normal daily calories, they eat it within three to four hours. And so they just keep eating until it's gone. So they're definitely ready for more food at that point, but it is a huge question of how do we translate this observation, because that control group that's eating whatever they want, you know, is in a mouse colony, where they've been bred to be sort of fat and lazy. And things have been tweaked to sort of ensure optimal reproductive success, right, that's the measure of how healthy your mouse colony is, is how fast the pups come out for the next generation. And so a lot of the laboratory strains we have up here are kind of obese compared to wild type caught mice, right? If you just went out in the field and caught some mice, they're much leaner, and they eat much less than the ones that we have in the lab.

Nick Jikomes 52:41

And there's also a distinction to be made between the metabolic consequences within cells of calorie restriction, per se, versus the behavioral consequences. So as someone who you know, for five years, I worked in a mouse lab, where we were studying neuroscience stuff to do with feeding behavior. So I work with a lot of food restricted mice, one of the first things you notice about a mouse, it's food restricted, is they really want to eat, and so they are constantly moving and searching and digging for food. So how much of the consequences of calorie restriction have to do with the the underlying metabolic shifts per se, versus the fact that the organism is now just more active?

Joe Baur 53:27

Yeah, no, that's a that's another thing that's been hard to control for. And you know, and it's kind of counterintuitive to a lot of people too, they assume if you're short on calories, you just kind of huddled in the corner and try to conserve energy as much as possible. But But like you said, what they actually do is forage for food all the time. They're moving around. So but I can tell you is that, you know, people have done side by side comparisons of calorie restriction and exercise, or even combinations of both. And for sure, calorie restricting. So if you set this experiment up, in order to where you exercise one group, and don't exercise the other group, and then calorie restrict a third group till the body weight matches the exercising group. The calorie restricted ones live longer. I see. So yeah, so So I don't think physical activity alone can explain the benefit that you're seeing. But it's, yeah, it's definitely a complicating factor.

Nick Jikomes 54:19

And just to tie a couple of these threads together now, you know, I imagine that when calorie restriction is done, it it has an effect on some of those mTOR mTOR pathways and insulin pathways that were speaking up about before. So what does that look like?

Joe Baur 54:35

It's not as dramatic as as you might think. I mean, I think we've done some of these experiments looking at Tor signaling in calorie restriction, expecting it to be just shut off right looking to look like rapamycin treatment. And it definitely doesn't. I mean, in general, the tourist signaling pathways are down a little bit in the calorie restricted animals. But it's, they tend to adapt you know, a lot of these sort of signaling pathways when you first change energy intake seem to suffer wildly. And there's another one that we look at a lot called an APK, which is APK activated protein kinase. That's a typical energy sensor that detects when ATP levels drop. And when you start color restricting animals, you'll see that signal pathway Come on, that's one of the pathways that shuts down Tor signaling. You can see Tor patent, the pathway drop a little bit at first, but as the animals have sort of chronically adapted to these situations, the NPK signal goes away and the tour signals not so far off of normal wild type mice.

Nick Jikomes 55:29

What about? Well, there's, there's at least one compound I will ask about before I get to that. Obviously, people are always interested. I mean, diets diets are very popular. It's a very huge industry. Everyone's constantly interested in losing weight and, and taking care of themselves. What are, if any, the things that are found a diet that people can consume if they're eating the right foods, or taking the right supplements, supplements that have the clearest connection to aging and reducing aging? Well, you know, if you had if you had to list a few things, if those things exist, what are they and what are they actually doing inside of our bodies?

Joe Baur 56:14

Yeah, no, I'm not sure there's a perfect answer to that other than, you know, whole fruits and vegetables. I think, you know, there's a, there's a disappointing amount of like, what was sort of common sense knowledge all along? That is the best advice we can still get? Yeah, certainly people that did a lot of you know, for foods in particular fruits and vegetables, you know, do measurably better? I think there's a good argument to avoid trans fats. And, you know, and fructose, I say, in particular. But as far as naming, you know, why those fruits and vegetables turned out to be so good for you, it's still really hard, you know, that the thought was always that it was the antioxidant vitamins, right, AC and E. And, you know, based on that philosophy, there's a whole industry sprung up around supplementing those vitamins. And if you look out a meta analysis, looking back, there's almost no benefit from massive doses of antioxidant vitamins. But the fruit and vegetable data still hold, you know, so I think we just don't know exactly which of those molecules in there really is responsible.

Nick Jikomes 57:13

Interesting. And I've heard, I've heard that findings like this have been seen before, although I'm not familiar with the literature myself, where, you know, essentially, the experiment would be in a rodent, you give two rodents, the same diet, basically, they're going to consume the same number of calories and the same menu of nutrients, but one of them is getting those nutrients through supplementation. And the other one is getting it just through the the actual composition of the diverse diet it's given, then you tend to see that the the latter mouse is healthier, right, the one getting everything from like the the basically, the whole food diet is doing better in terms of overall measures of health than the one that's getting the same amount of calories in the same nutrients. But through that sort of individual supplements. Is that, is there any validity Validity to that?

Joe Baur 58:06

So I yeah, I'm not sure I can off the top my head think of a, you know, a really carefully controlled study making that point. But I think that's consistent with what I would expect and consistent with some of the human data suggesting Yeah, the taking the supplements is not as effective as it is having these things in food form.

Nick Jikomes 58:24

And is there is there any deep reason for that? So for example, is it because, you know, our bodies evolved to extract calories and nutrients from, you know, complex food matrices from you know, you know, actual pieces of organic material that we find in our environment? And we're sort of not our metabolisms really not built for an evolutionary sense, you know, sucking up single nutrients one at a time. And this is highly purified form.

Joe Baur 58:52

Yeah, I mean, I think in the vitamin D, calcium connection, right, there's definitely combinations of nutrients that we might take up more effectively when they're together. And they're certainly, you know, the, your body knows when you eat, right, there's all kinds of hormones being released in the stimulation of gut motility and things that all kind of work together, you know, and so that stuff arrives, you know, in the conditions, it's expected in the combination of nutrients it's expected in and so I think that's a, you know, an extraordinarily complex area of biology. And we don't know a lot of the specifics, you know, as far as where this applies, but I think it certainly does to a lot of these nutrients.

Nick Jikomes 59:30

So there's another molecule that's pretty, pretty famous in this in this realm. And it's the one that's always associated with red wine. So I suspect, you know, what I'm talking about, and what is this molecule and what do we actually know about what it does?

Joe Baur 59:48

Okay, so that's resveratrol, which I actually did my postdoc studies on that and published one of the studies in mice that that got a lot of attention initially. So this is a model kill that. I mean was known for a long time, but came to the attention of researchers through a screen for things that would activate one of the sirtuin enzymes. And so the idea was just to blow through a bunch of small molecules and see if you can find something that would make 31, which is the the human are the mammalian to an enzyme that looks the most like the yeast enzyme that was associated with longevity. So it took the mammalian form, it was screened against the whole library and resveratrol came out as the top hit that seemed to activate it the most. And so the work I was involved in at the time was that it had already been shown in that initial screen that afterwards that you could also extend the lifespan if you with the reservatrol treatment as hoped that if it was an activating the sirtuin enzymes in the controlled lifespan and used so my project in the lab, David's eclairs lab at that time, was to feed it to mice and see if it would also extend lifespan in mice. And so what we found was that, you know, obese mice fed a high fat diet and made obese they actually would normally have a shorter lifespan, and there was very little treatment improved their insulin sensitivity and it really potent anti diabetic effects. It drastically improved their fatty liver phenotypes they developed, and it prevented that shortening of lifespan. So they still had a normal lifespan, despite being obese on their spiritual treatment. In mice fed a normal child diet, instead of that unhealthy diet. It had no effect on lifespan. And so we published those results. And you know, part of the reason you're probably hearing about this more and more lately, there's been a lot of controversies along the way in the field, right. So at multiple levels, right, whether sirtuin enzymes really are involved in controlling lifespan at all outside of yeast, or even outside of that particular replicative lifespan model in yeast where it was originally discovered. There's at this point labs with conflicting data published in worms and flies showing that sirtuins do or don't extend lifespan in those organisms, in mice, at least overexpressing 31 in the whole body, which happened later on after our study didn't extend lifespan, which is still consistent with the idea that we also didn't see it with resveratrol treatment, any extension of lifespan and the mice fed in normal diet. And then, the next thing that became controversial was the assay used to find resveratrol in the first place. So sort of, after all, this was in progress. A couple of other groups showed that, in fact, Resveratrol is interacting with a sort of tag that was introduced to make this assay work for certain part of the natural system. And so maybe the the whole thing was an artifact. And that's going back and forth a little bit, some publications from the Sinclair lab have shown that depending on what substrate you use, it may work with some of the natural substrates you made, the assay may work in that that artificial tag on one substrate may have actually mimicked what some other substrates actually look like. But that's sort of, again, an agree to disagree at this point in the field. And it's clear, you know, that that for the original substrate that was used in that, in that assay that discovered was very tall being an activator of 31. If you take the tag off, it doesn't work anymore. So there's, you know, it's not nearly as straightforward as it first appeared.

Nick Jikomes 1:03:15

So, stepping back, and just taking a little bit more of a bird's eye view that I mean, there has been a lot of people, I mean, obviously since for forever, people have always been interested in finding the so called fountain of youth. You know, no one wants to get old and no one wants to age and have their body break down or anything. But it feels like in the last couple of years, there have been a lot of very prominent people, scientists included, that have been talking about the possibility that we can not only slow down aging, but potentially even reverse it. And there's very seems like credible people talking about humans potentially at some point, once we figure out enough, you know, living for hundreds of years. And there's startups popping up that are they're extremely well funded. How how much of this is hype, because of the normal human want for this type of thing? And how much of how much of how much are we really learning about aging the last couple years, that gives credence to the idea that we could significantly improve human lifespan to potentially achieve this within the lifetime of someone like you or me.

Joe Baur 1:04:25

Yeah, I mean, I mean, I don't, you know, I don't think there's anything out there that you can cite to say that that's necessarily going to be possible. What we can't do is disprove it either. And, you know, I feel like what's changed more? So is the mindset of some people to like, instead of, you know, boring the public by saying we don't know, we don't know, do we kind of present a vision of what might be out there? And I yeah, in that sense, I agree with it. I think. I think we don't actually understand fundamentally what aging is, you know, there's this idea that it was maybe caused by free radical damage, and, you know, just sort of metabolism over Time was causing damage, and we weren't repairing it fast enough, and that that's not held up right in the most models where you disable their ability to sort of repair or prevent you detoxify free radicals. Those mice don't really have the expected effects on lifespan. And this sort of the only real mechanistic theory on why we're aging in the first place, I feel like you know, is wrong, we don't have a replacement. And so I think, you know, these types of sort of aspirational statements, I think you, I hope are a rallying cry to kind of get to the point where we understand what it is what's really limiting.

Nick Jikomes 1:05:34

I see. So hold on, I just want to make sure I got that right. You're basically saying an oxidative damage. It's pretty intuitive, right? There's free radicals that form as a consequence of normal and tablets and all the time. Free radicals are just highly reactive molecules. And they just sort of literally rip things apart inside of ourselves. And so it makes sense, like, that's physical damage that's happening, of course, that must be related to aging and things breaking down some time. But But you're saying that if you disable in a rodent model, if you disable their ability to make repairs to this oxidative damage, this oxidative stress that happens, it doesn't really have that big of impact on lifespan.

Joe Baur 1:06:14

Right? So there have been probably 30 models made now where you increase or decrease the ability to deal with free radicals. And most of them have marginal or no effect on lifespan. I mean, I think the most impressive one is, is superoxide dismutase, right? You think of mitochondria, which are kind of the powerhouse of the cell where a lot of the metabolism is happening are a major source of reactive oxygen species, they produce super oxide, and superoxide. dismutase is the main enzyme responsible for detoxifying that. And if you make mice heterozygous for that, which was was done by Arlene Richardson's group, with the intention of proving the free radical theory of aging, right, he made mice that are heterozygous, so they have half as much of this detoxification enzyme, they get way more oxidative stress, they get so much damage to the nuclear DNA that they get more cancer. And their lifespan is exactly the same as

Nick Jikomes 1:07:00

Wow. Okay, so that means that there there are more mutations, and there is that cancer liability?

Joe Baur 1:07:07

Yeah, no, I mean, it's not a good thing to you know, to have damage, but it just doesn't appear to be the core cause of aging. Right,

Nick Jikomes 1:07:16

right. Right. Right. Yeah, there must be much more to the story than that. So what are I mean, I don't know. Can you sketch for us? Like, what are sort of the main? What are some of the main threads of thinking on what the the major the major mechanistic players in aging? Could be? I mean, what one of them? Is this oxidative stress idea, but you've just told us? You know, at the very least, it's not it's not the major driver, it seems at least in mouse models. Are there any other? Are there any other big schools of thought on what the major drivers of aging could be? And what kinds of mechanisms are at play?

Joe Baur 1:07:52

Yeah, well, there's a lot of interest in epigenetic aging now, right. So I mean, and that's, of course, tied in with this idea that there are epigenetic clocks, where you can look at the methylation signatures on your DNA in different spots and predictable do are, and maybe, you know, even get some insight into how far apart from your chronological age you've gotten based on your, on your health. And so, the thought there as far as aging is that you know that there are a lot of epigenetic marks that are controlling gene expression and sort of telling a cell how to be the right type of cell, and that maybe over time, some of those are getting lost. The problem is, this is where it's so insidious, right trying to get away from the free radical theory, because you want to say that things like free radical damage would cause you to lose those epigenetic marks, but you almost have to bite your tongue and try to, you can see that some of them could be lost just due to cell replication, which is a reasonable hypothesis. And so I think I think that that is one of the theories that's intact at the moment that that you may just lose some of the epigenetic information that code cells had to do their job. And eventually, they become a little bit blank tomorrow of a work cell phenotype, but they don't perform their functions. Exactly right.

Nick Jikomes 1:08:58

Yeah, I would love to dwell on this for a minute. Can Can you unpack for people? So what is DNA methylation? Just for someone who doesn't know what that is? And then what is this idea of an epigenetic clock? And because I see products like this all the time, I've seen them in ads targeted at me, right? You give a you know, a swab of your saliva or whatever. And apparently, this test is going to tell you, your biological, your true biological age, versus your your calendar age. So you know, if you're not taking care of yourself, yeah to do would be, you know, maybe I'm a 34 year old, but from the perspective of my DNA, or some other part of my body biology, I'm actually physiologically like a 40 year old. What are these clocks? And are those things actually accurate?

Joe Baur 1:09:45

Okay, so let's start with the factual part. So the methylation is a mark. It's essentially like a switch that can be placed on your DNA. And so it can control gene expression and be involved in different signaling processes. But as far as this clots, it's also occurring in parts of your DNA that we don't know of any function for, right, it's some to get some cases, far from genes, it just certain pieces of your DNA are methylated or not. And the person who came up with with a lot of this clock dogma in the first place was a guy named Steve Horvath who's really a statistician by training, and was looking at these methylation marks and came up with a combination of them that seemed to be able to predict the chronological age of people that the samples were taken from. And he really rigorously proved that statistically, without having any real biological insights into why these changes, you know, would matter. And he even made the point that many of the ones that he's actually looking at are the ones that are not near genes, not obviously switching genes off or on, it's really hard to sort of guess at why they would be important, or his guess is that they're not important that they're markers of something, right, and not drivers of whatever this aging process is, but But it started from that basis of just statistically that this argument was there. And it was really clear that you could predict chronological age for the sample by by reading off all these methylation marks whether and not just, you know that they're all off or all on but that some go up and some go down with age. And by taking enough of them together, you can get a signature that's pretty reliable, for about the ages for that particular sample. And so from there, the question has been, can you extend that to, you know, to actually say, your biological age versus chronological, and that's been much more controversial, right, you can do things that change the way the clock reads out, right? If you set it to, you have this system where you can predict someone's age. And you can ask them to sit, calorie restrict or fast or something and then measure it again, and it looks like they're a bit younger. But whether that's truly has any under the biological meaning is what's really causing all the controversy right now, right? There's some some groups sort of pushing that idea that you've moved the clock. So it looks like you're a younger person, therefore, you've rejuvenated yourself and other people saying, like, you know, those methylation marks don't mean anything, we have no idea. You know, there's no basis for making that claim.

Nick Jikomes 1:12:03

I see. I see. So, so in terms of where the science is at right now, you know, if I had a clocking in my room, I could physically go and turn the dial back an hour and be like, Look, it says it's an hour ago. But it's not clear whether or not I've actually turned back the clock, or I'm simply fooling myself, and it's still noon instead of 11am.

Joe Baur 1:12:23

Exactly. Yeah. And it may well be you know, that that time went back an hour. You know, we don't know, there's some encouraging data suggesting different interventions, like calorie restriction that we know will extend lifespan is also pushing the clock back or slowing it down. And that if you're, you know, obese, that, that it looks in general, that gets a little bit accelerated. So, you know, I mean, it's by no means disproven that this, this is gonna work. But it's not proven yet, either. And I think definitely, you're feeling right now, if you get onto the new people's Twitter feeds the pushback. Yeah, you haven't proven this yet. You can't, you know, go using it as the as the readout for health.

Nick Jikomes 1:13:02

I mean, so based on everything I've heard you say so far, in terms of things that regular people can choose to do or not to do? Is it fair to say that probably the single most impactful thing any of us could do that is very likely to extend our lifespan? To some extent, his caloric restriction?

Joe Baur 1:13:25

Yeah, I mean, I think that's, you know, that's the extreme one, right? I mean, there's, you know, diet and exercise versus the, you know, the things basically everyone should be doing, if you were going to take, you know, a stab, or you did something drastic, I think calorie restriction has a real good chance. But again, we don't have the ultimate effect on lifespan in humans, we only have that we know, it will improve your biomarkers, you know, they're predicting decreased incidence of many diseases.

Nick Jikomes 1:13:51

And one more question, calorie restriction that I'm not sure. I clearly articulated before. Is this. You know, is there a linear effect here? So let's just say, let's just say, I'm eating twice as many calories as I probably should. So I'm someone who eats a lot, and I'm clearly over eating, if I restrict my calories, so that I'm sort of eating the normal recommended amount of calories? Is that going to have a beneficial effect? Versus if I'm eating sort of the the normal amount, but then I really take it down to something below that. And is there is there a linearity to that relationship? Or is it? Or is there a nonlinear do you do I really need to go to, you know, 40% reduction from what a normal recommend diet recommended diet would be in terms of calorie content in order to see any effect. But

Joe Baur 1:14:45

no, there probably is a linear relationship. And, and then, you know, at some point, there's a an end, you know, to the benefit, too, right? And he's got a point we got off a cliff and people see that and studies like in flies where you can sort of just restrict them right down to nothing and You'd see there's a, you know, a bell curve where less than they wanted is optimal for lifespan, but then clearly, there's going to be a point where you're switching into starvation or malnourishment. And and certainly you do, if you take on this calorie restriction idea, you've got to sort of take responsibility for getting all the vitamins and minerals and things to because you have just that fewer number of calories, but you're completely malnourished, because you're spending them on you know, and white bread or something, you know, you're not going to be in good shape and clear. And, you know, people have looked at the survivors of famines and things where people have essentially had, you know, the, the calories of calorie restriction or laughs over long periods, and they clearly have health problems afterwards, you've got to make a commitment and put some effort into, to not knowingly, you know, do something detrimental with that. The other thing I'll say is even in the mice, you know, it varies by strain. And by gender, you know, when where that optimal point is. And so there have been some studies done recently where 20% calorie restrictions, but compared to 40%. And in some ways, the 20% works much better. And so you can imagine, you may already be over the starvation point, going to 40% as a human, most of the human studies, then 25%.

Nick Jikomes 1:16:06

And so in these calorie restriction studies, is it always? Is it always constant calorie restriction? Like you're taking the mouse? And then for the entire span of the study or the span of that mouse's life? It's on this calorie restricted diet? Or have you have people seen any benefits from intermittent calorie restriction, like you just take a day, a day long or two day long, fast, but you're only doing it for those one or two days, and then eating normally, outside of that you see that similar the same kind of

Joe Baur 1:16:33

effect? Yeah, so so all of the above very people have tried all kinds of these regimens. And the one I described as kind of what was the standard, you know, was the benchmark people measure other things against, but for instance, it became quite common to do calorie restriction, redo three meals a week. So it's 60% per day, but So on Monday and Wednesday, you get two days worth of food, and on Friday to get three days worth of food, which you can probably imagine is due to technicians not wanting to come in on the weekend. And it's been shown that you're taking that approach, you can also get lifespan extension that looks pretty equivalent to what you get with the, with the daily feeding. They're one of the oldest regimens is was every other day feeding. So in parallel to this sort of 60% of calories, people have instead been doing food every second day. And if you measure the food intake of those mice, it depends on strain again, or whether it's mice or rats, but typically they're eating 90% of the calories that the other group is eating, and especially in rats, that can extend lifespan, in some cases, more than the the 40% restriction every day. In mice, we found that the 40% restriction tends to work better than the every other day feeding.

Nick Jikomes 1:17:42

I see. I see it depends, but but in general, if you're calorie restricting with any pattern, there often is some kind of longevity effects that that you see.

Joe Baur 1:17:55

Yeah. And you know, people have tried different configurations, trying to isolate what the different effects are. And clearly, there's a main effect of, of just of calorie intake, you know, pretty much whatever you do, if it results in a reduction in calorie intake, that can get a benefit. But there also is accumulating evidence that just just fasting may be enough that, that if you serve people do like the every other day feeding regimen where they extend the time with food by a few hours and try to get that last 10% of calories back into the animals. So they're really eating the same overall calorie intake, but having this big fasting period, and still seeing some benefit of lifespan.

Nick Jikomes 1:18:31

Interesting. Interesting. I wonder if you know, I mean, I'm just speculating at this point. I wonder if that's simply related to the, you know, if you think in evolutionary terms, you know, animals almost never have perfectly consistent access to food, they're always to some extent going through through bouts of real hunger and food deprivation and bouts of, you know, food intake. Is the body somehow just expecting that kind of pattern?

Joe Baur 1:18:59

No, yeah. I mean, intuitively, I mean, your metabolism, you know, going from a feeling of fasting transition, you reverse a lot of things about your metabolism. And you can certainly, it makes intuitive sense, I think that your body would be used to having these cycles and that, you know, that you're sort of holding it in the Fed state indefinitely, you could really cause some long term problems.

Nick Jikomes 1:19:19

Yeah, it almost It almost reminds me of what you said about being sedentary, where it's like, if you're just not moving all the time. That's the real issue. At least get up and do that sort of 15 minutes of focused exercise to switch your body at least that little bit. I mean, it sort of feels like there's an analogy there, right, like, Okay, if as long as you just take a little bit of time to your body get hungry. You know, maybe maybe that's better than nothing at all.

Joe Baur 1:19:43

Yeah, no, I think that's there's definitely, I think maybe an aspect of sort of pressure relief, you know, that just needs a little something like that. He said.

Nick Jikomes 1:19:53

So, um, so what is your lab working on right now? What are some of the most interesting questions that you guys are pursuing today?

Joe Baur 1:20:01

So that's mainly focused on on na d, they've been a couple of different areas that we've been working in one of them is is trying to discover, you know how anybody gets localized within the cell. So one of the, the issues in this whole field right now is that we know a lot of mentation studies, right, where you just fill the body with an ad precursors and ad levels kind of go up and, and we see some benefit sometimes. And other times we don't, depending on the system, but we really don't know where in the boom, first of all, which cell types are important for a lot of these effects. And then even within the cell, there's different compartments of an ad, it's actually inside enclosed inside many different organelles. And we don't really know which organelles are getting more energy, if it's all of them are specific ones that responding are responsible for what we see. And so one of the key ones is the mitochondria, right, a lot of the key metabolism that's going on, and ATP generation is happening inside the mitochondria. And they have an ad inside that's separate from the rest of the cell. And so my lab for a while, it's sort of been focused on demonstrating that they do take up an ad from the cytosol. So from the surrounding part of the cell, that's how they get it, they don't make their own. Or they, at least if they do make their own in many cases, it's a minor contribution to where they're getting it. They're mainly taking it up from the cytosol. And and sort of identifying the transporter that does that. So we recently did, it was an orphan transporter club, just given the systematic name. So it was called SLC 25, a 51. And there was nothing, you know, no scientific literature on this transporter at all, except that it it showed up at a couple of screens is something that was essential, the cells would die if you deleted it. And so we were able to show that that is actually what's mediating the uptake of na d. And now our labs, you know, engaged in trying to discover, you know, what the consequences of that are. So if we blocked this pathway so that we then give supplements, but you can't get the energy into the mitochondria, do they still have any beneficial effect, I see this genes up or downregulated, in the first place is that doing something? So we see, for instance, if you look in databases of tumors, this gene does show up as one of the ones that's predictive of, you know, poor or better outcomes for different tumor types. And in particular, it's it depends on where it comes from. But in the kidney, it stands out that it's actually beneficial if you have high expression of this gene. And kidney tumors are kind of famous for relying on glycolysis for not using their mitochondria for energy generation. And so in the kidney, you can imagine if you if you switch this gene on, and you forced them to jam all the energy into the mitochondria, and they'd be revved up, but the cancers don't like that pathway for growth, they're relying on it on it working in the cytosol, you can see maybe that that would actually be a beneficial thing to drive it up in that type of tumor. But in other tumors, you might want to inhibit the pathway where they really are dependent on their mitochondria. Really looking for applications for this right now and seeing what basic understanding we can squeeze out of it.

Nick Jikomes 1:22:50

Interesting. What are some of the major areas that that the field of aging biology in general is working on right now? Are there one or two sort of big questions where there's a lot of activity and a lot of labs pursuing things aggressively?

Joe Baur 1:23:02

Yeah, I mean, I, so I think clocks, as we already sort of touched on, I think there's there's a lot of labs, developing new clocks, and and really trying to get, you know, more insight into how much biological meaning they really have at the end of the day. And so the other big areas of senescence, so the cells that we've touched on earlier, so it's, again, Jim Kirkland spent a lot of times looking for compounds that can selectively cause the senescence cells to die, and has been pretty successful in identifying some different combinations. And those have actually gone through a series of mouse trials and are already now now in humans. And I think it's become a really big question in the field of if you can eliminate all the senescence cells, is that going to be beneficial for lifespan? It seems to make mice live longer if you'd if you get rid of them.

Nick Jikomes 1:23:48

And I just feel like given the subject matter, I should ask this kind of question, you know, given who you are, and what your expertise is, and your knowledge of the science here and obviously your knowledge that we all share of what people get exposed to a by product marketing. Um, is there anything you know, is there anything that in particular that you were don't do beyond the obvious making sure that you're eating a healthy diet, making sure that you're getting some exercise, and the thing that we haven't talked about is probably relevant here is getting adequate sleep? Is there anything that that you do that you at least hope or think is likely to have a positive impact on how your body is aging? Are you buying any supplements that you think, you know, the evidence is strong enough that hey, it's, it's at least worth worth a shot to take this stuff.

Joe Baur 1:24:41

I'm not taking anything consistently. So I mean, I think the biggest thing for me is still this sort of lack of knowledge. So I mean, I'm very curious about a lot of the supplements and so I do techniques in my driver side at times, I've taken resveratrol at times just to, you know, to see if I feel subjectively like I'm getting any benefit and again, just just because these large scale clinical trials, you know, aren't forthcoming. And there's not going to be another way for me to really know. You know what I think about these things. But I would say yeah, I'm not I have not committed to, you know, to long term supplementation with anything at this point. I just whenever I get on this subject, do remind myself to eat a little healthier to make sure I'm getting that exercise a little more regularly. But But, yeah, supplements I'm still experimenting, a little bit of curiosity, but not committing.

Nick Jikomes 1:25:30

Got it? Well, Professor Joe Bower, we've gone over a lot of interesting stuff here. So I want to thank you for your time. Are there any final thoughts you want to leave people with on things that you think are worth re emphasizing things that you think people might want to know if they're interested in aging biology, or or even resources that you might point people to if they want to just learn more about the field if they're interested?

Joe Baur 1:25:56

Well, one thing I probably didn't work in and maybe shed is just to emphasize the the quit smoking part of living longer. That is certainly, you know, the one intervention anyone who's smoking can can take to to have a more immediate and dramatic effect on their predicted lifespan than anything else, right now. And, no, I'm not. Yeah, other than that, you know, just like I said, I think, you know, to eat healthy, make sure you exercise, like you said, Get get good sleep, and yeah, but I mean, those are really the key things.

Nick Jikomes 1:26:32

All right. Well, Professor Joe Bauer, thank you for your time. Thank you.

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