About the guest: Gary Churchill, PhD is a statistician & geneticist at the Jackson Research laboratory in Maine. His lab uses a systems approach to investigate the genetics of complex biological traits in health & disease.
Episode summary: Nick and Dr. Churchill discuss: his recent papers looking at the effects of caloric restriction & intermittent fasting on nearly 1,000 genetically diverse mice; how dietary restrictions affect longevity, metabolic health, immunity, and hundreds of biomarkers; the role of genetics vs. diet in aging; and more.
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*This content is never meant to serve as medical advice.
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Episode transcript below.
Full AI-generated transcript below. Beware of typos & mistranslations!
Gary Churchill 1:22
I'm a I'm a professor at the Jackson Laboratory. I've I've been here for more than 25 years now. I love living in this part of the world. I was born in Maine, and I live right next to National Park, and there's a lot of benefits to it. I became, I was originally. I got my degree in mathematics. I went on to get a PhD in statistics, and I've always been interested in genetics, and I came to the Jackson lab by circumstances of life and really became immersed in mouse genetics. So if I had to pigeonhole myself, I would say that I'm a mouse geneticist, and for the past 15 or so years, I've been focusing on metabolism and aging as my areas of interest, but I still retain that mathematics, statistics, data oriented mindset, so a lot of my work is is related to experimental design and interpretation of data.
Nick Jikomes 2:36
Yeah, yeah. And, you know, many people might not know this, but it's interesting that you have the statistics background, and then you went into the realm of biology and genetics. Genetics is a field. It's obviously a field of biology, but it has very rich history of a lot of hardcore statistics. And I think some people might not realize, like, how hardcore The stats are that a lot of people the chops and stats people have when they do genetics. Yeah,
Gary Churchill 3:05
genetics is a really quantitative field. I remember as an undergraduate, acing the genetics course, and all the biology majors were dreading it. So it's wonderful. It suits me very well. It lends itself to analytical thinking, but it also throws some real biology at you there. I mean, biology is complicated and messy. And I will say, before we get into it, that one of the challenges of dealing with this unraveling this story is that it's complex. And of course, you want to tell a simple story so that you know you communicate something that it's effective, but I think the complexity is real. Yeah, really shit.
Nick Jikomes 3:45
So yeah, and we'll get into that. It's gonna be reflected a lot, I think, in this paper that we're gonna discuss, just because, and this is often some of the most interesting stuff, where, you know, I think you have results here that are counter to what most people would have predicted and defy obvious explanation, and we'll talk about some of that. For background, many people might not know what the Jackson Laboratory is, but it's a very sort of important node in the research world. So what is Jackson labs? Of
Gary Churchill 4:15
course, the Jackson Laboratory is a nonprofit research institute. We're located on the Mount desert island off the coast of Maine, founded in 1929 by you know, moguls who came here for the summer and thought it'd be cool to start a scientific Institute. They did. We're most well known for mice. We do. Most of the researchers here work with mice as a model organism. Our focus is on using mouse models and genetic tools to investigate human health, really, that's in a nutshell. Mm. Um, and
Nick Jikomes 5:00
so you've got this new paper out that we're going to discuss that's really interesting. It was quite a massive undertaking, it looks like, and it has to do with the relationship between dietary restriction and health and lifespan. So this is a mouse study. We're going to unpack it. You used a lot of animals here, and you used specific types of mice, and we're going to get into all of that. I want to give people a general base here, some background on some terminology, some concepts, and some, you know, limitations and methodological issues that are often inherent to this kind of work that at least to some extent, you guys are getting around with this study. One of the things I want to talk about here is just mouse genetics at a basic level. So most experiments that are done in laboratory animals like mice are often done in inbred mouse strains. Can you talk about why that is, and the types of mice you used in this study and why? Okay,
Gary Churchill 6:00
inbred mouse strains like the C 57 black 6j mouse, those developed here at the Jackson lab, were developed to ensure that experimental results would be more reproducible. And inbred mouse is created by a long series of generations of brother sister mating, so that each of these mice inherits half of their genome from their mother and half of their genome from their father, and after many generations, those two genomes become more and more identical, so that In a sense, they're almost identical twins of themselves, and they can reproduce exactly the same genotype over and over again. So when we study an inbred mouse, it's really akin to studying one person, and they're also inbred, which is a little unusual in nature. There are some challenges that come with being inbred, and I know where we're going with this. So, yeah,
Nick Jikomes 7:07
yeah. So on the one hand, you know, having this relatively genetically homogenous inbred mouse strain or laboratory strain of animals, that can be a feature with respect to research, because it can give you more reproducibility. There's less genetic variability that's going to introduce variation and noise potentially into the results. On the other hand, as you say, it might be problematic from another angle to think about this, because, you know, inbreeding is not something you see in nature, and it's not necessarily going to, you know, we might find some things that reflect, uh, not what we would see in nature, in a more genetically diverse population, that might inhibit our ability to generalize results from these particularly bred laboratory strains to other species, including even ourselves.
Gary Churchill 7:58
I think the key word there is generalizability. If we study C 57 black six mouse at the end of the day, we're really limited in the scope of what we can say to just that particular mouse strain, and anything that we say about other mouse strains or other species like humans is extrapolation, and it may be true, but it's it's guesswork. So by working with the outbred mice, which I'll explain, if you would, we increase the generalizability of our studies to at least more mice, and we feel that that's going to increase our potential to generalize to humans, which is the objective here,
Nick Jikomes 8:47
and in very simple terms. So what is outbreeding here? Is basically the opposite of inbreeding. So you're creating genetic diversity. Is there anything more we should know about that
Gary Churchill 8:57
the outbred mice, the particular ones that I worked with in this study were originally eight different inbred strains that we mated together with one another, and we maintain them again for many generations. But instead of mating brother sister together, we randomized the mating so that just like people, the mother and father of the next generation, are not related to each other, and that makes the genomes all mixed up, and it makes every mouse in individual and unique. And that has some drawbacks, because we can't put the same genotype in two conditions. It would be fantastic to do this study and have the same genotype on all five diets, but that's we'll do that. We'll figure out how to do that. But the outbred mice, really, I think, I don't want to say there. Model for human populations, because they're not in some ways, they're they're a better tool for genetics, but they have the kind of heterogeneity and diversity that you see in humans, and I think that's exceptionally important for aging, because I think everybody ages in their own way. So each of these mice is going to age in its own way. Oh, by the way, outbred means the two copies of their genome are not identical, and that gives them a feature called hybrid vigor. So they're they're really healthy. General speaking, so,
Nick Jikomes 10:36
yeah, coarse grained level. Generally speaking, these mice sort of look and act obviously healthier. Presumably, they live longer than the traditionally used inbred mustains as well, I would imagine. Well, surprisingly,
Gary Churchill 10:47
no, their average lifespan is about the same. It's about 20 months, so a little shy of two years average. But what's different is the variance in the lifespan there are outbred mice. Can an inbred mouse will have a lifespan that's pretty within a window. There's a lot of randomness to it, and they almost always die of the same causes, like a 57 will almost always die of a lymphoma. They have their own built in genetic Time Bomb, so to speak. And the diversity mice, well, they display all kinds of lifespans and different causes of death. And we've had, we've had outbred mice live as long as four years and nine months, which I'm going to say it in dog years, is 140 it's a bit of as a
Nick Jikomes 11:48
joke. So I think what you're saying is the average lifespan of these outbred mice is about the same as as the inbred mice, but there's more variability in terms of how long the popular they live, population wide more variability in terms of the ways in which they succumb.
Gary Churchill 12:04
Yeah, I could have said that. Thanks.
Nick Jikomes 12:07
So basic concepts here, we're talking about dietary restriction and its impact on health and longevity. In these outbred mice, we've got calorie restriction, we've got dietary restriction, and then we've got intermittent fasting. What are the essential differences between these three things? Well,
Gary Churchill 12:24
yeah, the language we tried to be consistent within our paper, but it's not always consistent across all the literature. So what I mean here by caloric restriction is we fed the mice a standard Chow diet. That's a healthy diet. We figured out how much a normal adult mouse would eat, and we reduced the amount of food that we provide them by either 20% or 40% so they're getting 80% of the food they would normally eat, or 60% of the food they would normally eat. So those are the caloric restriction and intermittent fasting. There's a lot of ways to do intermittent fasting. Probably most of your listeners are going to be familiar with the 16 eight paradigm. It's very popular these days. People restrict their eating to eight hours a day. We did something a little different. Here. We did intermittent fasting, where we removed the food from the mice on Wednesday and we gave it back to them on Thursday or Friday. So they either went for 24 hours or for 48 hours without food. And I know people listening are thinking, well, I could do that. I could go 24 hours without eating, but you're not a mouse, yeah. And one of the things I want to emphasize, and one of my concerns about publishing this paper, is that people will look at these diets and they'll think, I should do that, and I would highly advise, no, you will not tolerate 40% caloric restriction. People barely tolerate 20% caloric restriction. When we fast the mice for one day or two days, it's a little hard to say what the equivalence is, but it would be like you fasting for two weeks.
Nick Jikomes 14:16
Yeah, yeah. Because, because they're small animals, their metabolic rate is different. You wouldn't
Gary Churchill 14:20
want to do that exactly, yeah. So my point is, these, these interventions, CR, and if, as we abbreviate them, they're pretty extreme, we needed a term to to refer to them both at the same time so that we didn't have to write CR. And if every time,
Nick Jikomes 14:38
yeah. So these are all forms of dietary restriction, but they're both dietary restriction,
Gary Churchill 14:43
and I use the word dietary restriction very broadly to refer to almost any kind of restrictive intake, timing or calories, yeah.
Nick Jikomes 14:54
And obviously everyone is inherently interested in health and in longevity, but I think the point you're. Trying to make here is we have to be very cautious about jumping to conclusions about humans here, because, you know, one day of fasting in a mouse is not equivalent to one day of fasting in a human. We're talking about fairly strong interventions here, and I think that would imply that all of the results we're going to talk about are right. We need to keep in mind that these are strong interventions and so any more mild forms of fat. So if I fast for 24 hours here, I should expect, if anything, weaker effects than what you saw on the mice, for example.
Gary Churchill 15:31
I would not argue with that, and I would also say that there can be benefits to reducing calories and to fasting. We just need to be a little careful. And what we're trying to do with the mice here is to push the envelope, because we're interested in the fundamental biology. Ultimately, we want to understand the mechanisms, and one possible outcome of these studies down the road would be to understand the mechanisms and find different ways to intervene so that we could use our understanding derived from calorie restriction to find other routes to improve health.
Nick Jikomes 16:11
And so I want to give people a basic sense before jumping into the results themselves of where this field, broadly speaking, sort of stood, and what some of the motivation to do this work was so obviously, people have been talking about calorie restriction and dietary restrictions of different kinds for some time. Intermittent Fasting is very popular. And I think sort of a headline summary of this field is that, in general, people often find that dietary restrictions like this tend to result in health benefits and increased lifespan. Is that basically what the thinking has been and how does this tie into what is known and unknown about what was actually causing these lifespan benefits from restrictions? Okay,
Gary Churchill 16:57
it's a little nuanced, but let's start with the dietary restrictions. Caloric restriction in particular has been known to extend lifespan in rodents for 100 years. Yeah, we we also have seen research in the past decade or two suggesting that not every genotype. So remember, if we look at inbred mice, if we calorie restrict, C, 57 black, six, they live longer. But it wasn't really clear that all mice would benefit from caloric restriction. And I think that was the biggest motivator. Well, I did this. It was the biggest motivator for doing this study without bread mice to ask the question whether caloric restriction would be universally beneficial, or whether there might be subsets of animals that really didn't benefit from it in terms of lifespan. Yeah, you know, lifespan is, really, is, is a measure of aging, and I would like to if you would help us come back to that point in a bit. The question I would ask, though, is, do you want to live as long as you possibly can, or do you want to be healthy while you're alive?
Nick Jikomes 18:20
Yeah, health span as opposed to lifespan.
Gary Churchill 18:22
So we did focus on lifespan as our primary singular outcome. But as you know from looking at the study, we measured everything under the sun related to health, everything, yeah, and in particular, these interventions improve metabolic health. And this is a this is a really good thing for people, because we have so many such a high prevalence of metabolic disease, and we saw these improvements in metabolic health in the mice on the diets. So extend lifespan, improve health, with some caveats. So
Nick Jikomes 19:01
another thing that you did here is, not only are using outbred mice, they're more genetically diverse. You used a lot of mice. This study involved almost 1000 mice. Obviously, this gives you statistical power. You also needed to do that more just sort of by necessity, because you don't have genetic homogeneity. So you need there's gonna be more natural variation from mouse to mouse. You're looking at, you know, five different cohorts of mice, mice that get to eat whatever they want all the time. You've got mice that have, you know, one day of fasting imposed on them, mice who have two days of fasting imposed on them. And then you've got the 20% and 40% restricted groups. They can eat as much as they want, whenever they want, but, but there's this limit on the total available calories to them. And as you said, just keep in mind everyone. We're not going to list every single thing that you guys measured, but you measured a lot. Can you give us just a basic sense for the diversity of measurements and biomarkers and things?
Gary Churchill 19:55
I will talk about the scale that the mice. From the first cage that we filled until the last mice died, spanned almost eight years. Wow. At the peak of the study, we had seven full time technicians just managing the phenotyping schedule. We really learned a lot. We did all kinds of clinical assays. We weighed them every week. We we put them in a in an NMR, an imaging machine to look at their body composition. We put them in metabolic cages for a week at a time to see their circadian rhythms and their metabolism, their activity, they went on wheels. We did multiple blood draws. They got echocardiogram. I'll stop you get the idea, yeah,
Nick Jikomes 20:50
everything like everything under the sun, yeah? Why
Gary Churchill 20:53
not? You're just gonna do this once, yeah, yeah.
Nick Jikomes 20:56
So very thorough, very, very massive study, eight years of time. It sounds like one last piece to mention maybe is, I think you looked at female mice only. Is that just to decrease? Is that true? And was that just to sort of decrease?
Gary Churchill 21:09
We looked only at female mice, and I think that's a that's a weakness of the study. But I'm gonna add that there have been so many studies that have been done only on male mice that I feel like it was fair to tip the teeter totter the other way. One of the issues with the diversity mice is that they are genuinely real wild mice, and in the wild, female mice tend to live together rather well, and male mice not so well always. It doesn't happen all the time, but if you leave male mice together for a long time in a cage, and you deprive them of food, they fight, yeah, once the mice start fighting, you know, they get injured and you're obliged to euthanize them. Yeah, yeah. We felt that the investment we made in each mouse by the time it's two years old is, you know, $10,000 it's a lot,
Nick Jikomes 22:09
wow, yeah, that's interesting way to think about it. You you invested, you know, $10,000 of, you know, supplies per mouse. Yeah, ouch. Um, but anyway, so you've got almost 1000 female mice in this study. What's the first basic result here? So you've got these five different groups of mice that are in five different feeding schedules, basically, what's this headline result here? In terms of how lifespan differed, raw lifespan differed between the groups? Well, the
Gary Churchill 22:39
basic result is that these dietary interventions all extended lifespan. And you might say to yourself, that's not a surprise, but I feel like it was somewhat surprising to me, especially with the two day intermittent and the 40% caloric restriction, because I felt that one of the likely outcomes is that these interventions would have such severe detriments that we would shorten the lifespan of some animals, and honestly, I didn't see that. There was no indication that there was any fatalities due to the interventions. So that was a good outcome for us. But in, you know, in the strictest sense, as a statistician, I think what we've demonstrated here is that when we assign these diets at random, they extend the lifespan, and because of that, we have a causal relationship. Dietary intervention causes lifespan extension. And I'm looking at my notes here because I want to get this right, but I want you to think of a little a little circle with diet written in it, and a little circle over here with lifespan written in it, and an arrow that points from diet to lifespan with a plus sign on it and establish that. But why do we measure all that other stuff? I'm sorry, I'm not supposed to ask you questions.
Nick Jikomes 24:07
Well, I mean, you know, so, I mean, there's, there's some natural questions here is, yes, you know, these mice may be living longer, but are they more sickly? Are they more frail? Do they have less energy? Are they less healthy? In some sense, based on other measures, we might care about
Gary Churchill 24:21
what we saw and when you put let's talk about the 40% CR mice, because they are so extreme. All the mice on interventions lost weight. The 40% CR mice lost weight continually through their lifetime. They lost fat mass. They lost lean mass. This is not good. You would not like that. But we when we look at the mice, we handle them, they're really quite healthy. They don't have any obvious deficits. They're not sick. In fact, we know that we reduce the incidence of palpable tumors. So. They're likely not getting cancers while they're on these interventions. Their their blood glucose stabilizes, they don't get obese. I could go on and on, but when we looked a little deeper, especially when we looked at properties of the immune system, and we looked at the red blood cells, there were definitely indicators that these interventions are not are not universally good. I think you know, whenever you manipulate a complex system in any way, you're going to have good and bad, right? Yeah. And maybe
Nick Jikomes 25:37
something important to keep in mind as we go through some of the details is, you know, the mice in these groups did have lifespan effects. So 40% calorie restriction resulted in quite a substantial increase in lifespan. But as you said, and as we'll keep in mind as we go through some of these biomarkers and other things, I want to emphasize too, that, you know, these mice are living in assisted living for their entire lives. They don't have to worry about dense packing in large groups that might result in pathogen transmission. They don't have to worry about getting, uh, eaten by an owl or a coyote or a predator. And so I would imagine that some of the things that that we talk about, even though, even though these mice live longer with these dietary restrictions, such mice under such conditions, if sort of transposed into the wild might actually live shorter lives for various reasons. We can imagine.
Gary Churchill 26:23
This is the generalizability question. I can say that under these conditions, the dietary restriction extends lifespan. You were right. There are no predators, there are no pathogens. They live in a clean facility. We do house them in large groups because they're social. They like to be not packed in, but they like to live close to one another. Yeah, they're healthy mice. And they're healthy mice because they get a good diet and we take care of them. Veterinarians look at them every month and yeah. So
Nick Jikomes 27:00
getting into some of the results here, yeah, can you give us just a little bit more detail on how some basic measures changed across the lifespan in the different groups, body weight and body composition, adiposity, things like that?
Gary Churchill 27:15
Yeah, we saw some interesting differences between caloric restriction, intermittent fasting. And the one that really struck me is that mice who are feeding ad lib so all you can eat, which mice self regulate? They do a good job. They have healthy diets. They tend to grow and they gain lean mass almost throughout their entire lifespan. And the intermittent fasting mice, despite their weekly deprivation, if you would gain lean mass, they lose some fat mass. And you know, so they're, they're, they're leaner, but they don't lose that muscle. They don't get smaller. Caloric restriction mice lose everything. They lose lean mass, they get smaller. That's one thing we noticed. Another thing we noticed, and that is, I need to talk about red blood cells for a minute. You want to give me permission to do that?
Nick Jikomes 28:12
Yeah? Absolutely, yeah.
Gary Churchill 28:14
Red. Red blood cells are the most common red cell in your body. You've got trillions of these things, okay? And they not only do they deliver oxygen to your whole system, but they do all kinds of biochemical things while they're they're flowing around through your circulation. And red blood cell lives about 120 days in circulation. And the way that happens is, as they as red blood cells age, they tend to get bigger, and your spleen is constantly monitoring the red cells, and it'll identify the big ones and filter them out, so it's keeping the red cell population healthy. So one of the measures that we take on these mice is we look at their red cells. We know how big they are, we know how much hemoglobin they have in them, and we know their their distribution. We know how big they are and what happens in especially the two day intermittent fasting, but also in the 40% CR mysis, that distribution gets wider, and that tells us that the spleen is not doing its job efficiently. It's not, you know, the red blood cells, the way it should be. And this measure, RDW, it'll be on, on your on your report from your annual health because it's, it's typical clinical measurement from a complete blood count test is already known to predict lifespan in humans, and here we're looking at interventions that extend lifespan, but they also increase RDW, which reduces lifespan. And I, I and this. Is a pattern and a theme that comes up over and over again. And remember diet arrow pointing to lifespan with a plus sign. Now that arrow has hidden in it all kinds of things, and that's why we measured all kinds of things. We want to pull that arrow apart and find out, well, what are the steps along the way from diet to lifespan? And one of those things is RDW. So you picture an arrow from diet to RDW with a plus sign, but then rd W to lifespan with a minus sign. It's contradictory, right? And we saw this again and again. The diet makes something worse, but the diet extends lifespan. Yeah, and go on.
Nick Jikomes 30:52
I think we'll come back to that. But is, is the punchline here, that that is just mysterious at this point?
Gary Churchill 31:00
Is it mysterious? No, I don't think it's mysterious at all. I think that the diets don't have a singular effect. They do lots of things to the system as a whole. And if you think about what lifespan means, lifespan is how long the animal lives animals are going to live for a period of time that is, to a large extent, random, but it's also determined by many, many things. And they die of the first thing that kills them. And there are many ways to die, yeah, you know, if you have failure related to your red cells, or if you have other kidney decline or cancer. So diet affects lifespan, but lifespan is a complicated thing. We want to know. What are the components of lifespan that are affected by diet? And some of those are affected in a good way, and some of those are affected not so good way I
Nick Jikomes 32:01
see so. So for simplicity, if we think of our arrow, it's going from diet to lifespan. Let's just say, inside of that arrow, there's actually 100 different factors, 100 different ways, at least, at least for simplicity, let's say 100 and some the dietary restrictions are having some pattern of effect on all, or many of those things. And so even if some subset of those things goes down or becomes more negative, it's a bad effect. There might be a boosting or an increase or a positive effect on some greater number of other things, such that the net effect is that, as a population, you tend to see a lifespan extension. That
Gary Churchill 32:37
is the key as a population. So let's clarify something we said earlier. When we say diet ex, the dietary restrictions extend lifespan. Does that mean that you as an individual, could go on dietary restriction and you're guaranteed to have a longer lifespan? No, it would, on average, increase your chances. But when I say on average, I'm really talking about a population, and in this case, a large group of mice on dietary restriction, means, for whatever reason, some of them manage to live longer. So it's not that there's a guarantee that this intervention will extend lifespan, but it's going to do lots of things, and depending on luck of the draw and genetics, maybe it's going to extend lifespan or not affect lifespan at all.
Nick Jikomes 33:33
I want to talk a little bit about, you know, for a few minutes here, about metabolic effects and in obviously, when you when you restrict animals diet, whether it's the calorie restriction by 20 or 40% whether it's the one or two days of imposed fasting that some of the other mice got, obviously, this is going to have metabolic effects. It's going to influence things like glucose homeostasis, like insulin resistance, like daily energy expenditure. Can you talk about some of those variables, some of those big metabolic variables, things that we knew would change, and how they actually changed across the groups, and what the relationship was with lifespan.
Gary Churchill 34:10
Okay, when we talk about metabolic health, you have to keep in mind that the situation for modern humans is very different from the situation with mice in a mouse room. It actually there are a lot of scientists who would contend that caloric restriction works because we cure obesity and all the associated detriments that go along with obesity. Mice, at least the diversity mice, they don't. They don't necessarily get obese. Some of them do. Some of them don't. They're all different.
Nick Jikomes 34:56
So you're just saying the mice that had free access to food for their whole. Lives for the whole duration of this experiment. They gain weight on average throughout the lifespan, which is normal for animals, as they get older and grow and everything. But they weren't becoming obese,
Gary Churchill 35:12
right? So out of 1000 animals, 160 plus of them on the ad lib diet. We had one over diabetic mouse with a blood glucose that went up over 300 so they're generally healthy. But let's, let's come back to what the metabolic effects are. So the the diet causes a reduction in body weight, which is largely fat, so they're leaner, their glucose levels go down. What else? Their body temperature goes down. I would say that's not a desirable thing. They're cold. They're their activity is interesting, because when the mice are on if and they're not being fed, their activity is low, their energy expenditure is low, but then they refeed and they have high activity. If you go in the mouse room and look at the mice, the restricted mice are the active ones. They're popping up and down and jumping around, and that's because they know you're there, and they know where food comes from,
Nick Jikomes 36:22
they're getting excited by the presence of the human that predicts food. Yeah. So
Gary Churchill 36:26
even though the the impression is that they're more active, they're they're actually less active. I will say that 40% CRM mice retain their activity level throughout life really consistently. Um, did I digress too much? But no city goes down and the blood sugar stabilizes. And these all sound like really good things, and they are in a human context, they are good things, yeah.
Nick Jikomes 36:52
So, so you restrict the animal's diet, 20 to 40% of calories restricted, or they're on this one or two day a week fasting schedule where there's no food access, you're saying you see a lot of expected changes, stabilization of glucose levels, decreases in energy expenditure, decreases in body temperature, things that you expect to change that go in The expected direction and yet.
Gary Churchill 37:18
Okay, so this comes down to the statistical details of how we we understand the data. But let's suppose that the diets are working by reducing obesity, yeah. Then what should happen is, if I look at animals within one diet, yep, this is stratification. If I just look within one diet, if the reason that diet is extending lifespan is due to reduction in obesity, then the animals that lose the most weight should live the longest. Yes, that's the expected result. But what we actually see is the animals that lose the most weight live the shortest. So
Nick Jikomes 38:04
let's, let's say that again, so within a group, so you're restricting the calories that these animals can take in. So you impose that thing on on a group of mice, and they live longer as a population. The thinking is, okay. Well, you're reducing calories. Naturally, the mice will be leaner. They're less fat. And so if that is the reason they are living longer, then within that group, the ones that lose the most fat should tend to live the longest, and the ones that lose the least fat should tend to live the shortest. But what you're saying is that you observe the opposite, the
Gary Churchill 38:38
opposite, yeah. And so within a group, the ones,
Nick Jikomes 38:43
the ones that are the least lean, are tending to live longer. Yeah,
Gary Churchill 38:47
I would say that these diets, they cause extended lifespan. They cause reduced body weight. But if we look within a group and we ask who lost the most weight? They have shorter lifespans. And that is telling me that the reason for lifespan extension is not lost weight. What
Nick Jikomes 39:14
about body temperature?
Gary Churchill 39:17
It's the same story for body temperature. And I guess,
Nick Jikomes 39:20
naturally, sort of maybe a naive prediction here would be like, okay, if I'm restricting calories, the body has just got less metabolic activity going on. I'm slowing things down, I'm cooling things down, and therefore the engine will burn hot less often, and I'll live longer. Is that basically how people would think about it?
Gary Churchill 39:39
That is how people have been thinking about it, yeah. And
Nick Jikomes 39:43
then you see the opposite within a group. It's actually the ones that have the higher body temperature, that tend to live longer,
Gary Churchill 39:49
yes, and I'm going to put my interpretation on this, yeah. It is that I think the diets are stressful. They're stressful. All, yeah, and obviously, just think about it, someone takes away half your food. This is stressful, yeah? Um, the diets are stressful. Stress has some benefits. Stress has some downsides,
Nick Jikomes 40:13
like, are you want some stress, but not too much? Yeah. So
Gary Churchill 40:17
the animals that better tolerate the stress, they lose less weight,
Nick Jikomes 40:23
which makes sense, yeah, yeah. And
Gary Churchill 40:27
the the animals that are more sensitive to the stress, they're they're going to lose weight. I think weight loss is a really good indicator of stress. In a in a mouse, when they're stressed, they're going to lose weight, they burn more energy. And so I think that animals coming into a diet group that are already intrinsically more resilient deal with the stress of the diet better, and they gain the most benefit. And the animals that come into the diet, and they're already maybe not that robust, are going to be hit harder by the diet, they're going to lose weight, and they're naturally going to have a shorter lifespan. So
Nick Jikomes 41:09
did you have any any way to measure something like stress resilience by other means?
Gary Churchill 41:16
You know, measuring stress resilience is a big open question for the field, you can imagine that there are some ethical considerations. We're very serious about how we we handle animals, and of course, we want to avoid stressing animals, so the way we measured stress resilience was actually after the fact, during their lifespans. I told you how much phenotyping, how much measurement we made on these animals. There was a period once a year where they spent a whole month in the facility where we did all these procedures, where we weighed them and put them in the arm machine, and put them in public, pick
Nick Jikomes 42:03
them up. You have to disturb them.
Gary Churchill 42:06
And part of that, I think the biggest stressor for them is to be separated for the from the cage mates. Because when they're isolated, you know, they're looking for their for their cage mates, they know something's disrupted. They're they're not in their home cage. And what we noticed is during that month, almost all mice lost weight. No surprise, it's stressful, yep. So I thought, well, how much weight did they lose? And so we went through, and, you know, we we weigh them all the time. We weigh them at least once a week. So we went through and we blocked off that month from beginning to end, and measured how much weight did they lose. We found is that the more weight they lost, the shorter their lifespan would be. And this was true within every diet group. And again, like, like I was saying before, I think this is a measure of how resilient the animals are to stress.
Nick Jikomes 43:06
Yeah. So the idea here is, what's what's nice about this is you're finding something that cuts across all of the conditions. So within every condition, the mice might have access to food at all times. They might have 40% of their calories taken away. They might be on this intermittent fasting schedule for one or two days within each group. When you do this month of testing, you can measure how much weight they lost, and they would all lose weight because that's stressful and it just results in weight loss. But you're saying the ones that lost the least weight, which implies that they're probably more stress resilient, tended to live longer no matter what the feeding condition was,
Gary Churchill 43:39
yeah. Isn't that amazing, yeah. And it's
Nick Jikomes 43:44
sort of, you know, it sort of really does kind of start to twist and make change a little bit how you think about things like dietary restriction, as you know, it's not merely, uh, changing the pattern of food that an animal eats. It is a form of stress that must be dealt with by the organism,
Gary Churchill 44:03
agreed and stressors can have beneficial effects, because in you think of a mild stressor is enough to stimulate your body's homeostatic response. Your body will respond to a stress by bringing compensatory mechanisms on board. And if you stress an animal, an animal severely, you're going to do damage to them, and that's not good, so we avoid that. But if you stress them a little bit they and I can't prove this with the experiment that we did. We're going to do some more, but I think the diets could potentially also trigger these homeostatic responses and induce more resilience than. And then background, if that makes sense, yeah,
Nick Jikomes 45:03
and what? So one of the things that you found as sort of like an overarching thing is like figure three, for example. It's titled Health and metabolic traits change with age and diet, but are poor predictors of lifespan. So you guys measured all sorts of stuff, cardiac output, grip strength, prevalence of tumors act, you know, just wheel running, activity, all sorts of stuff, and you found that many of these things were changed by diet and did change across the lifespan, which were unsurprising, and yet they poorly predicted lifespan. Can you give us some examples there, and maybe, sort of, what sort of the overarching result was in your view?
Gary Churchill 45:49
Yeah, cardiac output. I forget which way it goes. See if I actually have figure three somewhere. Did we look at Yeah, yeah, I've
Nick Jikomes 46:00
also got it right here.
Gary Churchill 46:01
You know, I can't even read this thing. I I poured over every word for so long, I can't even do it. What did we put on there? Oh, fasting glucose, body temperature and frailty, hmm, I lost the question. Sorry, I
Nick Jikomes 46:20
got. Hold on, hold on. Let me. Let me pull this up here. So you measured about, basically, you measured a bunch of health and metabolic traits, and some of these change with age, as you would expect. You know, animals get more frail with age. You know, you expect something like grip strength to go down with age, I imagine. But nonetheless, even though they changed as a result of the dietary interventions, even though they changed across the lifespan, they were often poor predictors of lifespan,
Gary Churchill 46:49
right? Let's go back to the arrows, and if we think of it as the diet is causing changes in these traits, yeah. So the diet has an arrow that points to cardiac output, it has an arrow that points to grip strength, and it affects these things, but there's no arrow from grip strength to lifespan. There's no arrow, surprisingly, cardiac output to lifespan. So the diet has lots of other effects that are not intermediates for lifespan, yeah, yeah.
Nick Jikomes 47:28
And they're not, they appear not to be intermediates, even though many people would have expected them to be. Yes.
Gary Churchill 47:34
And again, improving metabolic health is a good thing, especially for people improving cardiac output, it's a good thing. So it's, do you want to live as long as you possibly can, or do you want to be healthy while you're alive? And I think some of these effects are definitely in the healthy direction. Um, they're beneficial and they're good and they don't necessarily extend lifespan, so we shouldn't equate good health with long lifespan.
Nick Jikomes 48:01
Yeah,
Gary Churchill 48:02
that's lunch line.
Nick Jikomes 48:03
Were there any things that that looked like? Were there any things that were clearly associated with longer lifespan that you would interpret as being like, less healthy or less desirable to have if one is alive? Oh,
Gary Churchill 48:20
absolutely, the weight loss, yeah, yeah. I think that that's, that's the big one, yeah,
Nick Jikomes 48:27
just losing all of that mass, including that lean mass, yeah, yeah. And I mean, so again, we don't want to anthropomorphize, but give us a set. So remind us again, how, how much so like in the 20 or 40% calorie restriction group, that's quite a severe restriction. Remind us how much fat and how much lean mass was lost there quite a bit.
Gary Churchill 48:47
Oh, that is a good they were, they were about half the size, yeah, be on an ad lib diet, yeah,
Nick Jikomes 48:54
yeah. So in a human being that would be, you know, that's imagine being, I don't know half, roughly half as big as you would have been,
Gary Churchill 49:03
yes and not desirable. Yeah.
Nick Jikomes 49:06
And do you think so things like that in these conditions? We mentioned this before, under these conditions, these things are associated with longer lifespan. But it's very easy to imagine that such a mouse living out in the real world, outside of assisted living, those things would actually be a huge liability.
Gary Churchill 49:23
Well, let's talk about the immune system for a minute. And a month is here, and I really did rely on my immunologist colleagues at the at Calico and at the Jackson Laboratory to help us understand what the immune system changes were. Yeah, and when animals went on these diets, the caloric restriction, one thing we noticed is reduced inflammation. And this is definitely a good thing, we saw fewer inflammatory macrophages. And we presume, based on that, that we have less inflammation, but there's a whole population of cells. That are called NK. They're natural killer cells, and their job is to go sniffing around for viruses, tumor bacteria, and set off the alarm bells and start the process of attacking the virus or getting rid of the bacteria or addressing the tumor. And these cell populations were were badly depleted by the diets. So a mouse in the wild would be exposed to all kinds of pathogens, viruses everywhere. And if that mouse were deprived of calories to this extent, its immune system would not function well and would not survive. And
Nick Jikomes 50:42
it's the basic interpretation. There's simply, that is it basically a common sense interpretation, the immune system is important and it's metabolically expensive. There's a lot of fuel that needs to run an immune system to deal with an infection, clear it out. And therefore, if you substantially restrict the diet like this, there's, you know, it's probably not surprising that the immune system is not going to be able to run at full throttle. I
Gary Churchill 51:06
think that's absolutely true. It's accurate. And there's another thing to know about the immune system, and it's a very knife edge thing, because when your immune system kicks in and it's fighting an infection, it does a lot of damage. So there's a real fine balancing act between how reactive your immune system is. We know with covid, for example, when people would die of this, it would often be because of the inflammatory effects that are the sequelae of the immune reaction, and, you know, not a direct result of the virus. So your immune system has to be kind of in this just right place, and in the dietary restriction, at least that component of the immune system, represented by the NK cells, is kind of down. It's not up to speed, so it won't protect them from viruses. The flip side is they don't have inflammation, yeah? Because their immune system's not overreacting to things. It's not
Nick Jikomes 52:19
Yeah, so they're probably, they're probably, on the one hand, benefiting from lower levels of chronic inflammation. They're less likely to have an immune system that's inflaming the body too much in response to an injury or something like that. On the other hand, there, they are more susceptible to infection. That's what I would guess. Yeah. If you were to put them out in the real world, everything
Gary Churchill 52:41
is context, yeah, yeah. The mice live in SPF, and we keep it pretty safe and clean for it.
Nick Jikomes 52:51
So the other there's another sort of major result here that I want to talk about. So it was really cool. You were using so many mice in the study for such a long time you have these genetically diverse mice, they aren't the inbred masterians that are typically used in experiments. So now you can look at actually genetic variability as as a variable. Here you can see how, how things vary as a function of the genetic distance between individuals within each of these groups. And there's a result here that I personally do not find very surprising at all that, I think is very important. I think some people maybe will find it surprising. Some people might find it, I don't know, a little upsetting or something sobering, maybe. And you know, obviously, when we're talking about this stuff, dietary restriction, these are interventions in human beings. We can choose to do things like intermittent, fast and calorically restrict and go on diets and things like that. And the whole point is we want to use, you know, we want to choose to do certain things that that are healthy for us, that are beneficial for us. But you've got a result here that speaks to just the role, the role that raw genetics played here. What was the relationship between the genetics of individuals and how long they lived. Okay?
Gary Churchill 54:01
This is a this is a tricky one to navigate. So we try and say, when we talk about nature versus nurture, genetics versus environment, it's always both, yeah and it to different degrees. And these mice are in really controlled environments. Sure never changes. They get good food. The same thing happens. There are no pathogens, no predators. You pointed these things out. So those constant environmental conditions really raise the impact of the genetic portion of the equation. I would guess, and I don't have to guess, because the data are out there that the heritability, the proportion of lifespan in humans that's attributable to genetics, is smaller, much smaller than the 24% that we saw here in the mice. Why is the why is the genetic of. Fact of interest to us, we can attribute 24% to the variability in the lifespan to genetic factors.
Nick Jikomes 55:08
So almost a quarter, which is quite a lot, right? Yeah,
Gary Churchill 55:13
it's a lot. It's really it's a whopper, and only I forget the number, but only seven or 8% to diet. Remember, everything's context dependent, so in this context, but the genetics gave me a ruler to measure how big the diet effect is. So remember, if you go on one of these diets, it's not a guarantee that you're going to live longer. It improves your odds, so to speak. And how much is it contributing relative to having a 90 year old grandmother, and you really want that 90 year old grandmother? Yeah, that's what this result is. Basically, there's nothing you can do about that. You can't choose that this, this is not, you know, not your fate. Though, there are a lot of things you can do within the hand that you're dealt to make yourself healthier and live longer. But, you know, it is what it is, and it's an important component of and there's a, there's a third component here, and it is everything else that we don't understand. Yeah, I'm gonna say that's 70% of it. I'll call it noise for today, but it's the randomness of lifespan,
Nick Jikomes 56:38
yeah, just the rate like, because there's so much in biology that is dependent on stochasticity, just that something happens to go one way versus the other, the bumps in the road, yeah, yeah, yeah. And that's yeah, that's important to keep in mind. I so I don't know if you could unpack this from this study, but I want to talk a little bit about the possibility of this. Is it possible that in different subsets of mice, for example, within each group, perhaps some mice with certain genotypes really, really benefit from caloric restriction with respect to lifespan, and maybe it's also possible that other subsets with different genotypic makeups are actually harmed by it? Is that? Is that possible or plausible here? This
Gary Churchill 57:23
is, this is absolutely plausible, and it's one of the things that we intentionally look for. Can we identify genetic loci that would separate mice that have longer lifespans on diet from shorter lifespans on diet. And we looked, and I would say a we, we might need larger sample sizes, which may not be feasible, but I also think that those genetic determinants are, are they're complex, and they're kind of distributed all around. They're they're spread everywhere. We did. We found one genetic locus that achieved the, you know, the threshold for statistical significance, which is a pretty high bar. It's on mouse chromosome 18. And what I find fascinating about this, this genetic locus that is predictive of lifespan and has a pretty substantial effect, almost as big as the diets is. It's also a locus for RDW, so now we have a location in the genome. We know that this location has some variability. It's different mice have different flavors. And the mice with one flavor that I'll call castanious, because that's the the name of the mouse strain that you know the the bad allele is the cast allele in this case, and these might remind
Nick Jikomes 59:04
people what RDW is. RDW is
Gary Churchill 59:07
the red cell distribution with trait that we talked about earlier that's related to shorter lifespan. So in addition to diet affecting RDW and lifespan, we have a genetic locus that affects RDW and lifespan, which is why I keep coming back to that trait. And I don't think that RDW, RDW is a measurement that we make, but it does tell us that there's something about the maintenance of red cells. That's really important, both in terms of genetics and in terms of response to interventions, and how these things affect lifespan. I might have got off the rails there, but there's a whole 75% of the. Genetics is still unexplained. We have this locus that has very large effect. We see it, yay. But most of the genetic variability is distributed all around the genome in lots of tiny little effects. Yeah, yeah. To me, this isn't surprising, because, you know, if there were large effects on lifespan segregating around the genome. Evolution would have cleaned that up. It wouldn't, you know, they wouldn't persist. So you expect a trait like lifespan or body weight to have lots of little, tiny effects everywhere, which genetics interesting for a statistician, maybe disappointing for someone who hopes to find the
Nick Jikomes 1:00:45
gene. It's yeah, yeah. It's not there. There is no there is no one thing, no, not even close. Um, what, what sort of what were, what personally surprised you most about any of the results that you got. Um, or defied your expectations from from what they were when you went
Gary Churchill 1:01:08
in? I should have been prepared for that question. It's a good one. I really think it has to be the thing that we already discussed, that the paradoxical effect of weight loss, it was really kind of obvious up front that the diet causes weight loss and that should improve health and that should improve lifespan. And I think that disconnect was surprising to me, and I'm sure it helped us get this paper published, because it seemed surprising to everybody, yeah,
Nick Jikomes 1:01:41
I mean, and it's perfectly logical. I mean, you know, we have an obesity epidemic basically, you know, there's lots of opinions here, but at a high level, right? People are just eating more than ever. In most cases, we're the obesity is bad for health, bad for lifespan. And therefore, if you counteract obesity and metabolic dysfunction more generally by restricting calories in an environment where most individuals are in, you know, calorie surplus, then it's logical to think that the lifespan extension is coming from from that. But that's not the case here, as you said, in each group, even though, you know, they lost weight and they had some some some of these metabolic effects that you would expect that that was not what was responsible for, the lifespan was actually the heavier animals in within each group that were living the longest for that group,
Gary Churchill 1:02:29
you got it. I did want to just go a little further on on the genetics discussion, because I think people have this fatalistic sense about genetics. Yeah. And I want to say, still, you know, I'm concerned about people reading the paper and going on these ridiculous diets, because the diets we put these mice on are really extreme, but there are a lot of things you can do. So I want to say, if your grandmother gives you advice, don't smoke. You know all these things, right? Exercise, exercise is big, eat, right, sleep, go to the doctor, nurture your relationships and enjoy life. All these things are proven to improve your health and your lifespan. And if your grandmother's 99 years old and she's telling you all this stuff, maybe she did take her own advice or not so, but it's a bonus to have the 99 year old grandmother, but within the hand that you're dealt within the constraints of your genetics, there's a lot of leeway, and there are a lot of healthy things that you can do. And this has nothing to do with my study, but it has a lot to do with with how I understand aging and and health. And, you know, it's, you know, personal, but I think it's good general wisdom.
Nick Jikomes 1:04:04
Yeah, yeah. I mean, one thing I want to kind of, well, there's a couple things I want to come back to. I want to talk about the stress, resilience piece a little bit more that seems like a very important piece here. I mean, do you agree with that? Do you think that's that's part of like, Would you say that's a central finding here, because it cuts across all of the groups, and where would you speculate or hypothesize that we could discover more about what's actually going on there at a mechanistic
Gary Churchill 1:04:30
level? Yes, the stress resilience. I do think that we could unravel some of the genetics of that. And I'm interested in how an individual can can improve their stress resilience. I think all the grandmotherly advice that I just gave is going to improve your stress resilience. No, I'm at a lot. Us. Do
Nick Jikomes 1:05:01
you think one thing that, like I would like to just riff on, as you mentioned, you use the female mice. They're housed together, so there's social conditions here. Do you think that's that's possibly or plausibly playing into this, the fact that these mice were co housed, they weren't lonely, they had some kind of social network. Do you think you know, the where they were in terms of social rank, the number of mice they had good relationships with, so to speak. Do you think that could likely factor into what their stress resilience levels were? Something like
Gary Churchill 1:05:30
that? Yeah, I think it's huge. And we did the we got special dispensation to house mice in larger groups than typical. One thing I had in mind when we by the way, we put the mice in a large format mouse cage, which is larger than the normal cage, and we put eight mice per so that there were, there were eight per group. And typically we'll do four. You never want to singly house a mouse. It's just too stressful. But we typically do four, but I thought eight would be good. And one of my thoughts on this was that as these mice age and they're going to die, there's going to be the first mice that die, and then the second and third, and then there's going to be a last mouse. And that last mouse is singly housed by definition. You really can't rehouse them after it's you know, they they have their friends and their social network, and they don't want to change. So I wanted to have not too many singly housed mice at the end of their lives. And we are interested in this question. We have some data, and I I can say that those singly housed mice, the last mouse doesn't live as long as the mice that have the social structure around them. But it's a bit of a tricky question. So because they're also the longest lived,
Nick Jikomes 1:06:50
yeah, yeah. And you know, the immune system results are also interesting and worth coming back to a little bit. So, you know, you have these immune system changes that were induced by the dietary conditions. You know, in essence, these significant caloric restrictions were, you know, impacting the immune system in significant ways that would presumably probably leave the restricted mice more susceptible to things like disease if they were living out in in the wild, where they would, you know, more likely encounter pathogens. Do you think it's likely or plausible that the the levels of dietary restriction that health conscious people are often imposing, things like 16, eight intermittent fasting, things like one or two days of fasting per week. Do you think those restrictions, self imposed in humans are big enough that we would maybe want to be cautious about the immune system effects? Or do you think that the restrictions in the mice are just so much bigger that we probably aren't seeing immune system deficits from something like a one or two day fast in a human
Gary Churchill 1:08:02
I don't have data to support that, but I will speculate that these self imposed interventions are not likely to have a substantial negative effect on system. Might be beneficial. Certainly the metabolic benefit is is real and it's important. But I also feel, based on how we drove lifespan extension in the mice, that the interventions are not going to be a magic transformation for your lifespan. And I'm going to go so far as say that I don't believe there's a little blue pill. I don't think there's one solution, because I think aging is multifaceted. It's not one thing. I don't think it's I don't think it's encoded in our genomes, and there's no internal clock that tells you how old you are. It's you know you may have, you may have some resilience in your immune function and some susceptibilities in your kidney function. So everybody's got a different set of variables that they have to address immune function really important? No, I don't think that the kinds of interventions that people are capable of self imposing are likely to really impact their immune system negatively.
Nick Jikomes 1:09:36
And, you know, I want to go back to sort of the frailty piece here. So some of these animals, especially on things like the 40% caloric restriction diet, you know, they they were much smaller than they would have been. They had a much lower level of not just fat mass, but lean mass as well. They were less muscular, basically. Do you have does like, Do you have any concerns? There, when you think about things like, things like, you know, the new GLP one, drugs, they seem to be having great success at helping people lose weight, but people are losing both fat mass and lean mass. Is there anything that your study says in terms of how people should think about that lean mass loss and how important it might be to preserve that.
Gary Churchill 1:10:22
I'm gonna dodge the GLP, one question. Okay, okay, I'm back in five years. And yeah, let's ask that one again. Yeah. I mean, that's obviously really, really, really important question. There's too much unknown for me to I'll speculate about some things, but, but not that one. But do let me come back to frailty, because frailty is really important, and I want to just describe a picture. I'd be happy to send it to you an email later, but I have a picture of two mice, and these two mice are both four years old. And what's interesting about a four year old mice is that they're ridiculously old. Mice don't normally get to be four years old. We had these mice on 20% CR, and in the picture, it's so beautiful. They just happen to be nose to nose, and they're they're sniffing each other, and you look at the one on the right, and the coat is smooth, the fur color is black. It's little bit of gray hair. The tail is straight. You look at the other mouse hunched back, you can see the hind end is wasting away. The tail has kinks in it. The fur is all tatty. But these two mice are the same chronological age. Yeah, I look at them, and I can see immediately with my eyes that they're the one on the left is older, you know, biologically older. And one of the real questions of our study here is, well, how do we measure that? How do we say, how do we quantify what our eyes can see? Look at an individual and you can tell that they're, I'm going to do air quotes, older in a biological sense. So two animals the same chronological age look to be very different in terms of their biological in biological age, we have a simple tool. It's a checklist with in our case, it has 32 items, and there's an equivalent checklist that's used in by gerontologists to examine people when they have a physical exam. But you know our checklist, we just go down, do we see gray hair? Now, gray hair is not going to kill you, right? Look, you know, but it's, it's a sign of aging. We look to see if they have cataracts. And by the way, it's cataracts. They're not going to kill me. They're unpleasant. And we ask a whole bunch of questions, just 32 simple things that you can look at, a mouse, flip them over, do they get back up on their feet? This is a fantastic measure of biological age. I love it so, and it's called the frailty index, and it comports with your intuitive notion of what frailty would be when you see it, yeah, yeah, thanks for asking. It's one of my favorite tools, and we use it all the time. And,
Nick Jikomes 1:13:20
you know, again, you know, as we said in the beginning, you know, we don't, you know, we don't want to over generalize results. We want to be super cautious when we're thinking about results from a mouse study and then talking about human beings. Is there any like, do you think the results are? Are Is there anything here that speaks to how people should think about things like intermittent fasting in their own life. Does this? Do you know? Do you have any opinions on whether or not that's likely to be a good idea for most people, especially people that are already metabolically unhealthy, and do results sort of speak to that at all?
Gary Churchill 1:13:59
I would say that if you are, if you are restricting your calorie input or intermittent fasting, and You Your goal is to extend your lifespan, you're not really going to achieve that necessarily. If you're doing these things to improve your metabolic health, I would definitely say that's a good thing. So I don't think there's no little blue pill and there's no diet that you would tolerate that would extend your lifespan, the way we saw, these must lifespans extended. So caloric restriction to be effective at extending lifespan has to be extreme, and it necessarily has good and bad effects on health. And so those bad effects are really undesirable, being cold, being hungry, not good.
Nick Jikomes 1:14:53
Yeah, yeah. And, I mean, there's a lot of, I mean, the longevity movement is really, really picking up lately. There's a lot of. Money going into the startup space. There's a lot of people doing very high profile things, people taking what they call the optimate optimal supplement stack and daily intermittent fasting and this, that and the other. There's even famous people online who've posted how much their body temperature has dropped and taking that as evidence that they're going to get a longevity boost. Do you think we know enough about the biology of longevity, generally speaking, for people to have that level of confidence that making those lifestyle changes is definitely going to extend their lifespan?
Gary Churchill 1:15:37
The answer is easy. You're asking my opinion, and my opinion is No, and I think I should be careful, but I won't at the moment and say that I think there's a general problem in biomedical research as a whole, where there's a push for translational relevance. I'm going to qualify that and say research that's translationally relevant, stuff that you can apply immediately to people and improve their lives, is incredibly important, and we should place a high priority on it. But there are things about health that we don't understand very well, and I think that this is our study with mice, most of the studies that I'm involved in are really trying to ask, well, what is the basic biology? What's really happening, you know, at the cellular, physiological molecular level, to drive these phenomenon? And as this study shows, there are sometimes some real surprises. And I think those surprises teach us as we go forward, that, you know, if we rush to the solution, we might actually do more harm than good. Again, be very careful, because there's some fantastic discoveries that have translated to, you know, cancer research is amazing, the things that have happened, but I think that in aging research, I'm going to say these things again, don't smoke, exercise, eat right, sleep, enjoy life, love your family.
Nick Jikomes 1:17:19
So yeah, and I think really do, yeah. I mean, I think you know, terrific on what you were saying. You know, we know more than ever. We've got more studies we can look to than ever when it comes to this stuff. But it's important to remember we don't know everything. In fact, there's still so much more we don't know than we do know that we should I like to remind people and myself, really, you know, we need to stay very, very humble, because even though we know more facts about the world, about biology, than ever, you know the space of knowledge we have is so much smaller than the space of ignorance that, you know, we should be cautious about thinking we know how to engineer the optimal life or
Gary Churchill 1:17:57
whatever. Yeah, the the iceberg metaphor is overused, perhaps, but this is it. I mean, we know what the top 20% of the iceberg looks like. We shouldn't fool ourselves to think that we see the whole thing. And I think for me, this is job security. It gives me I like learning, I like uncovering things, and there's, you know, essentially endless discoveries to make, and they're hard, and they take sweat and labor and seven technicians in eight years. Yeah,
Nick Jikomes 1:18:34
is so, yeah, I would love to ask you about that a little bit. So like, you know, you had to have a staff, you know, a fairly sizable staff, and you had eight years of time to do a study like this. Obviously, you know, it was worth it, in the sense of, I think anyone interested in this stuff and in this field would say, you know, this is, this is a great study. We're learning a lot from that we need to be doing this type of research. But you know something special about the Jackson Laboratory and where you're doing this research that enabled you to do a study like this, because, you know, a brand new assistant professor somewhere at a big shot University can't wait eight years to get a paper out. So what enabled you to actually do a project like this?
Gary Churchill 1:19:09
I think that the short term funding cycles are a special challenge for aging research, especially if we use a model organism like a mouse that can live three or four years, and we have to stagger the starts. The Jackson lab has a whole community of people who have all kinds of expertise in all aspects of biology, but there's a particularly dense concentration of people who know about mice, handle mice, and know how to phenotype, how to characterize mice and, you know, determine their health. So I was really lucky, and the staff members were just wonderful. One of my team members did over 5000 frailty exams. We had, we had 100,000 Now wait. We must have had hundreds of 1000s of body weights. And people were dedicated, and they're careful, and it's really important to be careful in research you want to put the numbers in the right column. And and the statistician that I had had working on this project, and the new statistician who came along and replace the first one are just wonderful, because they look at the quality, they fix the mistakes. So there's a lot of effort that it takes to do research, and you know, you have to pay people salaries. You have to pay for the facilities and the experiments. It's expensive. I feel really privileged. I feel really privileged to be able to do it. You know, society is has given me, and many of us scientists, has given us this opportunity. And I want to express my gratitude, hopefully I'll return something.
Nick Jikomes 1:20:58
Yeah, yeah. Well, I mean, yeah, you've returned this. And, I mean, this was a, this is a wonderful paper to read. It was, you know, just a massive undertaking, and people seem to be responding to it quite well. I think a lot of people were excited to dig into this one, just given the number of mice, the amount of, the amount of measurements and and just all, all of the stuff you packed into this, what's coming next for you guys? Are you following up on this particular study? What are you working on? Now,
Gary Churchill 1:21:25
I remember I said I was a statistician, and when I was an undergraduate, I talked to my statistics professor, and I asked, Why are you a statistician? And he said, Oh, it's because I can dabble in a little bit of everything, because everybody has data, and I can work on this, and I can work on that, and I feel like I would like to move on from this. I think there are some really important results that should and can be followed up, but they require a different skill set from what I have. And I'm going to say it, where we're really interested in looking next is related to stress resilience. So there are all kinds of stressors that people experience in life, and one that I'm particularly interested in, and it has the potential to affect half of the human population, is reproduction, pregnancy, birth, lactation. I haven't talked to a woman who said it wasn't stressful. And when we study this in mice, we can see how pregnancy and birth have short term and long term health effects. And I feel like I want to understand better, what are the long term health effects of just in mice, multiple pregnancies. And, you know, where does this go? Does it? Yeah, I think no matter what the answer is, it's going to be interesting, and you'll be talking to me in eight years. We've covered
Nick Jikomes 1:23:11
a lot. I want to thank you for your time. Gary, really interesting paper. Really loved reading this one. Any final thoughts you want to leave people with about this stuff or anything you want to reiterate about what we talked about today?
Gary Churchill 1:23:26
No, I have a couple little notes of the things that I really wanted to say. You want to live a healthy, happy life, and there are well known prescriptions for doing that, and don't go to extremes, and understand that a study like this is is intended to unravel fundamental biology, and it's not intended to give you a recipe for living longer. So I think that understanding that biology has the potential ultimately to give us better prescriptions for living longer. As we go on, we learn we do better, but please don't go on extreme caloric restriction
Nick Jikomes 1:24:18
and all right. Gary Churchill, thank you for your time.
Gary Churchill 1:24:21
Thank you so much. It was a pleasure. You.
Calorie Restriction & Fasting: Aging, Immunity, Health Biomarkers, Stress, Genetics | Gary Churchill | #183