#035 Gordon Lithgow, Ph.D. on Protein Aggregation, Iron Overload & the Search for Longevity Compounds

Alzheimer Prevention Discussion

That's what sort of hooked me into this, you know, basically the field of aging was looking at these worms where you can get rid of their IGF-1, you know, growth signaling pathway and literally...

"And people are just kind of amazed to see down the microscope a worm that's crawling around and behaving normally when it shouldn't be, when it should be dead. Totally."

Protein Aggregation Discussion

That's what sort of hooked me into this, you know, basically the field of aging was looking at these worms where you can get rid of their IGF-1, you know, growth signaling pathway and literally...

"And people are just kind of amazed to see down the microscope a worm that's crawling around and behaving normally when it shouldn't be, when it should be dead. Totally."

Extended Fasting Discussion

There's evidence, for example, in Alzheimer's disease that there's a metabolic problem that that happens before you start seeing aggregation of proteins so who knows how all these things interact with each other but but...

"There's evidence, for example, in Alzheimer's disease that there's a metabolic problem that that happens before you start seeing aggregation of proteins so who knows how all these things interact..."

Autophagy: Fasting

There's evidence, for example, in Alzheimer's disease that there's a metabolic problem that that happens before you start seeing aggregation of proteins so who knows how all these things interact with each other but but...

"There's evidence, for example, in Alzheimer's disease that there's a metabolic problem that that happens before you start seeing aggregation of proteins so who knows how all these things interact..."

Sauna: Heat Shock

There's evidence, for example, in Alzheimer's disease that there's a metabolic problem that that happens before you start seeing aggregation of proteins so who knows how all these things interact with each other but but...

"There's evidence, for example, in Alzheimer's disease that there's a metabolic problem that that happens before you start seeing aggregation of proteins so who knows how all these things interact with each other but but it's important i think that's that's firmly established now that this is a major mechanism of aging right yes well i remember um gosh it must have been like 12 years ago when i first read a paper of yours where I believe you may have been a postdoc because you were first author on this paper. And the paper was you had found that heat shocking worms. Actually, I think it was just at this early paper was a single heat shock and you increased the lifespan of the worm by like 15%. Yeah. And this was totally dependent on the production of something called heat shock proteins, or HSP. heat shock and you increased the lifespan of the worm by like 15%. And this was totally dependent on the production of something called heat shock proteins or HSPs, which people have heard me talk about before. And then you published again, showing that multiple heat shock treatments could increase the lifespan of the worm like even more robustly. So could you maybe talk for, you know, just a little bit about, you know, how heat shock is this type of hormetic stress and how this can have beneficial effects? I remember when I saw this for the first time as a postdoc and I ran into the office of my supervisor, Tom Johnson, and they said, look at this. This is amazing. He stressed the animals and they live longer. How is that possible? And he said, oh, right. You've just discovered something that John Maynard Smith published in Nature in the 1950s. And he pulled this paper, you know, he's drawn sure enough that John Maynard Smith, evolutionary biologist, had been looking at tradeoffs between reproduction and lifespan. And he had stressed, in this case, flies. He stressed the flies with a heat shock and they had lived longer. And it was kind of amazing that this was in the 1950s. And this was before our understanding of molecular chaperones and stress responses. And so they probably could never put that discovery into the context of the molecular and cellular processes that were going on. And what was going on was the animals were being stressed. They're ramping up their defenses against misfolded protein. Of course, proteins misfold during the heat shock. And as a result, these defense systems are actually acting against the normal aging process, which is also the misfolding of proteins. So it kind of makes sense to us now that these so-called hermetic responses are the production of molecular chaperones, also ramping up of autophagy, the process of breaking down proteins. And beautiful paper from Malene Hanson a few weeks ago showing autophagy is critical for this response to heat shock. So it's nice that things have come full circle and we've got a better understanding of what's going on there. It totally makes sense. So, I mean, if you think about it, like you said, you know, in the case of heat, you know, there's lots of examples of hormetic stressors. I mean, heat's one, there's fasting, there's a lot of xenobiotic, you know, compounds or xenohormetic compounds, like cumin. These sort of things can, they're slightly toxic in a small dose. And because of that small dose, I think dose is important. It activates, like you said, all these cellular stress response pathways that then help us deal with stress better. And guess what? Aging is a stress. So you're not only increasing things that help proteins keep their three-dimensional structure, but you're increasing antioxidant pathways and inflammatory. Mm-hmm. Mm-hmm. Mm-hmm. Mm-hmm. Mm-hmm. Mm-hmm. Mm-hmm. Mm-hmm. Mm-hmm. Mm-hmm. Mm-hmm. Mm-hmm. Mm-hmm. Mm-hmm. Mm-hmm. Mm-hmm. Mm-hmm. Mm-hmm. Mm-hmm. Mm-hmm. Mm-hmm. Mm-hmm. Mm-hmm. Mm-hmm. Mm-hmm. Mm- reading to sort of prepare to talk to you. And I came across that paper, and I was like, oh, this is awesome, you know, because I hadn't thought about it. Melina told me about this before the paper was published. She was sitting in my office telling me about this, and I thought, ah, this is fantastic. You know, and here's a mechanism now that really explains why a stress is actually leading to longer life. Yeah, and it makes perfect sense. Things like heat stress would increase, you know, the activity of machinery that we have to degrade proteins that are damaged, like the proteasome. And it would make sense that autophagy, which is another pathway to do that, would also be part of that stress response pathway as well. But what's really cool is that this is very relevant for humans, right? Because humans have heat shock proteins. Yes. And our heat shock proteins are also responsive to heat. Absolutely. So, I mean, this isn't like just understanding worms. It's something that's being translated to humans. And actually, there's a body of literature about pre-stressing organs ahead of surgery that's very interesting and might be relevant to this, where, you know, there's just better recovery from surgery if there's been a pre-stress. And similar literature on starvation or fasting ahead of various treatments for cancer, for example, or chemo. Yeah. So we might not know all the details there, but absolutely, I think this is really important. It's probably a neglected area, actually. I think that, you know, Melina's papers brought it back to light that these stresses are anti-aging and potentially beneficial. And we need to think about how you would modify the stress in itself for humans. Obviously, we don't want to stress people. Stress is damage, no doubt about it. But can we harness that endogenous machinery that counteracts the stress? And I actually think that's what we're doing with a lot of the chemical compounds that we discover extend lifespan, is that they are either hitting pathways that regulate stress responses, or they are providing a sort of, we call it, damn, I forget what we call it. Sorry. I think some of the chemical compounds that we discover that extend lifespan are actually doing this. They're harnessing the endogenous stress responses. Absolutely. Absolutely. They're either activating the regulators of stress responses or they're causing a segmental stress. So you're seeing a limited stress response or only parts of the stress response are being activated, but that's enough to give you beneficial effects. Yes. So I totally wanted to mention something before you jumped into the compounds that was related to the heat stress. And that is, there was a study, you may be interested in this, there was a study I read, it was published not too long ago, just a few years ago, where people were looking at the heat shock response in humans that were sitting in a sauna. So, of course, that would be a way that humans can activate their heat shock proteins. So, humans that sat in a 163 degree Fahrenheit sauna for about 30 minutes increased their heat shock proteins, including HSP70, by 50% or baseline. And that was actually sustained for about 48 hours. So that elevation stayed for around 48 hours, which is really cool because it's kind of like a take home, well, maybe we can activate our heat shock proteins from the sauna. And to sort of go one step further, because I've been sort of obsessed with heat shocking and sauna for probably since I started doing research many, many years ago and I was working on heat shock a little bit and HSF1 and all this stuff. But I recently went to Finland last November and there's a researcher there. His name is Yari Laukkonen. And he's been doing, he's a MD PhD. He's a cardiologist. So a lot of his focus has been on heart health. And the sauna is something that is ubiquitous in Finland. I mean, everyone has a sauna. Everyone. It's just ridiculous. So he does a lot of research on sauna. And he published a couple of studies that one came out in 2015, where he was looking at all cause mortality and sauna use. So men, this 2,000 men cohort, men that had used the sauna like two to three times a week had a 23% or 24% lower all-cause mortality. Wow. Men that used it four to seven times a week had a 40% lower all-cause mortality compared to men that only used it once a week. So it's like a dose response effect. But here's where you'll be interested. So he just published this paper last December, same cohort of men, but this time he was looking at Alzheimer's disease. And what he found is that men that use this on a two, three times a week had a 20% lower risk of getting Alzheimer's. If they used it four to seven times a week, they had a 60% reduction in Alzheimer's disease risk, which is really kind of cool because it goes with your molecular mechanistic work in lower organisms on the protein aggregation and the heat shock and the stress response pathway. Yeah, I spent most of my career just interested in worms. I mean, I thought if we can solve worm aging, that's fantastic. But over the years, this creeping realization that actually what we're doing could be important for people as well, making all these connections to disease and all the model organism people coming to this conclusion, working on flies and mice and yeast even, that these are basic mechanisms of aging. They're likely to be playing out in humans as well. And therefore, we should do something with this knowledge we've accumulated over the last 25 years. It's really time to try and translate that and do something that might be beneficial. Yes. Well, another thing that you've done, I think, is very relevant, is your work on iron. So you had looked at how excess dietary iron affects, again, I think, protein homeostasis. Absolutely, yeah. Well, this was inspired by my wife, Julie Anderson's, work on Parkinson's disease where many years ago she published a series of papers showing how important iron was, causing damage to complex one in the mitochondria through redox reactions. And then that very specific damage would play out all the way to neuronal death, the dopaminergic neurons. So we went back and looked at iron. Basically, we had a collaborator, David Killillia, who was able to show that iron levels become elevated during normal aging in the worm. We thought, well, that's interesting because that's what happens in human brains and other tissues. And so we did a couple of things. First of all, we fed exogenous iron. So we increased the iron levels in the media, in the diet. That accelerated aging. So it shortened it shortened their lifespan but also accelerated the accumulation of insoluble proteins so it accelerated this sort of molecular pathology of aging and the other thing we did was to feed the worms and a collator an iron collator and in that case the iron levels did not rise during aging the worms lived longer, and it protected against protein aggregation as well. That was going to be my next question, actually. Yeah, so it all sort of made sense. Right. So the iron that you're feeding these worms, is there any way that it could be physiologically relevant to humans, like the levels that you were given them? I believe so. I think the experiments in mice with Parkinson's disease, for example, those are around about the levels that you could be exposed to. And, you know, especially if you're working with metals, you're a welder or, you know, certain careers like that. And the epidemiology suggests that indeed that leads to increased risk of Parkinson's disease. So I think coming back to normal aging, I wouldn't be surprised if these kind of levels of iron are important. Are you familiar with the, there's a few gene polymorphisms and one is in the hematohemochromatosis gene. And people can get hemochromatosis where they're absorbing way too much dietary iron. So that seems like it could be something very relevant if someone's homozygous for those polymorphisms in that gene. It could be, and it'd be interesting to look at their aging characteristics and ask whether there's any sort of accelerated aging phenotype there. I know there's all sorts of problems, so I wouldn't be surprised if there was. And there's also, what's so funny is I didn't think about, you're mentioning Parkinson's and how Parkinson's, you know, is associated with iron accumulation and the mitochondria and this is, or damaging mitochondria and this is leading to death of dopaminergic neurons. But what I was familiar with was Alzheimer's disease and how there's, I know there's especially a cluster of polymorphisms. One is in the hemochromatosis gene. The other one's in the transferrin gene, which binds free iron. Together, if you have this right combination, I don't know how frequent it is in the human population it occurs, people actually have a five times increased risk of Alzheimer's disease. So there's definitely a connection between iron and obviously neurological diseases in general. And other metals as well. Other metals as well. Other metals as well. Yeah, you've looked at some other metals, right? Like copper. Yeah, copper and manganese. And I think copper is probably critical in Alzheimer's disease. And again, this is possibly an underappreciated aspect of neurological disease, partly because I think that it's difficult to think of ways to go after that as a target. So if you say, we're going to manipulate the levels of metals, well, a third or a half of all proteins have metals as part of their active sites. And the idea of treating a metal disorder is a little bit difficult to get your head around. And there are very few pharmaceutical companies in the world really go after metals. But I don know, I don't see why we shouldn't be asking the question, you know, can we modulate metals? Can we modulate the activity of metal transporters in particular tissues? And can we prevent the elevation of metals in tissues during aging? That basic prevention of elevated levels of metals could be enough to protect us against disease? Yeah, absolutely. I think it's a very important question. You know, people are supplementing with all sorts of vitamins and minerals, and some people are taking way too many."

Alzheimer Prevention: Prevention

I think some of the chemical compounds that we discover that extend lifespan are actually doing this. They're harnessing the endogenous stress responses.

"There's evidence, for example, in Alzheimer's disease that there's a metabolic problem that that happens before you start seeing aggregation of proteins so who knows how all these things interact with each other but but it's important i think that's that's firmly established now that this is a major mechanism of aging right yes well i remember um gosh it must have been like 12 years ago when i first read a paper of yours where I believe you may have been a postdoc because you were first author on this paper. And the paper was you had found that heat shocking worms. Actually, I think it was just at this early paper was a single heat shock and you increased the lifespan of the worm by like 15%. Yeah. And this was totally dependent on the production of something called heat shock proteins, or HSP. heat shock and you increased the lifespan of the worm by like 15%. And this was totally dependent on the production of something called heat shock proteins or HSPs, which people have heard me talk about before. And then you published again, showing that multiple heat shock treatments could increase the lifespan of the worm like even more robustly. So could you maybe talk for, you know, just a little bit about, you know, how heat shock is this type of hormetic stress and how this can have beneficial effects? I remember when I saw this for the first time as a postdoc and I ran into the office of my supervisor, Tom Johnson, and they said, look at this. This is amazing. He stressed the animals and they live longer. How is that possible? And he said, oh, right. You've just discovered something that John Maynard Smith published in Nature in the 1950s. And he pulled this paper, you know, he's drawn sure enough that John Maynard Smith, evolutionary biologist, had been looking at tradeoffs between reproduction and lifespan. And he had stressed, in this case, flies. He stressed the flies with a heat shock and they had lived longer. And it was kind of amazing that this was in the 1950s. And this was before our understanding of molecular chaperones and stress responses. And so they probably could never put that discovery into the context of the molecular and cellular processes that were going on. And what was going on was the animals were being stressed. They're ramping up their defenses against misfolded protein. Of course, proteins misfold during the heat shock. And as a result, these defense systems are actually acting against the normal aging process, which is also the misfolding of proteins. So it kind of makes sense to us now that these so-called hermetic responses are the production of molecular chaperones, also ramping up of autophagy, the process of breaking down proteins. And beautiful paper from Malene Hanson a few weeks ago showing autophagy is critical for this response to heat shock. So it's nice that things have come full circle and we've got a better understanding of what's going on there. It totally makes sense. So, I mean, if you think about it, like you said, you know, in the case of heat, you know, there's lots of examples of hormetic stressors. I mean, heat's one, there's fasting, there's a lot of xenobiotic, you know, compounds or xenohormetic compounds, like cumin. These sort of things can, they're slightly toxic in a small dose. And because of that small dose, I think dose is important. It activates, like you said, all these cellular stress response pathways that then help us deal with stress better. And guess what? Aging is a stress. So you're not only increasing things that help proteins keep their three-dimensional structure, but you're increasing antioxidant pathways and inflammatory. Mm-hmm. Mm-hmm. Mm-hmm. Mm-hmm. Mm-hmm. Mm-hmm. Mm-hmm. Mm-hmm. Mm-hmm. Mm-hmm. Mm-hmm. Mm-hmm. Mm-hmm. Mm-hmm. Mm-hmm. Mm-hmm. Mm-hmm. Mm-hmm. Mm-hmm. Mm-hmm. Mm-hmm. Mm-hmm. Mm-hmm. Mm-hmm. Mm-hmm. Mm- reading to sort of prepare to talk to you. And I came across that paper, and I was like, oh, this is awesome, you know, because I hadn't thought about it. Melina told me about this before the paper was published. She was sitting in my office telling me about this, and I thought, ah, this is fantastic. You know, and here's a mechanism now that really explains why a stress is actually leading to longer life. Yeah, and it makes perfect sense. Things like heat stress would increase, you know, the activity of machinery that we have to degrade proteins that are damaged, like the proteasome. And it would make sense that autophagy, which is another pathway to do that, would also be part of that stress response pathway as well. But what's really cool is that this is very relevant for humans, right? Because humans have heat shock proteins. Yes. And our heat shock proteins are also responsive to heat. Absolutely. So, I mean, this isn't like just understanding worms. It's something that's being translated to humans. And actually, there's a body of literature about pre-stressing organs ahead of surgery that's very interesting and might be relevant to this, where, you know, there's just better recovery from surgery if there's been a pre-stress. And similar literature on starvation or fasting ahead of various treatments for cancer, for example, or chemo. Yeah. So we might not know all the details there, but absolutely, I think this is really important. It's probably a neglected area, actually. I think that, you know, Melina's papers brought it back to light that these stresses are anti-aging and potentially beneficial. And we need to think about how you would modify the stress in itself for humans. Obviously, we don't want to stress people. Stress is damage, no doubt about it. But can we harness that endogenous machinery that counteracts the stress? And I actually think that's what we're doing with a lot of the chemical compounds that we discover extend lifespan, is that they are either hitting pathways that regulate stress responses, or they are providing a sort of, we call it, damn, I forget what we call it. Sorry. I think some of the chemical compounds that we discover that extend lifespan are actually doing this. They're harnessing the endogenous stress responses. Absolutely. Absolutely. They're either activating the regulators of stress responses or they're causing a segmental stress. So you're seeing a limited stress response or only parts of the stress response are being activated, but that's enough to give you beneficial effects. Yes. So I totally wanted to mention something before you jumped into the compounds that was related to the heat stress. And that is, there was a study, you may be interested in this, there was a study I read, it was published not too long ago, just a few years ago, where people were looking at the heat shock response in humans that were sitting in a sauna. So, of course, that would be a way that humans can activate their heat shock proteins. So, humans that sat in a 163 degree Fahrenheit sauna for about 30 minutes increased their heat shock proteins, including HSP70, by 50% or baseline. And that was actually sustained for about 48 hours. So that elevation stayed for around 48 hours, which is really cool because it's kind of like a take home, well, maybe we can activate our heat shock proteins from the sauna. And to sort of go one step further, because I've been sort of obsessed with heat shocking and sauna for probably since I started doing research many, many years ago and I was working on heat shock a little bit and HSF1 and all this stuff. But I recently went to Finland last November and there's a researcher there. His name is Yari Laukkonen. And he's been doing, he's a MD PhD. He's a cardiologist. So a lot of his focus has been on heart health. And the sauna is something that is ubiquitous in Finland. I mean, everyone has a sauna. Everyone. It's just ridiculous. So he does a lot of research on sauna. And he published a couple of studies that one came out in 2015, where he was looking at all cause mortality and sauna use. So men, this 2,000 men cohort, men that had used the sauna like two to three times a week had a 23% or 24% lower all-cause mortality. Wow. Men that used it four to seven times a week had a 40% lower all-cause mortality compared to men that only used it once a week. So it's like a dose response effect. But here's where you'll be interested. So he just published this paper last December, same cohort of men, but this time he was looking at Alzheimer's disease. And what he found is that men that use this on a two, three times a week had a 20% lower risk of getting Alzheimer's. If they used it four to seven times a week, they had a 60% reduction in Alzheimer's disease risk, which is really kind of cool because it goes with your molecular mechanistic work in lower organisms on the protein aggregation and the heat shock and the stress response pathway. Yeah, I spent most of my career just interested in worms. I mean, I thought if we can solve worm aging, that's fantastic. But over the years, this creeping realization that actually what we're doing could be important for people as well, making all these connections to disease and all the model organism people coming to this conclusion, working on flies and mice and yeast even, that these are basic mechanisms of aging. They're likely to be playing out in humans as well. And therefore, we should do something with this knowledge we've accumulated over the last 25 years. It's really time to try and translate that and do something that might be beneficial. Yes. Well, another thing that you've done, I think, is very relevant, is your work on iron. So you had looked at how excess dietary iron affects, again, I think, protein homeostasis. Absolutely, yeah. Well, this was inspired by my wife, Julie Anderson's, work on Parkinson's disease where many years ago she published a series of papers showing how important iron was, causing damage to complex one in the mitochondria through redox reactions. And then that very specific damage would play out all the way to neuronal death, the dopaminergic neurons. So we went back and looked at iron. Basically, we had a collaborator, David Killillia, who was able to show that iron levels become elevated during normal aging in the worm. We thought, well, that's interesting because that's what happens in human brains and other tissues. And so we did a couple of things. First of all, we fed exogenous iron. So we increased the iron levels in the media, in the diet. That accelerated aging. So it shortened it shortened their lifespan but also accelerated the accumulation of insoluble proteins so it accelerated this sort of molecular pathology of aging and the other thing we did was to feed the worms and a collator an iron collator and in that case the iron levels did not rise during aging the worms lived longer, and it protected against protein aggregation as well. That was going to be my next question, actually. Yeah, so it all sort of made sense. Right. So the iron that you're feeding these worms, is there any way that it could be physiologically relevant to humans, like the levels that you were given them? I believe so. I think the experiments in mice with Parkinson's disease, for example, those are around about the levels that you could be exposed to. And, you know, especially if you're working with metals, you're a welder or, you know, certain careers like that. And the epidemiology suggests that indeed that leads to increased risk of Parkinson's disease. So I think coming back to normal aging, I wouldn't be surprised if these kind of levels of iron are important. Are you familiar with the, there's a few gene polymorphisms and one is in the hematohemochromatosis gene. And people can get hemochromatosis where they're absorbing way too much dietary iron. So that seems like it could be something very relevant if someone's homozygous for those polymorphisms in that gene. It could be, and it'd be interesting to look at their aging characteristics and ask whether there's any sort of accelerated aging phenotype there. I know there's all sorts of problems, so I wouldn't be surprised if there was. And there's also, what's so funny is I didn't think about, you're mentioning Parkinson's and how Parkinson's, you know, is associated with iron accumulation and the mitochondria and this is, or damaging mitochondria and this is leading to death of dopaminergic neurons. But what I was familiar with was Alzheimer's disease and how there's, I know there's especially a cluster of polymorphisms. One is in the hemochromatosis gene. The other one's in the transferrin gene, which binds free iron. Together, if you have this right combination, I don't know how frequent it is in the human population it occurs, people actually have a five times increased risk of Alzheimer's disease. So there's definitely a connection between iron and obviously neurological diseases in general. And other metals as well. Other metals as well. Other metals as well. Yeah, you've looked at some other metals, right? Like copper. Yeah, copper and manganese. And I think copper is probably critical in Alzheimer's disease. And again, this is possibly an underappreciated aspect of neurological disease, partly because I think that it's difficult to think of ways to go after that as a target. So if you say, we're going to manipulate the levels of metals, well, a third or a half of all proteins have metals as part of their active sites. And the idea of treating a metal disorder is a little bit difficult to get your head around. And there are very few pharmaceutical companies in the world really go after metals. But I don know, I don't see why we shouldn't be asking the question, you know, can we modulate metals? Can we modulate the activity of metal transporters in particular tissues? And can we prevent the elevation of metals in tissues during aging? That basic prevention of elevated levels of metals could be enough to protect us against disease? Yeah, absolutely. I think it's a very important question. You know, people are supplementing with all sorts of vitamins and minerals, and some people are taking way too many."

Vitamin D: Blood Level

You know, iron is something that I don't, I think, you know, people should get their iron levels measured. They shouldn't just be blindly taking an iron supplement.

"Very cool. Well, I have a thousand questions about that. So, I mean, obviously, the question you probably get from every single person that you talk to about this research, and that is Thank you. working on it. Very cool."

Longevity: How To

Personalized medicine sort of interaction between genes and compounds. There's lots of interactions between drug metabolism and the way we metabolize drugs and the genes that we have.

"Well, that's a big debate right now as to how to do that. Of course, the worms are changing their behaviors as they age. They're becoming slower. They're eating less. They cease reproduction. Eventually, they become paralyzed, essentially not moving at all on the plate. So there's plenty of things to look at. Also, their tissues are changing, and you can look at the tissues themselves. And really, we're just kind of sorting out what the best parameters might be right now. Resistance to stress, for example, goes down with age. And so maybe we just look at resistance to stress at multiple ages and ask if compounds are able to maintain that resistance. What about compounds that are able to really work well when you stress the animal? So let's say you have a compound that is something that's like a xenohormetic kind of compound, which you may see a very small effect on lifespan, just under normal aging conditions. But what if you were to stress them? You add some sort of oxidative stress or something, and then you see a really robust... Do you think you might be missing some of those sort of compounds? I believe so. And I think that they might come out of our next series of experiments where even where we have a negative result on lifespan, we will look at healthspan. We'll look at stress responses and ask, well, is this something that's really making the animal healthier for longer? Which of course we're interested in, but maybe just fails to increase the maximum lifespan. Can I give you a, can I put a bid in for a compound you should look at? Yeah. Sulforaphane. Okay. Sulforaphane is... Are you familiar with sulforaphane? Okay. No, please tell me. All right. So, sulforaphane is a xenohormetic compound. It is produced in cruciferous plants. So, you know, anything from broccoli to kale to cauliflower. Oh, yeah. I remember that. So it is produced when the plant is, you know, crushed or broken, and it comes in contact with an enzyme called myrosinase, and then you produce sulforaphane. Sulforaphane is, to my knowledge, the most potent dietary, naturally occurring dietary activator of Nrf2 pathway. I've done a lot of reading about it. I've jed fahey who's at johns hopkins who worked with tallale who sort of discovered that it was the you know activator of this whole nrf2 keep one pathway and um so i'm sort of really familiar with the field and i was doing a lot of reading trying to figure out you know because in humans there's been a lot of clinical studies in humans showing it lowers inflammation biomarkers of inflammation in humans humans. It lowers, you know, biomarkers of oxidative stress in blood cells. It affects glutathione, just everything, right? And all sorts of cancer prevention studies, just, you know, Alzheimer's disease in animals. I mean, lots of animal studies. But I couldn't really find any lifespan studies. And I was looking specifically for Drosophila or Skelligin or something. And I I came across this paper that was published in Red Flower Beetle or something. I'd never heard of it. Anyways, they fed these red flower beetles sulforaphane and it extended their lifespan. And then they did some oxidative stress and it really robustly extended their lifespan. So I would be really interested to see if it does. I mean, I would bet that it does something in C. elegans. That's very cool. So for a frame. Okay. I will send you an email. Please do. And actually, you know, we are really interested in hearing stories like this. And we want other scientists and other people to make suggestions to the consortium for testing compounds. We have another 10 that are in process right now. But this is going to continue for the next few years. And hope to get through hundreds of compounds eventually. So we're looking for suggestions. Definitely one. Yeah, I would love to see, I mean, really love to see it. So that would be super cool. Well, Gordon, I really thank you so much for taking some time to speak with me about your research and how you're trying to look at all these various pathways as they relate to aging and protein homeostasis and these compounds that may extend healthspan and lifespan, all very relevant to us down the line. Hope so. So, pleasure talking with you today. Nice to talk to you. Thank you. And if people want to find you, they can find you at the Buck Institute for Aging. Absolutely. Yep. And if you want to learn more about your research, you'll be there. That's right. Thank you very much. Bada bing, bada boom. That's an episode. Thanks for listening. For those of you that have done 23andMe genetic testing and are interested from a non-medical informational only standpoint in learning about whether you might have some of the specific combinations of gene polymorphisms discussed with Gordon in the transferrin gene and the hemochromatosis gene, you can actually find out what your genotype is by running the raw data through the tool on my website. It is very easy to do and very quick. Learn more about that at foundmyfitness.com forward slash genetics. That's G-E-N-E-T-I-C-S, genetics. From there, you can also learn about certain genes involved in fat metabolism, vitamin D metabolism, omega-3 fatty acid metabolism, vitamin A metabolism, and more. Lots of really cool stuff, and I plan on continuing to add even more great reports on there as time goes on. It will only get better. So make sure to check that out once again at foundmyfitness.com forward slash genetics. If you're interested in receiving notifications about the very best podcasts, expanded show notes, articles, and other information I publish nowhere else, also make sure to go sign up for my email newsletter also found at my website. And finally, if you love this podcast or any of the cool stuff brought to you under the found my fitness umbrella, you can learn how to support it for as much or as little as you like. Even that metaphorical monthly cup of coffee or bundle of kale by visiting foundmyfitness.com forward slash crowd sponsor. That's foundmyfitness.com forward slash C-R-O-W-D-S-P-O-N-S-O-R crowd sponsor. Until next time, may your telomeres be long and your DNA repair enzymes be strong."

Sulforaphane: Cancer

How do you do that in worms? Well, that's a big debate right now as to how to do that.

"Well, that's a big debate right now as to how to do that. Of course, the worms are changing their behaviors as they age. They're becoming slower. They're eating less. They cease reproduction."