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

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

[Rhonda]: Hello, friends. Today, I’m sitting here with Dr. Gordon Lithgow
who is a professor at the Buck Institute for Aging. One of the cool things that I really like
that Gordon does is that he actually screens various compounds, both natural compounds
like vitamins and minerals and other compounds to see if they potentially could be longevity
compounds. And one of the ways he does this is by looking
at the effects on a tiny nematode worm called C. elegans to see if there’s any effect on
their lifespan. So maybe you can kind of explain what are
these C. elegans and… [Gordon]: Sure. C. elegans is a tiny one-millimeter-sized
roundworm. It’s found in rotting fruit, naturally. It’s found on the backs of snails, and it’s
the amazing genetic system that was suggested by Sydney Brenner back in the ’60s to study
neurobiology and neuronal development. In the late ’80s, it was adopted by Tom Johnson
and Mike Klass to look at longevity. And it’s a fantastic system to study aging
because, well, one it’s transparent. So you can actually see the tissues aging
in real time day after day. But two, it lives a very short time. It lives about 15 to 20 days, and that’s the
big advantage because you can go through lots and lots of experiments very, very quickly,
fairly economically, and therefore, you can study lots of compounds and look for things
that extend lifespan. [Rhonda]: Right. As opposed to, for example, people that are
looking at compounds and how they affect another model for a…you know, in another model. Like, mice, for example, how long do they
live? [Gordon]: Well, so a mouse in a lab is living
two or three years… [Rhonda]: Two or three years. [Gordon]: …and it’s incredibly expensive
to maintain the animals and, you know, these are million-dollar experiments to study longevity
in mice. Whereas with the worm, again, it’s very quick
and you can study lots and lots of individuals fairly economically. [Rhonda]: Yeah. It’s super cool. Actually, I started doing my early, early
research right after I graduated from the University of California, San Diego. Before I went to graduate school, I worked
in an aging lab using C. elegans. [Gordon]: Okay, there you go. [Rhonda]: So I’m very familiar with them as
a great model for aging. [Gordon]: People fall in love with them, right? I mean, they actually come in and they’re
a little worm but before long, they’re just devoted to, you know, all the biology and
all the interesting things that happen. I mean, you’re looking down the microscope
and you’re seeing all sorts of interesting behaviors. You’re seeing growth. You’re seeing, learning and memory even, and
then you start seeing this aging process taking over and one by one knocking back the functions
that you can see. And it’s really dramatic when you have a mutation
or a chemical compound that stops that from happening or slows it down. And people are just kind of amazed to see
down a microscope a worm that’s crawling around and behaving normally when it shouldn’t be,
when it should be dead. [Rhonda]: Totally. That’s what sort of hooked me into this, 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 can make them live 100% longer. I mean, it was incredible. And to think that this is the same pathway
that’s conserved in humans, it’s like, “Well, that seems very relevant.” You know, yeah, definitely, that was the thing
that got me really, really interested, was that just…and seeing it myself, seeing the
experiments, right? [Gordon]: Seeing it, that’s right. Seeing it in the microscope is really profound. [Rhonda]: So these days, you’re doing a lot
of work on what’s known as protein homeostasis or, I guess the word would be proteostasis
and how that’s involved in aging. And I’m not sure most people watching or listening
even have any clue why protein homeostasis plays a role in aging. [Gordon]: Well, so as you know, you know,
we take in our proteins and we break it down into essential amino acids and then we build
our own proteins and the worm builds its own proteins. And those proteins have a three dimensional
shape, and that shape’s important for our function, of course. And during aging, the general observation
is that the proteins lose their shape in various ways. For example, during Alzheimer’s disease, the
protein beta-amyloid loses its shape, undergoes various conformational changes, becomes toxic,
neurotoxic, but eventually ends up as an insoluble protein in amyloid plaques in a diseased brain. Now, that process happens in Parkinson’s disease
as well with a different protein, alpha-synuclein. But actually, we believe it’s happening to
thousands of proteins. And a few years ago, we published a paper
where we showed that many hundreds, if not thousands of proteins, undergo conformational
change during aging and come out of solution. And it so happens that those proteins are
enriched for proteins that determine lifespan. [Rhonda]: So when you’re saying out of solution,
you’re saying they’re insoluble… [Gordon]: They become insoluble. [Rhonda]: …can you at that point say it’s
an aggregate? Is that technically accurate? [Gordon]: Biochemically, insolubility is related
to aggregation. [Rhonda]: Precipitate, right? [Gordon]: Aggregation is the coming together
of insoluble protein in a single [inaudible 00:04:45]. [Rhonda]: So you’re saying these aggregations
or these insoluble proteins that are happening, you’re saying hundreds of proteins are happening,
with age, this is happening. You know, this is partly because of damage
that accumulates, correct? I mean, a lot of damage that damages DNA,
so things like, you know, reactive oxygen species, inflammatory cytokines, these things
are damaging our DNA are proteins as well. [Gordon]: Right. I mean, proteins sustain lots of damage in
the normal course of metabolism. But it’s actually not too clear as why this
particular set of proteins come out of solution, and that’s something we’re pursuing and other
labs are pursuing as well. Cynthia Kenyon’s lab discovered a very similar
mechanism around about the same time. And so I think we’re all really interested
as to why these proteins come out of solution and are enriched for proteins that determine
lifespan. That kind of suggests that the proteins of
insolubility or misfolding or conformational change in itself has something to do with
the aging process. And I think this is really important because
here’s a process that’s been studied for decades in the context of neurological disease, Alzheimer’s
and Parkinson’s and so on. But if the same process is happening in the
course of normal aging, it shows a connection between normal aging and disease and that’s
something I think that lots of us are interested in right now. What are the mechanisms of normal aging that
are likely to accelerate age-related pathologies and disease? [Rhonda]: Right. And if this is happening in not just our neurons,
if it’s happening in our endothelial cells that line our blood vessels, I mean, I often
think about that as another, you know, tissue that is prone to, you know, insoluble proteins
forming. I’m not sure if that’s actually accurate. [Gordon]: No, I mean, the amyloids form in
lots of tissues in our body. There’s very specific diseases associated
with that. But I think what we’re seeing is that this
amyloid formations is a more general aging process. It’s just going on probably in most of our
tissues, if not all, and maybe then drives disease pathology that becomes obvious to
us when we look at it as a disease. [Rhonda]: So it’s disrupting just normal tissue
function, whatever tissue that is, it’s disrupting maybe mitochondrial function, just, you know,
the everyday things that are happening aren’t happening as well and this sort of can, you
know, lead to or be part of what we call the aging process in a way. [Gordon]: Absolutely. You know, and it’s not to say it’s the only
aging process. It clearly isn’t the only thing that is changing. Everything is changing. There’s evidence, for example, on Alzheimer’s
disease that there’s a metabolic problem that happens before you start seeing aggregation
of proteins. So who knows how all these things interact
with each other, but it’s important. I think that’s firmly established now that
this is a major mechanism of aging. [Rhonda]: Right, yes. Well, I remember, gosh, it must have been
like 12 years ago, when I first read a paper of yours where I believed you may have been
a post-doc 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 shocking. 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, 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. [Gordon]: Sure. I remember when I saw this for the first time
as a post-doc. and I ran into the office of my supervisor, Tom Johnson, and I said, “Look
at this. This is amazing. You stress the animals and they live longer. How is that possible?” And he said, “All right, you’ve just discovered
something that John Maynard Smith published in “Nature” in 1950s.” And he pulled this paper, you know, out of
his drawer, and sure enough that John Maynard Smith, the 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 hormetic responses are the production of molecular chaperones, also ramping up of
autophagy, the process of breaking down proteins. And a beautiful paper from Malene Hansen a
few weeks ago was showing that… [Rhonda]: Yeah, I saw that. [Gordon]: …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. [Rhonda]: It totally makes sense, though. I mean, if you think about it, like you said,
you know, in the case of heat, 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 curcumin, these sort of things can…you know, 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 know, you’re not only increasing things
that help proteins keep their three-dimensional structure, but you’re increasing antioxidant
pathways and anti-inflammatory, just a whole host of things and autophagy, wanting to get
rid of or clear away damaged proteins, damaged cells. And it’s so funny. I hadn’t thought about heat shock increasing
autophagy before and I was doing some background 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. [Gordon]: Yeah, no, Malene 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, here’s a mechanism now that really
explains why a stress is actually leading to longer life. [Rhonda]: 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 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… [Gordon]: Yeah. [Rhonda]: …humans have heat shock proteins. And our heat shock proteins are also responsive
to heat. [Gordon]: Absolutely. [Rhonda]: So, I mean, this isn’t like just
understanding worms. It’s something that’s, you know, being translated
to humans. [Gordon]: 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… [Rhonda]: Chemo… [Gordon]: 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, Malene’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. [Rhonda]: Right. Too much is, yeah. [Gordon]: 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…damn, I forget what we call it. Sorry. I think some of the chemical components that
we discover that extend life span are actually doing this. They’re harnessing the endogenous stress responses. [Rhonda]: Absolutely, absolutely. [Gordon]: They’re either activating the regulators
of stress responses or they’re causing 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. – [Rhonda]: Mm-hmm. Yeah. 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, and 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, you know, a
way that humans can activate their heat shock proteins. So humans that sat in 163 degree Fahrenheit
sauna for about 30 minutes increased their heat shock proteins, including Hsp70 by 50%
over 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 in sauna for probably since I started doing
research many, many years ago and I was working on heat shock a little bit and HSF-1 and all
this stuff. But I recently went to Finland last November. And there’s a researcher there. His name is, Jari Laukkanen. And he’s been doing…he’s a…MD, PhD. He is 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 in sauna use. So men, this was like 2,000-men cohort, and
men that had used the sauna like 2 to 3 times a week had a 23% or 24% lower all-cause mortality. [Gordon]: Wow. [Rhonda]: Men that used it 4 to 7 times a
week had a 40% lower all-cause mortality compared to men only used it once a week. So it was like a dose response effect. [Gordon]: Incredible. Yeah. [Rhonda]: But there’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 the
sauna 2, 3 times a week had a 20% lower risk of getting Alzheimer’s. If they used it 4 to 7 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, you know, the protein
aggregation and the heat shock and the stress response pathway. [Gordon]: Yeah, no, 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 in 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 have accumulated over
the last 25 years. It’s really time to try and translate that
and do something that might be beneficial. [Rhonda]: Yes. 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 in worms? [Gordon]: Absolutely, yeah. Yeah. Well this was inspired by my wife, Julia 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 I in the mitochondria through redox reactions,
and then that very specific damage would play all the way to neuronal death, the dopaminergic
neurons. So we went back and looked to iron. Basically, we had a collaborator, David Killilea,
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
lifespan, but it 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 on a chelator, an iron chelator. And in that case, the iron levels did not
rise during aging and the worms lived longer and they protected against protein aggregation
as well. [Rhonda]: Oh, wow. That was going to be my next question, actually. [Gordon]: Yeah. So all sorta made sense. [Rhonda]: Right. So the iron that you’re feeding these worms,
is there any way that it can be physiologically relevant to humans, like, the levels that
you were giving them possibly? [Gordon]: I believe so. I think the experiments in mice with Parkinson’s
disease, for example, those are right about the levels that you could be exposed to, 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 risks of Parkinson’s disease. So I think coming back to normal aging, I
wouldn’t be surprised if these kinds of levels of iron are important. The… [Rhonda]: Are you familiar with the…there’s
a few gene polymorphisms and one is in the hemochromatosis 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 is homozygous for those polymorphisms in that gene. [Gordon]: 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. [Rhonda]: I know there’s all sorts of problems,
so I wouldn’t be surprised if there was. What’s so funny is I didn’t think about you’re
mentioning Parkinson’s and how Parkinson’s is associated with iron accumulation and in
the mitochondria 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, like, 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. [Gordon]: And other metals as well. [Rhonda]: Other metals as well. Yeah, you’ve looked at some other metals,
right? Like copper? [Gordon]: Yeah, and 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. You know, so if you say, you know, “You know,
we’re going to manipulate the levels of metals.” Well, you know, 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 bit…little bit difficult to get your head around and there are very few pharmaceutical
companies in the world who really go after metals. But, you know, I don’t see why we shouldn’t
be asking the question, ‘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. [Rhonda]: Yeah, absolutely. I think it’s a grand point question. You know, people are supplementing with all
sorts of vitamins and minerals and some people are taking way too many. You know, iron is something that…I think,
you know, people should get their iron levels measured. They shouldn’t just be blindly taking an iron
supplement, I mean, because that could be completely dangerous. [Gordon]: That’s right. Absolutely. [Rhonda]: And, you know, with these gene polymorphisms,
like, it’s sort of a pet topic of mine, so I’m sorry if I’m going off on this. But, we’ve sort of evolved in different regions
across the globe and there’s different food availability, different minerals in the soil,
things like that. And so we sort of, like, depending on, at
least this is the thought, depending on how much minerals were in the soil, what type
of food we had available, we sort of, acquired certain mutations that became more frequent
in the population that became polymorphism. So it may be some people… And you can see this when you look, that if
you look at, you know, a lot of different gene polymorphisms, a lot of them do have
to do with minerals. They have to do with vitamin intake. And so all these things are sort of different
in people. And so I think it is very relevant to look
at how this affects aging, you know, for multiple reasons. So I’m actually glad that someone is doing
it. Of course, the pharmaceutical drugs are always
thinking of it from a different angle and that may not be the way, but it’s all very
important. But sort of to kind of go on the next topic,
you’ve also looked at vitamins. And I was very excited about your most recent,
not most recent, but a recent publication of yours that had to do with one of my favorite
vitamins, which is not actually a vitamin. It actually is a hormone. [Gordon]: A hormone, yeah. [Rhonda]: But vitamin D. So you’d found some
really interesting findings with vitamin D. [Gordon]: Yeah. We were looking at a C. elegan strain that
was engineered to express A-beta, so human A-beta. Now, when you do this in the worm, you see
these tiny aggregates form, like mini plaques. And something about that is toxic and the
animals become paralyzed. [Dr. Parick]: So this is in their muscle cells. [Gordon]: It’s in their muscle cells, although
you can do the same in neurons as well. [Rhonda]: In whatever, okay. [Gordon]: But it always makes the worm sick. So this was a strain created by Chris Lincoln
in Colorado. And we were looking for chemical compounds
that suppressed the paralysis. So very easy, you look down the microscope,
if the worms are still crawling around after you’ve turned on the expression of the A-beta,
you’ve got something that’s protecting against the aggregation process. And Carla Mark [SP], post-doc in the lab,
conducted a screen on natural products. We look at all sorts of different ligands. This happened to be a natural product ligand. And came to the office and said, “Hey, Vitamin
D.” And we said, “Well, we’re not going to work on that because there’s a paper every
day on vitamin D. And surely people have been studying vitamin D for decades. There’s nothing new to learn about vitamin
D.” But the thing that intrigued us was when we started to look at the epidemiological
literature and realized that when you’re deficient, when humans are deficient of vitamin D, they’re
an elevated risk for many adult cancers but also neurological disease. And if you look at the spectrum of diseases
it almost looks like many of the chronic diseases of late life. So I thought, “This can’t be. Is this possible that vitamin D deficiency
is really some sort of accelerated aging? Is that’s what going on here in people?” So we thought we may as well follow this,
because there’s not a lot in the literature about A-beta and protein conformation and
aggregation and so on. So we did many, many other experiments and
found that indeed vitamin D had an effect, widespread effect on the proteome. So it was preventing protein insolubility
as age-related rise in protein solubility across hundreds of different kinds of proteins
and different organelles in the cell and different issues. [Rhonda]: So it was essentially helping the
proteins age better. [Gordon]: Exactly, yeah, suppressing this
phenotype of aging. And then we combined treatment with compounds
or feeding with vitamin D in this case with different genetic backgrounds. And so we discovered that there’s a requirement
for certain genes, transcription factors, and these are transcription factors that normally
respond to stress and they were back to stress. And it seems like vitamin D somehow is able
to elicit the endogenous defense system, detoxification systems. So it’s turning on those systems. [Rhonda]: Like, Nrf2 regulated? [Gordon]: Right, that’s right. Yeah, the oxidative stress transcription factor,
Nrf2. It requires Nrf2 in the worm to see the beneficial
effects on the proteome. How weird? So we’re following that up. But all this was new for vitamin D. We began to show this data to some clinicians,
experts in vitamin D metabolism in bone and so on. And they were really excited by this, which
is always nice when you study worms, suddenly you’ve got a clinician excited. And I think they’re excited because at the
heart of it, you could see how an effect on a global process like protein aggregation
which is associated with lots of different diseases could explain perhaps why vitamin
D deficiency is associated with neurological disease and other diseases. So it almost like was giving them a handle
on a potential mechanism that might explain a lot for what’s going on in the epidemiological
data. And we thought it was cool because when we
talk about vitamin D to your colleagues or friends or the general public, there’s a response. People are interested in it. It’s cheap, it’s readily available, many people
are already thinking about it in their own health. So it makes a connection between, you know,
the curiosity research we do in worms and actually people’s lives. So we’re enjoying working on it. [Rhonda]: 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, okay,
so do the worms make vitamin D? We make vitamin D in our skin from UVB radiation. [Gordon]: Correct. [Rhonda]: And I always thought of the worms
as being soil-dwelling but you mentioned at the beginning of the podcast that they actually
are on fruit. So potentially, they’re exposed. [Gordon]: They probably are exposed to light. Now, worms will run away from light. If you turn the UV light on in a microscope,
they’ll move. But they probably are exposed to a certain
amount of light. Now, do they make it in the wild? We don’t know. What we do know is that if we feed D3 which
is the metabolite you buy at the drug store. D3 is converted into 1,25-dihydroxyvitamin
D. So there’s two steps. One in the kidney, one in the liver in mammals
that does that conversion. Now, we know if we feed the worms D3, they’re
able to make the 1,25 vitamin D. So we think that there’s conserved metabolism between
mammals and worms that suggests that maybe the worms are really making it in the wild
as well. They’ve got the apparatus. They’ve got the enzymes. We also know that they have the precursor
to vitamin D that we have in our skin that we turn into D3. They’ve got tons of that in their tissues
normally. We actually feed the worm’s cholesterol as
part of their normal diet. [Rhonda]: Really? Oh, they have 7-hydroxycholesterol. [Gordon]: They do. They have 7-hydroxycholesterol in large amounts. So our expectation is, and we’d never really
been able to think how to do this experimentally, but if we took worms from the lab and took
them outside into the sunlight, we might be able to detect them making 1,25. [Rhonda]: Well, why don’t you just… There’s a couple of experiments I would think
about is, one, shining UVB on them, right, and seeing if that works, because that’s how
we do it. So UVB radiation hits the 7-hydroxycholesterol,
and then that’s converted by D3, that gets transported into the bloodstream, then two
hydroxylation steps later, you get the active hormone. [Gordon]: Right. [Rhonda]: So that could be one thing you could
do. The other thing is did you guys try feeding
1,25-dihydroxyvitamin D to the worms? [Gordon]: We did. Actually, we fed a whole bunch of different
metabolites of vitamin D. And basically, any metabolite that can be converted into the
active form is beneficial. [Rhonda]: Okay, cool. So that sort of makes sense. [Gordon]: It makes sense. [Rhonda]: Yeah. You’ll be interested to know, if you haven’t
already seen this literature, because I also have published on vitamin D and very obsessed
with it. Are you familiar with the work that was published,
geez, it must have been like 10 years ago now, but on the vitamin D receptor knockout
index. [Gordon]: Yes, yes, yes, yes. [Rhonda]: Have you seen those animals? [Gordon]: I’ve never seen them personally,
but I’ve certainly read about them. [Rhonda]: Seen pictures of them? Well, at four months of age, they’re both…you
know, if you have normal wild type mouse and you knock out the vitamin D receptor, then
you look four months, they look the same age. And then at eight months, that mouse looks
like a progeria. I mean, it doesn’t even look like a two and
a half year old mouse would normally look. It looks like some sort of progeria kind of
phenotype where there’s no hair, the skin is all wrinkled, their organs are all, like,
shutting down. I mean, it seems like a very progeria type
of phenotype. I don’t know if that’s… [Gordon]: Certainly, the paper suggests that
and there are specific measures that are absolutely in keeping thermal aging. There’s probably a lot of other things going
on as well, I imagine, that when you really seriously mess up vitamin D metabolism, it’s
going to have lots of effects. [Rhonda]: Yeah, that’s a given. [Gordon]: Yeah. But absolutely, very exciting when we went
back and looked at those papers and thought, “Oh, this could make sense.” [Rhonda]: Right. And there’s also, like, if you look at the
epidemiology stages in humans, we know that, for example, there was a very large meta-analysis,
like, 33 different studies that were looked at ranging from, you know, the year 1966 all
the way to 2013, so broad range of time, looking at people’s blood levels of 25-hydroxyvitamin
D which is the precursor and is the most stable form. And what the meta-analysis found is that people
that had blood levels between 40 and 60 nanograms per milliliter had the lowest all-cause mortality
compared to those that, you know, had lower vitamin D levels or even really, really high
ones. But there’s some randomized controlled trials
that have looked at giving people high dose vitamin D supplementation, like 4,000 IUs
a day and it improved cognition, whereas low dose, 400 IUs a day would be considered low
dose, that did not…had no effect. So I think there is certainly a lot of evidence
associative studies and also there’s some randomized-control trials that really does
point to the fact that vitamin D is regulating the aging process. It’s been shown to regulate telomere length. I think that it’s absolutely probably regulating
the aging process and this whole protein aggregation angle is new to me. I didn’t know that it really played a role
in that and that’s super cool because I do know that protein aggregation plays a role
in the aging process. So it kind of, you know… [Gordon]: Yes, it’s beginning to join up in
a sensible story. Now that said, we should be cautious. And I’m not an MD and I am not prescribing
vitamin D for anyone, although it’s likely that if you are deficient, you really would
benefit from coming up into a sensible range. At high doses, and these are usually very
high doses as a result of some accident, but obviously it causes mineralization and that
can be serious. And so, you know, I think it’s up to people
to talk to their physicians about it, to get tested perhaps for levels. It’s probably almost completely harmless to
be taking an additional 1,000 units a day on top of whatever is in your diet, but really
talk to your doctor about it. [Rhonda]: I think that’s excellent advice
and, you know, most people don’t get their vitamin D levels measured and I think that’s
exactly what people should do. You know, they should get their D levels measured
before and after supplementation. Both. I mean, it’s not a hard test to do. If you have health insurance, it’s covered. If you don’t, it’s still really cheap. I’ve done it. You know, it’s not an expensive test and it’s
very worth it, so I agree that it’s very important to get your levels measured and you don’t
want to just blindly start taking like 20,000 IUs. [Gordon]: Yeah. Especially if you’re a C. elegans. [Rhonda]: Okay. So the last thing I want to talk to you about
that is really super cool that you’re doing, is you’re involved…I know that the NIH set
up this program that was like this intervention testing program in mice, right? [Gordon]: That’s right. [Rhonda]: And they were looking at compounds
that could potentially affect longevity in mice. But in parallel, you are doing something really
cool in worms. [Gordon]: Yeah. I mean, the mouse program has been very successful. Rapamycin was the drug that emerged as being
robust and reproducible at all three sites where these experiments were conducted in
mice. But a few years later, I guess it was a feeling
that maybe we can accelerate this if we utilize the speed of the worm and also utilize the
great genetic diversity in Caenorhabditis itself. Caenorhabditis is found all over the world,
has incredibly large genetic diversity, and the thinking there is that, well, if you can
find compounds that work in not only different labs to the same extent, but also at different
genetic backgrounds, then you’ve maybe got a high value candidate to then take forward
into more expensive mouse study. So, you know, it made perfect sense to us. We were very fortunate to be funded with Monica
Driscoll and Patrick Phillips, the other two investigators involved in the study. It’s a large study with lots of people in
all of our labs. And we sat down for the first time to talk
about doing worm aging experiments and to work out how we were going to do this so that
we’re all doing the same thing. We were horrified, absolutely horrified to
see the differences between labs and protocols. It used to be the simplest experiments in
the world. You take worms, you put them on an agar plate,
you squirt a compound on there, you watch them every day until they all die. It’s the simplest thing in biology, except
we were all making our plates differently, growing our bacterial food differently, handling
our worms differently, everything was different. So it actually took us over a year to standardize
the protocols and start to see similar results even without treatment, just growing worms
and measuring aging. It took us about a year to really get that
done. But then we had this wonderful platform where
we could go in and say, “Well, let’s test some of the compounds that were already out
there and published and let’s test some compounds that have been looked at in mouse studies
and ask are they robust and reproducible?” And the results are mixed, to be honest. We do. We are able to find reproducible and robust
compounds that work in lots of different genetic backgrounds and extend lifespan in all three
labs. But we find also a great degree of variation
and different kinds of variation that we’d never imagined before. So I think it has proven to us that this is
difficult stuff, doing this, and we really need to pay great attention to the protocols
that we’re using and be able to communicate those and convey them to all of the laboratories
if we expect other people to be able to reproduce our findings. [Rhonda]: Yeah. And what sort of compounds are you… So there’s like a top 10 compounds that you
were looking at? [Gordon]: Yeah. I mean, we selected 10, as I said, just to
get started, and those included some compounds that we had published, including Thioflavin
T which is a compound that binds amyloids. And we hoped and we think it does promote
protein homeostasis as a result of this. It also turns on stress responses as we were
talking about earlier. So Thio T was one that we felt was going to
be robust. It turned out it was. It was robust and reproducible. [Rhonda]: So that extended the lifespan of
C. elegans and all the other… [Gordon]: Yeah, C. elegans, C. briggsae and
other species, C. tropicalis and other species. And there were some compounds that did really
well in elegans when they were first published but actually didn’t then do well in briggsae. So there could be many, many reasons for that
but it was kind of what we expected that different genetic backgrounds will respond differently
to a compound. And we found compounds that really didn’t
do anything at all under our protocol. Now that’s not to say they don’t work in someone
else’s hands in their protocol, but now I think we’ve got a deeper understanding of
the major effects of just subtle changes in the way we do experiments. So they don’t work in their hands but that
does not mean they’re not promising candidates. It just means we need to think about what
conditions they are going to work in. [Rhonda]: It seems like the compounds that
are working in multiple different species are probably, you know, the best candidates,
in my opinion. But, you know, the ones that are at least
working in some species are also, seems… I think alpha-Ketoglutarate was another one
that was in some. [Gordon]: Yeah. Yeah, it’s doing really well. I mean, it’s great when you go to a paper
and, you know, a really great paper that you like and you just are able to reproduce it. It’s fantastic. So alpha-Ketoglutarate was one of those candidates. Yeah, I mean, I think we also want to investigate
why compounds do not work in particular strains because that could tell us something about
genetic-specific responses to compounds. And this may become important as you move
towards humans where there may be particular metabolic pathways that we want to avoid engaging,
or we might have genetic information on that would suggest we shouldn’t be treating this
group of people. [Rhonda]: Right, exactly. Personalized medicine sort of, this interaction
between genes and compounds and there’s lots of interactions between drug metabolism and
the way we metabolize drugs and, you know, the genes that we have. So that [inaudible 00:37:06] actually makes
sense. But so the next step then is once you… So if you have like these compounds that seem
very promising that you have identified in the various species of worms, do you communicate
to the mouse community and they sort of potentially will look at those? [Gordon]: Absolutely, I mean we will publish
everything, positive and negative, with respect to life span effects, also healthspan, we’re
looking at healthspan. But obviously… [Rhonda]: How do you do that in worms? So what’s… [Gordon]: Well, you know, that’s a big debate
right now is 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 in 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 the compounds are able to maintain that resistance. [Rhonda]: 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 is 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 like stress them? You add some sort of oxidative stress or something
and then you see a really robust, like do you think you might be missing some of those
sort of compounds? [Gordon]: 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 the stress responses and ask,
“Well, is this something that’s really making the animal healthier for longer,” which, of
course, we are interested in, but maybe just fails to increase the maximum lifespan. [Rhonda]: Can I put a bid in for a compound
you should look at? [Gordon]: Yeah. [Rhonda]: Sulforaphane. Sulforaphane is…are you familiar with sulforaphane? [Gordon]: No, please tell me. [Rhonda]: So sulforaphane is a xenohormetic
compound. It is produced in cruciferous plants. So, you know, anything from broccoli to kale
to cauliflower. [Gordon]: Oh, yeah. I remember now. [Rhonda]: 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 interviewed Dr. Jed Fahey, who’s at Johns
Hopkins who worked with Talalay who sort of discovered that it was the, you know, activator
of this whole Nrf2-Keap1 pathway. 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 has been a lot of clinical studies in humans showing it lowers inflammation, biomarkers
of inflammation in humans, it lowers biomarkers of oxidative stress in blood cells, it affects
glutathione, just everything, right? And all sorts of cancer prevention studies
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 c elegans or something, and I came across
this paper that was published in red flour beetle or something. I’d never heard of it. Anyways, they fed these red flour 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… [Gordon]: Good candidate. [Rhonda]: …to see if it does. I mean, I would bet that it does something
in C. elegans. So sulforaphane. I will send you an email. [Gordon]: 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 we hope to get through
hundreds of compounds eventually, so we are looking for suggestions. [Rhonda]: Cool. It’s 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. [Gordon]: Hope so. [Rhonda]: So pleasure talking with you today. [Gordon]: Nice to talk to you, thank you. [Rhonda]: And if people want to find you,
they can find you at the Buck Institute for Aging. [Gordon]: Absolutely, yep. [Rhonda]: And if they want to
learn more about your research, you’ll be there. [Gordon]: That’s right. Thank you very much.

73 Replies to “Gordon Lithgow, Ph.D. on Protein Aggregation, Iron Overload & the Search for Longevity Compounds”

  1. OMG I didn't know Rhonda Patrick was pregnant. Congratulations!!!!! I've been watching your podcasts on JRE for years now, completely changed my life. Thank you

  2. Keto, Cold Showers, Sauna, Broccoli Sprouts Everyday Day Crew Thank you Rhonda. (edit) forgot to mention NoFap

  3. Some of you observant folk have begun sending well wishes and congratulatory statements. So I'll respond all at once… thank you! 😊

    On another note… If you found the discussion surrounding the hemochromatosis and transferrin gene polymorphisms interesting and have done 23andme, you can actually run your raw data through the foundmyfitness website to learn about your personal genotype (for informational, non-medical purposes). Learn more about how to do that at foundmyfitness.com/genetics.

    Additionally, if you just loooove the podcast, videos, newsletter or any of the other various things coming from FoundMyFitness, you can learn how to support the podcast in a variety of different ways, including a pay-what-you-can subscription, by heading over to foundmyfitness.com/crowdsponsor. This includes direct subscription options, patreon, and more.

    All of that said, one of the very best ways you can support the podcast also happens to be free! Just by passing it along to a friend. Thank you for your consideration!

  4. Watching this discussion take place with relevant references and definitions popping up on the bottom was an incredibly educational experience. Thank you and congratulations Rhonda.

  5. sucks if u live in canada. u don't get any vitamin d for half the year. but i think as of april 1st, u can get vitamin d from the sun.

  6. 1:11 "fairly economically" good save, wouldn't want them to cut funding eh wink wink nudge nudge know what i mean eh huh wink wink. good work

  7. Great suggestion @ 20:20 We take too many metals with vitamin pills. What I do is to cut the pill in 3 parts, so that there is never an overdose of something. A day of fasting can balance out the body and remove the excess.

    Another great trick is garlic, celery, and wasabi, which helps to remove damaged protein and heavy metals from the body.

    41:31 bada bing, bada boom 🙂

  8. love your channel Rhonda but omg they are soo complicated, and ive spent prob 20yrs studying nutrition! although i know a lot (prob 50%) of what you and your guests are saying, i have to rewind constantly and read or whatever tto fully grasp it all, lol maybe im an idiot but this stuff is far too complicated for even somoene that understands nutritiion and longevity and related topics. Most of us havent been to 10yrs of school to know all the super super details…. i guess what im saying is i wish you could do more interviews with people that are more 'down to earth' and that makes sense without the Layperson having to make their brains explode trying to understand lol, but then again maybe im an idiot. So if your trying to get important topics across to average people that havent been to upteen years of schooling about how a mitochondria does Whatever! LOL (you get the point lol ) your most likely going about it wrong =( , most people initially give your channel a chance because one , (just being honest not rude) your a very beutiful woman, two they are interested in Health and longevity. Its kinda like a personal trainer telling their clients about every detail on a microscopic level (books of info) on how the muscle responds and all the client wants to know is how to workout and make it effective hehe. BUT then again maybe your audience is super educated on the microscopic level and thats cool =) this is not meant to be a Rant or Bashing you of any kind, im just rambling and putting my 2cents in i guess. i will Continue to watch all your Vids happily , mainly cause i think your a very beutiful person (inside and out) and i can understand at least half of what you and your guests are talking about =) Sorry for such long post =( And CONGRATS on your Baby! And i hope you are not mad , i respect you a great deal

  9. Ok I finally accept it , I accept that my love is married and having a child .Dr can you please add time stamps to the different topics of discussion?

  10. Does anyone have any info on how good broccoli seeds are opposed to broccoli sprouts? I haven't started sprouting any but have started eating the seeds by just putting them over some salad.

  11. Meant humorously and really benignly: You felicitous mingle-minx! Good fortune!
    And also: Thank you for your contributions!
    You glow so brightly that the pressure of the photons is palpable. Good.

    (If you don't like this comment, please feel free to delete it. Or I shall on your request.)
    (From a tscherman cosmopolitan with best regards.)

  12. Dr. Rhonda Patrick…my personal health hero…my daily life health habits all are based in her advice…the smartest and sexiest woman and soon to be mother alive, congratulations Dr. Rhonda!

  13. Great stuff as usual from Rhonda. Now, here is a slight problem: an organism has only so much capacity to respond to stressors. If you respond to many stresses simultaineously you develop what is called allostatic load, that is a load on the stess response triggered by many unresolved stresses. All these pathways seem to go through the integrated stress response which reduces protein synthesis but increases the translation of micro RNA and seems to alter the translation program. If you took every so-called hormetic molecule and engaged every stress response system, you would collapse and die from stress overload. By the way, c. elegans is a good model, but only a few stressed worms live longer and while others die quickly. There is a bit of a statistical problem here.

  14. Triggering endogenous stress responses reminds me of how vaccines work on the immune system. Can we think of this as vaccine against aging?

  15. you and dr Michael Greger should be way more famous. ur value to the everyone on earth is so under appreciated.

  16. I don't have to wonder if your baby will be getting the right nutrition and no vaccines. I usually cringe when I see a baby thinking I hope they did their research so another baby isn't vaccine injured.

  17. Hello, I use a cast iron pan to cook, is that bad then? Because in the cooking process the food probably absorbed some iron from the pan?

  18. You may be interested to know that the University of Malta has been researching the use of heat shock protein extracted from the Prickly Pear on cancer cells and in the control of diabetes: http://www.timesofmalta.com/articles/view/20130926/local/Prickly-pear-extract-may-help-patients.487731 & https://www.um.edu.mt/__data/assets/pdf_file/0004/148441/Christina_Fiott.pdf

  19. rhonda is an inspiration. a model other health-nuts can follow, just imagine her physical beauty, her knowledge and articulation, and pleasant way of being. Now apply it to yourself, isnt it something like what we had hoped for ourselves? So i realized the sense of admiration I had for her for knowing and applying knowledge related to physical and mental health (against alzheimers or dementia, cognitive decline) is something I had for myself all along. And it makes me want to pursue my goals, i was imagining looking sexy like her and being articulate in my communication, and I was saying to myself "I want that ;o)"

    thank you rhonda

  20. love the channel. Im glad you are specific and dont dumb down the science, there are plenty of simple channels on youtube! congrats on the baby!

  21. You only touched briefly on iron/ferritin – wish you would do a whole show on unliganded iron's role in increasing aging and therefore age related diseases. "Normal" serum ferritin levels are defined as 30-200 ng/ml, a 10 fold range! Yet menstruating women lose the equivalent of one unit of blood per year and so have ferritin levels of 15-30 ng/ml while men have up around 145 ng/ml!!

    This is actually a toxic level long-term, and explains why men have much higher rates of cancer, heart disease and brain degenerative diseases like Alzheimer's and Parkinson's, and generally live significantly shorter lives.

    Huge topic, lots more to mention, (for example, iron supports excessive bacterial growth and associated chronic inflammation) but bottom line is, get your serum ferritin tested. If its over 50ng/ml, donate blood until you get it down around 20-30ng/ml. Each blood donation lowers it about 30-60ng/ml. Iron overload affects most Americans, not just those with Hemochromatosis!

    Decreased cancer risk after iron reduction in patients with peripheral arterial disease: results from a randomized trial.

    Ferrotoxic disease: the next great public health challenge.

    Are menstruating women protected from heart disease because of, or in spite of, estrogen? Relevance to the iron hypothesis.


  22. Congrats ! When you are back in the office I am curious about how this study fits in with your latest findings > http://neurosciencenews.com/microbes-alzheimers-neurology-3826/

  23. How about rhodiola? I've heard that it extends the lifespan in worms substantially. Any evidence for it fighting aging in humans?

  24. So many people are tip toeing on Vitamin intake… Why? because the ignorant MD community has not a clue. The last person I would consult on any vitamin is my MD. Clueless. When I asked the oncologist about vitamin K2, She responded, why are you taking potassium? I shit you not. And I am going to consult with her on vitamin D? Ha ha ha ha ha ha ha. I'll go to the researcher any day and every day.

  25. Short answer, no you can't delay or reverse aging ! low calories diet, maybe, but you won't get as much energy.
    I never even heard about reversing white hair to their original color, while these are easily accessible cells… CRISP-R ? Not sure it could help here.
    Not directly related, iron (supplements) is also very dangerous for women, when taken together with grapefruit, it can cause irreparable damages ! Never take both together !!! look it up in case of doubt, really.

  26. And the hits just keep coming…
    Thank you Dr. Patrick for an interesting and informative discussion with Dr. Lithgow!

  27. as a regular layman I usually watch your video's all the way through. Even not knowing a thing of the technical aspect. I'm just very interested in health. Thanks!

  28. Great video. Do you think that if the sauna available is at 200 deg F that less time will provide the same result in HSP increase?

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