Judith Campisi, Ph.D. on Cellular Senescence, Mitochondrial Dysfunction, Cancer & Aging


[Rhonda]: Hello, everyone. Today I’m sitting here with Dr. Judith Campisi
who is a professor of gerontology at the Buck Institute for Research On Aging. Judy has made significant contributions to
the field of Aging, particularly for her research on cellular senescence, which I’m sure we’re
going to talk quite a bit about today. I’ve personally been following Judith’s work
for several years so I’m very excited to be able to have the opportunity to have discussion
with her. So Judith… [Judith]: Thank you. Thank you. [Rhonda]: I’m ready to just jump in and talk
about all things aging. You know, most people when they think about
aging, they think about the passage of time, a chronological number, but there’s a lot
of molecular changes that occur with aging. [Judith]: Yeah, well it’s a biological process
and it has its roots in evolution or it has its roots in actually, gestation. But it is not just the passage of time for
sure. [Rhonda]: So can you maybe talk about some
of the molecular changes that do occur that can contribute to the aging process? [Judith]: It’s a good question. You know, right now, I think it’s safe to
say that most people who work on aging believe there are a few fundamental, molecular and
cellular processes that drive aging in multiple tissues which is why all of the diseases of
aging, even though they’re from very different tissues all begin to rise exponentially after
maybe 50, 60 years of age. But the truth is, we don’t know exactly how
many processes there are and we don’t really know precisely in each tissue what the major
driver is. So there are theories, the free radical theory
of aging, loss of mitochondrial function, the accumulation of senescent cells which
I’m sure we’ll talk about more. But for now, I think there are two things
we can say that these fundamental processes almost certainly are driving tissue health. As for what actually drives lifespan, we really
don’t know. [Rhonda]: Yeah, I guess that’s like an entirely
different topic, I mean, to some degree. [Judith]: I mean, they’re related, nobody
dies of good health. But the truth is that we don’t really understand,
for example, why a mouse lives three years and a human lives over a hundred years I mean,
if you’re lucky. And what it is that evolution had to do to
take these two organisms, which are genetically pretty similar, but have a 30-fold difference
in lifespan. [Rhonda]: Right, yeah. Just kind of on the same topic, did you ever
see that paper that was published? Maybe it was like 2015 I believe. It was out of Japan and the researchers had
looked at a variety of different cohorts of aging individuals. So they looked at people that were considered
elderly, so these were, like, 80 plus year olds, they looked at centenarians, they looked
at the semi-super centenarians, and then the super centenarian. And they looked at a variety of different
biomarkers. I believe it was something like 12 different
biomarkers. They were looking at amino senescence in the
immune system, but they were looking at telomere length, they looked at blood glucose levels,
insulin sensitivity, inflammation markers and kidney function like all sorts of things
in each going to age group. [Judith]: Cohort. [Rhonda]: Yeah, in each cohort. And what was found, sort of to my surprise
but not too much to my surprise, is that the only going to biomarker that was indicative
of successful longevity in every cohort was suppression of inflammation. [Judith]: Yeah, I did read that. I did read that, yeah. [Rhonda]: Whereas like telomere length affected
if you could live to be, I don’t know if it was 100 or the 80 group, one of the group,
one of the you know, earlier groups but…so that was kind of interesting because it’s
sort of to me you know, this whole idea of inflammation which causes… [Judith]: Inflammaging as Claudio Franceschi. No, this is the term that was coined by Claudio
Franceschi in Italy, yeah. And it really refers to the fact that well,
if a pathologist were to take a liver sample say from a 15 year old and a 50 year old,
he or she could probably instantaneously tell you who was young and who was old. One would be just looking at the structure
of the tissue but the other is he or she would look for what we call a low-level sterile
chronic inflammation, meaning low-level infiltration of some immune cells but no evidence of the
pathogen. And so this is a characteristic of almost
all aging tissues is this low level inflammation. [Rhonda]: Most people don’t really, I mean,
I think they hear the term inflammation, they don’t quite know what it means. [Judith]: Yeah. So they’re two important…well, actually
there are two major modes of inflammation, right. So one is acute inflammation. So you cut yourself, turns bright red, that
takes 24 hours. And you’ll die without that, I mean that’s
the acute response of your innate immune system that’s going to try to protect you from infection
but also start the healing process. That acute inflammatory response has to die
down after a few days because it’s destructive. The innate immune system isn’t very intelligent. It’s designed to kill non-specifically so
these innate immune cells make hydrogen peroxide, nitric oxide, bleach. [Rhonda]: Right, hypochlorite. [Judith]: Exactly, the whole idea is just
to kill non-specifically until your adaptive immune system can figure out what precisely
needs to be killed. So that’s your T cells and antibody response,
but that takes a few days so you need both. Low-level chronic inflammation or sterile
inflammation is similar to acute inflammation and that many of the players are the same
but of course, it’s at a much lower level. If it were that fulminant, you would probably
die very quickly because your tissues would fall apart. But nonetheless, with aging, there’s this
constant increase in these innate immune cells that infiltrate your tissue. And after a while, the tissue does begin to
degrade and lose its structure and loose its function. [Rhonda]: Yeah, so it’s not only you know,
affecting the tissue, it’s affecting going to DNA, it’s affecting… [Judith]: That’s right because these are damaging
agents and so it becomes like a feedback loop. You have going to cells that are being exposed
to these mostly oxidants and yet, then DNA gets damaged and then the cell responds to
the DNA damage and it makes things worse and you get into these feedback loops. So the question is what is the cause of that
low level chronic inflammation? Of course, the short answer is we don’t really
know but we have some clues, we have some ideas. Some people have argued that with age, the
barrier in your gut breaks down slightly. Not enough to cause bacteria to invade your
tissues, but enough to enable bacterial products to leak into your bloodstream and then of
course, your body is going to respond, “Oh, my goodness, is this an infection?” and so
you get this slow buildup of immune responses. The other hypothesis, major hypothesis is
that damage cells, which are what we now think are mostly senescent cells, are produced as
part of their response to the damage. Cytokines which then attract the immune system
and those are not mutually exclusive probably both. [Rhonda]: Right, absolutely. Can you explain what, the people who are listening
watching you know, what exactly a senescence cell is and how you know, it’s obviously that
you just mentioned it’s producing more of these inflammatory cytokines and which to
me sounds like it accelerates the aging process. But sort of just what is a senescence cell,
why do they form? [Judith]: Yes, very good question. So we now, we meaning the field now I think,
would agree that senescence can best be understood as a stress response. It’s the way cells have evolved a program
to respond to certain types of stressors. And the result of that response, that stress
response is twofold. The first is that cells will lose the ability
to divide, essentially irreversibly. So what happens is tissues begin to accumulate
stress cells that can no longer divide. The curious thing is that they also tend not
to die, or they don’t very easily die so they accumulate with age. Very slowly and gradually, they’re always
at pretty low numbers but they go up with age. The other part of that stress response is
the cells turn on a program that causes them to secrete molecules that we classify as being
bioactive. And the reason why that term is vague is because
there are probably 50, 60, maybe 70 molecules that these cells begin to secrete and so they
have many, many activities. Some of them are attract the immune system,
so they’re cytokines and chemokines that are immune attractants. Some of them are growth factors that will
alert the neighboring cells, because maybe now if you have a need for proliferation the
senescence cell itself cannot divide, but it may want to tell its neighbors, “Hey, start
dividing.” They secrete proteases that remodel the tissue
that would also help with regeneration and repair. And they also, now we know very new data from
our lab, they secrete bioactive lipids like prostaglandins and leukotrienes, which are
very important for modulating inflammation fibrosis but also, again, tissue repair. So the way we now think of the stress response
is that it’s a double-edged sword. There’s tons of data that go back two decades
or more showing that the arrest of cell proliferation is extremely important for preventing cancer. So that stressed cell is in danger of becoming
a cancerous cell and the stress response intrinsic to the cell says, “No way, you will never
divide again and therefore you cannot form a tumor.” So there are mouse models now and even some
people with mutations in the genes that regulate that growth arrest, and those people die in
early death due to cancer, the mice die an early death due to cancer. So we know the growth arrest suppresses tumorigenesis. The secreting factors we also now know can
be beneficial for tissue repair and wound healing. So we’ve shown, for example, in the skin,
senescent cells appear at the wound and they produce growth factors that help the wound
heal. That’s the good news. The bad news is, as these cells gradually
accumulate with age and don’t disappear, they begin to drive this process of chronic inflammation. And that chronic inflammation caused by senescent
cells is also a double-edged sword. On the one hand, it attracts the immune cells
that will eventually begin to cause tissue destruction and degeneration. On the other hand, the cytokines that attract
the immune cells can also have an effect on neighboring cells and cause them to not function
properly. So for example, some of the cytokines that
senescent cells produce cause what’s called an epithelial to mesenchymal transition. So what is that? Most of the organs in your body are composed
of epithelial cells and these are cells that absolutely must talk to each other. Mesenchymal cells are the support cells, like
in the skin, the epithelial cells are the outer layer, the support cells are in the
dermis. Those are the mesenchymal cells. They don’t need to talk to each other, they
need to signal. They’re basically telling the epithelium what
to do. Now, when an epithelial cell becomes more
mesenchyme-like, it stops talking to its neighbors and that means the tissue is going to start
losing function. And so, senescent cells can change epithelial
behavior so that the tissue doesn’t function very well and it can attract the immune system
which will cause then the destruction of the tissue do alienate immune cells. So that’s the bad side. The good news is there are very few senescent
cells in young people, and below age 50 or 60 you don’t see very many of those cells
in tissues but with after about the midpoint of our lifespan, they become detectable. And now, you can imagine that those cells
as they build up, they start to drive the pathologies that we associate with aging. [Rhonda]: Probably also start to cause more,
yeah, cellular senescence. And so a couple of questions sort of popped
up when you’re talking about sort of the double-edged sword and how cellular senescence on the one
hand, it’s a function of a stress response that occurs to protect you from cancer and
so the cell stops dividing. You know, and then, the senescent cells of
course are then making all sorts of various different secreted proteins like you mentioned
and that can have…sometimes, it can have good effects if you’re talking about wound
healing and things but also it can attract the immune system and cause you know, more…basically
activate the immune system to make more of these hypochlorite hydrogen peroxide warfare
things going on in the cell which can also damage the cell even more. But the other thing is the growth factors
that you mentioned that they’re secreting and you know, let’s say, as you are aging,
you have accumulated more damage. And let’s say now that that damaged cell is
you know, supposed to undergo senescence because that’s the stress response to protect you
from cancer. But in the presence of excess growth factors,
that doesn’t actually always happen, right? [Judith]: No, it can start the process of
cancer. [Rhonda]: So it’s kind of ironic that various,
the very thing that it’s protecting you from it’s also now at some point possibly now,
making it more susceptible to at least as you get older. [Judith]: Exactly, I mean, there’s very good
data now in mice from our lab and other labs that the presence of senescent cells can drive
late-life cancer especially those cancers that are pre-malignant and poised to become
cancerous but they don’t have the mutations that are needed for a full-blown cancer. But under the stimulation, the growth stimulation
of a senescence cell, these cells can now start proliferating, they pick up more mutations
and then eventually, they become fully malignant. [Rhonda]: Exactly. I think I read you did some experiments out
of your lab where you guys injected these malignant cells into animals with and without
the senescence cells. [Judith]: That’s exactly right and with senescent
cells they converted to full-blown malignancy and you know, eventually kill the animal. So you know, you should be depressed, right? If you don’t have this process, you die of
cancer. If you do have this process you’re still going
to get cancer. I mean, we’ve struggled with this, we in the
whole field have struggled. What do we do about this problem? And the good news is, there are now mouse
models. We don’t know if this will work in humans,
but in mice we can selectively cause senescent cells to die, so finally we can make them
go away. And when we do that there are health benefits. I should point out, not necessarily an extension
of lifespan but definitely an extension of health spans. So our lab has done this, our colleagues lab
at the Mayo Clinic has done this. There are now a number of labs that are working
on the strategy of causing senescent cells to die. And this was initially done with transgenic
mice. Of course, we can’t make transgenic people,
but there’s an army of people looking for drugs that will do what the transgenes can
do. And some prototype drugs have been published. In mice, they’re prototypes because they’re
not yet ready for people but you know, and there are companies that are working on these
things. So the good news is I think the strategy of
tuning down the bad effects of senescence is on the way. That’s on the horizon for sure. We will still have to be careful how we apply
those drugs, right? If you’re going in for surgery you don’t want
to take drugs that will kill off senescent cells because you need to heal the wound from
the surgery. So there’s going to have to be some intelligent
discussions about when it would be appropriate to take these drugs. The good news about the drugs though is that,
from the mouse models, it’s not as though senescent cells you know, blossom at some
point after some age. They just gradually accumulate. So what that means is you don’t have to take
a drug that kills senescent cells every day. You may have in mice you can apply them every
few months and in people, maybe every few years. So this could be interesting strategy to improve
health by incrementally knocking down senescent cells every so often. [Rhonda]: Yeah, so you said that with these
studies that cleared away the senescence cells, the health span was improved, meaning I guess
the tissues, the organs aged better and things like that. But I thought I remember a study, maybe it
was the Mayo Clinic study where there was a mouse model. Perhaps, it was an accelerated aging mouse
model where they did have a lifespan extension of like 20%. [Judith]: No. So that was an increase in median lifespan… [Rhonda]: Median lifespan, okay. [Judith]: …but not an increase in maximum
lifespan. And I should have distinguished between median
lifespan and maximum lifespan. So the increase in maximum lifespan was not
significant. The increase in median lifespan was significant
and so that’s what we call health span. The animals still died but they were healthier
in many respects. You know, it’s interesting so what did they
die of? It’s not as easy as it might seem to determine
what kills the mouse. Actually, even in people sometimes going to
pathologists put “Heart stopped.” We don’t know. [Rhonda]: Yeah, we don’t know, okay so there
was an increase in the median lifespan which is still very important because now you’re
having more of these animals which are living longer but they’re…. [Judith]: They are living healthy. [Rhonda]: …healthier, so right. [Judith]: And of course for humans this is
amazing if you…I mean, what people dread about old age is those last years of life
when going to you go through a nursing home and people are, they’re barely mobile and
you know they can’t hear, and they can’t see, and they’re depressed for good reason. But you know, I think the image now of being
able to be vibrant and then who knows what will do you in the end, but you know, we will
die but I think what we mostly fear is those last few years of life where the quality of
life is very poor. [Rhonda]: Where you’re degenerative, and you
know, a lot of these diseases that are degenerative diseases aren’t necessarily like going to
kill you right away or going to as you said you could have you know maybe macular degeneration
or sarcopenia. It’s something where it’s just a little slow
and miserable and you can’t function as well. [Judith]: And then brain going to degeneration
of the brains. I mean, dying of cancer is no fun but I think
many people fear even more, this loss of cognition. It’s like you lose yourself and then the incredible
burden on the family. And so the idea is to try to compress that
period of morbidity so that the last years of life going to you die maybe have a heart
attack on the tennis court and you’re winning. There’s a lovely quotation from Thurgood Marshall. He was our first black Supreme Court justice,
this was in the 1960s and someone had the nerve to ask him how long he plans to live,
a lifetime appointment right, you know. And he said, “I plan to die at 110 from a
bullet wound from a jealous husband.” [Rhonda]: That’s pretty funny. Talking about the brain, you just mentioned
the brain. I’ve always been curious about what tissues…if
certain tissues accumulate more senescent cells than other tissues, including in the
brain. [Judith]: Yeah. So we and others have looked at senescence
in the brain. Based on the markers we have, so I should
also preface this by saying, we don’t have perfect markers for senescence cells. There are many markers, and so we tend to
have some confidence that we say a cell is senescent if we look at multiple markers and
we say, “Well, it’s a good chance, this is a senescence cell.” So the best markers that we have have been
used in the brain by a number of laboratories and it seems that the cells that are more
likely to become senescent in the brain are astrocytes. [Rhonda]: Splitting cells. [Judith]: Exactly and so that’s interesting
from two points of view. The first is there are probably more astrocytes
in your brain than neurons. Yeah, people don’t realize that but going
to there are lots of astrocytes. The second is it’s the astrocytes that give
rise to brain cancer. So again, consistent with the idea that the
stress response protects us from cancer at least for a while. We’ve studied human astrocytes and I can tell
you they amount to classic senescence response including producing all those pro-inflammatory
cytokines, and growth factors, and proteases. And we even have new evidence that astrocytes
as you know, help protect the neurons from certain types of toxicity like neurotransmitter
toxicity, and we can show that when astrocytes become senescent they become less effective
in that protective response. Yeah, so again you know being able to get
rid of those senescent astrocytes could be beneficial for preserving brain function. Now, once neurons die, that may be too late
so we have to distinguish between the ability to prevent degeneration in the brain versus
reversing it. I think reversal is going to be much harder. [Rhonda]: It’s always much harder for reversal. [Judith]: Yeah, yeah. [Rhonda]: Is the senescent cells that occur
in the astrocytes, do you think that also going to because as we age brain inflammation
also increases. Do you think it’s a contributing factor? [Judith]: Yeah, we definitely think that’s
a contributing factor. It may not be the only factor, but definitely. [Rhonda]: Well, there’s now going to lots
of evidence showing that you know, a lot of cytokines in the periphery can cross the blood-brain
barrier with a variety of mechanisms, including this newly discovered lymphatic system that’s
connected to the brain, the meninges or something. [Judith]: Exactly, that’s right. So that’s interesting. So you don’t necessarily even have to have
astrocytes senescence to help contribute to neurodegeneration. It could be in your liver or your skin. [Rhonda]: Exactly, exactly. So sort of like just sort of all connected. Maybe we can talk a little bit about the mechanisms
that lead to cellular senescence. I mean, we mentioned inflammation, sort of,
you mentioned it’s a stress response, it’s just the stress but you know specifically… [Judith]: What are those stresses? [Rhonda]: What does are the…like I know
the main mechanism I always think of when I think of cellular senescence. [Judith]: DNA damage? [Rhonda]: DNA damage. [Judith]: Yeah, for sure, anything that causes
severe or persistent damage to the genome will drive cells into senescence. It makes sense because that puts you at risk
for mutations, mutation puts your risk for cancer, so the cells want to shut that damaged
cell down. But there are other stresses now that we know. We recently showed, for example, that having
bad mitochondria in the absence of DNA damage…so this is just mitochondrial dysfunction if
you will. And we could show that you could cause mitochondrial
dysfunction by any number of means. Five or six different ways of causing the
mitochondria to fail to produce the energy that they need and to produce more free radicals,
even in the absence of those free radicals getting to the nucleus cause the cells to
senesce, so they will senesce in response to bad mitochondria. What’s interesting is the cells senesce, they
stop dividing. They do start secreting molecules but it’s
a different complement of secreted molecules. So we can now pretty much determine whether
a cell has become senescent due to DNA damage versus bad mitochondria based on their secretory
profile. There’s overlap, don’t get me wrong there’s
overlap but there’s also distinct features that the mitochondria are responsible for,
bad mitochondria are responsible for versus damaged DNA. [Rhonda]: What would you say the main distinctive
features? [Judith]: So one of the main distinguishing
features is with DNA damage, there’s a pathway that increases cytokines like IL-6, IL-8,
these are very prominent pro-inflammatory cytokines. That doesn’t happen with bad mitochondria
so that loop is pretty much not activated. But then other molecules are activated that
can also be pro-inflammatory but through a different pathway. [Rhonda]: Wow, so this, kind of, is very extremely
interesting. I wonder why that is and I wonder what, like,
if there’s different going to functions of these senescent cells. But the secretion of some of these pro-inflammatory
cytokines and the attraction of immune cells to that going to to that area, one would think
would then cause that senescent cell to be cleared away. [Judith]: Yes, yes, and it probably does happen. But it probably doesn’t happen efficiently
enough, or with age maybe we make senescent cells at a higher rate. So several labs, not our lab but several other
labs have shown that senescent cells express molecules on their surface that can target
them for being killed by the immune system, and the immune system can do that and it does
do that. Nonetheless, we still see this increase with
age. [Rhonda]: But the immune system declines with
age, right, function of the immune system does. Do you think that may contribute? [Judith]: Well, that’s a big unanswered question. So what happens with so-called immune senescent
is primarily the adaptive immune system. [Rhonda]: That’s actually the good part of
it. [Judith]: Exactly, exactly and this is why
you become more susceptible to certain types of infections with age. So the adaptive immune system tends to decline
with age. The innate immune system if anything increases
in activity with age and it’s the innate immune system that clearly targets senescent cells
for clearance. So for example senescent cells express on
their surface ligands for natural killer cells and natural killer cells will then attack
those senescent cells and kill them. Nonetheless, senescent cells still accumulate
with age. So we’re considering several possibilities. So one is maybe you’re just making them too
fast, the immune system can’t keep up. The other is that although the innate immune
system doesn’t decline with age per se, it does change and it could change in a way that
it becomes less efficient at clearing senescent cells. So that’s a big open question, we don’t know
the answer to that. And the third possibility is that some senescent
cells may develop mechanisms to protect themselves from immune clearance and we’re sort of still
studying that now. And we think maybe all possibilities are still
open. [Rhonda]: Geez, I have so many things that
I want to talk about it which order because I’m going to forget. So talking about these changes in the adaptive
versus the innate immune system sort of reminded me of Dr. Valter Longo’s research, who I interviewed
a few months ago. And he was talking about how this prolonged
fasting in mice, which is about 48 hours or translates to like four days in humans which
is quite a long fast, but was able to just very robustly clear away damaged cells, presumably
senescent cells well. Also caused cellular death, but followed by
a massive and robust increase in stem cell proliferation sort of replenishing the population. But what was so interesting was that, it seemed
to at least in aging mice, if you did this in aged mice, it normalized the difference
between the innate and the adaptive. So like you were mentioning, the adaptive
immune system declines with age, but this fasting sort of like replenished somehow I
guess the adaptive maybe some of the stem cells. [Judith]: In the bone marrow, yeah, yeah. [Rhonda]: Yeah, so you maybe have more of
a 50-50 ratio like you do when you’re younger. So what would be interesting is if you like
somehow did that experiment where you caused going to disinvesting and going to sort of
regenerated that adaptive immune part, I guess of the immune system. And then like gave some chemical to cause
senescence and see if there’s any change in… [Judith]: Well going to a lot of Valter’s
work also has to do with the side-effects of chemotherapy, right. So he was able to show that with this intermittent
short-term fasting, even in humans, he could not only improve the efficacy of chemotherapy
but prevents some of the side effects. So we’ve shown very recently using mice, a
transgenic mouse model, that some of the so-called genotoxic chemotherapies, chemo therapies
that damage DNA, definitely causes senescence. And if we eliminate those senescent cells
in our transgenic mouse model we can eliminate several of the side effects, several of the
bad side effects of chemotherapy. So one possibility is that what the fasting
does is it might eliminate senescent cells. More likely what it might do we think is dampen
mTOR activity. So just to remind you, mTOR is the kinase
which is highly conserved from yeast all the way to humans and it’s a nutrient and growth
factor sensing kinase, so high nutrients, high TOR activity. And what has been shown in yeast, and worms,
and flies, and mice is that if you dampen…you can’t get rid of TOR activity, you need it
for life. But if you dampen TOR activity either genetically
or with the drug rapamycin, which is known to target one arm of the TOR pathway, you
can extend lifespan. And what we showed recently is that what rapamycin
does or dampening TOR activity does is it also suppresses primarily the inflammatory
arm of secretory phenotype of senescent cells. So it could be that fasting, and rapamycin,
and the secretory phenotype of senescent cells all come together around the TOR pathway,
and that it’s really TOR activity that’s driving both the aging phenotypes, the side-effects
of chemotherapy, and may partly explain the benefits of the short-term fasting that Valter
is a proponent of. [Rhonda]: Interesting. So if it’s dampening the secretion of these
cytokines from the senescent cells but it’s not actually getting rid of the senescent
cells. [Judith]: It’s not so far as well, we’ve shown
that either genetically or pharmacologically with drugs like rapamycin suppresses the secretion
of senescent cells but it doesn’t kill them. So unlike some of these other drugs at least
your so-called senolytic drugs that actually kills senescent cells, the mTOR drugs, the
mTOR dampening drugs suppress the ability of the senescent cells to secrete. And the effects last longer than the application
of the drug in the sense that we know that part of that secretory pro-inflammatory secretory
phenotype is due to a feedback loop. And what dampening mTOR does is it breaks
the loop and the loop takes time to reestablish. So even after you withdraw the drug, you still
get suppression until eventually the loop reestablishes and then the cell starts secreting
again. So you might think that if you were to fast
for four days going to every few weeks, you might have more benefit, certainly more benefit
than taking a drug like rapamycin which has side effects. [Rhonda]: Right because you’re not only going
to when you’re fasting, you’re also clearing away the damaged cells in theory. I mean, we don’t know how much of that’s occurring
in humans yet, we do know, in mice that happens. [Judith]: Yeah in mice, that happens. [Rhonda]: And then the other thing, this kind
of goes back to the mitochondria induced senescence that we talked about a minute ago is that
we know that fasting increases NAD levels and so the NAD plus, NADH ratio. And that sort of is very interesting because
this mitochondrial induced damage, I think has something to do with declined immunities. [Judith]: It does actually. So that’s what we’ve shown is that this mitochondrial
dysfunction induced senescence we call it mitochondrial dysfunction associated senescence
or MiDAS. So we call it the MiDAS phenotype. It really has to do with this altered NAD,
NADH ratio, and that’s one of the drivers. Interestingly, so when you change that ratio,
you activate a kinase called AMP kinase. AMP kinase is a major regulator of p53, p53
is a major regulator of both senescence and apoptosis. So that could be the link of why in Valter’s
paradigm, you get reduced inflammation that could be due to suppressing the secretory
phenotype but also increased apoptosis because you now have activated p53. [Rhonda]: Right, exactly. Yeah, so just got sort of lost and the question
I was going to ask you but the… [Judith]: One of them is going to…yeah,
I don’t know if you can ask this question but it’s worth discussing is the stem cell,
the regenerative process that Valter has seen. So we also know that the secretions of senescent
cells can have very profound on stem cell proliferation and function. So it could also be that by dampening the
secretory phenotype of senescent cells, you now release those stem cells from the suppression
that was due to those secretory phenotypes and therefore allow them now to do what they
do best, which is to proliferate and regenerate a tissue. So all of things really probably tie in to
each other, I mean they’re all interrelated. [Rhonda]: So the growth factors that are actually
secreted by the senescent cells do help with stem cell growth? Because of senescent cells like if this happens
in a stem cell, you’re depleting the stem cell pool and it’s contributing to the stem
cell aging. [Judith]: Both are probably true, both are
probably true. So we have shown in the skin, for example,
that with age, senescent cells do accumulate. But if you clear those cells you don’t get
much benefit, and that’s because by old age you’ve depleted the stem cells. So once you’ve depleted that stem cell pool,
you can’t go backwards or at least you can’t very easily go backwards. But two labs have now shown that senescent
cells can also produce growth factors or factors that help neighboring cells reprogram to stimulate
regeneration and they do it again by their secretory phenotype. So it’s again this double-edged sword. Some of the secretions of senescent cells
dampen stem cell activity and others promote stem cell activity. [Rhonda]: So the mitochondrial induced senescent
cells, what’s their function? I know the DNA damaged induced ones are you
know, obviously are protecting from cancer. What’s the purpose? [Judith]: What is the evolutionary purpose? [Rhonda]: Yeah. [Judith]: Well if you have a cell with bad
mitochondria, you probably want to clear that cell, prevent that cell from propagating,
because then you’re going to have clones of cells with bad mitochondria. And we know that that causes all sorts of
degenerative diseases, neuro degeneration as well as muscle degeneration. And so it probably is also protected but not
so much against cancer but against accumulating degeneration within a tissue. We know for example that people who are born
with mitochondrial DNA defects, eventually the bad mitochondria expand and so that’s
not good for an organism. So there probably is a protective mechanism
to prevent the propagation of cells with bad mitochondria. [Rhonda]: Okay, well that makes more sense. I guess going to at a certain point, your
mitochondria, if you don’t have you know, a really bad defect in mitochondrial DNA,
your mitochondria will repair themselves through fission/fusion. I mean yes, right, isn’t fusion also part
of how this exchange all their mitochondrial content and the damaged one sort of fixes
itself to some degree? Although, I guess that gets deluded. [Judith]: The bad ones also get eaten up by
the lysosomes. [Rhonda]: Right, yeah so I guess there’s multiple
mechanisms. Do the mitochondrial induced senescent cells,
they produce the growth factors that affect stem cells? [Judith]: They produced some growth factors
yes, they produce for example, amphiregulin, which is a EGF-like growth factor. So they do, they do. So where we’re still struggling with trying
to understand you know, what aging phenotypes are caused by genomic damage, what aging phenotypes
are caused by mitochondrial… [Rhonda]: Muscle atrophies. Do you find more muscle tissue, mitochondrial
induced? [Judith]: Well, we find more senescent cells
and we find them in the heart but we don’t know how they got there. It’s a big unanswered question as to when
you see a senescent cell in vivo, which we do in human tissue and mouse tissue with age,
they accumulate but what caused them to become senescent? Is it mitochondrial damage, is it genomic
damage, is it metabolic imbalances? We really don’t know yet, it’s still one of
the big unanswered questions. [Rhonda]: Yeah, that sort of leads me into
the preventive sort of questions I had and that is you know, we do know that there are
lifestyle factors that affect mitochondrial health, that affect DNA damage, that affect
telomere length going to and these things are obvious to a lot of people. I mean, a lot of work out of Elizabeth Blackburn’s
lab with Elisa Powell, they’ve done some really great work and a lot of its associative studies
where they’re looking at telomere length and various lifestyle factors but they’ve shown
for example going to that exercise is very important and people that are that are sedentary
have shorter telomeres than people that are physically active. People that are stressed have shorter telomeres. Actually, people that have low vitamin D have
shorter telomeres, omega-3, sugar accelerates the aging process at the level of telomere. So all these factors and telomere length also
is a major regulator of cellular senescence. [Judith]: Oh yeah, I think the best way to
think about telomere length is that when the telomeres become too short…so telomeres
form a structure that caps the ends of the chromosomes and makes sure that the cell doesn’t
mistake that chromosome end for broken DNA. Because the cell will try to fix that broken
DNA by fusing it to another broken end, and you don’t want that to happen with your telomeres. So when the telomeres become too short, that
cap structure then is disrupted, and now the cell thinks it has a broken DNA and it will
try to fix it if it can, but if it can’t it will cause senescence. So short telomeres are in a way a subset of
DNA damage which again is a major driver of senescence. So I mean, telomeres tie in exactly to the
whole thing. [Rhonda]: Don’t telomere sort of take the
hit for DNA damage as well? [Judith]: Well, they have a fairly high proportion
of the nucleotide guanosine, right? And that base is pretty susceptible to oxidative
damage, so it becomes like a sensor for damage. It’s not the only thing that will cause DNA
damage that is oxidized guanine but telomeres are good sensors of whether there’s oxidative
damage. [Rhonda]: Do you agree that things that at
least have been associated with DNA damage and telomere length in humans and associative
studies may likely be the same things that help prevent the accumulation of cellular
senescence? [Judith]: Yes, yeah, to some degree exactly. I mean, I don’t want to oversell the idea
that senescence can explain all of aging. It’s like telomeres can or DNA damage can’t. But we think it’s an important process and
it’s tied in to other things that may intersect with the senescence pathway and including
things like telomere length and genomic damage but also things like exercise. So there’s a recent study that I thought was
really interesting. This was a study that looked at lifespan longevity
in obese people. So both groups were obese, but they compared
obese people who with sedentary with obese people who were moderate exercisers. And there was something like an 8-year difference
in life span. [Rhonda]: You’re kidding. [Judith]: No, even with the obesity, moderate
exercise in general protected the longevity of obese people. And so, imagine what it does for people who
are not obsessed. I think exercise is probably the single most
important intervention that cuts across multiple diseases. So sarcopenia which is going to muscle loss
with age major cause of going to you see people sitting in wheelchairs like this, it’s horrible. The only intervention, effective intervention
is exercise. And we know that exercise can have some effects
on senescent cells in vivo but we don’t know how it works, we don’t know precisely what
it does. [Rhonda]: What about the stress response pathways
it activates? I mean, exercise is a type of hormetic stress
so it’s a little bit stressful and activating all these. [Judith]: Yeah so that’s one idea is that
it’s hormetic stress meaning it’s low level stress that then primes everybody else, all
your other stress responses to be hyper-vigilant. And so then when a bad telomere comes along,
or an insult from radiation or high sugar because you just couldn’t resist that last
brownie, you’re better able to deal with that stress. It’s one hypothesis. I think there’s still you know, an ocean of
ignorance around how exercise seems to be so beneficial for so many indications of aging. Again, aging not necessarily maximum lifespan,
healthspan. [Rhonda]: Yeah, it does seem to affect many
different diseases of age as well in addition to sarcopenia, cardiovascular health. I mean going to cardiorespiratory fitness
is also very tightly correlated with longevity. [Judith]: And there are some groups now that
are studying the effects of exercise on side-effects of chemotherapy and showing benefits of again,
mitigating some of those side effects simply by an exercise regimen. And we’re not talking running marathons, we’re
talking sort of moderate but persistent exercise. [Rhonda]: It’s fascinating. I’ve read a couple of the studies, at least
the animal studies where they can sort of force them to run a little bit more on this
running wheel and it is like there was a very robust response in terms of at least in combination,
I think with the standard of care treatment where I want to say something like 50%. It was something very like, really you know,
like that’s very…you know, I’ve always thought about it as sort of when you’re exercising
you’re forcing your mitochondria to work harder and you’re producing more reactive oxygen
species and cancer cells don’t like that. I mean going to so who knows? [Judith]: Yeah, I think yeah, mechanism so
far unknown but lots of possibilities. [Rhonda]: Right what about the hope for a
clinical assay for measuring things like cellular senescence or at the very least, DNA damage
in people? [Judith]: Yeah so that can be done. I mean, I know of at least a couple of companies
that are doing this. Usually, they use peripheral blood and there
are very good antibodies that will detect persistent DNA damage. So you can you can stain these blood cells
and get a sense of what your DNA damage load is. There are good markers for senescent cells
now. We always recommend that you use two or three
but we can probably assess the load of senescent cells. The difficulty lies in tissue specificity. So peripheral blood is easy going to buccal
swabs are easy because they’re accessible. But you know, you really probably want to
know how many senescent astrocytes you have in your brain, and you know, brain biopsies
are not going to be approved very soon. So that’s the difficulty is we can get a general
idea from those easy to access tissues but there are tissues we might want to know about
that are not going to be easy to biopsy. [Rhonda]: Is there a correlation between let’s
say, if you were to look at cellular senescence in white blood cells or leukocytes between
that and the heart or the brain? [Judith]: Yes, yes there is, and of course
the work that really exemplifies at the most is the work on telomere length where you take
you know, peripheral blood that’s mostly what’s being used now to assess you know, telomere
length. But you look at the data and of course there’s
enormous scatter in the data, there’s always a young person you know, who’s down with the
length that’s equivalent to a 90 year old and 90 year old who’s up there with the equivalent
of a 16 year old. And part of that I’m guessing is due to the
fact you’re measuring one tissue and you don’t know what the history of that. You know, when was the last time you had a
cold? That’s going to affect you know, how many
t-cells you have with bad telomeres or not. And so human data tends to be messy in that
sense. [Rhonda]: It’s very messy. I’ve actually seen this quite a bit because
I’ve done a lot of work with Dr. Bruce Ames and I’ve measured DNA damage in people and
lean people, obese people, after a certain you know, giving them an insert intervention
and I do this by measuring phosphorylated H2AX. But I’ve seen even looking at different age
groups like you know, sometimes like the 20 year old will like look like a 70 year old
and you’re like, what happened going to here? And sometimes the obese people look really
great but most of the time obese have higher levels than lean. But there’s certainly there’s a lot of variation. There’s a lot of variation. [Judith]: Yeah, and I think that variation
is twofold. The first is you know, we’re people. We are not genetically identical the way our
mice are. So there’s going to be individual-to-individual
variation because we’re not genetically identical. But the other interesting aspect is that we’ve
taken in our mice…we have transgenic mice in which senescent cells activate a protein,
a luciferase that we can then measure by luminescence in the whole animal. So we can follow the appearance of senescent
cells in living animals by looking at this luminescent signal. So we start with say 12-month-old mice, so
that’s a 35 or so year old person, very low signal. And then as these animals age, the luciferase
signal goes up, and up, and up. Then you look at the error bars. Genetically identical animals sometimes in
the same cage and the error bars get larger, and larger, and larger. So that says there is stochastic variation
that’s not due to genetic differences that causes identical animal to have some with
a high burden of senescent cells, some with a low burden of senescent cells. And this is true for virtually every aging
marker that has been looked at. The error bars get larger, and larger, and
larger. So, we call this stochastic variation. We don’t know whether it’s malleable, meaning
we don’t know whether you could make things less variable or more variable. We don’t know whether it correlates with health
of the animals, but it is a very common feature of aging is that things that go wrong do it
almost randomly. [Rhonda]: And there’s no idea of what’s causing
it? [Judith]: Well, I mean, you know that if you
take a bunch of cells, identical cells, genetically identical cells and you apply some toxin and
then you look at damage, you get a Gaussian curve, meaning there are some cells that don’t
respond very well. Most of the cells respond a certain way and
then some cells that are super responders. And so it probably is just the messy nature
of biology. We have all these pathways that are intertwined,
and by chance one configuration makes the cells super responsive and another configuration
makes a cell less responsive and if that’s true of cells, and it’s definitely going to
be true of something as complicated as a mouse, much less a person. [Rhonda]: Right. so I have just a couple more questions, couple
more wacky but just a circle back walk, since I have you here, I know we’ve been talking
for a while. But back to the NAD levels that reminded me
of this whole new field as sort of semi new, I guess on you know, different precursors
of NAD that you can get like nicotinamide riboside, nicotinamide mononucleotide. I know nicotinamide riboside at least in humans
has been shown to increase NAD levels at least at very high levels. What do you think? Do you think that any of those, and I know
that there’s been some animal studies showing it increased health span so that the tissues
were aging and some organs were aging better. Do you think that any of those effects of
the increased energy had to do with lower cellular senescence? [Judith]: That’s a good question. As I mentioned, we know that this mitochondrially
driven senescence, it’s definitely driven by this alteration in the NAD-NADH ratio so
it’s possible. We haven’t really studied those precursors
directly on senescent cells, but yeah. [Rhonda]: It’s interesting. – [Dr. Judith] Sounds like a grant I should
write. – [Dr. Patrick] Yeah, there you go. And then one more question about before I
get to the other wacky question was what do you think about some of these, like people
call them, “Fasting mimetics” I don’t like that. I think there’s too many things going on with
fasting, but you know, that have been shown to clear away damaged cells like spermidine
or the hydroxy citrate, or resveratrol. Do you think that’s something? I mean people are taking these to like clear
away senescent cells. [Judith]: Yeah, we’ve explored some of those. Some of them have no effect on senescent cells
which doesn’t mean that they might not have health benefits but it just doesn’t act through
senescence. Resveratrol for example, we don’t see any
effects on say pro-inflammatory cytokine secretion or anything that we think might be important,
but that doesn’t mean that it’s not doing other things. I much prefer red wine. Cells don’t like it. [Rhonda]: Cells don’t like it. The other wacky question that just came to
my mind was, so I’m thinking about cellular senescence, not the mitochondria cellular
senescence but you know, the DNA damage induced cellular senescence, as a protective effect
against cancer and that’s why it’s evolved. I mean, we have that because we don’t want
to die of cancer young. What about animals like elephants? They have a relatively long… [Judith]: I don’t think it is that they don’t
get cancer, I think what’s amazing is that they’re so big, right, and they have so many
cells. And so you would think that there should be
ways, there should be super ways they have of protecting against cancer because it’s
a hell of a lot of cell division to go from a single elephant egg and sperm, you know
a zygote going to to an elephant which is so big. And there have been some studies on looking
at for example, tumor suppressor mechanisms in some of these animals. P53 right, they have extra copies of p53. [Rhonda]: Do they have any cellular senescence? I was just wondering if anyone’s looked at
it? [Judith]: I don’t know that anyone has looked
but I would be surprised if they don’t. I mean, we’ve seen cellular senescence in,
or we, meaning the field, has looked in a number of vertebrate species and it seems
to be common amongst all vertebrate species. [Rhonda]: Does it occur in lower organisms? They only live in weeks? [Judith]: Well it does. Based on the markers we have some people have
looked in C. elegans and they don’t seem to find it there but then, C. elegans is unusual
in that the only dividing cells and the worm is the germ line. But in Drosophila going to there is a small
fraction of cells that undergo division in the gut and there is some hints that there
may be senescence that occurs in the gut of the fly and that kind of makes sense because
one thing that happens with age in the fly is they get this gut hyperplasia, it’s almost
like colon cancer in the fly. But they don’t have the vast number of dividing
cells that say, we have, our a mouse has. So it’s possible that it might be found in
Drosophila. [Rhonda]: Okay, and what about that…just
now one triggered a question. Does cellular senescence occur in more rapidly
proliferating cells? Is that like the gut in a human? [Judith]: It can. I mean, the gut is different I think because
remember, those cells are programmed to die. [Rhonda]: Right, kind of like the immune system
I guess? [Judith]: Or some of, yeah, some immune cells. I mean, but if you think about say something
like the skin so again, those cells are programmed to die but then there are these basal epithelial
cells. It takes a long time. So unlike the gut where there’s very rapid
sloughing off of those cells takes longer in the skin. And of course people do get skin cancer and
they always come from the basal keratinocytes. This is certain types of skin cancer, right,
not all. I mean, not melanoma for example which comes
from melanocytes. But so those cells can transform even though
they’re programmed to die and we do see senescence in the basal layer of keratinocytes in human
skin. So maybe. [Rhonda]: Does that contribute to collagen
breakdown and other stuff? [Judith]: Well that’s the idea is that it
could because they’re making a lot of proteases that will destroy collagen. Yeah, but I mean going to nobody really knows,
yeah. [Rhonda]: And so, with all your research that
you found you know, throughout the years on cellular senescence and just aging in general,
do you have any practices that you have sort of gleamed from your own research that you
incorporate into your own lifestyle? [Judith]: Yeah, so you know, moderate exercise,
although I always seem to be busier than I like to be. You know, a good diet. I don’t smoke, eat your veggies but then there’s
this genetic component which says you should choose your grandparents very wisely. [Rhonda]: And that’s sort of difficult to
do. So Judith this has been a very illuminating
conversation. I really enjoyed it. [Judith]: Thank you for your interest. [Rhonda]: Very interesting and I look forward
to I’m going to continue reading about your research, I can’t wait to learn about all
the new things that you discover. But for people that want to learn more about
your research, do you have a website or just the Buck Institute? [Judith]: Yes, they can go to the Buck Institute
website and you know, there’s websites for the individual faculty members. [Rhonda]: Right, I know if you just google
Judith Campisi, The Buck Institute’s like the top hit so they can learn more about your
research there. [Judith]: Yes. [Rhonda]: Okay, well thank you, Judith. [Judith]: Thank you, thank you.

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84 thoughts on “Judith Campisi, Ph.D. on Cellular Senescence, Mitochondrial Dysfunction, Cancer & Aging

  1. In this 1-hour long conversation, we discuss….
    • 00:00:52 – The concept of antagonistic pleiotropy, which is an important evolutionary biological explanation for aging whereby a gene may be understood to exhibit more than one trait where at least one of these traits is beneficial to the organism's fitness while yet another trait may be detrimental to that same organism's fitness.
    • 00:01:32 – What the fundamental molecular processes of aging are and some of the on-going research and general thought is surrounding these processes.
    • 00:04:05 – The essential differences that a pathologist would observe if they looked at and compared the tissues of a young person with a much older person… even beyond structural differences.
    • 00:05:00 – The qualities of the two major immune responses and how our innate immune response is both our best friend when it comes to keeping us alive — but may be our worst enemy when it comes to keeping aging at bay.
    • 00:05:27 – The infiltration of immune cells into our tissues that occurs as a function of aging and the role of damaged or senescent cells in attracting these immune cells.
    • 00:07:16 – The changes in gut permeability that happen with age and how that may increase our susceptibility to chronic, low-level inflammation.
    • 00:08:36 – The evolutionary biology explanation for why we have the mechanism of cellular senescence in the first place.
    • 00:11:46 – The problem of senescent cells and the characteristics they possess that ultimately drive their ability to further their own accumulation. This is done through a feedback loop whereby the burden of senescent cells itself further increases their accumulation and, thus, associated pathologies.
    • 00:12:29 – The role of senescent cells in an "epithelial to mesenchymal transition," which facilitate loss of appropriate tissue function and even cancer metastasis and progression.
    • 00:13:36 – Why diseases of aging, despite occurring in vary diverse tissue types, all begin to crop up simultaneously after 50 or 60 years of life.
    • 00:16:30 – The clearance of senescent cells as a valid life extension strategy, where some animal research has shown a median lifespan increase by as much as nearly 25% in a mouse model of accelerated aging.
    • 00:17:50 – Why it might be a bad idea to kill off senescent cells just before surgery or when you might need acute tissue repair.
    • 00:18:55 – Why tackling cellular senescence may be a strategy that is best employed at strategic intervals rather than every single day.
    • 00:22:53 – Preservation of brain function and how supporting brain cells called astrocytes seem to be simultaneously the most likely type of brain cells to become senescent and also, perhaps unsurprisingly, to be the ones to give rise to brain cancer.
    • 00:26:04 – How mitochondrial dysfunction, even in the absence of DNA damage, can cause cells to undergo senescence.
    • 00:26:34 – The interesting observation that senescence from damage versus energy crisis (failed mitochondria) demonstrates a markedly different and uniquely identifiable phenotype of cellular senescence.
    • 00:28:41 – The change in immune strategies that occur as a result of aging and how that's reflected by a change in our number of lymphoid versus myeloid lineage cells.
    • 00:29:09 – Some of the current thought surrounding why we build up senescent cells as we age in spite of the fact that our immune system actually actively plays a role in clearing these cells.
    • 00:30:40 – The effects of prolonged fasting on the activation of hematopoietic stem cell self-renewal (Dr. Valter Longo's work) and the role this may play in rebalancing lymphoid and myeloid lineage cells.
    • 00:34:34 – The diverging approaches towards improving healthspan by taking action against senescent cells: use of senolytic drugs (which kill the cells) versus the use of drugs that dampen mTOR, such as rapamycin, which leave the cells alive but ultimately suppress the inflammatory aspects of their secretory phenotype.
    • 00:35:34 – How periodic prolonged fasts might mimic some of these effects associated with an mTOR dampening drug like rapamycin since fasting is itself a way to temporarily reduce mTOR activity and rodent research suggests it may clear these cells as well.
    • 00:37:33 – How the secretions of senescent cells can affect the regenerative capabilities of stem cells.
    • 00:38:14 – Some of the complexities behind scenarios in which cellular senescence may play a positive role in skin health, especially through the secretion of growth factors involved in repair as part of the senescence-associated secretory phenotype (SASP).
    • 00:41:29 – The open questions regarding the potentially differing origins of senescent cells between various tissue types (e.g. muscles vs. heart) and whether these cells are tied to the type of senescence associated with mitochondrial dysfunction… or… the other phenotype which is more commonly associated with various types of cellular damage.
    • 00:44:14 – The reason why telomeres are disproportionately the recipients of damage when nuclear DNA damage occurs.
    • 00:45:26 – The surprisingly large effect of exercise on lifespan that can occur in spite of (sustained) obesity.
    • 00:47:47 – The benefits of exercise in mitigating some of the side effects of chemotherapy.
    • 00:48:51 – The practicality of a consumer available clinical assays for DNA damage and the challenge of assessing tissue-specific senescence without the use of invasive biopsy.
    • 00:54:45 – Some of the interesting studies showing that nicotinamide riboside (a form of Vitamin B3) may improve tissue aging and mitochondrial function and whether this might be associated with reductions in cellular senescence or not.
    • 00:55:55 – The effect of so-called fasting mimetic compounds (e.g. hydroxycitrate, resveratrol & spermidine) on senescent cells.
    • 00:57:15 – The interesting capacity for cancer resistance in elephants, possibly conferred, in part, by extra copies of the tumor suppressor gene TP53.
    • 00:58:11 – The possible existence of cellular senescence as a conserved mechanism in some lower organisms.
    • 00:59:20 – How some rapidly dividing cells, such as keratinocytes in the basal layer of our skin, tend to undergo senescence more often whereas other rapidly dividing cells, such as those in the gut, tend to undergo programmed cell death as an alternative to senescence.

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  2. Very interesting! It had me wondering whether Hyperbaric Oxygen therapy could be effective in regenerating the Senescent cells…Interesting to me, as I am a technical diver, and can easily do dives in 20 to 30 feet of water breathing pure O2….and combine that with my ketogenic diet….If you think there is anything to this, I may start doing this a couple of times each month 🙂
    Closest article I found almost on point with this follows:
    " Cell cycle synchronization of tumor cells by exposure to hyperbaric oxygenation (HBO) may increase the efficacy of chemotherapy or radiation by placing cells into a chemosensitive portion of the cycle. The purpose of the current study was to examine oxygen pressure-dependent relationships with respect to the cell cycle in prostate tumor cells in vitro. LNCaP cells were grown in an incubator at 21% O2 and then exposed to 100% oxygen at pressures up to 6 atmospheres (atm) for 1.5 h. Cells were then returned to the incubator and evaluated for DNA content by propidium iodide and new DNA synthesis with a pulse-chase experiment. Cell cycle effects were evaluated by flow cytometry. Exposure to HBO increased the percentage of cells synthesizing new DNA in a dose-dependent fashion: 0 atm, 44%; 6 atm, 65%. Cells that synthesize new DNA accumulate in G2/M as a function of partial pressure of oxygen. These results suggest that HBO induces cells to enter the cell cycle and accumulate in G2/M. Cell cycle synchronization and entry of senescent cells into the cell cycle suggest that HBO may be a useful adjuvant to chemotherapy or radiation in the treatment of prostate cancer. There are two potential mechanisms of action that may make HBO efficacious in the treatment of prostate cancer. HBO may potentiate cancer chemotherapeutic agents that cause damage to DNA during DNA synthesis or HBO may inhibit cell division causing accumulation in G2/M."

  3. As a college student going into health science, I show your awesome videos to many of my peers for that extra dose of wonderful information.

  4. You are becoming one of the most influential scientist. Can you mention some of those supper anti-inflammatory substances ?????

  5. I'm losing some hair on my forehead and a lot of my hair is turning white.I think I'm aging faster than most people my age because not too many people my age have white hair. my age is 68 ….I noticed you don't monetize your videos…you can make some extra money by monetizing them..looks like i need to do more fasting also.after watching your video

  6. • Great interview! Lots of good information, much appreciated.
    • Re: five-day fasts, I've done a couple of them, followed by re-feeds, since learning about them in the interview with Dr. Longo, and love how they leave me feeling. I'm planning on doing one fast a month for a while, and keeping an eye on the results.
    • I found the passing reference to spermidine supplements interesting. I haven't found a supplement, but have been eating foods high in spermidine (but very low in protein), like mushrooms and corn, during the fasts.
    • As a side note, I read recently that the supplement Quercetin also appears capable of targeting and killing senescent cells, and may make resveratrol more effective when they're taken together. PQQ, found in green tea, also appears to kill senescent cells. And caloric restriction (particularly a low calorie/high fat diet) appears to slow aging in both laboratory animals and, some evidence suggests, human beings.
    • Re: brain cells senescence, it is perhaps related to the accumulation of amyloid plaque, which can be removed by some nutrients, including folate and the sugar Trehalose.
    • Finally, a suggestion: It would be fun to see an interview with Dave Fisher, the man who's been living on 1600 calories a day for the past twenty years. Fisher was born in 1957, and looks maybe like he's in his mid-thirties. Unlikely I suppose, as he's not a scientist. But it would be interesting to learn more about his protocol, and the dramatic results.

  7. Thanks Dr. Patrick, a fan, … but this all sounds like Quorum Sensing, as a fan of Dr. Bonnie Bassler also. This is the mechanism that I have theorized for Metastasis – Once a quorum is formed we see Antagonistic Pleiotropic responses … [Williams GC – 1957] and Dr. Campisi is describing the same Quorum Sensing function that we see for cancers (Metastasis) … but following a different evolutionary path … seems that all this can be regulated by blocking the "Cellular Communications" or more interesting … "Redirect".
    ps … the "unknowns" mentioned points right at your "Buddy" Dr. Ames' – Triage Theory ….

    70 Going On 100 … or maybe 70 Going On 128 … the Hayflick Limit … or if a fan of Ray Kurzweil … then this is all a Moot Point …

  8. So good: deserves another viewing. Scientists keep going even though the popular creed seems belief over science.

  9. fascinating discussion – Dr. Campisi's work is impressive, as are her knowledge & communication skills. a 6 hr interview would have flown by. thanks for choosing her Rhonda – one of your best to date. now I feel obliged to give you some money. 🙂

  10. What I get from this is there is a need for a balance for the proper amount of senescent cells.
    Once there are too many of them, then we need to get rid of them.

    Easy to know, hard to do 🙂

  11. This is one of the best videos that I have ever watched. It would have remained completely engaging had it lasted for many more hours. Thank you so much – I plan to become a sponsor of your show now.

  12. If elevated innate inflammation may drive aging, does this mean that inducing stress via hormesis (egcg, tumeric, sulforaphane, exercise etc) is activating acute inflammation rather than innate?

    So high levels of IGF1 in the brain is good, but ideally low everywhere else?

    Also, can anyone explain why for the non-super athlete, Peter Attia recommends exercises that work the fast type2 twitch fibers?! He also supplements with leucine during his workouts as a boost to mtor1. What's the mechanism?

  13. Mitochondria heteroplasmy rate. Check out Dr. Doug Wallace, the world's leading expert on Mitochondria.

  14. There is also a double edged sword with autophagy I saw in some studies. Just something that brought awareness.

  15. Awesome, as always! The annotations are incredibly helpful for the layman like myself 🙂
    Thank you so much!

  16. Fascinating as always. Thank you so much for the work on your interview technique also (I know it's tempting to jump in as you often have amazing insights) but this interview where you allowed to her to speak fully was so much easier to watch. Best health show on Youtube!

  17. Fabulous interview, confirmed my theory on cell life. Listened to this multiple times. Aging is a bitch, but there are things we can do about it. Rhonda, please do a vid on antiinflammatory diet and lifestyle, in addition to fasting. I could certainly fast 1 day/week.

  18. Hey Rhonda! Not sure if you'll even reply to this, but what is your opinion on seres therapeutics microbiome drug they are trying to get to market? Will this method be effective? Or is it a dead end? Your reply would be amazing! Thanks

  19. you are simply the best. these videos seriously help me survive work some days. makes my brain so happy (:

  20. Incredible interview. Thank you Dr. Rhonda Patrick!! Sounds like everyone should incorporate a 4 day fast into their lives. How often do you think they should do this? Every year maybe?

  21. Why senescence just don't die? That is evolutionary point beyond senescence cells? Why immune system just don't kill them? Here we don't understand something.

  22. Notice that fasting works without scientists knowing how it works. If I had waited for permission from scientists to fast I would have either died or become a basketcase.

  23. Loved Judith Campisi's insight here! So interesting and she did a great job of conveying highly technical information simply enough for me to grasp.

  24. i hear a lot about how certain things are as a result of evolution, I just never hear how they know that to be so. It's just always assumed from the start, but never actually discussed . Like we have no idea why things age, or why certain organisms age differently than others, but we're 100% sure that it's a result of evolution for some reason

  25. God drives life span. Why not discuss the hayflick limit on cellular division? Oh I get it, you really don't know.

  26. Nick Lane has a chapter in The Vital Question about the trade off in age and reproductive rate between, for example, rats and pigeons, and that the two are reciprocally related.

  27. 47:00: Other than the hormetic effect exercise, aerobic exercise also moves the lymph, and nourishes the cells with fresh oxygenated blood. Can't just look at the sub-cellular level!

  28. Thanks for your videos on such interesting topics and the way you make them comprehensible for the public! 🙂 I really enjoy your videos!

  29. Learn to fast. It's an acquired skill. That serves us better and faster than any drug treatment, no matter the diet. Next, get a glucometer and eat to keep blood glucose low. You'll need it when you become diabetic anyway, so may as well learn to use one. Fasting cures all the stuff Dr. Patrick gave great info about. How can she not know about that?

    We are hyper-carnivores. Dr. Salisbury did experiments on human diets and published in 1888. Anyone making diet recommendations needs to know that research upside down and backwards.

  30. Just because aging isn't well-understood so far doesn't mean it will remain this way in the immediate future. As long as the current anti-aging experimental treatments such as stem-cell and gene therapy keep working and improving, understanding everything isn't essential.

  31. Next to lifestyle factors radiation (EMF) could play a big role that senescent cells accumulate in the body. EMF is a silent killer which is not directly visible but with lab tests could be a proven fact.

  32. Hey Rhonda, thanks for your informative videos, I'm currently studying nutritional science in Germany and I have to say that your Podcast were one of the main reasons to go into this area 🙂 . I was wondering if there isn't also a sociological viewpoint from which you could look onto diseases such as depression. What I'm suggesting is that although such neurological diseases as depression and Alzheimer's have neurophysiological/biological consequences, might there not also be contributing factors found more in the epigenetic terrain which is leading to the physiological changes in the human brain and body in general, such as the loss of social activity/ community in old age? Do you have information on the way experiential stimulus is influencing body physiology? For example the loss of a loved one will certainly influence the brains physiology.

    Best Regards,
    Jakob Bühner

  33. Thank you so much Rhonda. You should win a nobel prize or something for distributing this information so readily. Taking your notes word for word.

  34. Wow, at 33:00 where she mentions mTOR and rapamycin it's almost as if Dr. Peter Attia presented this word for word in his video 'Peter Attia – Reverse engineered approach to human longevity'. In that video at 40:30 he literally writes out her words "yeast flies worms mice(mammals)" on the chalkboard and goes on to rave about rapamycin.

  35. makes me sad more and more i get into the matter of reverse aging cancer the more i notice how far away we actually are.

  36. Great interview. Re: her comment that it might be best to rid of senescent cells every once in a while, (instead of constantly worrying about it), I've been doing a four to five day fasting mimicking diet once a month to get rid of senescent cells. It's nice to have confirmation that this is likely a helpful thing to do.

  37. I wonder if it is possible that the immine system becomes cytokine resistant over time with years of signaling from an ever increasing number of senescent cells… And in doing so requires more and more pro-inflammatory molecules before it is targeted for death by the immune cells… Thereby increasing systemic inflammation and cancer risks?

  38. In the discussion around mice and people's mortality for unknown reasons, "heart just stopped" makes me think of stem cells. AFAIK that is quite common towards the end of life, the heart cells are not replaced fast enough, or at all. I believe this is where stem cell therapy needs further research. I understand that we can not make stem cells from skin and fat cells. In regards to rapamycin, that may be risky to use for the sole purpose of dampening mTor. There are other molecules that are safer that also target mTor/p53 such as Berberine which I use daily.

  39. You see the design and still believe in evolution !?!? "Cells evolve" because they just thought so !!! Just go to Yahweh and ask to be saved.
    fasting eats senescent cells.

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