[ENG] ☕ Il Caffe' Dell' Alchimista- Coffee with the Alchemist ⚗️ Dr. Aubrey De Grey

Episode Transcript
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(00:00):
Welcome to another coffee with the Alchemist. Today we have the honor of having
a real pioneer in the realm ofbiohacking and longevity. He is the author
of the mitochondrial free radical Theory ofAging and co author of end Engaging.
He is generally recognized as one ofthe world's leading experts in longevity research.

(00:24):
A fellow of the Gerontological Society ofAmerica, the American Aging Association, and
also the Institute for Ethics and EmergingTechnologists. He has a BA in Computer
science, studies in bioinformatics and aPhD in biology from the University of Cambridge.

(00:47):
Doctor Aubrey de Gray is the Presidentand CSO at the Longevity Escape Velocity
Foundation and co founder at the ScienceResearch Foundation. Join us as we deep
into the fascinating world of longevity sciencewith Aubrit the Gray. In this episode,

(01:07):
we will explore the latest about rejuvenationtherapy, the future of aging research,
and the profound implications from human healthand longevity. Among the topics you
will see in the show notes,we've managed to cover quite a lot,
from the reason why Aubrey is nota piano player to the role of missus

(01:29):
to the mitochondrial free radical theory ofaging, diving deep into the mechanism functions
of the raising drugs on longevity andresearch including rappromising and a Man and many
many others. We will finally divedeep on the a Longevity Summit and the
work the Aubrey is currently doing.So without further ado, dear listeners,

(01:53):
let's welcome to the show. Aubreyde Gray A small book of questions.
But I don't know. Let's let'sgo and uh, let it be so
I really thank you and and Istart sharing with this is this thing we

(02:14):
have in common we have we wereborn the same day, so every twentieth,
just a few years apart. Anduh, and I want to start
with a curiosity about you is becauseI heard somewhere that you you you are
a potential piano player, right,a potential word piano player? Not at

(02:34):
all? No, no, SoI think I know what you are referring
to. When I was very young, when I was like eight years old,
my mother wanted me to practice thepiano. And I have told this
story a few times publicly, sothat's why I think you had probably heard
about it. The thing is thatI did not want to. I was

(02:55):
reluctant and resistant to this, butsomehow or other, I already had a
great desire to understand things, includingunderstanding myself. So I thought about the
question why do I not want topractice the piano? And I realized pretty

(03:16):
quickly that the answer was not theobvious one. The answer was that the
best possible outcome result of practicing wouldbe that I would become a good pianist.
And I immediately realized that, youknow, that wasn't good enough.
That you know, there are alreadyplenty of good pianists, so you know,

(03:38):
I would not be making much ofa difference to the world. And
that was the first time when Irealized that making a difference to the world
is how I wanted to spend mylife and my time. And over the
next decade or so that gradually,you know, crystallized. I realized that
I definitely didn't ever want to havekids, because kids are something that's very

(04:00):
time consuming, and yet a lotof other people are perfectly good at having
them. And I also realized thatI wanted to be a scientist of one
sort or another, because scientists arethe people who make the most difference to
the world in the long run.And so eventually I decided I wanted to
go into artificial intelligence research because Ifound when I was fifteen and I started

(04:25):
writing software, I found that Iwas pretty good at it. So I
thought I'll do that. And thenin my late twenties I found out that
in fact there was a much moreimportant problem to work on, namely the
biology of aging. I had previouslyalways known that it was a more important
problem than any other, but Ihad not known that nobody else was really

(04:48):
working on it, that people hadbasically given up. So I thought that
won't do so I switched fields.Well, that's great because things it's in
the you evntioned in the late twenties, twenties, you got the late last
But well you you have done inthe twenty years plus something what people are

(05:08):
not doing in eighty. So youhave do this self reflection and this these
changes in your life that are verymuch So this is a that's great.
So and then finally we are weare two days. Oh no, not
to days. I in nineteen ninetynine, and then your book with go

(05:29):
outor and Engaging is I think it'stwo thousand and seven. So it's already
a few years now, so well, I started with this question, so
what has changed or if some,if so many things has changed from the
engaging the major the major changes thatI mean a new new edition will fix,
right, massive masters have changed havechanged. But the great thing,

(05:54):
and the main reason why I havenot written a second book like that,
is because nothing big has changed interms of the nature of the problem and
the kinds of solutions that we couldcome up with. The progress that has
been made has all been within theframework that I set out back there.

(06:15):
So now we have for each ofthese seven different types of damage, we
have more than one approach to fixingit, whereas back in the twenty years
ago we only had one way foreach of them. And that's great.
It means that we have a betterchance of succeeding more quickly than we otherwise

(06:36):
world. But we have not hadto, like you, add another category
another category number eight, or youknow, rethink any of the approaches that
were previously looking plausible. So that'sreally great news. Now. Of course
that might be a case for mewriting an update anyway, but it takes

(07:00):
a long time to write a book. So I've had a other priority.
That's a very good yeah. Andindeed this is linked to human biology and
humanity and human being, which isnot easy to I mean, we're talking
about twenty years, which seems alot, but it's nothing you can compare
with it with the human biology.And so and I start linking. So

(07:25):
for sure, nothing has changed interms of definition of aging, which I
just mentioning here. So it's thelifelong accummulation of damage to the tissues,
cells, and molecules of the bodythat occurs as an intrinsic side effect of
the body normals operation, which arethe key words, and the intrinsic side
effect of the body and normal operation. Yes, because and then we go

(07:47):
to your theory and what is inyour book. So just for our listeners,
because we have plenty of YouTube videoway you showed it a lot of
sly I have a few years justback up. But is so you mentioned
that nothing has changed about the sevendeadly thing. But your approach of to

(08:11):
edging is about this intrinsic side effects. So instead of looking at the complexity
of the human biology all the mechanism, side metabolism, etc. So you
said, okay, this is thisis going if you touch. And this
is something I see in the bioackingcommunity. If you tweak something and you
want to intervene in such a complexsystem, this is the butterfly factor.

(08:35):
Let's say you don't you never know, so, so that's why you focus
more on the So this is happening, damage is happening, so let's focus
on maintenance. So can you pleasesummarize of this, this switch shift of
the view. Yeah, sure,so you have it exactly right, the

(08:58):
body of the machine. But it'san extraordinarily complicated machine, which means that
if we try to adjust the wayit works, then we will have unintended
consequences. And it's very difficult tocommunicate how bad this problem is. You
know, how insanely complicated the humanbody is and how little we know about

(09:22):
how it works. And that realizationthat the body is just so complicated that
we can't tweak it is really themain reason why by the nineteen seventies and
nineteen eighties, people in the biologyof aging had basically given up on the
idea of ever doing anything about aging. But that's because they were not thinking

(09:45):
like engineers. They were thinking likebasic scientists who try to understand things just
for the sake of understanding them,and because of that, they overlooked the
fact that the machine that we areworking with is still a machine. In
other words, its function is determinedby its structure, by its composition,

(10:07):
and therefore, the only reason thatwe start to function less well when we
are old is because our bodies havea different composition as time goes on.
And of course the reason they havea different composition is because of these side
effects, the changes that happen towhat the body is made of as a

(10:28):
result of the body's normal operation throughoutlife. Now, this was not something
that anyone really disputed. They justweren't thinking about it in that way because
they didn't see any reason to thinkabout it that way. And the reason,
of course, is that when youare thinking about a machine this way,
you can sidestep your ignorance of howthe machine works. The key thing

(10:52):
about the human body and about anymachine, really, any machine with moving
parts, is yes, it accumulatesdamage, but the machine is set up
to tolerate a certain amount of thatdamage without any significant declining function. It's
only when there's more than that thresholdamount that we start to see problems.

(11:13):
So that means putting taking the nextstep. That means that these changes that
are happening to the body throughout mostof life before they have become problematic,
they are not really participating in metabolism. They are side effects that are harmless.
They are inert and that means thatif we try to reverse those changes

(11:35):
to repair that damage, then wewill be doing it without interfering in this
network of processes that we don't understand. We can let metabolism carry on creating
damage at the normal rates because wewill be repairing the damage after metabolism has
created it, though before there isso much damage that we get sick.

(12:00):
And because we are doing it,then we are essentially doing, as you
say, preventative maintenance. We arenot interfering in how the body works,
and therefore we have a much betterchance of success. Well great, great,
Yeah, this is I'm an engineer, so I fualdly understand at the
end of the age in definition,the body can tolerate some damage, but

(12:22):
too much of it because this isa disability. So and this is linked
to what you mentioned. And myquestion is now we're going to do some
My question coming from reading the bookThe Role of Romantic stressors in this picture
because the romantic stressus you will stress, and then we link with the mitochondrial

(12:43):
quotations, et cetera. But yeah, this is another point. So in
all of our message in this picture, how does it work? Because we
are stressing body? So does itwork? HOMESSI doesn't really figure in this.
Homes this is the phenomenon where thebody responds in a way that it
already knows how to do without anymedicine, right, responds to a stress.

(13:09):
And the reason that homesis is interestingis because very often when the body
is responding to a stress that istemporary, like an infection for example,
the body continues that response. Itmaintains that response after the stress has gone

(13:30):
away, so that thereafter it isif you like, protecting itself unnecessarily.
Well, now, of course it'snot really unnecessary. If we think about
it from an evolutionary perspective, whatthe body is doing there is simply optimizing
for future events, because any stressthat has happened once is more likely to

(13:50):
happen a second time than a stressthat has not happened once. Right,
So we can think of the adaptiveimmune system as an example of hormesis though
it's not normally described as one,but it should be because what's happening in
the adaptive immune system is that youhave cells called naive cells, naive T
cells and B cells, which areable to react to a huge, huge

(14:18):
range of potential infections and other threats, and they do, but they are
rather slow to do so they haveto figure out how to react. And
then the specific very tiny minority ofcells that are what's called cognate for the

(14:39):
infection, in other words, thatare appropriately arranged so that they can fight
the infection, they expand to largenumbers. They get rid of the infection.
But the hormetic part, the adaptivepart, is that after the infection
has been defeated, the cells don'tjust go away. Most of them go
away, but some of them areretained what are called memory cells, and

(15:01):
so if you get the same infectiona second time, years later, then
the response of the immune system ismuch more rapid than it was the first
time around because these memory cells thatthey remember what to do and they are
they are configured to expand and respondmuch more quickly, so you get rid

(15:24):
of the second the second time,you get rid of the infection much more
easily and much more rapidly than youdid the first time. That's that's interesting
because my curiosity is more about let'slet's let's go back to the mitochondrial the
survival of the slowest I think rightmodel. Yeah, so if correct me,
if I'm wronger, this is avery simplicistic way. So I invite

(15:46):
everyone to read the book because it'snot technical. It's like read some very
very nicely. So is the mitochondriayou mentioned. There are some intentions that
is a sort of self protection fromfrom death from mitochondria. So they protect

(16:10):
themselves. They're not not producing sosurviving, so not doing the the oxidaty
phospoliations cycle, basically not doing thedamage to themselves producing free radicals, and
then these remain, they remain there. There are others that are more active
that working perfectly, but they producesome free radical, they produce a TP

(16:33):
perfectly working, but they damage themselves. And for this reason, when we
are lysosomes got wrong acting, lysosomesare acting on the good ones that are
deteriorating themselves because they are working.But the lazy ones, let's say call
lazy the one that they're not producingTPA they are there survive. So in

(16:56):
the end we will we have thecycles that the lowest one are replicating and
with the same defects in DNA defects, and so we have a multitude of
these mutations that they are doing nothing, and in the end you have the
the cell which is surviving only becausewith the minimum amount of a TP from

(17:22):
holyicis and A. You have somewherein the books something about electrons that are
going out because of N A Dand ADHD cycle. It needs to be
there, and the electrons are thendamaging potentially L D L. This is
the cascade. So I'm really summarizingI don't know any pages of this book
in a few words in this isthis thing valid? And then when I

(17:48):
talk about toromatic stress like an intenseworkout or cold or hit stress, I'm
expecting an intense workout is having thegood mitochonduct run faster and to damage themselves
faster. So is this right?Not exactly? So everything you said about

(18:11):
my model, this survival of theslowest thing, and the second part of
it involving what goes on outside thecell, which is called the reductive hotspot
hypothesis, all of this is nicelyelegant, but it is still unproven.
Nobody really knows whether these hypotheses arecorrect. There are other hypotheses out there

(18:32):
about how mitochondrial mutations matter, howthey contribute to eventual declining function in late
life, that are also still notfalsified. So we don't yet know whether
this model is correct. But Istill like it even though it's nearly thirty
years old. Now, the partthat I want to correct you on is

(18:56):
the hometic part. So it's actuallya curious thing. It's often called the
exercise paradox. Why exercise is notbad for you? You know why it
doesn't seem to the shortened life because, as you say, exercise involves using
more calories, creating more ATP,doing more electron transport. But we have

(19:19):
actually understood for a long time whythis is not bad for you. The
answer is that mitochondrial electron transport hasa very nonlinear relationship to free radical generation.
The remarkable thing is that when amitochondrian is working well, pushing electrons

(19:45):
along the chain flast and making alot of ATP, it doesn't make many
free radicals. The most dangerous mitochondriathe ones that make the most free radicals
are ones that are not being usedas much as they could be. In
other words, they are not makingmuch ATP. Now, of course,
the amount of ATP you make dependson how much ATP you are consuming,

(20:07):
so it depends on the availability ofADP, right among other things. So
an extreme example of this is whenyou have an athlete, someone who's using
a lot of energy over a longperiod of time and then they abruptly stop
doing so they stop training, forexample, then they are not using much

(20:30):
energy, and if you like,they have too many mitochondria in their muscles
and so on, and the resultof these mitochondria are not working very they're
not making much ATP. And thoughthat I say, are the ones that
make more free radicals, and thedetailed mechanics of this about why that's true,
that's pretty well understood. Now,Okay, so what happens. What

(20:51):
happens is that mitochondria get destroyed reallyquickly. Not just damaged mitochondria the way
that you described a moment to gomitochonjury in general, the system just goes
after mitochondria and gets rid of someof them so that you no longer have
this surplus and the mitochondria that remainwill have enough work to do so they
won't make too many free radicals.Wow, oh okay, perfect, Thanks

(21:15):
for a clif. Let's let's jumpback, jump back a little bit to
another longevity escape velocity in practice.So there is one slide and which presentation
when it is mentioned the first onethousand years old is probably ten years younger
than the first hundred and fifty yearsold. Is this correct? And can

(21:37):
you please explain a little bit totamborize this. Yeah, I very much
still believe that that's probably true.Of course, we don't know for certain
because it's the future, but yeah, I think it's probably true. The
reason is simple. It is thatthis approach to postponing the health problems of
late life, this preventative maintenance damagerepair approach, by the time, what

(22:00):
happens is you'll take someone who's alreadylet's say, sixty years old or maybe
older, and you will repair thedamage that they have so that they become,
if you like, biologically younger again. And that means that it will
be a while before they become biologicallythe same age that they were when you
treated them the first time. Now, during that period, people like me,

(22:22):
the scientists will be continuing to improvethe therapies. So if you think
about, okay, why does somebodyneed the therapist to be improved, the
answer is because the therapies will notbe perfect. If you take someone who's
sixty and you rejuvenate them back tobiologically forty, one has to ask,
okay, why aren't you rejuvenating themback to biologically twenty, And the answer

(22:42):
is because the therapists don't work oneverything. The damage that accumulates in the
body throughout life comes in many differentforms, and some of those forms are
inherently more difficult to repair than others. So the first generation damage of therapies
will repair let's call it the easydamage, but not the difficult damage.

(23:03):
We can use that as the definitionof the distinction between easy and difficult.
Right. So then twenty years later, when you're sixty year old is now
eighty and they're back to biologically forty, they won't really be back sorry,
back to biologically sixty. They won'tbe really biologically sixty because they won't have
any easy damage. They'll only havedifficult damage. Right, Because the easy

(23:26):
damage you can repair it often ifyou like. So that means that if
we just carry on using the samemedicines, the same damage repair there,
it's not going to have any effect. You know, the person's carry on
getting older, they'll get older moreslowly than they otherwise would because they won't
have any easy damage, but they'llstill get older and sick and eventually die.
They won't do so, of course, the goal is then to figure

(23:48):
out how to fix that. Andof course we've had twenty years, right,
so we will have been able toimprove the therapy so that some not
all, but some of the difficultdamage will have become easy. It will
have become repaarable. So that meanswe will be able to re rejuvenate the
same people when they are eighty withthe amount of damage that they had when

(24:11):
they were sixty, even though thatdamage is inherently more difficult to repair.
So that means we can give themanother twenty or thirty years and so on.
And that's what longevity escape velocity isall about. It's staying one step
ahead of the problem. Now whatthat means in terms of lifespan? Will
you quoted this one way in whichI say this? There are many other

(24:32):
ways to say it. But ifwe ask Okay, how soon are we
going to get someone age one hundredand fifty. Well, it's certainly not
going to happen anytime soon, becausepeople take a while to get to that,
But the people who are going toget there, the first people who
are going to get there, arepeople who would naturally live to let's say
one hundred and ten. You know, the oldest people who can live to
one hundred and ten without this medicine. So those people tend to get to

(24:56):
one hundred and ten not by bysurviving in a very bad state of health
for a long long time, butrather by staying healthy for a long long
time. So they will be biologicallysixty only when they're like eighty five or
something like that, right, interms of the amount of damage they have
in their body. So we takethose people, let's say someone's eighty five,

(25:18):
when these therapies come along, wecan still rejuvenate them by twenty years,
because they've still got twenty years leftin them, right, So they're
not at death's door. And thatmeans that we've got a chance of getting
them out to one hundred and fifty. But we might not quite catch up.
We might not quite be able todo this, However, it's going
to be tight. Someone who's seventyfive, right, will have much much

(25:44):
better chance of making the cut,of making it to longevity escape velocity and
letting science, letting the medical researchstay one step ahead of the problem.
And if you do that, thenage an age of one thousand is easy
to get to because you can lookat today's mortality rates, your risk of

(26:07):
death when you're not dying from aging, right, you can say, well,
okay, so but I think someonegets to the age of twenty six,
right, they're not going to dieof aging anytimes there, So what
is there chance in the western worldtoday of not getting to the age of
twenty seven? And the answer isless than one in a thousand. So
if you keep that same probability peryear, right, however long ago you

(26:29):
were born, then you know thatgives you what is it life spent?
And you know that's the only differenceat the moment. Every year that goes
by during adult life, you becomeyou are ten percent more likely to die
that year than you were the previousyear. Right, If we get rid
of that ten percent, then onethousand years old, if just an inevitable

(26:51):
mathematical consequence, it scares the livingday outside of people when we talk about
this, when we point this out, but it shouldn't. First of all,
it's just math. You can't arguwith it. And secondly, what's
wrong with staying alive? You know, if you if you're healthy, perfect,
Yeah, everything right and fully todo. So you mentioned that this

(27:11):
easy and complex are difficult, andat this moment, uh before talking about
love intervention or something more but advanced, what do you think in practice diet
access and nutrition, the exercize,lightest postuously h these are normal. We

(27:32):
don't know love intervention. What doyou think is in order the most impactful
one and the right So, ofcourse the only way to answer that question
is to subdivide it into well,into two questions really a short term one
and a long term one. Iwork on the long term. I'm interested
in developing the early stage research toidentify ways to get to longevity es capabilcity

(27:59):
to actually you know, repair damagecomprehensively. We don't have that today.
So if you want to do somethingtoday to to to extend your healthy lifespan
and therefore your total lifespan, thenyou've got to try you know, less
effective measures and the less effective measuresthat are available right now pretty much all

(28:22):
revolve around famine. They revolve aroundsomehow or other not eating as much as
you would like, or tricking thebody into thinking you're not eating as much
as you would like even when youactually are. Things like that. And
what that's all about is why that'suseful is because it has been useful evolutionarily.

(28:45):
You know, it has been acase of something's happening in the real
world, and therefore evolution has hadthe motivation the pressure to develop ways to
optimize. Now you have to ask, then, okay, what optimization is
needed. It's it's pretty straightforward.If you're in a famine, then there's

(29:08):
not much point in having offspring becausethose offspring will die of starvation before they
can have their own offspring. Soit's evolutionarily more advantageous to hunker down and
do your best to survive the famine. So it's the kind of changing of

(29:29):
metabolic priorities. Right. You canput energy into maintenance or you can put
energy into growth and reproduction. Nowthat's all very well, and sure enough,
it translates into what we would predict. Animals that are given less food
than they would like live longer thanones that they're given as much food as
they would like. But here's therather irritating detail. Animals that have a

(29:56):
longer natural lifespan get less of abenefit of this sort. If you're a
mouse and we do this, ora rat normally lives a couple of years,
right, then we can get maybefifty percent increase in lifespan if you
put them in a suitably diminished withcalorie state for their whole lives. Less

(30:19):
than that if you start late inlife, if you start in middle age,
but you can still get maybe tenor fifteen percent. Not so bad.
However, if you do the equivalentexperiment with longer lived species like dogs,
for example, which has been done, then you get much less like
if you If you do it withdogs for their whole life, you only
get about ten percent increase in lifespan rather than fifty. If you do

(30:42):
it with monkeys you might get acouple of percent if you're lucky. Conversely,
if you go down to really shortlived organisms like nematode worms, you
can multiply them by five by afactor of five, right, just by
this kind of approach. So wehave to ask why is that true,
and actually it's pretty easy. Again. It comes down to looking at the

(31:03):
evolutionary selective pressure. It's simply thatlong famines are less common in the real
world in nature than short famins,which means that the selective pressure to optimize
for long famines isn't there. Sowe just have an inherently weaker response to
famine than what short lived species likemiceore rats do. And the same thing

(31:27):
applies to these things called calorie restrictionmimetics that are drugs that trick the body
into thinking it's in a famine whenit isn't right, because of course they
are activating the same pathways, thesame change in metabolic priorities that actual famine
does. So you wouldn't you can't. You could never expect to have a

(31:51):
more extreme effect from a calori restrictionmimetic then you would get from calori restriction
itself. All right, So thisis all rather unfortunate, but first of
or even a couple of years ofincrease in lifespan is better than nothing.
I know you're not going to getI don't believe you're gonna get anywhere near
a couple of years unless you startearly in life. You know, not

(32:12):
if you start at age fifty orsixty. But still, you know,
even six months is better than nothing. Plus it probably makes you healthier,
especially in the modern world. Inthe modern world, of course, we
don't most of us don't treat ourselvesvery well, and we are you know,
sometimes overweighths and so on. Colorrestriction there or color restriction. Mimetics
may have a considerably more significant effecton healthy lifespan, even if it doesn't

(32:37):
really extend total lifespan very much.And so you know, I'm definitely in
support of these things, but onealways has to take into account the logic
I've just outlined, which tells youthat this is not and never will be
the holy grail. It will neverget us to longevity, escape velocity.
Great, they're perfect I full fullyunderstand. Yeah. And the color and

(33:00):
we we know that people in extremecolorI deffice they have issues with reproductive seats.
It is perfectly light, so they'reissues with And then you mentioned that
the drugs are I think preferring topat forming, were provising this thing.
These are mimetics I think also spermitin is as well, and are all

(33:20):
only in the same space. Andand I have a quick ones or another
that are okay. One is animnbut I think I don't know if this
is related is acting the same wayand others are less common, but what
n men is acting the same wayor is But so all of the ones
you've just mentioned, rapamcin, mattForeman, and a man these work in

(33:44):
different ways, and in fact,we believe that most of them work in
multiple ways. So I'm just goingto abbreviate. But they are all the
ways in which the main ways inwhich they work are all one way or
another. Stopping the body from usingis the way it normally does. Raper
Micin is a bit of an exceptionbecause what rapimycin does is it has an

(34:07):
impact on protein synthesis. So ratherthan actually calories that are missing, it's
amino acids that are missing. Youknow, basically you're not getting enough.
We make most of our amino acidsfrom proteins that we eat. Some of
them we synthesize from other amino acids, but there are things called essential amino

(34:29):
acids where we can't do that.So, yeah, you need proteins,
you need amino acids in order tomake new proteins. And the mechanism of
RAPPERMCIN is to slow down the creationof new proteins, which is equivalent from
the point of view of what thebody sees to not having enough amino acids

(34:49):
to make the proteins from in thefirst place. Foreman works by slowing down
the respiratory chaine, the electron transportchain that you talked about earlier. In
particular, it inhibits complex one,which is the first part, and that
again, you know, it's asif we're not getting enough calories because complex
one gets its electrons indirectly, mostlyfrom sugar and also from fat fatty acids.

(35:13):
NAD is a slightly more complicated case. So any MAN is a precursor
of NAD, right, it's sinceit is absorbed better than NAD and it
is then converted into NAD in thebody. The same is true for the
other NAD precursor that's popular these daysand are on nicotinamide ride aside. Okay,
so what's going on there is youare increasing the amount of NAD that's

(35:39):
available in the cell. Why wouldthat look like calorie restriction. The answer
is that NAD is a kind ofreservoir. What happens is that each molecule
of NAD either has or does nothave two electrons that it carries around,
and it gets those electrons from someplaces like glycolysis or whatever, or the

(36:00):
crab cycle, and it gives themto complex one. And so basically,
if you've got more NAD and you'redoing the same amount of glycolysis and so
on, then still the total amountof electrons in the NAD reservoir is the

(36:22):
same. So the proportion of thereservoir that is occupied is smaller because the
reservoir is bigger. Right Now,that's the kind of thing that the body
senses. It doesn't sense absolute amountsof things. It saidences proportions of things.
So the body looks at its NADreservoir and it says it's not as

(36:44):
full as it normally is, andthat is recognized interpreted by the body as
the body just not having enough electronsin the first place, in other words,
not having enough calories. Right,So that's how it worked, this
thermostat. There is a thermostat.Yeah, really nice. I didn't know

(37:05):
that. That's a good, goodpoint, And I assume Burber is still
doing the same although so all,yeah, all of these other things that
appear to have some good effects workwell, at least it seems they probably
work in more or less the sameway. But the ones that you've just
touched on are the most prominent andthe best understood. Okay, there are

(37:31):
some others that maybe are not directlyimpacting, but I don't know if it's
impacting. It's a m and Idon't know if you what you experience or
your so it's still a bit controversial, and it really shouldn't be the first
work that was done on followings inthis work in this area we're done by

(37:52):
a splendid professor named Laura Dugan whenshe was at U c l A.
I had her along to one ofmy early conferences in probably tooan and five
or two thousand and seven to talkabout it. Fantastic work. And the
thing is it wasn't actually C sixtyitself. It was C sixty with a
little bit of chemical modification done toit. A few corboxy groups were attacked,

(38:14):
and essentially it works like a superduper antioxidant, something that can soak
up electrons really really well. Andyou know that's that's definitely got value.
You want to soak up electrons especiallybecause carbon because C sixty is lipophilic,
so it tends to go into membranes, whereas most antioxidants don't do that,

(38:36):
and the ones that do tend toonly work in conjunction with ones that don't.
For the classical example, the vitaminE, which works in conjunction with
vitamin C, and if you don'thave enough vitamin C, then actually vitamin
E becomes prooccident, not antioxidant.So C sixty is really promising. And

(38:58):
then it kind of just got buriedand forgotten, and Laura Dugan got some
you know, overly bureaucratic administrative joband and wasn't pushing it hard enough.
And then some people had to gousing regular NORMALCY sixty and they mixed it
with olive oil, which also hasantioxidant property, well, not exactly antioxidant,

(39:22):
its oxidation resistant. Uh, Andthen the results were a bit of
equivocal. It looked very impressive,but people tried to repeat it and they
couldn't really get it to work,and it might have only been the olive
oil having the effect and so on. But now things are improving the whole,
so Laura has re emerged and isthe main scientific founder of a new

(39:45):
company that pushing forward with the originalwork that she did, and so I'm
very hopeful that this will have anew lease of life. Quite I'm quite
optimistic. This is promising good.And you mentioned so I medal in blue
Methyline blue. Yeah, okay,that's another curious one again, something that

(40:07):
hasn't been looked at nearly enough.Really only one group up in Scotland had
had a good look at it severalyears ago. Now I believe it definitely
needs more attention. I don't reallyknow how Methyline blue worked. So the
last two one one is your opinionon restral. Res vitral is a tricky

(40:30):
one because certainly the early work thatwas done had some experimental problems. It
often happens. It's nothing to beashamed of, but the early work that
was done was somewhat misinterpreted. Andwhen people tried to improve on res viratral
and make chemicals that were similar butworked more powerfully, again, that was

(40:51):
you know, maybe some of itworked, maybe it didn't. Glack Sir
Smith Clein spent a great deal ofmoney trying to make it work by buying
fur trice and so on. Youknow, it's hard to say, but
the mechanism whereby res viritrol may workin so far as it may or something
or things like it work. It'sclosely related to the whole bitiness of NAD

(41:15):
that I mentioned earlier, and ofcourse that's why David Sinclair got into NAD,
having worked originally with rest ferritrol.You know that there may be mechanisms
relating to the protection of DNA.There's something very important that NAD is used
for other than transporting electrons around thatI mentioned earlier, which is to do

(41:38):
with DNA repair. That's something calledpolyADP ribos polymerase, which is an enzyme
that's involved in DNA repair and itconsumes large amounts of NAD. Now that
NAD is recycled afterwards, but stillif you've got damage to a DNA,
you don't want this kind of thinggoing on too much, so that there
may be some role there. Yeah, it's more complicated, Yeah, okay.

(42:00):
And the last is about water andthere are two. One is very
maybe who is hydrogenated water something thatis very I don't know if you heard
about it, if you know aboutadding hydrogen water and if it's got some
benefits, Yeah, I don't reallybelieve in any of that, you know,

(42:22):
changing the pH of water, whichis kind of what it's about,
honestly. You know, pH isa very fundamental property of biological fluids,
and it's a property that the bodyworks very hard to maintain constant. In
fact, a very famous biologist centuryago, nam JBS Houldine, who was

(42:44):
a bit crazy and did self experimentationto the extreme. He tried to change
the pH of his own blood byone unit and he succeeded, but he
made him very thick, and heowned it very very briefly. So don't
do that. And you know,but so people say, people say,
you know, alkaline water and alkalanders, or that it might be good for

(43:04):
you, but I honestly don't believea word of it, because the body
will correct for it very very quick. Yeah, yeah, same, I'm
monostasis. But but the H twowater apparently is adding H two that is
doing something. But the last aboutthe things is deuterium water. Because you
started talking and about the uterian water, I don't know, many many years

(43:27):
ago where now only recently came cameto the wider audience. What about Yeah,
okay, so there is a confusionhere that I need to correct because
I have never talked about generated waterat all. I have no real reason
to believe that deuterated water has anyvalue. Okay, the thing that absolutely

(43:52):
does have value is deterated fatty acids. Maybe the iteration is also valuable for
certain other molecules, but the fattyacids are the one that get the big
attention right now. And this againcomes down to free radicals, because it
turns out that fatty acids are ahuge play a huge part in free radical

(44:12):
downage. What happens basically is thatcertain free radicals can oxidize a fatty acid,
and when they do, the fattyacid becomes capable of essentially passing on
the oxidation state. And it's worsethan that. The reaction is not just

(44:34):
a chain reaction. It's a chainreaction that can brush, so you can
get multiple different oxidation oxidize fatty acidsjust from one initial event. The chemistry
of this has been well understood formany, many years, and it's also
why olive oil is good for you, because olive oil, it turns out,
does not have the substructure that allowsoxidation to happen easily. But it

(44:58):
turns out that other fatty acids dohave this substructure, which is called bithalilac
carbons al y l I. See, they can be protected from oxidation by
replacing the particular hydrogens that are thatare linked to those carbons with you two

(45:19):
it. This makes the carbon hydrogenbond stronger and less oxidizable. And so
it turns out that it's possible tomake deuterated fatty acids. It's now actually,
over the past few years, becomevery easy. You can make lots
and lots of it, very cheaplybecause it's a nice clever catalytic reaction that
was discovered. And these fatty acids, because of this chain reaction thing,

(45:45):
can be supplied in the diet andyou don't even need to supply all that
much of them. You can givepeople or mice or whatever these fatty acids
in perfectly tolerable quantities in their dietand they are cumulate a respectable proportion of
deuterated fatty acids in all of thattissues, and this slows down oxidation and

(46:07):
it appears to have really dramatic effects. So right now that work is just
moving towards clinical trials. It's beenin clinical trials already for certain childhood diseases,
congenital diseases that are characterized by reallyhigh oxidative stress. But I really
strongly believe in this technology and Ithink it's a tragedy that it's taken so

(46:29):
long to hit prime time. TheLongevity Summit Dublin and the Longevity Declaration,
so I have the recently what isit about? Okay? First of all,
Longevity Summit Dublin. So this isthe conference that I run every year
in Dublin, of course in Ireland. It's coming up on June the thirteenth
through sixteenth this year. Of course, registration is still open. The scientists

(46:52):
who want to submit abstracts for presentationat the post session are still that's still
open as well. Strictly speaking,the deadline has passed, but in fact
I tend to accept things late.And the speaking lineup of you know,
is absolutely stellar. As always.I have been running these conferences for more
than twenty years now. They startedout in Cambridge in England, then they

(47:14):
moved to San Francisco, then theymoved to Berlin and now they're in Dublin,
and you know, they have beenvery very effective in you know,
promoting ideas, in getting people involvedin the field who have gone on to
make big, big contributions, andso I always get really the top speakers,

(47:36):
but also I bring in speakers thatyou haven't heard of, people who
don't think of themselves as gerontologists even, or people who are you know,
unknown in one way or another,and that has been a huge part of
why these conferences have been so successful. Also, of course, there's they're
not just the talks that the recreation, there's the informal interactions as they call

(47:57):
it. So, you know,a big part of what I introduced into
gerontology conferences world. Having free alcoholevery evening made a huge difference, and
other people have copied me on thatover the years. But yeah, so
that's coming up now the Dublin LongevityDeclaration, which it gets its name because

(48:19):
it was first launched a year agoat Longevity Come at Dublin in twenty twenty
three. It's all about getting theword out to the world, to the
general public and to policy makers anddecision makers that the expert community now feel
quite optimistic about the time frame forbringing aging under medical control. Historically,

(48:42):
I've been optimistic and I've been outthere making a massive nuisance of myself for
a long long time, but I'vebeen pretty much the only person doing that.
I have been able to get intothis position where I'm working independently and
I'm funded by philanthropy. But allof my colleagues are in this much worse
position, where they professor ships atuniversities and they're funded by the government,

(49:02):
and they have to, you know, they have to be terribly politically correct
all the time, and so theyhave been unable even if they wanted to
to get out there and say thekinds of things that I say. This
started to change in maybe five yearsago, six years ago, when David
Sinclair wrote his counterpart to my book. You know, if he'd written,

(49:25):
if he'd written a book that wascalled Why We Age and Why We Don't
Have To ten years earlier the wayI did, he wouldn't be a professor
at Harvard anymore. He'd have beenfired, right. But there you go.
So that's happening now, and Ineeded I realized, we realized that
there was great value in demonstrating thatthis is now the consensus view of the

(49:50):
expert community. So it's not justme and David up there. On the
signatories of this thing, there's morethan one hundred luminaries from the biology aging
most of the top people have signedit up, signed up to it,
and that's that's huge. It makesall the difference. So of course it's
early days, yet it's been outthere for like eight months something like that.

(50:12):
Uh, And so we've got allthe expert support that we want.
We'd like two other types of support. We'd like support from scientists who are
not gerontologists, but who are youknow, really important to really recognize people
who've won Nobel prizes, that kindof thing, right, And we're working
on that. And the other thingis we want the general public. We

(50:34):
want people to come out and signthis in large numbers. At the moment,
we've only got a couple of thousandsignatories from the general public, and
that's not nearly good enough. Wewant a couple of hundred thousand. And
you know that's why I'm going tobe working to make happen perfect. We
will support and I will link allthe links to the show notes. So

(50:55):
since we are wrapping up, Idon't step you out. What are your
next and how our listeners can supportyour work? Or what you're doing your
foundation or work. So ever sinceever since about two thousand and five,
I have been supporting research in thisarea, and of course the things that

(51:17):
I have always chosen to support havebeen the things that are most neglected by
other people. Back then, therewere a lot of things that were neglected,
and so I had a lot ofthings to work on. Now I'm
very pleased to say that most ofthe things that I needed to fund back
then have moved forward far enough thatthey are in the private sector. There

(51:38):
are startup companies that are much morewell funded, simply because investors tend to
write bigger texts than donors do,and so that's all wonderful, But there
are some things that remain that arestill not not working well enough to be
investable, and therefore they still needto be supported philanthropically. My previous organization,

(51:58):
Sends Research Foundation, and is doinga lot of that very good work,
not as much as I would like, but it's doing some and so
that's good. But my new organization, LAV Foundation is doing something that only
became possible quite recently, and thisis now, I firmly believe the single
most important thing that we need todo the single thing that will make most

(52:21):
impact per dollar. That is combiningthings that already work now things that already
work. First of all, I'mtalking about mice. I'm not talking about
humans, because that's what I do. I work on early stage staff.
And when I say work, Imean work a little bit. I mean
they and if they give a certainamount of extension of healthy life and total

(52:43):
life to mice. Even when youstart the intervention in middle age, when
the mice are maybe one and ahalf years old, they would normally live
to two and a half, whichI do extend that, but nothing gives
more than a couple of months ofincreasing lifespan on its own. So the
question is what can we do ifwe put a lot of such interventions together

(53:05):
in the same mice at the sametime, And what we are hoping to
achieve and what we're planning to achievein the long run anyway, is a
whole year of extension. So wetake mice that are one and a half
years old, they would normally liveto two and a half on average.
We want to get them out tothree and a half on average. And
of course some mice live a bitlonger, so the maximum life span.
Typically it's about nine months longer thanthe mean life span, so they would

(53:30):
normally the maximum would be like threeand a quarter. We want to get
it out to like four and aquarter. The more the better. If
we get more than that, somuch the better. But that's why we're
starting, and so early last yearwe started our first experiment in this area
with four interventions wrapper mice in isone of them. The other ones are
all bona fide damage repair, puttingin young stem cells, putting in more

(53:53):
to loomerase, and also getting ridof sinescent cells using a synolytic. And
the key thing is we are keennot just to try them all and see
what happens, but also to learnas much as we can. So it's
a big, big experiment. It'sgot one thousand mice, five hundred males,
five hundred females, and that's becausethere are ten treatment groups. There's

(54:17):
a group that's getting all these interventions, as of course a control group that's
not getting any of them, andthen there are four groups that are getting
just one of them, just tovalidate that we are doing the experiment correctly.
And then there are four treatment groupsthat are getting three out of the
four interventions, because those will bethe ones that show up antagonistic interactions,

(54:38):
where two interventions are somehow canceling themselvesout by mechanisms that we don't understand.
So this is going to be aspectacularly informative experiment, and it already is.
I mean, the mice are morethan two and a half years old
now, and sure enough it seemsto be working. I put our updates
regularly on social media and on ourwebsite the f So yeah, it's going

(55:02):
well, but maybe not well enough. You know, we want it to
go really well. And so thisis not the last step here. We're
doing this experiment, but we wantto start the next experiment of the same
kind. The next one we wantto do in the same overall design,
but we want to use for differentinterventions. One of them will be deuterated
fatty acids. One of them willbe partial reprogramming. The we're called the

(55:28):
Yamanaka factors supplied to to the tothe mice to make their celves more stem
like. Then we're interested in albumin, which is the most abundant protein
in the plasma in the blood ofall mammals, and there is reason to
believe that if you put in newalbum in you can get a rejuvenating effect.

(55:52):
You get the idea we're going toSo the design of this this new
study is again prominently shown on ourwebsite LVF dot org. The thing is,
though these studies are damned expensive,they're real informative. So when I
say they are the most value formoney, I really mean it. I

(56:15):
really believe that. But the moneyis a lot. This first experiment costs
three and a half million dollars,and most of that because it's a thousand
nice right, it's a lot ofnice And most of that money had to
be spent near the beginning of theexperiment or at the beginning get to buy
the mice. We had to youknow, and the interventions, because most
of the interventions are rejuvenation, they'redone once at the beginning and then you

(56:37):
just wait, right and they're verylaborious, you know, replacing you know,
giving a thousand mice, well actuallyfive hundred mice a by marriage transplant.
You know, that's a lot ofwork. So the second experiment,
it's going to be the same.It's going to cost a lot. It's
going to cost a few million dollars. And I am personally trying to raise

(56:59):
that right now. So anyone who'slistening to this podcast and who is in
a position to contribute, then pleasedo every little help. That's really you
know, that's that's that's the maingoal of Perfect. Thank you, thank
you very much for your time.You're wrapping up. I think you're breaking

(57:20):
up a little bit the connection,but we have at the end of our
our call. I hope you thiswould be there would be a follow up.
I don't know when, but yeah, I will link all the details,
I will follow you and then yeah, I know that you post periodically
on x or Twitter or Twitter updatesand on social and any anything else we

(57:42):
can do for I can do foryou. I think you've covered the main
things, the longevity studies that we'redoing in my the longevity declaration, and
of course the longevity is on itin Double Perfect. So then thanks again
all great, thanks for for yourtime. I really got your work,
and let's keep updated. Then Iopen it to have you again here.

(58:07):
Absolutely thanks for having me, Patand I have a good one. Bye.
Did you like this episode? Ifso, simply subscribe comes up and
click on the notification bell not tolose any opportunity in the future, and
remember sharing and scaring, even forthe coffee even better the next time.

(58:29):
See you soon.

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