Harnessing Cell Reprogramming to Restore More Youthful Gene Expression: Yuri Deigin at EARD 2023
Summary
TLDRIn this informative talk, Yuri Deigin introduces the concept of partial reprogramming, a promising approach to address aging by rejuvenating cells at the epigenetic level. He discusses the potential of gene therapies to reverse cellular hallmarks of aging, drawing on observations from nature that demonstrate aging's malleability across different species. Deigin highlights the role of epigenetics in aging, citing examples from social insects and mammals that exhibit lifespan variations controlled by epigenetic mechanisms. He further explores the safety and efficacy of partial reprogramming in vivo, as shown in studies that have successfully extended lifespan and improved healthspan in mice. The talk concludes with future directions for research, including tissue-specific therapies and the development of targeted gene delivery methods, offering a glimpse into the potential of partial reprogramming to transform human health and longevity.
Takeaways
- 🧬 Yuri Deynahan from Youth Bio is leading the development of gene therapies based on partial reprogramming to address the issue of aging, aiming to slow it down or even reverse it.
- 📈 Aging is a complex process with no consensus definition, but it involves cellular damage accumulation and various manifestations of aging which can be reversed at the cellular level through reprogramming.
- 🌐 The diversity of aging across different species indicates that aging is malleable and under genetic and epigenetic control, suggesting it's not governed by a universal physical law like the second law of thermodynamics.
- 🐝 Observations from nature, such as the honeybee and the black garden ant, show significant differences in lifespans despite sharing identical DNA, highlighting the role of epigenetics in aging.
- 🦋 The monarch butterfly and the Indian jumping ant are examples of epigenetic control of lifespan within a single species, demonstrating the potential for lifespan extension through epigenetic reprogramming.
- 🧬 Epigenetics refers to the control of gene expression, which varies not only between different cell types but also changes with time, including in response to aging.
- 🔄 Rejuvenation of cells is possible, as evidenced by the resetting of aging hallmarks during reproduction in various species, including humans.
- 🧪 The process of cellular reprogramming was first shown to be possible in 1962 by John Gurdon, and it was further proven that cells can be reprogrammed back to an embryonic-like state in 2006.
- 🐭 Partial reprogramming in vivo has been shown to rejuvenate cells and extend lifespan in mice, with one study demonstrating a 50% increase in lifespan in a fast-aging mouse model.
- 🛠️ While the exact mechanisms of how partial reprogramming leads to rejuvenation are not fully understood, hypotheses suggest it may relate to the early embryonic processes triggered by reprogramming factors.
- 💡 The transcriptomic and physiological rejuvenation induced by partial reprogramming has been observed in various studies, indicating a shift towards a more youthful gene expression pattern and improved cellular function.
Q & A
What is the main topic of discussion in the provided transcript?
-The main topic of discussion is partial reprogramming, its potential in addressing aging, and the various aspects of aging that can be manipulated through this process.
What is the goal of partial reprogramming in the context of aging?
-The goal of partial reprogramming in the context of aging is to slow down, and ideally reverse, the aging process by rejuvenating cells on a cellular level.
What is the significance of the variation in lifespans among different species as mentioned in the transcript?
-The variation in lifespans among different species signifies that aging is malleable and can be influenced by genetic and epigenetic factors, which is important for understanding how aging can potentially be manipulated.
What is epigenetics and why is it relevant to aging?
-Epigenetics is the control of gene expression, which determines which genes are expressed and when. It is relevant to aging because it controls the aging process and can be manipulated to potentially extend lifespan and rejuvenate cells.
How does the transcript suggest that aging is not a universal biological law?
-The transcript suggests that aging is not a universal biological law because it highlights the diversity of aging patterns and lifespans in nature, indicating that aging can be influenced by biological factors rather than being a fixed law.
What is the role of epigenetic reprogramming in social insects as mentioned in the transcript?
-In social insects, such as honey bees and ants, epigenetic reprogramming allows for different roles within the colony to have vastly different lifespans, demonstrating that epigenetics can play a significant role in determining aging and lifespan.
What is the significance of the observation that epigenetic clocks are synchronized across different tissues?
-The synchronization of epigenetic clocks across different tissues indicates that aging is an epigenetically controlled process and that manipulating epigenetics could potentially influence the aging process across the entire organism.
What is the concept of 'rejuvenation' in the context of the transcript?
-In the context of the transcript, 'rejuvenation' refers to the process of restoring cells or organisms to a more youthful state, which can be observed during reproduction and is a potential goal of partial reprogramming therapies.
What is the historical significance of the experiments by John Gurdon and the creation of Dolly the sheep in relation to cellular reprogramming?
-The experiments by John Gurdon and the creation of Dolly the sheep were significant because they provided evidence that the DNA of differentiated cells still contains all the information necessary to create a complete organism, refuting the idea that cell fate is irreversible.
What are the potential therapeutic benefits of partial reprogramming as discussed in the transcript?
-The potential therapeutic benefits of partial reprogramming include rejuvenating cells, extending lifespan, improving tissue health, and potentially treating or preventing age-related diseases.
What is the current status of human trials for partial reprogramming therapies?
-As of the information in the transcript, there are no human trials underway for partial reprogramming therapies, but some companies are close to initiating clinical trials for specific indications.
What are the future directions for partial reprogramming research as mentioned in the transcript?
-The future directions for partial reprogramming research include studying tissue-specific approaches, finding tailored factors for particular cell types, and developing targeted delivery vehicles for specific organs or tissues.
Outlines
🧬 Introduction to Partial Reprogramming for Aging
Yuri Deynan introduces the concept of partial reprogramming as a potential solution to aging. He discusses his role at Youth Bio, where they are developing gene therapies based on this concept. The goal is to slow down or even reverse aging by addressing it at the cellular level. Deynan explains that cellular damage accumulates with age, and reprogramming can reverse these hallmarks of aging. The challenge lies in applying this in vivo, within an already formed organism like humans. He also touches on the diversity of aging across different species and the idea that aging is malleable and under genetic control, suggesting that it can be manipulated.
🌿 Observations from Nature on Aging and Lifespan
Deynan presents observations from nature to illustrate the variability of aging and lifespans across different species. He discusses the vast differences in lifespan, from days to thousands of years, and how closely related species can have significantly different lifespans. Examples include rock fishes with lifespans ranging from 10 to 200 years and the Indian jumping ant, which can change its lifespan based on social conditions. These examples highlight the plasticity of aging and suggest that it is not dictated by immutable physical laws but is influenced by biology and potentially可控 by epigenetics.
🐝 Epigenetic Control of Aging and Lifespan
The speaker delves into the role of epigenetics in aging and lifespan, using examples from social insects like honey bees and ants, where identical DNA results in vastly different lifespans based on social roles. He also discusses the Indian jumping ant and monarch butterfly as examples of epigenetic reprogramming that can extend lifespan. Deynan emphasizes that epigenetic changes are not only under genetic control but also within the power of a single organism to adapt to its environment. He mentions epigenetic aging clocks, which show that gene expression levels change with age, and suggests that manipulating epigenetics could potentially control aging.
🦋 Epigenetic Life History Manipulations in Insects and Mammals
Deynan provides further examples of epigenetic control over lifespan, focusing on the mon butterfly and the monv, a small mammal, which can adjust their development and sexual maturity based on seasonal changes, effectively extending their lifespan. He then connects these observations to humans, discussing epigenetic clocks that measure biological age and how they are synchronized across various tissues and species. This synchronization suggests a strong epigenetic influence on aging, indicating that epigenetic reprogramming might be a viable approach to rejuvenate cells and extend human lifespan.
🔬 Cellular Reprogramming and Its Potential for Rejuvenation
The speaker discusses the historical context of cellular reprogramming, starting with the disproval of the Waddington Dogma, which stated that cell fate is irreversible. He cites experiments by John Gurdon and the creation of Dolly the sheep as evidence that cells can be reprogrammed. The breakthrough work by Shinya Yamanaka and Takahashi in 2006 demonstrated that skin cells could be reprogrammed into an embryonic state, challenging the idea of irreversible cell fate. Deynan then explores the possibility of using reprogramming to rejuvenate cells, citing research that shows reprogrammed cells are both epigenetically and physiologically rejuvenated.
🐭 Partial Reprogramming In Vivo and Its Effects on Aging
Deynan describes the transition from in vitro to in vivo reprogramming, highlighting the initial challenges and the breakthrough by Alejandra Campo and others in 2016. They showed that partial reprogramming, when done for a short duration, could safely rejuvenate cells in vivo without causing organ failure or teratomas. This approach was found to prolong lifespan in a fast-aging mouse model by up to 50% and improve various biomarkers of aging. The speaker also presents a hypothesis on how partial reprogramming might work, suggesting a connection between the reprogramming factors and the embryonic epigenetic age.
🧪 Practical Applications and Future Directions of Partial Reprogramming
The speaker discusses the practical applications of partial reprogramming, emphasizing that while the exact mechanisms may not be fully understood, the observed rejuvenation of gene expression patterns and physiological improvements in cells and tissues can be harnessed for therapeutic purposes. He cites several studies that demonstrate the rejuvenating effects of partial reprogramming on various tissues and conditions, such as muscle regeneration and spinal degeneration. Deynan also addresses safety concerns, referencing a study that showed no adverse effects from long-term, repeated induction of reprogramming factors. He concludes by outlining future directions for partial reprogramming research and its potential as a preventative therapy for healthy individuals.
💡 Final Thoughts and Q&A on Partial Reprogramming
In the final part of the script, Deynan summarizes the potential of partial reprogramming to extend lifespan and improve health, even in wild-type mice. He highlights a study from Rejuvenate Bio that demonstrates the feasibility of using gene therapy to deliver reprogramming factors systemically. The speaker addresses questions about the evolutionary rationale behind aging and the potential for human trials of partial reprogramming therapies. He speculates on the future of systemic approaches to reprogramming, emphasizing the need for tissue-specific and targeted delivery methods. The script concludes with a discussion about the step-by-step progression towards broader applications of partial reprogramming in both disease treatment and healthy individuals.
Mindmap
Keywords
💡Partial Reprogramming
💡Aging
💡Youth Bio
💡Cellular Damage
💡Epigenetics
💡Evolution
💡Gene Therapy
💡Rejuvenation
💡Transcriptome
💡Therapeutic Benefits
💡Lifespan Extension
Highlights
Introduction to partial reprogramming as a method to potentially reverse aging.
Youth bio's focus on creating gene therapies based on partial reprogramming.
The challenge of applying reprogramming to already formed organisms.
Observations from nature showing the diversity and malleability of aging.
Examples of different lifespans in nature, highlighting the potential to manipulate aging.
The role of epigenetics in controlling aging and lifespan.
Evidence from social insects showing epigenetic control over lifespan.
The Indian jumping ant as an example of epigenetic reprogramming affecting lifespan.
The monarch butterfly's season-dependent lifespan as an epigenetic example.
Epigenetic clocks as evidence of aging being under epigenetic control in humans.
The process of cellular reprogramming and its historical milestones.
How reprogramming can rejuvenate cells both epigenetically and physiologically.
Partial reprogramming's potential to reverse cellular hallmarks of aging.
The first successful in vivo application of partial reprogramming to extend lifespan.
Hypothesis on how partial reprogramming may work at the epigenetic level.
Observations of rejuvenation at the transcriptomic level post partial reprogramming.
Demonstration of physiological rejuvenation in tissues following partial reprogramming.
Studies showing partial reprogramming's therapeutic benefits in various mouse models.
The safety and efficacy of long-term partial reprogramming demonstrated in a study.
Recent findings that partial reprogramming can extend lifespan in wild type mice.
Future directions in partial reprogramming research and development.
The potential for tissue-specific partial reprogramming therapies.
The possibility of using partial reprogramming in clinical trials within the next few years.
Challenges and considerations for systemic approaches to partial reprogramming.
Transcripts
[Music]
all right well let's get started we're a
bit early so we might have some
stragglers coming in late but uh today
I'd like to talk to you about partial re
programming I'm Yuri denan has had a
very nice introduction I am leading
youth bio so where we are creating Gene
therapies based on partial reprogramming
and so today just want to talk to you
about this paradigm
and give you an overview of what it can
do and of course the problem that we're
all collectively trying to solve is
aging and ideally would like to slow it
down maybe even uh reverse it uh well
ideally would like to reverse it and one
way that we can do this is with partial
reprogramming because on the cellular
level it was actually able to do these
things uh because moving forward with
aging you see all these homeworks of
Aging
um this is a
pointer but anyways I won't use the
pointer um where uh moving forward with
aging you you have all sorts of cellular
damage accumulating or other
manifestations of Aging but then you can
with reprogramming reverse all the
cellular Hallmarks amarate all the
cellular Hallmarks of aging and so the
next challenge is then to take this and
accomplish this on a level inv Vivo on a
level of already formed organism because
you know within the context of a single
cell is great but we are unfortunately
trillions of cells which already formed
and that's the challenge and this is
what we're doing at youth bio and many
other companies also are doing with
partial reprogramming trying to harness
the rejuvenating power of reprogramming
and apply it to already formed organisms
like
ourselves and before we dive too deep
into the details of partial
reprogramming let me just take a step
back and you know talk about what aging
is and we we all have our own
definitions and unfortunately there's no
consensus in the field as badim uh very
eloquently presented but I think we have
some observations from nature that we
can make that can give us a general idea
of what aging is and what aspects of
Aging we as already aged organism would
really like to amiliar it and let me
just start with some observations from
nature which again some of you already
heard from previous talks but uh I guess
uh it's um very important for us to take
a look at the big picture and not just
focus on kind of human aging or or Mouse
aging because in nature there's just so
many different modalities of aging and
the variation in lifespans is just huge
uh as shown here it's you know within a
million times between different species
some species live just a few days other
species live for a few years a few
thousand years and even within mammals
themselves as again V mentioned there's
100 times difference between lifespan a
mouse lives 2 years a whale lives 200
years and so the variation is just huge
and all which means that aging can be so
diverse and so we have to figure out
what aspects of it we really can uh
manipulate and also the
diversity uh between lifespans is
present in even very closely related
species like here Rock fishes which is a
single genus some rock fishes live for
just like 10 years and others live for
200 years years and it's the same genus
and here we have two species one of well
the flagfish actually lives to 18 years
but there is some rock fishes that live
even lower and it's a smooth Continuum
of lifespans like 50 different species
of rock fishes between 10 years in 200
years and so this tells us that aging is
is quite malleable and it's within the
power of evolution obviously but very
quickly vary the lifespan so even in
closely related species it can vary so
so so great
and even after environmental conditions
change species can adopt very quickly
Again by changing lifespan on
evolutionary time scales of course
quickly uh adapting to changes in the
environment and like I mentioned not not
only aging is not Universal the patterns
of Aging also very variable and so to me
this means that there's no like physical
law it's not the second law of
Thermodynamics about entropy that makes
us age the something different something
in biology that makes us age um and so I
I think of that's actually good news
because you know we couldn't do anything
about fundamental laws of physics but we
can definitely do something about
biology and uh to me it's pretty obvious
that U aging is under genetic control on
species level obviously it's the genome
that determines life histories of
species and the speed of aging and
consequently how long a given species
typically lives and
and of course you know within
individuals of a single species there's
variation but it's always within the
confines of put put upon the species by
The genome and uh also in some species
the speed can change can vary based on
environmental factors if there's a
famine or a drought that can actually
extend species and I think this is the
mechanism behind caloric restriction
that actually is kind of programmed into
the genome that if a species needs to
adapt to the environment if there's some
adverse environmental conditions its
biology can extend its
lifespan but um the the next few
observations that I'd like to highlight
is to me they show that aging is not
just under genetic control but also it's
within epigenetic control and so it's
within the power of you know a single
organism potentially to adapt to the
environment as we'll see in some social
insects but of course for our purposes
if we can manipulate epigenetics
potentially we can manipulate aging
because as I show in next few slides
there's a very strong epigenetic role in
aging and uh before we get into the
epigenetic control of Aging just a few
words about epigenetics what it is and
just broadly speaking it's control of
gene expression there's different
mechanisms within our genome that
control which genes get expressed when
in what what type of cells and as a
multicellular organism this is a
necessity because we have you know close
to 200 different cell types all of them
have the same DNA but there's very
different types of genes that
combinations of genes that have to be on
in skin cell versus say a brain cell
also epigenetics controls not just on or
off but there's like a volume level on
different Gene uh genes and the
expression of genes and the volume knob
can vary with time and even like a
circadian written like within the
24-hour cycle genes go up and down in
expression levels and of course with
aging we have epigenetic aging clocks
methylation clocks and we know that the
expression level of different genes and
transic clocks of course changes with
aging in in a very similar way between
some subsets of genes in a very similar
way across you know all individuals of
the same age which is the basis for
having these clocks in the first
place and uh let me just share a few
observations from nature which show that
aging and lifespan are actually under
epigenetic control at least in the in
these
species um the most clear examples come
from social animals where
they the animals share identical DNA but
their lifespans can vary by orders of
magnitude so for example here we have
the honey bee and queen bee lives for
for years while a work worker bee lives
for just a few months or um yeah weeks
in the summer and so even a more large
disparity is observed in ants the black
garden ant is a like a record uh keeper
the black garden ant queen bee that can
live up to 30 years which is like when
you think about it I think it's it's
mindboggling that a small insect can
live longer than a horse or like twice
as long as a dog uh and yet again worker
ants live just for for one or two
years um another example that to me is
even more powerful is the Indian jumping
an because here it's even in the context
of the same individual that indidual can
be epigenetically reprogrammed during
its life if you know the conditions are
right if the queen dies these gamergates
there're called they're reprogrammed
into breeders and that extends their
lifespan by several several times and so
this shows that you know within the
confines of your genome epigenetics can
can vary to a large large degree your
aging and so again epigenetic
reprogramming you know we see this an
example in insects and then I think we
can learn from it and hope that in the
context of our biology we can also use
it with partial reprogramming to
accomplish uh similar similar goals of
extending our
lifespan another example that I really
like is the mon butterfly because
previously we had social insects which
have different social roles so you can
kind of say that maybe they have
different life history programmed in the
genome it's just like kind of One
Direction that's picked when you know
the they're being during embryogenesis
and they're they're kind of stuck in
their genetic program but of course you
know the other example of the Indian
Garden end show shows that you can
actually change from one life history to
another which has a greatly extended
lifespan but monarch butterfly butterfly
is a different story because there's no
different social roles there just you
know one kind of social role but
depending on the season in which the
butterfly is born that can greatly vary
their lifespan if they're born in the
summer they live for like a month but if
they're born in the winter or in the
fall I'm sorry they can live for up to 9
months because they have to survive the
winter they go down to Mexico to over
winter they breed there and then they
come back and so this again shows that
you know epigenetics can greatly vary
lifespan even within the context of a
single social
role uh those were insects but even some
mammals have a similar epigenetic life
history manipulations the monv it's a
small in Montana uh they have this life
history that if they're born in the
spring like the mon butterfly they
mature within the same season season and
die actually within the same year but if
they're born in the fall and again they
have to overwinter they can pause their
development pause their sexual maturity
and actually they live for much longer
because of this so again you can see
epigenetic modulation of
lifespan and of course you know insects
and rodents are great but we're a little
selfish we want to see what's up with
our human biology do we have some
indications that epigenetics also plays
an important role in our aging and at
least for myself I see this in
epigenetic clocks that the answer is are
yes because we have epigenetic clocks
that you know by now we have a lot of
data that it's not even just humans it's
also in like 190 different species of
mammals and you have a lot of conserved
elements between the species a clock
built on human uh cpg human kind of data
Works in chimps uh so you can also just
use a human clock and you can tell how
all the biologically all the chimpanze
and so again this all all ties back for
me into the uh very strong role
epigenetic plays in our aging and
so uh not only that but of course the
epigenetic clock is synchronized across
many tissues in cells that are so
different as a neuron and a blood cell
of course you're born with the neurons
that you're going to die with and blood
cells they divide and replicate on a
daily basis but yet they
show if not the exact same very similar
epigenetic age and that's true across
many different tissues and so this
conserved nature of these epigenetic
clocks between tissues between species
to me highlights or points in the
direction or strongly at least for me
points in the direction of Aging being
epigenetic control and so so you might
say okay great you know aging is up
under epigenetic control but can we
actually do something about it can we
change our epigenetics is Rejuvenation
even possible in the context of um you
know fully formed organism and of course
obviously we we know that during
reproduction Rejuvenation is absolutely
possible and in nature we see
Rejuvenation happening quite frequently
and it just seems that in in mammals
it's reserved for reproduction we see
the rejuvenating event being being uh
taking place during reproduction for
Reproductive cells for gamuts and of
course when we talk about humans uh we
have our reproductive cells our eggs
females not us but female eggs they're
the same age as the mother they're 20
year 20y old cell 30y old cell so
they've been subjected to this Aging for
these decades and yet after
fertilization all the Hallmarks of Aging
are amiliar and of course you get a
newborn baby with age zero reset aging
and
um of course uh not only we observe this
in in humans in mammals we we observe
this in many different species for
example in yeast which is U kind of
special example because they're
unicellular single cell organism which
is kind of both sematic cell and and a
gamut but yet we see that if they're
dividing asexually they don't uh uh
exhibit this rejuvenation process a
Mother cell eventually will will die but
if they're forced to divide sexually
which usually happens under adverse
conditions but if we can force it in a
lab they do go through this process of
Rejuvenation and you can if you keep
doing this this kind of Mother cell
never gets old it can keep uh dividing
and keep getting the kind of new lease
on life every time you induce G
gametogenesis the sexual reproduction in
yeast and but of course we observe this
in in many different species as I
mentioned in mice we observe that
there's damage getting cleared after
fertilization and
uh in nematodes Sy Canon's team showed a
while back that this also happens just
before fertilization and emods are a
little different because they they're
self fertilizing their hermaphrodites so
they know when the fertilization is
going to occur so they can clear the
damage just before
fertilization and in frogs in in frog
ooc sites frog eggs we also see this uh
process taking place that there's active
Rejuvenation happening after
fertilization and of course vadim's team
the the great paper that he already
cited that showed that epigenetically we
also observe that epigenetic age uh is
diminished and occurs the minimum occurs
soon after fertilization not not exactly
at the moment of fertilization but
there's actually an active process
presumably an active process of
the reduction of biological age which
reaches a minimum uh after during
gastation um so the all of this implies
that there is active Rejuvenation
happening during the the reproduction
process of after fertilization
process and uh well let me kind of bring
it back to reproduction and tied to
reprogramming and just give a brief
historical overview of how we came to
know this wonderful process of cellular
reprogramming and then again I'll try to
tie it back to germ line
Rejuvenation and before reprogramming
proved it wrong there was this wton
landscape or wton Dogma that said that
uh cell fate is irreversible and cells
start this kind of stem cell State on
top of the landscape and they roll down
their respective paths towards terminal
differentiation where they end up as a
skin cell or a brain cell and they can
never go back and then this Dogma was uh
soon proven false it was formulated in
1940 but already in 1962 there was first
evidence that this Dogma might be wrong
and j John gon provided this evidence by
taking a nucleus from a skin cell and
putting it back of a frog and putting it
back into a frog exg cell and producing
a completely healthy new frog which
meant that the all the DNA necessary for
the you know all all of the cells of the
organism were still present in the skin
cell oh and also before in the wton
Dogma times the thought was that maybe
in differentiated cells DNA is somehow
kind of removed from irrelevant DNA is
removed from the cell so the cell only
retains the DNA it needs to be a skin
cell and so it can never go back to
being a stem cell because it actually
doesn't have the DNA and John Gordon
proven this wrong it it said no DNA is
still there you can for any cell type is
still present you can take a skin cell
and the the DNA is is there and
unfortunately there was like a 30-year
pause in this area of research and the
next uh well it's it wasn't even a
breakthrough it was essentially a repeat
of the John giren experiment came 30
years later in 1996 when Dolly the sheep
the famous Dolly the sheep was cloned
and then subsequently there were many
other animals there were cloned and it
just repeated this uh evidence that all
of the necessary DNA is still present
and you can take a somatic cell and it
can essentially become a a gamut and all
of the necessary DNA is still
retained and the the next breakthrough
that fully refuted the wton Dogma came
in 2006 with SH yanaka and and Takahashi
showing that actually the process is
completely reversible can take a skin
cell and even within the context of that
particular cell inducing uh using some
defined factors which later came to be
known ASAC factors you can induce the
cell all the way back into embryonic
State embrionic like state ploton state
the stem cell at the top of this uh
wington landscape that we saw
previously and uh so basically they show
that the wton Dogma is completely wrong
you can move pretty much back and forth
in in in any direction even laterally if
you kind of use the right reprogramming
factors you can go from like a neuron
into a skin cell being
reprogrammed and so that Discovery spark
Talk of the possibility of like is it
possible then to epigenetically
rejuvenate cells which uh for kind of
our purposes is what we're all here uh
trying to accomplish using this Paradigm
of reprogramming to actually rejuvenate
cells
and of course it was very soon showed
that the reprogrammed cells are not only
epigenetically rejuvenated they're also
physiologically rejuvenated and first
evidence of this came in in 2011 from
Jean Mar CL te ins who show that the
reprogramming process actually
rejuvenates cells and urates several
Hallmarks of aging and uh after that
there were actually many other groups
that looked at various other
manifestations of aging and various
other cellular Hallmarks of aging and
this diagram just kind of combines all
of the knowledge that you already saw
this diagram
that during the reprogramming process
all of the cellular Hallmarks that we
observe are rejuvenated and
ameliorated and of course the next
logical question was that can we do this
in Vivo can we actually use the power of
reprogramming in Vivo to rejuvenate
cells and the first attempt uh was not
really successful I mean it was
successful because it worked like inv
Vio reprogramming worked but
unfortunately the mice died so um from
that standpoint it showed that it's
possible to reprogram sell in Vivo but
uh in in this first iteration uh they
let reprogramming commence fully and
that killed the mice by you know within
just two weeks because they got liver
failure organ failure and uh of course
the the even the title of the paper was
very gloomy it said reprogramming in
Vivo produces teratomas n IPS cells with
tooy features basically teromas are
these cancerous tumors that we really
don't want as a consequence of
reprogramming and the Breakthrough that
showed that you can actually do this
safely in Vivo and effectively came in
2016 with Alejandra Campo and others
from the sulk Institute under the
um guide of Juan Carlos espo bmon and
they show that actually you can do this
safely if you do it partially so you
have to keep reprogramming partial you
have to do a very short duration of
reprogramming to avoid this you know Pur
potency to avoid celles actually going
back up the Waterton landscape because
in Vivo that's not something we we want
or can afford because we have to let the
stells stay as they are we have to let
keep the skin cell as a skin cell the
brain cell is a is a brain cell
otherwise we they lose function and you
know you can die you can you know liver
failure can kill you very quickly and
moreover they they showed but that by
using this approach this partial
reprogramming approach you can prolong
lifespan in this particular fast aging
Mouse model pic Mouse model by up to 50%
if you compare it to the first control
group and their mice they you know even
visually they looked younger but more
importantly based on um you know
biomarkers of Aging like listed here you
know cesson cells DNA brakes uh
inflammation levels based on those
biomarkers the treated mice were younger
than the Tre untreated mice and their
tissue histology looked better and many
other um biomarkers that they looked at
the mice treated with partial
reprogramming look better than untreated
ones now of course you know the big
question uh by now after a lot of other
groups have replicated similar results
that partial Rogan does seem to
rejuvenate you know tissues and and even
animals um the next question is how does
it work how does partial reprograming
work unfortunately we don't have an
answer yet we don't know how it works
exactly I mean we know it works on the
level epics but how exactly that causes
rej ation we don't yet
know but we have some kind of ideas and
maybe we can formulate some hypothesis
and here's you know my attempt at
formulating one hypothesis and we have
to look at you know what do the yanaka
factors do and I mean we know that the
the you know o for so 2 and an are key
factors for maintaining stemness in in
ploton cells embrionic stem cells also
we know that they are OCT four and so 2
are transcription factors in that they
can access closed chromatin they can
unwind it and start you know expressing
previously uh silenced genes but what is
mentioned less often though is that OCT
4 and socks 2 are also the key factors
in triggering this maternal to zygotic
transition that happens during early
embryogenesis and this is when the
maternal genome gets silenced and the
embryo's own genome starts getting
expressed
and this starts at the BL blastula stage
and finishes in in a gastrula after
implantation and so I keep coming back
to vadim's excellent paper uh that
showed that embryonic epigenetic age is
minimal not right after feralization but
actually at the gastrulation stage and I
can't help but wonder if the two
processes might be connected and maybe
the
same uh networks of genes that are
responsible for Rejuvenation that we see
after embryogenesis that are triggered
by you know the o four and so 2 during
the maternal to zygotic transition could
be also triggering some of the genes
that can produce Rejuvenation that we
see during
reprogramming so this is you know this
is one hypothesis that I have and um it
gives new meaning to this quote that
Oliver already quoted that you know it's
gastrulation that's the most important
time of your
life uh okay Switching gears from like
what could happen how it could work to
actually what actually we observe and we
we observe that partial
reprogramming already rejuvenates the TR
cryptome it rejuvenates the gene
expression pattern that we see in the
cells that undergo the partial
reprograming process and so while the
exact mechanism of you know how it
happens might still be unclear from a
practical standpoint from a drug
development standpoint I think we can
already start to use these results and
use these observations for creating
therapies that we might not fully
understand and I think we still don't
understand how aspirin works but we
still you know we're okay with taking it
and I think I think in the context of
partial reprogramming we we might not
still we might not fully understand how
exactly works but we we can still try to
create therapies that could be
therapeutically
beneficial and um yeah and there there
have been several studies that showed
the this Rejuvenation at the
transcriptomic level and uh other levels
basic basically showing that
reprogramming induces a more a shift
towards a more youthful pattern of gene
expression which is for our purposes
basically you know the levels of
expression of key genes that we see in
cells that undergo partial reprogramming
are closer to the younger pattern than
they are to the original older pattern
that the cells started with before
reprogramming and so I think this is
very as I mentioned very important
practical result that we we should seize
upon and harness the the reju in power
of reprogramming for therapeutic
purposes and that's what we're doing at
youth bio and many other companies are
doing as
well and uh yeah also it's not just the
gene expression pattern also
physiologically there's uh data that
shows that partial reprogramming induces
physiological improvements in the cells
and tissues in Vivo that in the tissues
that uh undergo partial reprogramming So
Physical physiological Rejuvenation
which is you know probably more
important because you gene expression is
great but at the end the end of the day
you want your cells to be performing and
your tissues to be per performing at a
more youthful
level and this is another hypothesis why
Rejuvenation bip partial reprogramming
is possible at all and the hypothesis
goes because the reprogramming process
is gradual and it's gradual in both the
rejuvenating aspect and the cell
identity changing aspect of it and so
here we we have the the graph of kind of
the two processes side by side and if
you put them kind of one underneath each
other you can potentially uh find this
therapeutic window where you you already
have accomplished some Rejuvenation but
you have not yet gone beyond the point
of no return of the cell identity
changes so you can still maintain your
cell identity you can still remain a
skin cell but you already have
accomplished some Rejuvenation and
that's why partial reprogramming is you
know potentially able to work at all
because once you stop reprogramming
genes expression the the cell retains
its identity but it has been rejuvenated
by the process of
reprogramming and uh since the 2016 o
Campo paper there have been over a dozen
other experimental confirmations of
their findings that reprogramming
induces some degree of Rejuvenation and
also prolongs lifespan in several
different Mouse models that pric Mouse
models but also in Wild type mice and I
just want to show you some results that
I find particularly
compelling uh so here's an interesting
study because it showed that even a
single bout of partial reprogramming can
prolong lifespan and it's not it's not a
huge result in terms of the increase in
lifespan but I think it's it's an
important result because it shows that
uh it can the result can persist so even
a single administration of reprogramming
can result in uh both in a progeric
mouse mod so they have two mouse models
that they use the pic Mouse model fast
aging Mouse model but also a wild type
normal aging Mouse model and they showed
that both can exhibit this prolongation
of lifespan by partial
reprograming here's a study from David
Sinclair I'm sure you've all heard about
this study from 2021 where they uh were
able to use partial reprogram to promote
neuronal regeneration after uh injury
and even restore Vision in in mice and I
think now they're they're build building
upon this as a therapy for glaucoma if I
remember correctly that they're trying
to get into clinical trials actually
shortly um this I like this study it
showed that partial reain can improve
muscle regeneration after after
injury wound healing and I mean for the
interest of time I won't go into in too
much detail but there's as I mentioned
over a dozen Studies by now that showed
various aspects of partial reprogramming
that can produce various therapeutic
benefits this is wound healing partial
repan can improve wound healing um
partial rean can slow spinal
degeneration which is I think yeah also
very unpleasant aspect of Aging that a
lot of people unfortunately experienced
my own father had that had to have back
surgery because of spinal
degeneration also this study uh I I
really like this study from the Belmonte
group there's a follow-up study from
2022 where they showed safety of
reprogramming because a lot of the
Skeptics of reprogramming say that okay
it's great that you can you know use it
for just a few months at a time but
you're bound to run into problems if you
keep expressing these ploty genes on a
repeated basis for you know for too long
you're going to you know at some point
they're going to cause some some cancer
or something that well in this study
they uh had this 10mth treatment period
where they periodically were expressing
uh reprogramming factors and they they
saw no adverse effects in fact they saw
benefits in terms of as I mentioned
tissue Rejuvenation and so in this they
also reported tissue Rejuvenation but I
think more importantly this paper is
important because it showed the safety
of this approach and actually ampa at
all themselves have shown not only did
they use pric mice they also study in
Wild type mice in normal aging mice that
35 weeks of repeated induction of yaka
factors were not associated with any
teratomas or any other adverse adverse
effects um but in the bont study besides
besides safety they showed multiple
benefits of partial reprogramming in the
tissues of mice so not only were these
10mon long periods of partial
reprograming safe they were also
therapeutically efficacious and
beneficial and finally a lot of the
Skeptics uh of partial reprogram were
saying okay we only saw life extension
in pric mice in fast aging mice talk to
me when you can prolong lifespan in a
wild type aging Mouse model well here's
the recent preprint from rejuvenate bio
in which they did exactly that they took
a wild type Mouse model and and using a
gene therapy approach they were able to
show that partial rearing can extend the
lifespan of these really old mice
because they actually administered the
gene therapy at a very Advanced age for
a mouse 124 weeks and again it's not a
transgenic Mouse model it's just a
regular Mouse and you have to deliver
these reprogramming genes into you know
an already formed animal and so they use
the a delivery me method and they' using
that they've been able to extend
lifespan by again not nothing
groundbreaking but uh it was still a
positive life extension which as a proof
of concept shows that you can do this
safely in Wild type animals and moreover
do it using a gene therapy approach
because again there's a lot of Skeptics
that say you know gene therapy you can
deliver it into enough number of cells
in or form organism to produce a
meaningful therapeutic benefit well I
think this paper shows that you actually
can and we just have to build upon this
to get more and more effective into
targeting different isssues and so this
kind of is a nice segue to my final
Slide the future directions I think we
have to study uh different aspects of
reprogramming and I think by now we
already know that partial reprogramming
really needs to be kind of tissue
specific some tissues have to be avoided
as I mentioned the liver it's probably
the tissue you really want to avoid
because it's so amable to reprogramming
and can actually kill the mice but also
in terms of different combinations of
factors you have to find the tailored
factors for a particular cell type and
so I won't again go into interest of
time into the future directions too
deeply but there's I think a lot of the
things that we need to explore
collectively as a field of partial
reprogramming but and I'm very
optimistic that once we're able to
accomplish these things we'll have
therapies that initially will produce
meaningful therapeutic benefits in the
context of existing diseases and this
will get us to FDA approval get us on
the market and so then as future steps
we can start you know kind of build
collect uh combinatorial therapies that
Target several issues and then can be
used in healthy people as a preventative
therapy that can rejuvenate a healthy
person bring down their biological age
and thereby you know hopefully um slow
down their aging and maybe eventually
even reverse aging and so okay with that
uh I thank you very much for your
attention and if you have any questions
and hopefully might still have five
minutes for questions uh would love to
answer them thank
you thank you Yuri yeah we have a few
minutes for questions does anybody have
them yep back
here my question there's only two if
there's only two factors and they're
intrinsically encoded why hasn't
Evolution just turn these on whenever
resources are abundant why are these
shut down what's the evolutionary reason
why these aren't just active and keeping
all organisms kind of longer lived well
Evolution doesn't want us longer lived
Evolution obviously wants us dead so and
and again you know you can you can have
uh I think different schools of thought
about the evolutionary benefits of Aging
or is aging an adaptation or just a uh
kind of unfortunate uh thing that
Evolution chose not to deal with or does
evolution actually benefit from a
turnover of generations so yeah and you
can have its own conference on the the
different concepts of Aging so but in in
some animals like uh for example in
jellyfish uh actually they can
reactivate essentially or go back into
to embryo or polyp and uh Evolution was
able to find this but I guess other
animals Evolution actually kind of
doesn't want them to be immortal or
doesn't want them to live longer than
that it's optimal for their particular
ecological
niche so that's at least my view hello
uh oh sorry go ahead yeah I just wanted
to ask you are there any human trials
underway uh and are you recruiting more
trials let's see in some other countries
where maybe the laws might
allow right so not not yet but there are
some companies that're close to to
potentially close to clinical trials one
of them was David Sinclair's life bio at
least kind of from what was publicly
available I think they're looking into
uh some eye indications for some reason
I think I think glaucoma but they might
be targeting something else um and other
um well I think companies are close to
clinical trials in some existing
diseases particularly maybe with hoptic
stem cells or CTI therapies that might
use uh reprogramming partial
reprogramming to rejuvenate those cells
so we might see something in the clinic
you know within the next 3 or four years
but not yet but uh in terms of using
other jurisdictions definitely there
it's on on the mind of developers
especially within longevity prospera is
one of these kind of pioneering
jurisdictions as is you know Colombia
and Mexico they've been trying say
toomer Gene therapies or cloth Gene
therapies so it's you know it it's
possible and maybe eventually even
partial reprogramming will will use one
of those jurisdictions for for for its
clinical trials but not
yet we have time for one more
question
okay hi uh this is an from new um I have
a question just maybe if you could
speculate in terms of you know this
partial and yet systemic approach to
Repro programming on epigenetic level
right so we know that epigenetic changes
very very differently depending on the
tissue on the organ and so on so it's
not the same rate it doesn't really
change the same way Etc um so can you
speculate on what would be the
appropriate let's say vectors to use in
the future like when and where we will
be exploring the field to really
approach that systemically cuz the same
way as we're doing with Gene therapies I
mean you can squirt something into the
eye you have plenty of vectors but
systemically it's very very difficult so
we're not there yet but maybe if you
could just kind of speculate where we
where we think we might be going yeah
absolutely and and I think you you
nailed it and this is essentially you
know the the Paradigm that we're we're
going with with at youth bio where we're
using tissue specific approaches for
specific cell types and So eventually
the way we see long-term future of
partial reprogramming for for healthy
people uh that need multiple tissues
targeted is that we'll use targeted
combinations of factors potentially
delivery vehicles you know with
preferential tropism to that particular
cell type or particular organ that
would' like to Target and So eventually
it'll be a combination of therapies that
also might have uh different uh inductor
molecules because right now you have to
induce the expression of of partial
reprogramming so but to first you know
to get there and not to try to boil the
ocean you just use a particular cell
type or particular organ and in the
context of existing diseases like for
example Alzheimer's and and the brain
and you target that and if you can
provide a therapeutic benefit using
partial reprogramming and get that
therapy approved and you can then you
know build upon that and eventually if
you have uh you know gene therapy
approved for Alzheimer's you can then
use it off label and maybe even longterm
use it for healthy people as as a
preventative therapy of course not
probably not the brain but some other
tissues like for example skin
Rejuvenation you can start with wound
healing but eventually you can use it
for cosmetic applications for example
and so this is kind of the the the way I
I see you know the step by step of
getting there start with you know
particular one tissue but then
eventually get into combinator
combinatorial
therapy all right uh I guess uh yeah
that's it uh in terms of time so thank
you thank you again thank you very much
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