Harnessing Cell Reprogramming to Restore More Youthful Gene Expression: Yuri Deigin at EARD 2023

Summary

In 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

00:00

🧬 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.

05:00

🌿 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.

10:02

🐝 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.

15:02

🦋 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.

20:03

🔬 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.

25:04

🐭 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.

30:04

🧪 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.

35:06

💡 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.

Keywords

💡Partial Reprogramming

Partial Reprogramming refers to a process in cellular biology where cells are induced to revert to a more youthful state without completely changing their cell type. In the context of the video's theme, it is a method being explored to combat aging by rejuvenating cells at the epigenetic level. The script discusses how partial reprogramming can reverse cellular hallmarks of aging and has been shown to extend lifespan in mouse models.

💡Aging

Aging is a natural process involving the gradual decline in functional capacity and an increase in the likelihood of disease and death. The video discusses aging as a collective problem that the speaker and the field of biomedicine are trying to address, with the ultimate goal of slowing down or even reversing the process. The script provides various examples and studies related to aging, including the use of partial reprogramming as a potential intervention.

💡Youth Bio

Youth Bio is mentioned as the company where the speaker, Yuri Denan, is leading efforts to create gene therapies based on partial reprogramming. The company's focus is on harnessing the rejuvenating power of reprogramming to address aging. It represents the practical application of the concepts discussed in the video, aiming to develop treatments that could potentially slow down or reverse aging processes.

💡Cellular Damage

Cellular damage refers to the harm or deterioration that occurs at the cellular level as a result of aging or other factors. In the script, it is mentioned as one of the manifestations of aging that accumulates over time. The process of partial reprogramming is presented as a way to reverse this damage, potentially restoring cells to a more youthful state.

💡Epigenetics

Epigenetics is the study of changes in organisms caused by modification of gene expression rather than alteration of the genetic code itself. The video discusses the role of epigenetics in aging and how it can be manipulated to potentially control aging. The script provides examples from nature where epigenetic changes lead to variations in lifespan and aging patterns.

💡Evolution

Evolution is the process by which species change over time through genetic variation and natural selection. The script touches on the evolutionary aspect of aging, suggesting that the diversity in lifespan and aging patterns across species is a result of evolutionary processes. It also raises questions about why evolution has not favored constant activation of rejuvenation mechanisms.

💡Gene Therapy

Gene therapy is a field of medicine that involves changing or altering the expression of genes to treat or prevent disease. In the context of the video, gene therapy is being explored as a method to deliver partial reprogramming factors to cells in the body, with the aim of rejuvenating them and potentially extending lifespan. The script mentions gene therapy as a future direction for applying the findings from partial reprogramming research.

💡Rejuvenation

Rejuvenation in the video refers to the restoration of cells or organisms to a more youthful state. The script discusses various examples of rejuvenation in nature, such as in honey bees and certain mammals, and explores the possibility of achieving similar rejuvenation through partial reprogramming in humans.

💡Transcriptome

The transcriptome is the complete set of RNA transcripts produced by the genome. The video discusses how partial reprogramming affects the transcriptome, leading to a rejuvenation of the gene expression pattern observed in cells. This change in gene expression is indicative of the cells reverting to a more youthful state.

💡Therapeutic Benefits

Therapeutic benefits refer to the positive effects or improvements in health that result from a medical treatment or intervention. The script mentions several studies that have shown partial reprogramming can have therapeutic benefits, such as improving wound healing, promoting neuronal regeneration, and slowing spinal degeneration.

💡Lifespan Extension

Lifespan extension is the increase in the maximum or average lifespan of an organism. The video discusses studies that have shown partial reprogramming can lead to lifespan extension in various mouse models. This is a key outcome that supports the potential of partial reprogramming as an anti-aging intervention.

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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