TransVision Madrid 2025 Summit: Blasco, Magalhães, Crespo-Barrios, Muñoz-Espín, Coles, Hartenstein

Episode Transcript
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Speaker 1 (00:00):
Greetings and welcome to the United States Transhumanist Party Virtual
Enlightenment Salon. My name is Jannati stolierof the second and
I am the Chairman of the US Transhumanist Party. Here
we hold conversations with some of the world's leading thinkers
in longevity, science, technology, philosophy and politics. Like the philosophers

(00:22):
of the Age of Enlightenment, we aim to connect every
field of human endeavor and arrive at new insights to
achieve longer lives, greater rationality, and the progress of our civilization.

Speaker 2 (00:39):
Aging is a natural process, but it's a process which
hurts our health and well being.

Speaker 3 (00:47):
We are lucky to have longevity researchers developing rejuvenation therapies.

(01:17):
Welcome to Transvision twenty twenty five.

Speaker 4 (01:27):
So our next speaker is Spain's National Cancer Research Center.
She's the director of that and leading telemere research at
the heart of aging and disease. Not only that, Maria
Blasco is also one of the five co authors of
the article of the wholemarks of aging.

Speaker 3 (01:46):
At that time.

Speaker 4 (01:47):
It was the Nine hall Marks of Aging that was
written in twenty thirteen. I'm sure all, if not most,
of you are aware of the nine hallmarks of aging
that was written is the most searched article when it
comes to longevity. And of course now three more have
been added, so we have twelve homemarks of aging at
the moment. So Maria Blasco is joining us to talk

(02:07):
more on the topic. So please give it up for Maria.

Speaker 5 (02:17):
Thank you very much, Thank you very much for the invitation.
Is a pleasure to be here. So we all know here.

Speaker 6 (02:22):
I think that in order to be able to prevent
and to cure the majority of the diseases that kill
us associated with aging, we know we have to understand
agent at the molecular level, and one of the causes
of aging, the one I have been working with for
more than thirty years now, is the shortening of structures.

Speaker 5 (02:41):
That protect our chromosomes that are called.

Speaker 6 (02:43):
Kilomers in this review that was mentioned before. We consider
this a shortening of the diillomers as one of the
primary causes of aging because it can lead to other
causes of aging. When the dillomers become critically sure this
leads to other well known of aging. So tilam shorten
associated to sell division, and this happens all the time

(03:04):
in our organism. In order to regenerate tissues and this
is what can lead to ultimately to all the courses.

Speaker 5 (03:10):
Of aging and to tissue aging.

Speaker 6 (03:12):
Recently we have reviewed the hall marks and in Hollmark
as it was mentioned, but I wanted to bring to
your attention that if there was nothing to compensate for
this tilamar shortening, life wouldn't be possible, It would be
not possible to maintain the species. And in fact, there
is an activities called telomerase. It was discovered by Carl

(03:32):
Greater and this blackburn that is able to elongate tillamars,
or telomerase in mammals for instance, is activated in the
prepotency stages of embriadic development and there it presets tilmer
lengths and the new individual will have to live.

Speaker 5 (03:47):
With these tillovers.

Speaker 6 (03:48):
However, when we are born, telomerase is shut down in
the majority of tissues and this causes the progressive tilam
shortening as we leave th age. And we know that
tilmer length is rarely meeting in humans because there are
mutations in telomeris or other genes that are important to
maintain telomers. Then these individuals are going to have a

(04:09):
short lifespan and are going to develop a number of
diseases called tilomere syndromes. So we know these tell us
that telomera tilmerlenz is really limiting. But also even if
you are not mutant for ptolomeris for any of these
routines that are important to maintain tilome length, we also
know that there is a correlation between the tilomere length

(04:29):
and the likelihood of developing a number of diseases.

Speaker 5 (04:33):
So til meerlin has.

Speaker 6 (04:34):
Been considered a bio marker of aging. And I have
to say that I founded a company many years ago,
it is called Life Lengths that is devoted to measure
these tilomers and to see the value of these measurements
for as a prognostive factor for many diseases in humans.
Till omers matter, but not only humans in mice. And
this was the I think pioneer work that was done

(04:56):
more than thirty years ago and that I contributed to
that showing that really short tilometers are sufficient to cause aging.
And this was demonstrated by generating mice that lack telomeres.
We could demonstrate that this mice age because of tilam
is shortening. But also later on we also show that
if we are able to maintain tilomes loan for longer

(05:17):
times in mice. Again, doing transgendic mouse models for telomerase,
we were able to show that not only short tillomers
lead to aging, but if you maintained terms.

Speaker 5 (05:26):
Longer as this delays aging.

Speaker 6 (05:29):
And I think this shows the importance of tilever lens
for aging, but not only in humans and mice. If
something is important really has to be conserved in evolution,
it has to matter in evolution. And we did recently
well not so recently, at work by seeing whether any
parameter associated to tilomeers could explain actually longevity throughout different species.

(05:50):
And in this case we need a collaboration with the
ZEO of Madrid, and we look at species of birds
and mammals. Birds and mammals are very distant in evolution,
and we found that the tilomere lens adverse, it does
not correlate with longevity. We already knew that from mice
and humans. But we found that the rate of tilam
shortening could be adjusted to a mathematical function called power law,

(06:13):
and it could predict the longevity of a given species.
So we found, for instance that elephants and flamingos they
are very distant in evolution, but they share the same
rate of tilam shortening and they shared the same longevity.
So here an example of alpigenetic factor, the rate of
tilam shortening, which is more important than genetics to explain longevity.

(06:35):
So what would you do if you have short tillamers?
How can we use this information to develop treatments for
disease is associated with aging? First of all, we did
a proof of concept to see whether by activating telomerase
we could delay aging. And this is not a trigenic mouse.
In this case, we use gene therapy. We use the

(06:56):
necessiated viruses to deliver telomerase into adult miles and to
see whether this was sufficient to delay aging. We thought
was in any deligious effects in miles and this was
published already many years ago, but we show for the
first time that a therapeutic treatment, in this case telemerating therapy,
would delay many different conditions of aging. In fact, there

(07:19):
was no deligious effects because the mice actually longer both
when we treated with telomerites. The one year of age
or two years of age cancer which is something that
of course work. It has because cancer cells have the
ability to maintain telomeres, and this is because they activate telemeris.
Apparently was also delayed and the explanation for this is

(07:39):
that the show tilomeris lead to chromosomal instability, which is
also the origin of cancer. So it's clear that this
telemeriting therapy could be a promise for the treatment of
different the generative diseases of aging, and throughout this year.
These years my lab has been focusing in generating mouse
models for these diseases and demonstrating the therapeutic value dis

(08:00):
tellamrizine therapy. So we show that in in part mouse
model we show a hebetic effect of the telemerigine therapy.
Then we have been focuses also in the so called
tilame syndromes, which are diseases associated to very very short tilomers,
and we show that this tellamazing therapy had a theaopetic
value in a plastic anemia, which is one of these

(08:21):
tilama syndromes. And more recently and we'll be telling you
about that, mainly we have been focusing in pull maary fibrosis,
which is one of the most prevalent tilame syndromes. Not
only pull manifibrosis can be originated typely by mutations in
telomeras of tilamergines in the familiar cases, but is now
estimated that about fifty percent of the cases of pulmary

(08:43):
fibrosis could be associated to the presence of short tilamers.
So this for us became a paradigmatic disease to prove
the therapeutic potential of this tellamrigine therapy, and we have
been also working in kidney fibrosis and liver fibrosis as
you will see. So the idea is that when there
is damage to when the tilmers are short, this leads

(09:04):
to the lack of ability of the land to regenerate
upon damage because short tillamers regeneration. We have shown that
and many roofs have shown that, and because of this
lack of regeneration, then you have this inflammation fibrosis, and
this is a terminal disease. The treatments that we have
now in the clinic, they do not cure patients, and

(09:26):
we think they do not cure patients because the problem
remains there, which is the presence of short tilomers which
impair the ability of lancense to regenerate. So one of
the quertions we had is which cell type is the
important one, which cell type tilamers matter the most. And
for that we had a collaboration with Astraseneca in the
US and we identified that by generating knockout models in

(09:52):
different cell types in the LAND in which we induce
TILM or dysfunction by removing one of the tilmar binding
proteins or sheltering use telmar damage let's say, in individuals
in different cell types in the LAND, and we saw
that the only cell type, the relevant cell type was
the alveolar type two cells. So this is important for
us to know that we should target telomerase to this

(10:15):
cell type. This is the cell type matters. Let's say
we have been in preclinical models. We have shown that
we target telomerase to this alveolar type of cells in
the LAND. In a mouse model of pumari fibrosis that
we have developed that is a combination of short tilometers
and a damaging agent to the land, we.

Speaker 5 (10:33):
Show that in the mice where.

Speaker 6 (10:35):
We have diagnosed fibrosis and we treat with the empty vector,
the fibrosis progresses. But in the mice that we diagnose
with fibrosis and treat with the telomerase vector, the fibrosisis robation,
is a stop or is reversed. So this is telling
us that there is atabetic value of the telomerat therapy
in this mouse model. If we isolate the alveolar type

(10:56):
of cells that have been treated with telomerase, we can
see that there are decreased inflammation and decreased in repair
pathways and they have active telomerase, indicating that we are
reversing let's say the cellular events associated to short tilomeres.
Of course, we are worried about cancer. I mentioned that before.
We have no evidence that this the lomerating therapy can

(11:17):
lead to more cancer in the longevity startita show you before.
And nevertheless, we wanted to push and see what will
happen in the land if at the same time that
you put the lomerase or before you put the lomerase,
you activate an oncogene, well known on cogene that leads
to land cancer, which is k RUS.

Speaker 5 (11:34):
So we did this safety.

Speaker 6 (11:35):
Experiment seeing whether by forcing cancer in the land, having
or not tlomeris matter and the results were very clear.
Either if we put the lomerise before or after the
oncogene activation, this didn't change the number of mice with tumors,
the size of the tumors, or the agressivity of the tumors,
again indicating on the safety on the telumerating therapy approach.

Speaker 5 (12:00):
That we are using.

Speaker 6 (12:01):
So all these led us to think that this would
have a value in humans and that maybe some cases
of pumari fibrosis in humans could benefit from this telomerating
therapy strategy, and we we funded a company which is
called Tilmers Therapeutics and which is trying to bring this
to the to the clinic hopefully hopefully soon. So I

(12:25):
wanted also to tell you that, however, maybe not all
patients with short tilamers due to mutations in tilamary bindings
may benefit from a telomeous activation. And we will learn
this recently by making studying a mutation that has been
describing in humans recently which leads to pullmlifibrosis. It's not

(12:49):
a mutation in telomera. It's a mutation in a protein
called pot one protections of tilm ie, which is one
of the tilameri binding proteins. There are some mutations in
pot one that lead to cancer and some mutation pot
one that this is the only one that has described
so far that lead to.

Speaker 5 (13:05):
An aging phenotype.

Speaker 6 (13:07):
So we are a basic lab and we wanted to
study what was doing this mutation by generating a mouse
that carries this mutation.

Speaker 5 (13:17):
And when we saw that the mice had.

Speaker 6 (13:19):
Shorter dilometers the same as the humans carrying this mutation
in pot one, and they had more tilmer damage we
saw we then thought, okay, maybe this is the same
as a teloma is snock out. We are going to
generate generations so this POT one mutant and see where
your tilama is short and like in the teloma is snockout.

Speaker 5 (13:39):
And this is what we saw. So it seemed that.

Speaker 6 (13:42):
This mutation were recapitulating a teloma is deficiency. As you
can see here this is the dilomellans, but it also
recapitulates the phenotype.

Speaker 5 (13:52):
So this pot one mutant is identical to.

Speaker 6 (13:55):
A teloma is deficient mutant, and different generations of the
two mice have exactly the same phenotypes in terms of weight,
little size, or pathologies. Is the first mutation that actually
is like not having telomerase And actually we see that
if we combine involve mutations, this is episthetic. So it's

(14:19):
telling us that one is somehow regulate this. But one
mutation is affecting the activity of telomerase, and actually we
cannot correct the short tilam phenotype in this mice if
we over express telomerase.

Speaker 5 (14:32):
So this is telling us that in.

Speaker 6 (14:34):
The case of this particular mutation, I'm not going to
give you the detest the published was the paper.

Speaker 2 (14:40):
Was just published.

Speaker 6 (14:42):
But you have a protein that is able to bind
to the telomeres, that is able to bring telomerase there,
but the lomaris cannot work with these mutations. So this
tells us on the importance of the studying all these
all these human mutations in order to select with patients could.

Speaker 5 (14:59):
Benefit from from the telamerigin therapy. Of course, And I want.

Speaker 6 (15:05):
I think I have If I have five minutes, I
would like to mention what we're in with kinney fibrosis
palmentary fibrosis. As I said, this is a paraigmatic disease
for us because there are these families that had cat
re mutations in celumbris and till our minding proteins that
that developed po many fibrosis. But a much more prevalent
disease is kinney kinney fibrosis, and this disease is increasing

(15:29):
with the demographic aging. So we wondered a few years
ago whether short tilometers were also at the origin of
this other type of fibrosis, right, And for that we
generated a mouse model in which we saw that short
tilomeers were the origin of fibrosis. Because we had normal

(15:50):
mice and we challenge them with something that produces kinney fibrosis.
Nothing happened because we use a lot of those. But
we have a mice with short tillomers and we use
these same loados of the damaging agent, in this case,
folic acid. The mice developed full blonde kiney fibrosis. So
this is telling us that short tillmers are at the

(16:12):
origin or are contributing to the origin or kiney fibrosis
in a mouse model. And this was already published, and
we also found something unexpected. It was also that short
tillomers were contributing to plasticity changes in the cells. In particularly,

(16:32):
we're contributing to what is called episcilial to SMaL transition,
which is a phenomenon that is at the at the
basis of cancer, but is also the basis of some
fibrotic diseases. So this is interesting because it's telling us
that short tillomers per se are able to induce these
plasticity changes from epacilia to camal transition. And this may

(16:55):
explain why short tillomers, on top of leading to commo aberasions,
can also lead to cancer by inducing these epithelial to
missing about transition. So in this case, and just to
finish to tell you that we are also trying to
see which is the which are the relevant cell types
in the kidney where we will have to target the.

Speaker 5 (17:16):
Long raise and I tell you that we have.

Speaker 6 (17:20):
It's recently that the fibroblasts or the perisites are not
relevant because when you induce the themdysfunction there, you don't
induce kinney fibrosis in an acute manner. However, we found
recently that are the epithelial cells again like in the
case of the land the ones that that doesn't matter,

(17:42):
as well as the basal cells in the kidney. So
the epithelial cells paper was just published also, and this
is just to show you that just by inducing themtsfunction
in these compartments, in these epithelial cells, we induce kinney fibrosis.
And the same happens if we induce this in the
basal compartment in this case is a much more severe

(18:05):
phenotype with hydronephrosis, which is a kidney disease and which
this is an interesting model for this kinney disease. But
you can see also that when we induce tilme dysfunction
in basal cells, we have fibrosis in the kidney. So
we think that in general these short films may be
contributing to different types of fibrosis in the organism and

(18:27):
we are for that also interested in the studying, for instance,
liver fibrosis in the lab.

Speaker 5 (18:33):
So I will.

Speaker 6 (18:33):
Finish here with with the group in the Sineio, and
I have to mention that the gene therapy was done
in collaboration with the group of Fatima Bosch in the
University at Barcelona and the funding of the group.

Speaker 5 (18:54):
And I will finish here many things tosting.

Speaker 4 (19:06):
Thank you so much, Maria. So we have one last
speaker for this session and it's car Pedro de Machales
who is a chair of a molecular biogerontology at the
University of Birmingham. He's also chief scientific officer at Youth
Biotherapeutics and really a genomics pioneer decoding the complexity of

(19:27):
aging and its translational future.

Speaker 7 (19:30):
So I give it up too.

Speaker 8 (19:32):
Thank you very much, thank.

Speaker 9 (19:33):
Thank you very much, and thank you, thank you, thank you,
and thank you.

Speaker 10 (19:40):
Gratias Jose.

Speaker 9 (19:43):
Plasid Saqi and Madrid and Engles.

Speaker 10 (19:49):
But I will speak in my talk will be in English,
so yeah, so thank you. Let me start with my conflicts.

Speaker 9 (19:54):
As you mentioned, so, I'm also CSO of Youth Biotherapeutics.
I'll briefly mention some of our recent or claracter on
but I'm also an advisor and consultant for a few
other companies and investors, so I have some conflicts of interest.
And as we've heard already, of course we have a
major challenge of this silver tsunami of the aging population,

(20:17):
which which tackling aging.

Speaker 10 (20:20):
Is a priority.

Speaker 9 (20:23):
And I mentioned curing aging here actually because I think
we should be ambitious in what our long term goals
are we should aim to Ultimately, if you work on
Alzheimer's disease, you want to cure Alzheimer's disease. Perhaps that's
not possible now, and therefore you try to improve the
lives of patients for now, but the ultimate goal is
to cure Alzheimer's disease and same for aging. Our ultimate

(20:46):
goal is not just to improve lives, of course we
want to do that, but also to develop interventions that's
slow and eventually stop and reverse aging. I'm not saying
that's going to be possible anytime soon, and I'm saying
that's going to be possible with occurring technologies, but that
is the long term goal. And interesting enough, it raises
a number of ethical issues which I think mood can

(21:07):
already mentioned today, which I think is important for US
scientists to address. And I mean one of my other
heads in the Oxford hero Institute of Ethics, we've been
working on this manuscript on arguing why it is ethical
to intervene in aging to radically extend human longevity, and
that's I think that's a discussion I'm happy to to

(21:28):
have with anyone. I think it's important for US scientists
in the field to have as well. Now so because
as I mentioned in a previous paper, our goal is
to allow people to be as healthy as possible for
as long as possible, even if that long is a very.

Speaker 10 (21:45):
Long time, so tryumph.

Speaker 9 (21:50):
Having said that again, I'm not saying it's going to
be possible anytime soon, and that there's I think a
lot of caveats to this. One of them is that
we still have a poor understanding of the drivers of
human aging.

Speaker 10 (22:02):
We know of a number of hypotheses.

Speaker 9 (22:03):
We've had a great talk from Maria Blasco just now
on tilomeres. We know DNA damage, epigenetics, oxidative damage, mitochon.

Speaker 10 (22:11):
Geus andes and cells and so on.

Speaker 9 (22:13):
So we have a number of processes molecules that change
with age, but we still have a limited evidence empirical
evidence that these are drivers, that there are causes of aging,
and so we still do not understand the process of
aging well enough now, and of course this is.

Speaker 10 (22:33):
A major challenge. Now.

Speaker 9 (22:35):
I would say in this context as well that I
think sometimes we tend to focus a lot on the
lamp posts, and it's important to also be open to
other hypotheses. So one hypothesis I'm interested in, what I
call a software design flaw, is essentially that perhaps aging
is not a result of errors. Perhaps we don't age
because of molecular damage, although certainly contributes to summaging pathologies

(22:57):
like cancer, but it is primarily a product of regulated
gene programs that are regulated during developmental processes. So that's
an alternative hypothesis. I don't have time to go into details,
but the idea, very very briefly is that we have
developmentally programmed, genetically encloded changes.

Speaker 10 (23:17):
That start early in life and are optimized.

Speaker 9 (23:20):
Their trajectories are optimized for reproduction, for maturity, and the
hypothesis is that this is as a form of antagonistic potropy.
They become detrimental later in life. So for example, the
timers begins to involute when you're about age three, presumably
for some biological evolutionary reason, and discontinues until later in

(23:42):
life and becomes detrimental. So we could be perceived as
a software designed flaws as a detrimental process or beneficial
process early in life.

Speaker 10 (23:51):
They become detrimental later in life. Of seeing aging as
I don't like.

Speaker 9 (23:55):
To work program I like to work programmatic and if
it's actually I can mention caloric restriction if it's very well,
because Clive McKay actually tested caloric restriction under the assumption
that it will slow growth rates, and that the hypothesis
that if you slow growth rates, you can extend lifespan
and slow down aging, which caloric restriction does just like rapamcin,

(24:16):
just like growth rmone idea if you want mutations in mice.
So the major pathways we know the mation methods for
retarding aging in mice, actually all of them fit this
programmatic view of aging. I mean, having said that there's
still many, of course, open questions in the field, I
mean one of the things we did, with a number
of experts, including some of them here today, is create

(24:39):
this list of one hundred open questions in longevity and
aging science to serve as a roadmap to the field.
And perhaps not unexpectedly, many of these focus on understanding
mechanisms of aging, understanding why we age. I still think
it's crucial to then develop better interventions. And because I

(24:59):
think we have this limited understanding of the mechanisms of
aging and the theoretical basis of aging, there is still
no proven way of slow in human aging. And I
think part of the reason is because we don't have
a strong theoretical framework to which base our interventions.

Speaker 7 (25:20):
Evan said that there has been.

Speaker 9 (25:21):
Advances, of course in pre clinker models in animal models.

Speaker 10 (25:25):
We've heard about that today already.

Speaker 9 (25:27):
But I do feel or concerned that perhaps we are
reaching a plateau.

Speaker 10 (25:32):
So Michael again also mentioned the ITP today.

Speaker 9 (25:36):
So what you see here are the effect sizes of
longevity drugs in mice from the ITP study, which is
the benchmark, the most robust.

Speaker 10 (25:47):
And the most actually.

Speaker 9 (25:49):
Very large sample size in terms of testing interventions for
longevity in mice. So you see on topics other slices
span in a bottom is MAXIMALM Lizeman and that's the
effect sizes of the compounds that extend lifespan in the ITP.
I just can see they're not having such big effect sizes.
It's the maximum I think is about sixteen percent in
terms of maximum lifespan, which is a stronger predictor of

(26:12):
effects on aging, and that's from rpromisin which was discovered
I think Michael showed this every center Old Nature is
two thousand and nine if I remember correctly, so sixteen
years ago, and we haven't done better since then. So
we haven't really although we are discovering more longevity drugs,
they're not really pushing the boundaries of how much we
extend longevity in pre clinical models, and and we still

(26:35):
haven't extended lifespan in my more than caloric restriction which
was discovered roughly a century ago. So in a way,
we're not really pushing these boundaries.

Speaker 10 (26:45):
Now.

Speaker 9 (26:46):
Sometimes you can say, okay, well, but maybe my intervention
improves health to some degrees. I'm not a fan of
the health span approach or the handsped framework. I think that,
of course we want to extend lifespan with good health.
We do not want to extend lifespan in a period
of de crapitude. We do not we want to minimize suffering,

(27:08):
we want to minimize disease. But if we are retarding aging,
then there should be a lifespan effect. Ultimately, mortality is one.

Speaker 10 (27:18):
Of the principle.

Speaker 9 (27:21):
Outputs of aging, because aging increases our mortality exponentially once
you reach about age thirty, and that's the same in mice,
only much faster. So if we are retarding aging, it
should have modern health benefits, it should have lifespan benefits.
So I think that's also important to mention now when

(27:41):
you look at them as the current focus of longevity pharmacology,
these are pathways and processes that are quite largely I'm
sure you'll be familiar with it, like oxidative stress and mitochondria, targeting,
senescence cells with analytics and well other therapeutic approaches as well,
and mediators of.

Speaker 10 (28:00):
Caloric restrictions like m TOWR and other plus.

Speaker 9 (28:03):
So these are the current focus of the main companies
or the companies in space which it is relatively narrow.

Speaker 10 (28:11):
I think there is.

Speaker 9 (28:12):
A problem that I'm concerned about is that I think
we need to be more creative in longevity biotech. We
need to have a more diverse set of approaches. Again,
most companies and most that are working under the lamp
posts instead of branching out and being more ambitious and bolder,
which I think we can be as a field if

(28:33):
we want to.

Speaker 10 (28:34):
Now to give one example.

Speaker 9 (28:37):
For which I'm sure you're familiar with, this was from
some months ago, this big biotech company that runs some problems.

Speaker 10 (28:45):
I'm sure you're aware or most of you.

Speaker 9 (28:47):
Should be aware that this was Unity Biotech based in
the US, which focused on developing s analytics, these drugs
that ablates.

Speaker 10 (28:56):
And ESM cells. And this is perhaps not particularly in
the light.

Speaker 9 (29:01):
Of the data of the biology of SINESN cells in aging,
namely the fact that it's now clear that senesse and
cells have normal physiological functions. I mean, we know they've
they work as tumor suppressors and their roles in inflammation,
but it's now clear as well that they play important
roles in development, in.

Speaker 10 (29:21):
Tissue regeneration, in vascular structure.

Speaker 9 (29:24):
There's excellent work, for example from a group in Needs
showing that if you're blade senes and cells it can
disrupt the vasculature in mice and actually shortened lifespan of
the animals, even in beta cells in mice and humans.
So it's not clear that senescen cells are not there.

Speaker 10 (29:45):
They're not like cancer cells that you just want to destroy.

Speaker 9 (29:48):
You cannot just destroy all cines and cells or there
will be detrimental and unfortunately we still cannot discriminate between
harmful senessem cells and physiological import portents and as themselves.
And so again it goes back to the basic biology.
We need to understand the basic biology better in order
to then develop effective interventions. So in terms of, for example,

(30:13):
the work we're doing in our lab, a lot of
what we do is in terms of developing computational systems
biology machine learning methods that tackle the complexity of biology.
So I think one of the problems we have, of course,
is that many things change.

Speaker 10 (30:29):
Many things change with age.

Speaker 9 (30:31):
You know our body, well, our genome is twenty thousand
different protein coding genes. God knows how many known coding genes.
So we have this massive complexity.

Speaker 10 (30:41):
Of biology that we still do not understand.

Speaker 9 (30:44):
But thanks to you O mix approaches and analytical approaches
and data sciences approaches like machine learning and AI, we
can gain insights and try to make sense of the
complexity or tackle the complexity of biology and gain you
insights to identify new drugs or new genes that are
important for aging and longevity. So I mean, I don't

(31:07):
have time to go into We've done a number of methods.

Speaker 10 (31:10):
Developers by show a very quick.

Speaker 9 (31:12):
Example of some of the work we've done in terms
of predicting longevity drugs with a machine learning so you know,
you can look at machine learning as a classification algorim.
So we tend to use what's called supervised machine learning
methods where you have a certain class of could be genes,
could be could be drugs, and then you look at

(31:33):
the particularly that particular characteristics you know, chemical characteristics of
drugs for example, which deans they target, which pathways they target,
and then you use a machine learning method to predict
new drugs with those characteristics, and so we've done this
for worms. We've done recently as well for mice. And
one of the I think success stories is that we've

(31:55):
employed these in silico methods to identify a new gyroprotector,
a new longevity drug called remandine. Now remendin is already
used in the clinic. It's an oral and t and
pretensive drug that it's so said, it's already approved for use,
not in the UK actually, but it is in France
for example. And then we did various experiments in c
elegance which I don't have time to show now, but

(32:18):
it extends a lifespan in both young and old worms
when you fed it a well particular two hundred micromolar dosage.

Speaker 10 (32:25):
So we show it's a new geroprotector.

Speaker 9 (32:27):
We've also done collaboration we've had in Gladyschev in Boston
Conni Huiewald. We also show that in mice we can
it induces when you feed romanity into mice, it induces
gene expression signatures or molecular signatures. There are similar to
other life extending interventions like coloric restriction. We haven't done

(32:48):
lifespan experiments in mice. That's obviously if I what I'm
trying to get funding to do is to do a
full lifespan study. But we can argue that it's a
promising geroprotector and we can repurpose.

Speaker 10 (33:01):
This drug for other clinical uses.

Speaker 9 (33:04):
I'm not showing here, but real menadin is actually an
ortopogy activator in human cells. Data from David Rubinstein in
Cambridge for instance, and others, and data from our lob
in c elegance, so it perhaps could be repurposed for.

Speaker 10 (33:16):
Treating neuroggenety diseases.

Speaker 9 (33:18):
And we're trying to get funding to do a small
experimental medicine approach with romanadin.

Speaker 10 (33:25):
So I think it's a good proof of.

Speaker 9 (33:28):
Concept of how we can use this computational analysis to
identify new longevity drugs that we'd then tested experimentally in
animal models. So in the last few minutes, I'll go
back to some of the work we've been doing with

(33:49):
youth Bio so as I said, I'm CSO of youth Biore.
The company is based in the US, but we then
do collaborations with different loves, including primarily only Alexandro Campo,
one of the pioneers apart actual reprogramming. I mean again
Michael introduced partial reprogramming.

Speaker 10 (34:04):
Our goal is.

Speaker 9 (34:04):
To develop gene therapies that restore useful profiles using OSKM.

Speaker 10 (34:11):
So that's our goal.

Speaker 9 (34:13):
And we've been doing some work on Perkinican models in
particularly well mouse models, as I said, well one hundred
and others.

Speaker 10 (34:19):
And recently.

Speaker 9 (34:22):
And so recently, just a couple of weeks ago, we
had this very positive feedback from the FDA regarding doing
a gene therapy trial for Alzheimer's disease. So this would
involve you might have seen this recent news on Huntington's
disease gene therapy as well. It's a similar procedure which

(34:42):
is essentially a brain surgery where you inject a viral vector,
in our case with OSTM in decades I think with
the DNA silencing vector. But you inject lenty viral vector
into the brain during brain surgery into the hypocampus to
then express we SKM. So so that is that's the idea,

(35:03):
which I think is of course, I mean, I think
again it goes back to what I was saying earlier
that I.

Speaker 10 (35:08):
Think we need to be bolder.

Speaker 9 (35:09):
I mean, there are obviously less risky approaches we can take,
and other companies are doing so. But I think that's
that's the way to go, is to try to be
ambitious and bold, and of course hopefully if this would work,
then it would be transformative for Alzheimer's disease patients. And

(35:30):
so what I've told you is that you know, of
course aging is a major biomedical challenge where all of
that we're well aware of that, and we need to
tackle aging and develop interventions for aging. But it remains
a mystery of biology in the sense that we do
not yet understand.

Speaker 10 (35:48):
Why we age.

Speaker 9 (35:50):
I am aware that we have the hallmarks of aging
that Maria mentioned earlier, but those are not imperially proven.
Some of them there is some evidence, but there's no
conclusive evidence that any of them are drivers of human aging,
and so we need to be open to other ideas.
I mean, perhaps we age because of tilomeres, perhaps we
age because of DNA damage.

Speaker 10 (36:11):
We do not know yet.

Speaker 9 (36:12):
There may be something else that we're missing. And so
in that context, I've told you about this idea of
programmatic aging, the software designed floy hypothesis, which I think
it's been very under explore and underrated, which is something
we're very keen to study. And I think again it's
very important to have a strong theoretical framework and molecular

(36:34):
slash mechanistic understanding of the process is driving aging to
develop better interventions.

Speaker 10 (36:39):
We need to be driven.

Speaker 9 (36:40):
By the science to develop better interventions. I've told you
that we are developing some longevity drugs. Yes I didn't
show you, but the number of longevity drugs we're developing
or we're discovering in preclinical models has been increasing in
recent years, but not very effect sizes, and.

Speaker 10 (36:59):
I think there is a concern.

Speaker 9 (37:00):
So again, I think we need to be more creative
in how we approach the problem of aging if we
want to have major impact, if we want to extend
lifespan more. I've told that some of our work on
in silico computational methods, in particular in application of machine
learning to identify new longevity drugs.

Speaker 10 (37:17):
We've actually have several results on this topic.

Speaker 9 (37:20):
But actually one example is a proof of concept inly
that real menadin is a new geror protector extends lifespan
andc elegance.

Speaker 10 (37:27):
It induces similar changes.

Speaker 9 (37:29):
In minds to for example, caloric restriction and inactivates autopagies.
I think there's a lot of potential for real menedin
for drug repurposing in the context of other age related diseases.

Speaker 10 (37:38):
And lastly, I told.

Speaker 9 (37:39):
You about our work with Youth Bio in terms of
doing a gene therapy trial for Alzheimer's disease, which is
what we're going through fundraising to try to do. Which again, yes,
I think it's ambitious, it's risky, but it's bold and
I think it's what the field needs.

Speaker 10 (37:52):
And so with that, thank you very much.

Speaker 9 (37:54):
I mean, any pre prints and pds will be available
on our law website and feel free to contact me.
I can help in any way. Thank you very much
for your time and attention.

Speaker 3 (38:05):
Thank you so much.

Speaker 4 (38:07):
How yes, please stay, and I'd like to welcome Maria
and Michael up on stage again and hopefully we have
a talkative audience because I'm going to start to see
if the audience have any questions. Initially, does anyone have
any questions?

Speaker 11 (38:21):
Yes?

Speaker 4 (38:22):
Do we have volunteer with a mic helping us otherwise
we have his grim ages going down for every second
he hands over the mic.

Speaker 8 (38:36):
Yeah, the end?

Speaker 3 (38:40):
Oh or refirst?

Speaker 7 (38:42):
All right?

Speaker 12 (38:42):
Since I got the micros wellerful talk to all of you,
and I arrived just in time for the second half
of Michael's talk, so I really enjoyed the session. I
could think of half a dozen questions, but let me
just start with one. For the drugs that you are
now looking at. If you've already shown or that aim

(39:06):
has shown that it has the molecular signature of a sarmometic,
then why are you interested in it since we already
have the alometics that work perfectly well?

Speaker 8 (39:20):
Did anyone.

Speaker 7 (39:24):
Again?

Speaker 4 (39:25):
I think also the sound speaker here is a bit
so or could you just.

Speaker 12 (39:31):
You're looking at a new drug agraill melodine that has
the molecular signatures of thermetic right why? I mean, we
already have the aarmimetics, so what why would you look
at another one?

Speaker 5 (39:44):
Would that be for you?

Speaker 8 (39:46):
Yeah?

Speaker 10 (39:46):
I think I understood the question.

Speaker 9 (39:47):
The question was, we're looking at drugs that induced similar
signatures to crs or crmetics.

Speaker 10 (39:54):
But why are we doing that given that we already
have this cr mimetics, right? Okay? So well, because in
mice there's only a limited amount of.

Speaker 9 (40:04):
Interventions for which we have gene expression data, and so it.

Speaker 10 (40:09):
Was not just CR. I mentioned CR, but actually it's
not limited to CR.

Speaker 9 (40:13):
There were other longevity drugs for which you can derive
gene expression signatures as well. Vadim Kladishev did at work,
and so when you look at will Medadin, for example,
we can see that there is greater than expected by
chance or statistically significant overlap, which is longevity drugs.

Speaker 10 (40:30):
It doesn't mean they work exactly by the same mechanism.
We don't know. I don't think they do.

Speaker 9 (40:37):
Necessarily, but it means that they are inducing longevity signatures
that are similar to other longevity drugs like caloric restriction,
which I think is reassuring if you at least go
into the assumption that there is some overlapping processes across
different longevity drugs.

Speaker 10 (40:53):
Does this answer the question kind of?

Speaker 4 (40:56):
Kind of anyone wants anyone wants to add anything? No, okay,
thank you all, Bree and I knew we had someone there,
and yes, too far.

Speaker 2 (41:10):
Did we have a mic, Yeah, but it's just too far.

Speaker 4 (41:13):
Maybe someone can pass it alone.

Speaker 10 (41:18):
Thank you.

Speaker 13 (41:20):
You were talking about gener therapy on theromedas it has
been tested on mice. Tomorrow, in this event that Paris
is going to talk about she has proven this gene
therapy on herself, and I wanted to know your opinion
on this story. On this event, there are a lot
of people who are talking about pushing the boundaries of science.

Speaker 7 (41:42):
How far can they be pushed.

Speaker 4 (41:45):
Pushing the boundaries on science and how far can they read?

Speaker 6 (41:47):
Generally, here's the question is pushing the boundaries in science.
So I think in science we have to be bold,
as we heard them on the talks this morning, actually,
but I think there there are has to be done
right to the regulatory agencies. And at least in our case,
we believe fully in the tell amazine therapy as a

(42:10):
promising way really to to treat the different diseases of aging,
because we have shown that in the in the mouse models,
and we think talamars are important for aging because if
you shorten them then you age faster. If you elongate
them us you delay aging. So there is a lot
of evidence in clinical models. At least our way to

(42:32):
go would be to through this company called Tilamar Therabeltics,
try to bring this to the to the clinic, try
to bring telemagin.

Speaker 5 (42:40):
Therapy for the treatment of these UH.

Speaker 6 (42:42):
Diseases like bull Mariy fiberses.

Speaker 14 (42:48):
We have none on yes, yes, thank you all for
the stellar presentations. I have a brief question for Michael Ringle.
Thank you for your clarity.

Speaker 7 (42:57):
Michael.

Speaker 14 (42:57):
Do you see mitochondrial client the loss of ATP and
rise in ross as the more fundamental overarching problem that
should be integrated with epigenetic reprogramming to solve the mystery
of aging faster in a twenty eighty way?

Speaker 7 (43:15):
Yes or no? And why I'd value your most critical.

Speaker 8 (43:19):
Reflection mitochondria question.

Speaker 5 (43:23):
Do you hear Michael?

Speaker 8 (43:24):
Did you hear the question?

Speaker 15 (43:26):
I have the tmerity answer the question since it's addressed
to me when one of the authors of the Hallmarks
of agenting is standing behind me. But as Jean Pedro
pointed out, exact causality is still debated. I think for
all the hallmarks, there's evidence that amelioration of them can

(43:48):
ameliorate age related disease, so I would include mitochondria as
well as all the others within that. I do think
the most stringent test of whether something is truly upstream
and causing aging is if I reverse it? Can I
completely reverse age?

Speaker 8 (44:08):
Right?

Speaker 15 (44:08):
So not slow it down? Not amiliated a little bit
can I truly completely rejuvenate and the only thing that
I know of that does that, And it's not in
the context of whole organism yet maybe it will be.
But in the context of individuals cell is this epigenic reset.

(44:31):
So the most strendent test, I think there's only one
hallmark that could pass it with existing data. I do
think it's actually the upstream causes still, you know, with
the range to be proven. But it's at least a
reasonable hypothesis. But that's not to say that action on
all of the other ones can't have value, you know.

Speaker 10 (44:54):
I mean I.

Speaker 15 (44:56):
And some of the downstream things you do around that, right,
exercise and core constract and manage to sleep, all of
which have value. But I think if we're looking for
a true is that we need to deal with the epigina.

Speaker 5 (45:10):
Maria. Would you like to add anything? Would you like
to add anything to that? No?

Speaker 3 (45:14):
No, one more question.

Speaker 4 (45:17):
Yes we have one there.

Speaker 16 (45:21):
Hello, This is a CHRISTO for Michael. In order to
use the rap amicine to block the emptor protein is
a natural molecule of the normal cell. What part do
we need to tell the rap amin in order to
block or to regulate or to modulate the molecule raprimise.

Speaker 15 (45:43):
So I'm not sure I heard it exactly, but basically,
what do we need to address m tour as a target?
In essence, so there are there are medicines already approved.
They're not approved for use as a geror protective, they're
approved for transplant patient and they're originally actually approved for infection.

(46:03):
They need to be tested. I am a big believer
in evidence based medicine. If you're going to prescribe something
for a given indication, whether that be slowing down aging
or whatever it is, you should prove it. You should
need to prove that it's safe and effective and a
regulated trial based approach. And so there has been some
work done in that regard, and I hope there'll be
more work done. There are three agents that have shown

(46:25):
efficacy in the ITP in mice of a ten percent
or greater maximum life ban extension. One of them is
wrapped bison, which works structly on an intour. I think
they should be tested in the humans in a control
clinical trial to ascertain whether they can address features of
age related disease.

Speaker 4 (46:43):
Okay, yes, first of all, let's give it up for
Michael Maria and Kyle, thank you so much for sharing
your knowledge.

Speaker 17 (46:49):
Thank you for back.

Speaker 4 (46:57):
Okay, before the break, we heard about theory and the
visions of longevity, where we are, where we're heading, and
what's possible. Now we're going to turn more into applications,
as in how does basic research really translate into therapies
and interventions with real world impact. And for this session,

(47:18):
we have three really knowledgeable speakers who will talk from
very different perspectives and they'll be talking fifteen to twenty
minutes each.

Speaker 3 (47:26):
Then at the end we'll.

Speaker 4 (47:27):
Have Q and A sessions as we did before. Please
give it up.

Speaker 3 (47:30):
Whose crespos?

Speaker 4 (47:31):
Let's give them a hand round of applause so we
can get some energy in the room.

Speaker 11 (47:41):
Thank you very much.

Speaker 18 (47:42):
I want to be especially thankful for my computational team,
Lucas Samora, than Quintana fer Martinez and also one also here.

Speaker 2 (47:51):
We're going to talk about the project.

Speaker 18 (47:53):
I'm going to make a brief presentation of the First
of all, I would like to make a brief preview
to see if we have a solid line in the
previous part, so maybe we can move forward and you
can see the continue or where we're doing. We are
going to discuss about anti orthogenics, and we're going to
also discuss about a new culture that we are going

(48:14):
to introduce, which is a sub net. We will see
what is that but later on. And finally we are
going to talk about briefly about possibility that we will offer,
which is a membership inside regionalatics.

Speaker 2 (48:27):
I made a PhD in.

Speaker 18 (48:28):
Aery space engineering. But the good point is that we
have some trictory and I would like to know why.

Speaker 2 (48:33):
I think it's solid.

Speaker 18 (48:35):
I'm very honored to say that we make work in
antioregenerative that may they borded on different complexities of different
kinds of antiodogenerative for example antiogenesis, which is different for the.

Speaker 2 (48:49):
Onco antiogenesis, but also.

Speaker 18 (48:51):
Limphoan giogenesis or teiogenesis.

Speaker 10 (48:53):
Or vasculogenesis the novel.

Speaker 18 (48:54):
They are different kinds and different kinds of treatments is different,
whether it is that anti orthogenics ore is, for example,
pulmonary hypertension. But the good point, I'm very honored to
say that someone with more like sixty five thousand Google
scholar citations made work similar, very similar, and I'm very
honored to say that if someone with very high reputation

(49:16):
like him did that and put his name on. That
means that maybe and just maybe we were doing the
things in the proper direction. And then another previous one
that I want to say is that by twenty twenty
sarch copy two there were some findings about the micro
and gieopathy and we could see the twenty two there
was twering connections between the coronary microvascular disease which is

(49:40):
one of the main key problems with the angina pectorist
symptoms in long COVID patients, which is a kind of
chronicle disease after the pandemic, and by that time there
was a main concept about this autonomia.

Speaker 2 (49:53):
But I was very fortunate that.

Speaker 18 (49:55):
In the Cardiovascular Institute of Spain, someone who is for
me is very wise man, both.

Speaker 2 (50:02):
Professionally and intellectually a scanner.

Speaker 18 (50:04):
They said to listen to that and two years later
they found the evidences. I presented to someone who found
some evidences with that and they received the include the
community Madrid. You so with that, so maybe and just
maybe we have an interesting line for the future. Or
what you're going to see right now is that I
founded So that give me the confidence for funding regeneratics,

(50:28):
which means by informatics and regeneration regionative by informatics and.

Speaker 2 (50:32):
That future line.

Speaker 18 (50:33):
We have a mid goal which is anti regenerative and
immunal regenerative, which means the regenerations of blob vessels, but
not one blow that also lympho and immunal regenerations.

Speaker 2 (50:45):
We plan open.

Speaker 18 (50:46):
A hospital by myth seven eight for self reprogramming therapy.
We have any interesting discussions in Dubai but also here
in Spain with different actors, and the long goal, of
course is going to be let's clinical resovenation.

Speaker 2 (51:01):
But you know what I mean. So I think that's
the strategy.

Speaker 18 (51:05):
But maybe I'm just maybe we are not interested in
direct investors.

Speaker 2 (51:09):
I'm going to explain politely why because.

Speaker 18 (51:12):
If the company I am fully compromised with, the company
is a personal project and I want to give the
maximum quality. I have some affections after the pandemics and
I'm one hundred percent sure that I want high quality
outputs of it. So maybe I'm just maybe directing vectors
could expect after multiply by four the value of the

(51:36):
company to make a set of and I maybe I'm
just maybe it's not interesting for the for the long term.
But I do interest in membership program and insights products
that are highly they are highly profitable and could indect
capital to the Regioneratics in the long term. So of

(51:56):
course direct investors are very welcome for the size project
to caming to and well twenty and twenty five, it's
been a great year. We have one gold medal in
mathematics in the computational Team Mathematics of Spain and other
medal in biochemics.

Speaker 2 (52:16):
We have our own know how in antiathroogenics.

Speaker 18 (52:21):
We have check matter protection and three my protection in Spain.
And also we are doing in the US and European Union.

Speaker 2 (52:30):
And we have incipient.

Speaker 18 (52:31):
Collaborations in the US and also in Senna with robotics
labs because we need to escalate the data for many
aspects to integrate machine learning the experimental part. And we
are very honored that in a few minutes we are
going to have the pleasure to talk to someone which
is a doctor Piccardo who is has been and sorry

(52:58):
a post doc of of the Davis in Claire lab
and is a chief scientific officer of Legacy Life and
we will we will discuss it in in a few minutes,
we will have the pleasure of having so conversation with him.
And while antiogeny antiathogenics murders, Well, vascular inflammation is the mayor,

(53:23):
not the mayor.

Speaker 2 (53:23):
But let's see that. Let's say it's one of the
major drivers.

Speaker 3 (53:30):
And we will.

Speaker 18 (53:30):
See that the vasculature also is the fastest in aging.

Speaker 2 (53:36):
And well, there is a kind of not a kind
of there is.

Speaker 18 (53:40):
A feedback between hyper pervision and low grade systemic inflammation.
And of course the vascular events are the physics first
cause of death. Unfortunately, so athlegenics is a kind of
ticket type bond. So I think that's interesting. It's not
me who is saying this. They are very recent journals.
You can see here that in the Vastulow system the

(54:01):
senoproteins basically mid age onwards and triples the seno proteins
with the rest of organs. And there is also a
tool a sense of the vascular system if you have
continuous several infections of Sarkov two, so even if you
feel a symptomatic of sarch kby two.

Speaker 2 (54:22):
The aging clock, vascular aging clock.

Speaker 18 (54:24):
Is saying another thing. And its top journalists who who
say that this is very recent. We were already discussed
in the in the past one year ago specific micro
rnage that involves in crosstalk conversations to reverse the arthogenics.

(54:44):
Of course, with many limitations because this is a very
early discipline, but we think it was interesting and it's
a very complex problem, not only at the patient level
but also cellular protemic and trust tal level.

Speaker 2 (55:02):
There is no magic.

Speaker 18 (55:03):
Pill for this, so cellular crosstalk is important, but also
a new concept that I think is also important, which
is cell net It's a kind of game with the
words with internet, but what is cell net set neet
is actually there is a kind of neural need work
but chemically driven with all cells. It's not just a

(55:27):
cellular cross talk, but it's a huge coordination and this
is very important for example for gastrulation or for example
for mayor vascular morphogenesis, which is the major kind of
There are many kinds of angia or regenerative.

Speaker 2 (55:43):
This is one of them, so very complex processes.

Speaker 18 (55:47):
We will see that a little bit later, but just
to see the complexity of the program considered, and.

Speaker 2 (55:53):
That due in the.

Speaker 18 (55:56):
Eight eight anti inflammatory agents and if you with the
same and inflammatory agents you change the distribution.

Speaker 2 (56:05):
You've chained completely different results for the amerkers.

Speaker 18 (56:08):
This is actually for human medical vascular intertereal cells, which
is very common for experimentation. It's very complex, but it's
a kind of a problem that you have to engage.
Which is the right combination of a safe box, you know,
of a bolt, which is the right combination because there
are a lot of combinations. Well, I think that maybe
Regeneraties is doing a good job in guessing in the

(56:31):
minimal number of iterations, in the minimal number of experiments,
which is the solution that you have, And maybe we
could be useful with this small contribution to other companies
that want to make less experiments.

Speaker 2 (56:44):
To find the goal treatment that they would require.

Speaker 18 (56:46):
So to give a particular, very simplistic scenario of what
I'm doing, consider, for example, these cyto kinds for inflammatory
to drive the set into an initial inflammatory state, and
then we are trying to recover where the initial estate
with different anti inflammatory vector. Of course, we have some
markers to see how the things are going on. The

(57:07):
point is that after the initial inflammation we are able
to analyze the complexity of the problem. And after that
maybe you have to make a preciple component analysis or
another filtered algorithm techniques, but eventually you perform machine learning
and only two iterations you have the two persons only
two percent of the initial inflammation, which is a clinical

(57:30):
zero inflammation. So of course there are many study limitations.
I'm not completely happy with that because we have to
test that into we have to test it, we have
to test it in vivo.

Speaker 2 (57:42):
This is just in Cilico.

Speaker 18 (57:44):
So it's fine, but we need experimental validation always. And
the good point is that we have enough data. We
were able to do a deep learning to predict with
serial iterations the results and in the air level you
have the number of tests, so two hundred tests and

(58:04):
basically the results.

Speaker 2 (58:05):
Overlapped the reality with the production.

Speaker 18 (58:07):
So I think it's been a good job made by
Lucas which is here.

Speaker 2 (58:13):
I'm very happy with my team, by the way, and
it's great.

Speaker 18 (58:17):
But we are very lucky to have here, doctor Picardo.
I don't know if now you can connect with us.
Maybe the technical team can show the image. Let's see
if we have the privilege of having the image there.

Speaker 2 (58:38):
Maybe Oh, thank you be very welcoming. Is right, it's
a pleasure to have you here.

Speaker 18 (58:45):
The Chief Scientific Officer of Legacy Life and also made
a post doc with the Davis Sinclaerk.

Speaker 2 (58:51):
Thank you very much.

Speaker 11 (59:05):
I know you can.

Speaker 2 (59:06):
You can hear him.

Speaker 18 (59:08):
He was in the Harvard Medical School and we are
very lucky because he can't do the experiments that we require.

Speaker 2 (59:14):
We have interesting collaborators.

Speaker 19 (59:16):
I'm gonna introduce myself and the company that I represent,
and I'm happy to support Josse and the Regeneratics team.
So we're very excited about what we can do together.
So I'm gonna basically present the way we're going to
interact on valid day process model and trying to share
my screen with you guys. Probably you can see now,

(59:41):
and I'm gonna go ahead, and I'm so jealous I
could be in Madrid right now share with you an
excellent audience right there. My name is Israel Pitcharlo Casas
and the chief scientific officer for Legacy Life Labs. So
this is a company based in Pittsburgh and aspend in
Colorado in the United States, and we decided to partner
with Regeneratics and the Process team because we are very

(01:00:05):
interested in modeling, not only uh the Secret Tonics which
were very interested in into which is a tool that
we want to use in earth to improve and extend
health tand in people.

Speaker 8 (01:00:20):
And using some of these.

Speaker 19 (01:00:22):
Models that he's developing, we're trying to to find tune
you know where which diseases and which uh inform you
into uninformed decision making how we can make better therapeutics.

Speaker 8 (01:00:36):
You know, starting in the biologics point of view.

Speaker 19 (01:00:39):
I used to do the research that Bavid Simpler lot
Harvard before, and we used to study peptides and now
were interesting the same the same components that are floating
around in the blood and you know, you know, the liquids.
So the the the case study we're trying to push
with a model that what's describing it was, you know,

(01:01:03):
trying to use specific and complex structures.

Speaker 8 (01:01:07):
It could be like therapeutics cells. It could be therapeutics
as biologic.

Speaker 19 (01:01:11):
You know that may contain multiple uh, you know, many
multiple cargoes and the exosomes, which are particles that are
normally released by all the cells, especially the ones that
are very very interesting, the ones that are released by
stem cells. The idea for us is to profile the cargo,

(01:01:32):
which are basically all the proteins, enzymes, RNA and the
metabolids that are contained within these particles in order to
produce data sets that we can fit into the model.
And the idea for us is to you know, create
based on these all mix and systems biology type of

(01:01:52):
platforms to create measurable state vectors you know, that we're
going to fit into into the model. So then we
can identify specific levers or specific components of these particles
based on how the cell that they are going to
be absorbing or being affected by these exostems for instance.

Speaker 8 (01:02:14):
We can use in order to engineer, engineer further.

Speaker 19 (01:02:17):
So in order to do so, we know we have
created like a three phase type of approach in which
the id for us is to start not only characterizing
the particles, but also interrogating you know, how the effect
and specific cell autonomous assets we can identify the effects

(01:02:39):
of these particles and the responses of the cells and
then creating iterative models of proteomics and transcriptomics for the
most part in order to answer what are the changes
in the cell responses. The phase two is actually characterized
by identifying how the cross between different cells that that

(01:03:01):
release a particular flavor of existomes.

Speaker 8 (01:03:04):
You know, can be affecting.

Speaker 19 (01:03:06):
Cells for instance, in terms of the inflammation patterns and
the reversal of such patterns. And then finally the face
three is characterized. How we can validate all these findings
obvious like a loop model in order to inform better
outcomes in vible and particularly in formation inflammation and seriosclerosis

(01:03:28):
as an outcome. So as because well defining you know,
his aggregating sources, normalizing a common schema for you know,
all the contents in the in the cell that they're
you know, being deceased. Then you know, pretty registering some
of the possible valio markers and changes phenotypic changes that

(01:03:53):
are happening that we can predict based on literature and
also with clinical asses and so on.

Speaker 8 (01:04:00):
And then for us.

Speaker 19 (01:04:02):
You know, the way we can compliment you know, his
his models to identify actually these molecular changes in the
film based on how we use our.

Speaker 8 (01:04:13):
Products that we're developing also here in the United States.
So that is, you know, by grounding the athology and.

Speaker 19 (01:04:20):
Producering the antiathogenic target state, for instance, as a disease model,
we will have a much more clear and well defined
objective that we can optimist later. So this is sol
for now for me, but a be happy to continue
and expand this conversation you know, offline, and I hope

(01:04:41):
you know that I say we can, we can continue
this exploration and collaboration for the Thank you very much.

Speaker 2 (01:04:49):
Thank you, thank you.

Speaker 18 (01:04:50):
If I had close to here, it's always it's a
great honor to have you, to hear you. And also
personally it is a great person I can confirm that,
not only professionally but also personally.

Speaker 2 (01:05:07):
Thank you very much, Ryal. So now I'm.

Speaker 18 (01:05:15):
Going to follow with the last part of the of
the slide. Maybe in the team we can okay. So
basically this.

Speaker 2 (01:05:30):
Is something that connects with the last part.

Speaker 18 (01:05:35):
I think it's very interesting because we take into a
coney in our models that something that we knew intuitively,
that is, the cells are able to adapt and to react.
And how is that possible that because very probably there
were a kind of machine learning inside the cell intracellular

(01:05:56):
and those evidences have been recently published.

Speaker 2 (01:05:59):
This is in Stember one month ago.

Speaker 18 (01:06:02):
One month ago, they were able to restore one one
hundred bits of information and do and perform machine learning
with the molecules directly intracellular. So this is machine learning
proteomics driven and it's just been published in Nature and
Nature by Americal Engineering. And this is key because it

(01:06:22):
aligns with our last model.

Speaker 2 (01:06:28):
Sorry again, this.

Speaker 18 (01:06:32):
Is like the zipping with with the television. Maybe something
something happened. I cannot move this light forward.

Speaker 2 (01:06:47):
Okay, okay, thank you.

Speaker 18 (01:06:51):
So actually we really we released about something. I'm going
to make a kind of a spoiler of the next slide.
But we tried to make a huge study because we
were able to control the Protemis and the Trusty Tom
at a cell level, but not to control but smaller
steps of controlling.

Speaker 2 (01:07:09):
Okay, maybe it's more harness to say that, but we
were an epic failed.

Speaker 18 (01:07:15):
Okay, as in say, in the normal convention when we
try to simulate the antiatherogenics process at the mariocardium level,
so intercronary and microvasculature around the interracronary, we failed, and
we wonder why we failed.

Speaker 7 (01:07:35):
And maybe when we.

Speaker 18 (01:07:37):
Attended to the traditional convolution model, that is in the
normal artificial intelligence of I don't know, Alpha fool and
GPT they probably used the normal convolution more.

Speaker 2 (01:07:52):
But maybe they have of course in the as a
industrial secret more things.

Speaker 18 (01:07:58):
But we find out that probably is because there are
not true convolutions in time. The cells make that kind
of artificial intelligence. It's not that dificial, it's by your
I eight and they are able to do that. But
they interact in the real time, So molecules are not
going to flip in each iteration. Numerically, when you have

(01:08:20):
when you do an iteration, the numbers flip.

Speaker 2 (01:08:23):
There is a clitching numbers. But the cells don't do that.

Speaker 18 (01:08:26):
They remember everything and mathematically that's a convolution.

Speaker 2 (01:08:31):
A true convolution needwork.

Speaker 18 (01:08:32):
So we made a new kind of true convolution neural
network that I call it true code because true coin
is Spanish mean trick, so true con and with this
new model were we were finally able to control inflammation
at the cell net, not only cell therapy, but cell

(01:08:54):
net therapy.

Speaker 10 (01:09:05):
Now, okay that was the trick.

Speaker 2 (01:09:12):
Sometimes it worse, but yeah, now I have it. So
the point is that always a bit.

Speaker 18 (01:09:18):
But this is a real play conversation of the cells.
It's a pity because I should have expanded. There is
some ripples, small ripples in the in the waves and
this is a real time talking simulation between many kinds
of cells.

Speaker 11 (01:09:36):
And the first.

Speaker 18 (01:09:39):
The first window is proteomics. The second window is traskitomic
which is slow one minute, okay, and then you have
a stabilization of the signal in partlish and finally the.

Speaker 11 (01:09:53):
Markets and this is the result.

Speaker 18 (01:09:55):
We were able to control the inflammation the grain bread
is but green is not an inflammation. But at least
control the inflammation in the acadium. Well, let me tell
you a very fast membership program. Why it's important because
very probably, at least at the beginning, only billionaires and
only developers are going to be in maybe in the

(01:10:17):
future clinical immortality, but for now certain net reprogramming therapies,
or you are an early bear and you are in
a membership program. Of course I also obect myself to
do a social compensation of that.

Speaker 2 (01:10:30):
This is the curve of the membership.

Speaker 18 (01:10:33):
The prices are low at the beginning because of course
it's like a normal investment.

Speaker 2 (01:10:37):
There are risks and nothing is guaranteed.

Speaker 18 (01:10:40):
But comparing with the prices and million euros it's zero
point is nothing because Christian or Ronaldo and others they
spent like one million euros for monitoring, so this is
I think, this.

Speaker 2 (01:10:51):
Is for life. This is a unique payment.

Speaker 18 (01:10:53):
So of course you can split it in different quotas,
but I think it makes the deal. Yeah, here you
have two example, but there are many people in the
shadow wasting massive amounts of money, so I think that's admissible.

Speaker 2 (01:11:05):
The membership idea to join with us and contact.

Speaker 18 (01:11:10):
If you are an excellent student, please contact to us.
You know the excellency the standard that we ask for.
But contact with us. Also, if you're an intermediate, you
know that you will receive three.

Speaker 2 (01:11:21):
Percent of someone who is interested in that.

Speaker 18 (01:11:24):
And finally, if you have a research group, we are
very interested on that.

Speaker 2 (01:11:29):
Yeah, this is the lastest life. Thank you, so thank
you very much for your attention.

Speaker 18 (01:11:34):
I want respectfully in the three languages and say good
I alsoso, praise and issue gratias.

Speaker 2 (01:11:42):
And which is attest for certain field? Thank you Colesey.

Speaker 4 (01:11:53):
We have our next speaker who is group leader in
Cancer Early Detection at the University of Cambridge and is
exploring senescence and cancer as key aging mechanism.

Speaker 2 (01:12:04):
We saw him briefly.

Speaker 4 (01:12:06):
Before and he's here back now to have his presentation.
Please give it up for Daniel Muno's espin.

Speaker 20 (01:12:14):
Okay, so thank you again to Jose and Maria Cordon
and the rest of the organizers for this opportunity today.
This is a pleasure. My name is Daniel Minnufeespin. I'm
professor at the University of Cambridge. So these are my disclosures.
I'm co founder of Sentences Bio. To them, going to
talk about the role of sen essence in land cancer

(01:12:35):
and agen After that, I'm going to present some novel
therapeutics detection tools that we have developed in my laboratory
and in the last part I will present transfer reprogramming
as an antitomorogenic therapy.

Speaker 10 (01:12:49):
This is something very new.

Speaker 20 (01:12:50):
So first of all, let me please introduce a verson
essence to you. During the course of life, ourselves are
exposed to multiple sources of damage and stress. The accounts
for replicative stress, geny damage, oxidative stress, oncogenical stress. Our
cells are exposed to viruses, bacteria, pollutants, and when these

(01:13:13):
cells cannot repair this damage, they implement the STENESSM program.

Speaker 11 (01:13:19):
So sus an essence is a process of terminal.

Speaker 20 (01:13:22):
Aging and these cells are characterized by the implementation of
a stable cell cyculor rest and appotent pro inflammatory phenotype.
So when these cells accumulating tissues, they can promote a
number of h retid disorders including eurotical disorders, cardiovascular diseases, fibrosis, diabetes.

Speaker 11 (01:13:43):
And also cancer.

Speaker 20 (01:13:45):
And we know by preclinical studies, by a number of
techlinical studies that if we target these cells with cenotherapeutic approaches,
for example snolytics, which are drugs able to kill these cells,
there is an amelioration of all of these pathologies and
even a reversion of these pathologies. So, in collaboration with
Professor Martinez Barbera at UCL, we have developed this mouse

(01:14:08):
bysisting FDR mouse allowing us to track and to trace
peysisting positive cells, which is a main biomarker of senescence,
with AF fluorescent protein and cherry, and also to.

Speaker 11 (01:14:19):
Ubiliate these cells with exteriotoxin.

Speaker 20 (01:14:22):
And we cross this mouse model with a terras driven
line cancer mouse model because we wanted to understand the
role of solar senescence in lane karcinogenesis. What we found
by using this model. What we found is that there
is an accumulation of populations of senes and macrophages at
the very early stages of carcinogenesis. The seness and macrophages

(01:14:45):
regulate multiple factors of immuno superassion and we define biomarkers
at the cell surface of these senes and macrophages. For example,
for our two what we determine with our experiments by
pharmacogenetics approaches, by synolytic approaches, and also by immunotherapy is
that if we ablate these populations of senescent macrophages, then

(01:15:08):
there is a dramatic reduction in the tumor barden in
these lengths of the mice. The most important thing is
that this correlates with an increased survival of this mice.
This is a very long experiment of two years. The
most important part is that even a thirty percent of
this mice, even developing multiple pre cancer solutions, they never
progress to cancer, so this can be a potential This

(01:15:32):
is a proof of concept of a novel strategic therapy
to prevent cancer and to intercept cancer in populations at
high risk of langercinogenesis, for example of heavy smokers and
age people with smoking sposure. This also highlights, in correlation
with the talk this morning from Omninoscope, of the importance

(01:15:53):
of a healthy immune system to tackle disease and also
of the importance of immunos essence as a driver of carcinogenesis.
We valuated these with human samples from patients with cancerus lations.
We observe how these senescent macrophages accumulated in prema lignan tumors,
but not in the advance carcinomas.

Speaker 11 (01:16:15):
So this is a proof of concept that we can use.

Speaker 20 (01:16:17):
This strategy to eliminate these populations of senescent macrophages which
are carcinogenic. One interesting thing is that in naturally H mice,
what we observe in the absence of any oncogenic stress
is that there is an accumulation in the lengths of
the same populations of senescent microphages are regulating the same

(01:16:40):
biomarkers of immunosuppression. And if we go now to H
mice and we induce lung cancer with orthotopic transplantation, what
we have found now is that they accumulate this ciness
microphages which come in the particular old mice. They come
from non classical monocytes from marrow, and these populations of

(01:17:02):
non classical monocytes have an array of biomarkers which are
conserved with factors of bad prognosis of lancarcinogenesis in humans.
So we think these are the bad cells that we
have to target in therapeutic approaches, and we are doing
now this proof of concept. Another thing that we have
found is that if we inflict damage in the lungs

(01:17:23):
in normal mice and also in middle aged mice, middle
aged mice can recapitulate, for example, people fifty years of
What we found is that if we inflict damage in
the lungs, there is a higher tubo progression in the
case of the middle aged mice when compared to the
GWNT counterparts. The conclusion of this is that damage and
aging creates a permissive niche for the onset of cancer

(01:17:46):
and for the progression of cancer cells, and then these
mice have a very reduced survival. The sellular type that
accounts for this phinotype is against an essent populations of
cancer cells and cells of the temo micro environment, including
in macrophages that are able to secret digvita ligance. And
what we found in these studies that if we target

(01:18:07):
the tjvida A signaling with an inhibitor, we can rescue
this phenotype and then we can reduce dramatically the tymor
barden and increase the survival of the mice. And we
have recently published this in nature aging. This has been
accepted in nature aging. Now what we have done is
using more physiological models of land cancer with these terro

(01:18:27):
driven lankarginogenesis in mice with oncogenic care activation, and we
treated the mice with the stereotoxin to reduce the numbers
of senescen cells. So you can see how the senescence
cells in red are reduced, and this correlates with a
dramatic reduction in the tumor barden.

Speaker 11 (01:18:45):
And in the number of cancer cells in the mice.

Speaker 20 (01:18:47):
So the conclusion of this experiment is that senescence is
protomoogenic in the context of h mice and that we
have now to define what are the therapeutic targets of
these cells in order to do a lot more efficient medicines.
So now I'm going just to show a few examples
of drugs and therapeutics develop in my laboratory. As a
proof of concept, we develop nanocarriers drug delivery nano carriers

(01:19:11):
to target senesm.

Speaker 11 (01:19:12):
Cells in this case chemotherapist.

Speaker 20 (01:19:15):
You can see how they can induce senescence in the
blue stain tumor that you can see in the picture.
So when we treat mice bearing subputaneous tumors. With chemotherapies
we can arrest establish the tumors, but only when we
combine chemotherapies with therapeutic nanoparticles to target senescence we can
completely eliminate the tumors. This nanoparticles targeting senescence not only

(01:19:38):
work in the context of cancer, but also in lang fibrosis.
Senescence is a factor that strongly promotes lang fibrosis. You
can see here in this threely rendering of these lengths
these gray areas which are fibrotic areas, and when we
treatd these mice with therapeutic nanoparticles to target senescence, you
can see how the tissue is completely regenerated in the

(01:20:01):
lane and this also recovers the palmonari function of the mice.
We have developed as well a prodrug able to kill
senessm cells that we validated in this model of lancardinogenesis
almost completely reducing the tumor barden in the mice. This
prodrag to targets and essence was also tested by the

(01:20:21):
Left Foundation and they found that this was energistic together
with rapamcing with the activation of the telomerase and the
transplantation of hematopogetic stem cells to increase the lifespan of mice.
We have developed also the textual modalities for the assessment
of servers and essence.

Speaker 11 (01:20:37):
These are nanojags, which is a.

Speaker 20 (01:20:40):
Sensor able to with a photocoustic tomography property to determine
the seness and burden by imaging and this works in
mice in tumors when treated with chemotherapies and undergoing the
accumulation of cells. This is how it works and you
can see in this video how in the right part
there is a.

Speaker 11 (01:20:57):
Tumor which is positive for the accumulation and cells.

Speaker 20 (01:21:01):
We have developed as well another intervention which is non
invasive for detection an assessment of senescence in the urine
and this works in the context of chemotherapy, induce senescence
in cancer and land fibrosis with chlorometric assays and also
with spectroscopy methodologies. And just to finalize, so this is
a summary of my talk. These are the therapeutics we

(01:21:23):
have developed in cancer, in aging and also in lange fibrosis.

Speaker 11 (01:21:26):
This is the company we have co founded.

Speaker 20 (01:21:28):
I want to thank Kennes Code for being an advisor
of the company. We have developed a key and just
to mention in just thirty seconds that we explore transcend reprogramming.
We hypothesize that maybe if we express the Jamaica factors
in cancer cells, this can result in benine tumors on
in increased tumor BARDEN in de mice. But what we

(01:21:50):
found is that by expressing the Jamaica factors in transcend reprogramming,
what we found is that in the left part you
have a normal tumor and in the right part a
tumor work.

Speaker 11 (01:22:00):
The Jamaica factors are.

Speaker 20 (01:22:01):
Expressed in a transient manner and you can see how
this results in apoptosis and in the death of cancer cells.
And this was also confirmed by experiments with a CARES
driven and cancer model. And you consider how the activation
of the Jamaica factors in particular of four and Kala
four results in a reduction of the.

Speaker 11 (01:22:22):
Tumor of arden.

Speaker 20 (01:22:22):
So this is a proof of concept and we want
to move these to early phase clinical trials. So the
conclusion of this study is that the transiit reprogramming in
cancer cells results in apoptosis. So this is an antitomogenic
mechanism that we want to move to early phace clinical trials,
and the taken message of this talk is that now
we're in a position of privilege to implement these henolytic

(01:22:44):
therapies and transientd epigenetic reprogramming for the first time to
ameliorate aging and to promote redugnation and regeneration.

Speaker 11 (01:22:52):
Thank you very.

Speaker 20 (01:22:53):
Much to the people in my laboratory, to all of
our responsors, also particular thanks to these darkly Sands scolar
I'm also I gould be happy to hear from any
investors or any pharmas or groups interested in our research.

Speaker 17 (01:23:06):
Thank you very much, thank you, Thank you very much
Daniel for that.

Speaker 4 (01:23:17):
And as Quose also mentioned earlier this morning, we had
a super centennion here in Spain who became one hundred
and seventeen point five years old, who unfortunately died last year,
but Natalie sequenced her so she probably has a lot
of exciting information on this too.

Speaker 2 (01:23:35):
But enough about that.

Speaker 4 (01:23:37):
Let's give it up for Natalie Coles.

Speaker 21 (01:23:47):
Hello everyone, my name is Natalie Coles, and I will
just give you a brief introduction.

Speaker 3 (01:23:52):
Of myself while they put up my slides.

Speaker 21 (01:23:55):
So I have been doing super centenary and research for
about seventeen years now, and I'm mostly on the clinical
side of the research, so that involves mostly coordinating and
getting the samples to send them.

Speaker 3 (01:24:08):
To other researchers to do what they need to do.

Speaker 21 (01:24:11):
So my talk is titled super Centenarians and Further Advancements,
and specifically this talk is about the case and life
and findings of Maria Bronas. So this is a picture
of Maria Bronas the day that I actually took the sample,
so you can kind of get an idea of what
kind of shape.

Speaker 3 (01:24:31):
She was in for someone who was one hundred and sixteen.
And as you can see, she's doing fairly well.

Speaker 21 (01:24:37):
I mean she also looks younger, she acts younger or
acted younger, and was very aware. And where she was
at the time when we visited her was in a
lot Corona, Spain, and this was on May seventeenth of
twenty twenty three. So who was Maria Brons and why

(01:24:58):
did we want to study her?

Speaker 3 (01:25:00):
And the answer is at the time.

Speaker 21 (01:25:03):
Maria Brynas became the world's oldest verified living person on
January seventeenth, twenty twenty three, following the death of the
previous title holder, Lucillo Randon. She held the title until
her death till August nineteenth of twenty twenty four, and
Maria Brynas lived to her advanced age, and what made

(01:25:25):
her so interesting was not only did she live longer,
but in order to do that, she bypassed cancer, dementia,
cardiovascular disease and demonstrating a separation between extreme longevity and
the typical health decline associated with aging. And she became
an example of healthy aging to the world while she kept.

Speaker 3 (01:25:47):
The title of the world's oldest person. So this is
the team.

Speaker 21 (01:25:52):
So, as many of you may or may not know,
we often get a lot of false claims.

Speaker 3 (01:25:57):
So in order for me to be able.

Speaker 21 (01:25:59):
To conduct this research, we need for the super centenarian.

Speaker 3 (01:26:03):
To be validated.

Speaker 21 (01:26:05):
So this was a very special team because the person
who validated her at the time was currently the validator
for the Guinness Book of World Records and his name
was Robert Young. And then we had doctor Manelis Steller
who conducted pretty much all the research on this particular case,
and he is actually based here in Spain. He is

(01:26:28):
director of the Cancer Epigenetics and Biology program at Belvige
Biomedical Research Institute.

Speaker 3 (01:26:35):
He's also a professor and a.

Speaker 21 (01:26:36):
Physician and then I myself was able to get them
the blood sample which they use for most of the analysis.
And my title currently is Director of super Centenarian Research
at LV Foundation. I have also previous and the Gerontology
Research Group, and I have previously published with UCLA Stanford

(01:26:59):
Plos one, and now with this particular case with Cell
Reports and Medicine. So what samples were obtained from Maria Bronas.

Speaker 3 (01:27:10):
Next slide please, So what we were able to obtain.

Speaker 21 (01:27:17):
From Maria Bronas was actually very significant.

Speaker 3 (01:27:21):
It was more sampling than we have.

Speaker 21 (01:27:23):
Ever conducted or that I have ever conducted in the
past on any other super centenarian. So this is why
this is not just a very special case, but it's
also historic.

Speaker 3 (01:27:36):
So we collected a total of peripheral blood.

Speaker 21 (01:27:39):
Saliva, urine, and stool at different times. Most of the
analysis from this publication were performed on the blood material
obtained at the time of her being one hundred and
sixteen years and.

Speaker 3 (01:27:54):
Seventy four days.

Speaker 21 (01:27:56):
So what did we find that contributed to her longevity?

Speaker 3 (01:28:01):
So during the blood.

Speaker 21 (01:28:02):
Analysis, one of the things that we found was that
she possessed uncommon genetic variants and this this is related
to a strong heart, brain, and immune system function. She
also last lacked most genetic risk factors that are common

(01:28:25):
in age related diseases such as Alzheimer's and cancer. This
is a really big deal because we see that most
people who get these illnesses get them as early as
seventy or eighty, So for her to be one hundred
and sixteen and never had cancer or Alzheimer's, it's a
big deal. And the most noticeable findings pertain to her telomeres,

(01:28:50):
her B and T cells, and the structural chromosomal variants.
So the B cells are important because if you notice
this chart right here, you'll see that Maria's Maria Bronas.
What represents the B cells here is that really large
chunk of red okay off to the left.

Speaker 3 (01:29:12):
There, And so B cells are age associated.

Speaker 21 (01:29:17):
B cells normally increased with age, and these were very
abundant in Bronus's blood.

Speaker 3 (01:29:23):
That makes sense because of her being as old as
she was.

Speaker 21 (01:29:28):
But what I will say is I don't think that
we feel that we know enough about this, because there
is there are some hypotheses that think that anything.

Speaker 3 (01:29:37):
That is above normal.

Speaker 21 (01:29:41):
Might be something that theoretically could have some benefit to
it considering that they live so long. So I think
that when it comes to these B cells, we need
to study them a bit more to know that how
that might have been useful or extremely more significant than
just what we already know with Maria Bronas. But in summary,

(01:30:02):
while some of her B cells showed the typical signs
of aging expected and super centenary, and other aspects of
her immune profile, including the presence of a big amount
of T cells, was also very important because those are
important for fighting and fighting off infection and just recognizing

(01:30:23):
them quickly.

Speaker 3 (01:30:27):
So here we see that.

Speaker 21 (01:30:31):
Sorry, the combination of expanded cytotoxic T cells and robust
mitochondria function pointed to exceptionally resilient immune systems.

Speaker 3 (01:30:46):
Which protected her from age.

Speaker 21 (01:30:48):
Related diseases and other factors.

Speaker 3 (01:30:54):
She also had structural.

Speaker 21 (01:30:55):
Variance and that was also very significant. I won't get
too much into the technical aspects of that because that's
all in the publication.

Speaker 3 (01:31:05):
And I didn't memorize that.

Speaker 21 (01:31:07):
But that's important because what it is is basically that
it is protective. We see a lot of DNA damage
and this can cause more differences in the way that
the sequence is structured, and by having these particular variants
and protective mechanisms. It it protected the structure of the DNA.

(01:31:34):
So with the microbiome, they were also able to find
a lot of different things about that, which is that
she basically had a very youthful microbiome and her gut
microbiome diversity and balance were similar to those of a
young child and not normally associated with an elderly person.

(01:31:56):
She also had it also reduced inflammation. And another thing
that was significant about Maria Bronyas was that she also
adhered to a Mediterranean.

Speaker 3 (01:32:10):
Diet, so lots of fruit, lots of vegetables.

Speaker 21 (01:32:14):
Many of you have might might have seen in the
newspaper that she was also known.

Speaker 3 (01:32:19):
To eat three yogurts a day.

Speaker 21 (01:32:22):
And with no sugar, and this contributed to having a
high rate of positive bacteria that was much higher than
people her her age or younger, and so this also
contributed to having a very resilient immune system. We also

(01:32:42):
did your analysis and her urine and other sample showed
retain hypermethylation of repetitive genetic elements that typically lose methylation
with age. So this is a protective mechanism and she
showed more of this than what we normally see in
regular patients, which may have contributed to her genomic stability

(01:33:05):
and the protection against disease. Another really interesting thing that
we were able to gather from Maria Bronas that previously
we really had no knowledge about and we still don't
know enough, was that.

Speaker 3 (01:33:24):
Not only she was exposed to to pandemics, so not
just the Spanish.

Speaker 21 (01:33:28):
Flu as a child, but she also was exposed to
COVID nineteen when she was one hundred and thirteen. And
what was really interesting about Maria Bronyas is that not
only did she survive COVID, but she actually was asymptomatic.
So there were a lot of people that we saw

(01:33:48):
youthful that were passing away and Maria Bronyus got it
at one hundred and thirteen and asymptomatic, was totally fine,
did not get hospitalized, and overcame it very easily. So unfortunately, we,
like I said, we don't have enough data, but we
suspect that this plays a huge part in her longevity

(01:34:09):
because as you now start to put together the pieces
of the findings, we see that everything is conducive to
that kind of outcome. We see that she had an
exceptionally large amount of T cells, which is kind of
the soldiers of the immune system who are able to
recognize and attack quickly, and that she had an abundance

(01:34:30):
of We also see that she had a large amount
of B cells, and even though those accumulate with age,
you're so part of the immune system. So this was
very very important, and not only was it important to
the researchers, it became extremely important to the Spanish government.

Speaker 3 (01:34:50):
Here in Spain. Maria brought a lot of attention to.

Speaker 21 (01:34:55):
The fact that the elderly were a very vulnerable population
and that they were not being protected enough, and she
actually became an advocate for the elderly and participated in
kind of an advertisement and helping promote vaccines for the

(01:35:17):
elderly and in nursing homes. So one thing we also noticed,
and what was she said to have among traits of
her personality, was that she was a very generous person.
She was kind, she was smiling all the time, and
she was very grateful for her title of world's oldest person.

Speaker 3 (01:35:39):
And one of the things.

Speaker 21 (01:35:40):
That she also attributed to her longevity was the philosophy
for a long life included an orderly lifestyle, a balanced
diet and staying away from toxic people. And so I
think it's something to sort of take into consideration. If
many of you you hear in the audience want to

(01:36:01):
live to be a super centenarian.

Speaker 3 (01:36:04):
We believe a lot of that is genetic, but there are.

Speaker 21 (01:36:07):
Things that you can do to not only honor Maria Bronas,
but also honor yourself and find ways to mitigate things
that contribute to accelerated aging, so diet, lifestyle and just
making sure to just be happy and stay away from

(01:36:30):
toxic people. So that's pretty much the majority of my talk,
and from what I understand, we're running a bit late,
so I can answer questions at the coffee break.

Speaker 3 (01:36:42):
But if any of.

Speaker 21 (01:36:43):
You would like to know more or get into the
real details of the science on the technical aspects, you
can find the actual publication with like I said, the
detail the technical aspects of the findings.

Speaker 3 (01:36:57):
In cell reports.

Speaker 21 (01:36:59):
And also if any of you would like to contact
me for collaborations or just to know more, or if
anyone is interested in getting involved, we do need and
we're looking for people who are interested in assisting with
validation here in Spain, just because it's an area where
we don't have enough researchers, and we would definitely like

(01:37:22):
to give credit to all super centenarians if they're able
to get validated.

Speaker 3 (01:37:27):
And that's all. Thank you for listening.

Speaker 4 (01:37:37):
Thank you very thank you very much, Natalie, and thank
you also to Jose and Daniel.

Speaker 22 (01:37:44):
We have a fantastic session about Madrid and why Madrid
is the mouslone Jebal's city in the European Union and
Spain the mouslon Jebel's country in the European Union. And
for that we have our ceremony all the way from Sweden,
but she was in Switzerland and now she goes to Dubai,

(01:38:06):
sabb fontan per se.

Speaker 2 (01:38:10):
Thank you, thank you.

Speaker 3 (01:38:14):
Great to see.

Speaker 17 (01:38:15):
That many of you are back.

Speaker 3 (01:38:16):
I hope you're energized.

Speaker 4 (01:38:17):
We have a really interesting I mean, I would say afternoon.

Speaker 3 (01:38:21):
But early evening ahead of us.

Speaker 4 (01:38:23):
And this next session is like we say mentioned, it's
about Spain and Madrid and why or also congratulations too
that it has the highest life expectancy in Europe according
to certain studies. Now I just want to mention iconic
author Hemingway once called Madrid the most Spanish cities of

(01:38:47):
all cities, swooing over its people, over its climate, and
over its refusal to sleep. So one wonders could these
be the key ingredients? No sleeping, lots of tapas, lots
of early mornings, csts fiestas to why the Spanish people

(01:39:08):
are said to be the most long lived. Well, we
have three experts who will dive into maybe not that
specific topic, but topics around what makes Spain and Madrid
so vibrant and youthful. And first up we have Lars Hertenstein,
who is from a partner at McKinzie and Company, and
they have released a research that is healthy Cities, Healthy Growth,

(01:39:31):
Spain's opportunity to shape the future of the longevity agenda.
So let's hear more about this and I hand the
word over to Lars.

Speaker 7 (01:39:41):
Give it up for Lars, Yeah, thank you very much.

Speaker 23 (01:39:50):
The McKinsey Health Institute is an independent institute within McKinsey
that looks at underinvested areas of health and one of
those is healthy longef I'm going to talk about this.
It is now to begin with talking about the healthy
longevity in Spain and Madrid and asking a German living
in Paris, I feel slightly miscast given that the healthy

(01:40:13):
longevity here is higher than any of the places I
come from. So I'm not sure what I can exactly
teach you here, but anyway I've been asked to do that,
I tried to speak to the subject nevertheless, so I'm
going to do three things. I'm going to talk briefly
about healthy longevity in a way that is overall understandable,
and to combine some different angles. And then about Madrid

(01:40:34):
in Spain in particular where the status is there right
now in terps of healthy longevity. And lastly what one
might do going forward. Overall, I have a background in
medicine as well as many years ago in economics and
political science, so don't be surprised that I'm going across
different disciplines a little bit as I'm speaking about this.

Speaker 7 (01:40:55):
So just some basics.

Speaker 23 (01:40:57):
There's a great success story in terms of life expectancy
if we take it from the global level, right, So
there's a twenty year increase in the nineteen sixties. However,
we are paying an incredibly high price for this. For
every additional year of life, we are spending six months
in less than great health.

Speaker 7 (01:41:16):
That's a terrible price to pay.

Speaker 23 (01:41:18):
On some level so imagine that every additional year we
are spending was actually a year in good health. That's
what this is about and what I'd like to explore
with you today. So one can say what we want
to do is that we want to square the life curve.
So the normal course of life is that we have

(01:41:39):
a rebolutely long period of decline where you know, some
have restricted brain function, You may not be able to
remember your children, people may be in continent, back pain,
all sorts of things that make life less interesting, less worthwhile.
But the ideas can we live as long as pass

(01:42:00):
before in good health? And our as making the Health Institute,
our claim is that yes, it's possible, we can add
forty five billion years of higher quality life globally. That's
six years per person just by knowing what we already
know how to do. So just to connect a little
bit some of the different talks we have been seeing

(01:42:21):
here during the conference, right there three different angles on
healthy longevity. First of all, there's the celluar level, the
hallmarks of aging we've heard about today, where the intervention
in the end is about are we having their puttings?
Are we having new drugs at some point on the horizon, right, that.

Speaker 7 (01:42:40):
Still is a research question. Mostly. Then there's the individual level.

Speaker 23 (01:42:44):
The initial consists of thirty to forty trillion cells, and
that has to do a lot with what we do
every day, what we put in our bodies, what we
expose to in life. Yeah, how we move. Also of
course healthcare, even though it's one of many parts. And
also what's an overall state of being? And then I'm
going to get to that when you talk about the
city is a population level right on a community level, on.

Speaker 7 (01:43:08):
A city level.

Speaker 23 (01:43:09):
But just I think these three frames are important to
kind of also organize all the different things that we're
hearing really talk about healthy longevity. So this just as
a reminder, we've further and I'm not going to be
labeled this too much, but there is from a science perspective,
a tremendous increase in the research on these hallmarks on
the biomedical perspective on aging over the last ten years.

(01:43:32):
So now let's talk about Spain. So Spain is doing
terrifically well. If you look at healthy longevity. Now, if
you only look at the slide quickly, you say seventy
plus one years, you think that's not too much, But
that's a healthy life expectancy. That's how many years you
can expect in good health, right and there. If you
take a global level, Spain is doing very very well

(01:43:54):
in the European Union leading and seventy one plus one years.

Speaker 7 (01:43:59):
That's really good.

Speaker 23 (01:44:01):
Eighty six percent of the overall life expecting from eighty
two point seven years.

Speaker 7 (01:44:04):
Is a bit more now.

Speaker 23 (01:44:05):
Because those are globally comparable data from twenty twenty one.
So if you now look at cities their Madrid holds
a very privileged position. So therefore I think you need
to teach me something those of you that are living here,
many of you what to do about this. But Madrid
is essentially leading on healthy longevity globally. I think one

(01:44:28):
way to look at this rare than going in a
deep in a deep causal analysis. It's a little bit
more like like Las Meninas by Velasquez in Raprado, which
is an accomplishment of a huge cultural achievement. If you
want in the same way, the healthy longevity doesn't have
like individual causes, hasn't happened by designs. Meninas is basically

(01:44:52):
depicting the accomplishment of decades and centuries of court life
in a painting, and so the healthy longevity results is
a cultural achievement where many things, diet, Mediterranean diet, ways
of life, come to small portions, come together and produce that.

Speaker 7 (01:45:09):
It hasn't happened by design, it has emerged by and large.

Speaker 23 (01:45:13):
Of course there are also initiatives and so forth, but
that will be my perspective on that.

Speaker 7 (01:45:19):
But it's a very fortunate starting position.

Speaker 23 (01:45:22):
So now, investing more in healthy shongevity has enormously high returns.
And the analysis that we are showing here that we
did globally and we are showing some of the Spanish
numbers is basically only predicated on intervention that we already
know how to do today and so we can add

(01:45:42):
by only doing that for Spain or also the world,
about twenty years of healthy days per person a year,
and also has enormous GDPM. Back that one hundred and
eighty four billion US dollars of GDP for Spain alone
is what can be achieved there. And the return on

(01:46:04):
investment from a societal level, even for a city or
for a country.

Speaker 7 (01:46:09):
Like Spain that is doing very well, is very high.

Speaker 23 (01:46:12):
So healthy longevity is a good business for a country
to invest in healthy longevity is a good business for
a country. So and now if we look at where
does that come from, what is a disease burden that
can be addressed with non interventions, Nothing fancy, no, no drugs, nothing,
only things mostly that we already know how to do.
So number one is surprisingly smoking cessation, even though smoking

(01:46:35):
rates have gone down, but it's still such a killer, so.

Speaker 7 (01:46:37):
Very very important.

Speaker 23 (01:46:39):
And then the next one, if you combine a theme
around the next one that is collectively bigger, I would
call it metabolic health. The metabolic health is really an
incredibly important driver of health. So further improvements in metabolic
health that then need otherwise to heart disease, diabetes and
so forth, is very important. But also treating the complications

(01:47:00):
of metabolic health for those that already have complications.

Speaker 7 (01:47:03):
So those are the low hanging fruit.

Speaker 23 (01:47:06):
So to speak, that one can think about, and I'm
happy to talk offline. Also what we also published on
this where the value comes up, that is essentially a
labor or an employee based perspective, where we people live longer,
can work more, and so forth, but without making any
undu assumptions visa via the current legal situation.

Speaker 7 (01:47:25):
So now who of you thinks.

Speaker 23 (01:47:27):
That cities are an important driver of healthy longevity going forward,
I think silly to do some convincing here, so I'll
do it.

Speaker 7 (01:47:36):
Yeah, So cities are incredibly important, arguably.

Speaker 23 (01:47:39):
The most important composite driver of health, because the majority
of the world population is going to live there, and
especially the people that are older than sixty are going
to with majority live in cities going forward and already today.

Speaker 7 (01:47:53):
And it's also where.

Speaker 23 (01:47:54):
Their enormous powerful stakeholders that can change our life, world
employers and so forth. It can influence how we live,
how we eat, how we move, and there's enormous power
therefore in cities to change things for more healthy longevity.

Speaker 7 (01:48:08):
And there's enormous disparity within cities.

Speaker 23 (01:48:11):
So I don't have the numbers for Madrid on this one,
but like there are some cities London or Chicago or so,
where there's within one city there is thirty years of
difference of life expectancy. So the dimensions are different, but
it's more or less like this in every place, and
difference is always an indicator therefore that there's potential to
do better. So now this is the one slide that

(01:48:32):
our team has put together where I'm going slightly the
ara out my expertise, but there's a lot going on
Madrid already and any of you will recognize the initiatives
depicted here.

Speaker 7 (01:48:42):
So there are a lot.

Speaker 23 (01:48:43):
Of institutions that are influential in the space of health
that if one to change things going forward, there is
therefore an infrastructure that can be supportive for healthy longevity.
I don't want to put any words in anybody's mouth,
but that can contribute to any efforts to enhance health
and longevity. And that's why cities have an enormous potential

(01:49:06):
that some other places don't necessarily have.

Speaker 7 (01:49:09):
So what can cities do about this?

Speaker 23 (01:49:11):
So like maybe just first to theory and then some
practice or not theory, but like a little bit of structure.
There are essentially four things that city can do. Number
one is public awareness and health literacy.

Speaker 7 (01:49:23):
That can be role modeling.

Speaker 23 (01:49:24):
This can be campaigning, This can be behavioral interventions.

Speaker 7 (01:49:28):
But that's number one.

Speaker 23 (01:49:30):
Then number two is what I only alluded to before,
is cross sector mobilization. If the big stakeholders in a
city you really are aligned to drive something whatever be
it a change of diet, you shave of stress or
sleeping partners, whatever is identified or smoking or was identified
as a critical driver, and that particular cities can be

(01:49:50):
enormously impactful if I go clockwise. Policies and regulations that's
maybe the most discussed in some ways, sometimes a little
bit more on a country level, but also of course
regulatory aspects that a city can control. Where can you smoke?
It depends on the city by city, where can you
do different things. Then lastly, infrastructure design that obviously takes

(01:50:11):
longer time, but especially with bicycle pathways and so forth,
other things that promote active mobility. There is a very
very dimension also social health and how people come together very.

Speaker 7 (01:50:22):
Important from the infrastructure perspective.

Speaker 23 (01:50:25):
So now let me just end on a couple inspirational
examples or in examples that I find interesting where cities
have come together to really do something different. And one
I think is interesting from Europe here is a little
bit through different world regions in Amsterdam where there was
a decided effort to do something about childhood obesity.

Speaker 7 (01:50:45):
Childhood obesity, I.

Speaker 23 (01:50:46):
Don't need to belabor the point now, but it has
extreme long term perspectives, right, So I think if you
want to do something for your child, the metabolic health
of your child.

Speaker 7 (01:50:54):
That's a very good thing to look at.

Speaker 23 (01:50:55):
And Amsterdam has really had a cross sector mobilization effort
to do something about childhood obesity in school and also
with very good results. Singapore is overall very important example
because they've succeeded to also in the health system go
a little bit more from a treatment to prevention, where
there's strong incentives for preventative treatment, for example, no copay

(01:51:17):
for preventative treatments where there is copay for treatments, and
so really a shift in the priority with the health system.
Very interesting. But to kind of pick something out that's
very city specific. Over a decade now, a physical step
challenge that has by now be amplified to other areas.
That has enormously that has really increased the physical activity
of people and very importantly also gotten people who are

(01:51:40):
not physically active into more physical activity, as opposed to
only harnessing a few people that are already physically active
to kind of participate in some kind of challenge. So
getting people in a different physical activity status at population
level Singapore very nice example.

Speaker 7 (01:51:55):
They've also done other things.

Speaker 23 (01:51:56):
Another inspirational one I think is Abu Dhabi or something
that I personally know something about or from personal experience,
and a place with very poor metabolic health and high obesity, by.

Speaker 7 (01:52:08):
Where the top level of the stakeholders have decided.

Speaker 23 (01:52:11):
To really do something on this in a three sixty
degree way and really looking at all of the different
possible diventions. What kind of food is being serves, how
people being educated, what kind of role modeling do we need,
what are the regulatory measures that we need, what is
happening in schools, what happening in the households, to really
have many, many, many different interventions at the same time

(01:52:33):
to really make a difference on in this case one
area arguably the most important one also for Spain or
for Madrid based on the analysis that we have done,
which is metabolic health.

Speaker 7 (01:52:44):
So let me just close here.

Speaker 23 (01:52:46):
I'm very happy to also have conversations afterwards in the
margins topic that I'm very passionate about.

Speaker 7 (01:52:51):
And maybe last.

Speaker 23 (01:52:52):
Comment is, sometimes one feels those looking in healthy longevity
individually are getting stressed trying to chase healthy longevity. Maybe
a little bit, but sometimes it feels a bit like
you know, chasing for a butterfly or so maybe and
the more you chase it what difficult is to get
So maybe sometimes it's also good to sit down and

(01:53:13):
have a good glass of something. Maybe, and that may
be the right recipe at times. So I think important
not to be too stressed about it on an individual level,
but in a population level, very important priority area to
look at cycle.

Speaker 7 (01:53:27):
With that, I pass on the microphone.

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