I don't think aging is one thing.
I think aging is multiple different things.
And therefore I think it's highly likely that there are
different mechanisms that are driving the evolution of this
phenomena. So actually my own pets favorite
theory for what drives aging is that I'm a big fan of this
entropy model of aging. And basically what this relates
to is this idea that a cell or a system goes from an ordered to a
disordered state. And we believe that one of the
major drivers of this is cell division.
Welcome to EHA on Plot, the official podcast channel of the
European Hematology Association EHA.
I'm your host Isabella Rivera. Today we're joined by Doctor
Michael Nielsen. Dr. Nielsen is a division head
at the German Cancer Research Center and group leader at the
Heidelberg Institute for Stem Cell Technology and Experimental
Medicine in Germany. Doctor Mason is one of the
organizers of EHS Research Conference in 2026, Recon 2026.
And as an appetizer today, we're going to have a discussion about
hematopoiesis and how it changes during aging.
Thank you for being with us today.
Thank. You for having me?
So to start off, what do you mean by the traditional HSC
centric view of hematopoietic aging?
Why do you think everything is centre in HSC?
Well, when we think about how the hematopoietic system changes
and evolves during the process of aging, it's a really
attractive concept that the hematopoietic stem cells, these
cells that we think last throughout your lifetime and
they're essential for the ongoing production of blood
cells and responding to stress when you get depleted of mature
cells that these alterations that would be permanent and
progressive should be enacted at the level of hematopoietic stem
cells. And there are various kind of
conditions where we know that the hematopoietic stem cells,
their functionality is altered often detrimentally during
aging. So it kind of makes sense
logically that these permanent changes would be as a result of
the stem cells getting functionally compromised during
the ageing process. What is the main evidence that
supports this? CSC centric.
So I think that there are many lines of evidence that show that
hematopoietic stem cells lose their functional potency during
the process of ageing both in humans and in experimental model
systems like the mouse. So for example, in humans, if
you think back to criteria where we look to employee in terms of
looking at donors for stem cell transplant, we're typically not
using older donors in that setting because there's a higher
proportion of a graft failure in that setting.
And that's thought to result from this loss of functional
potency of the hematopoietic stem cells.
You can see this really nicely in in the mouse setting as well
and where paradoxically the number of immunophenotypic stem
cells increases with time. However, the number of
functional stem cells declines with time.
There also were the lines of evidence, and I think we'll talk
a little bit later about clonal hematopoiesis, but I think this
is another kind of excellent line of evidence that something
happens at the stem cells level where there's a clonal
contraction in the stem cell pool that now impacts on blood
cell production and the evolution of a wide range of age
associated diseases. So I think there's lots of
evidence that the stem cells alter with aging, but where I
think there's a big gap in knowledge is exactly how that
might impact on a lot of the clinically relevant features of
aging, the predisposed towards disease.
So for example, immune dysfunction, is that really
driven by altered biology of the hematopoietic stem cells or
other cell types, Anemia of aging, is that really driven by
alterations in the stem cells progenitor cell compartment or
something further downstream? And I think that that's
something that's very difficult to address mechanistically, but
I think it's a really important question.
But I think up until now we focused a lot on the
hematopoietic stem cell compartment, so.
You argue that this view is too narrow to focus on HSCS is too
narrow. What are we missing?
If we focus only on HSCS, what else is there?
OK. So I think that before I jump
into why we should look outside HSCS, the hematopoietic stem
cell compartment, it's probably important to kind of take a step
back and think about broadly what is aging and what does that
look like in different individuals.
And often times the way that we study this, we'll kind of use
something like an experimental mouse cohort, young and aged,
and basically look at the things that change on average in those
populations in terms of the composition of the blood, the
bone marrow, the functionality. And clearly one of the the
problems with that is that aging isn't just a kind of a process
where you go from A to B directly.
I think that actually aging is going to multiple different
destinations and potentially also at different rates.
So if you think about humans, not everybody looks the same in
terms of how they elicit age associated phenotypes and not
everybody develops exactly the same kind of malignant or non
malignant age associated hematopoietic pathologies and
people develop those at different time points.
I think historically we've written that off as alterations
in the environment or genetic predisposition.
But I can tell you in our experimental mice that are
inbred or mice look very different in terms of their
hematopoietic composition, old age.
So I think that it's kind of problematic to think of aging as
a single thing, like we, for example, think about acute
myeloid leukemia. In reality, that's a spectrum of
different diseases with different drivers that have
different aggressiveness and I think aging is the same.
Now if we kind of pivot back in a very long winded way back to
the question about hematopoietic stem cells and what we're
missing, I think that if we just focus in on that population, we
probably miss a lot of important information.
So I think it's possible that a lot of the phenotypes that
develop during aging aren't necessarily as a result of the
hematopoietic stem cells being altered.
So if our focus is predominantly on the stem cells, we missed
that and we're looking in the wrong place for a mechanism
that's driving the phenotype. Now I think there are certain
things that are driven predominantly by hematopoietic
stem cell dysfunction. So I think in a range of
different hematologic malignancies, it's quite clear
that the hematopoietic stem cell was likely the cell of origin
that became dysfunctional and then later on evolved into a
full blown leukemia. So I'm kind of proposing a more
holistic view where we maybe take a step back, don't just
focus on one cell compartment. And actually, even if we're
interested in hematopoietic stem cells, try to really assess
whether in the more mature cell types or for example, in the
niche, whether this is the thing that's really driving the
disease phenotype. So the more mature immune cells
show ageing phenotypes and that are independent of age.
Yeah, I think that there are a number of clear examples of
that. So if you think about defects in
the adaptive immune system that evolve during aging, these are a
major cause of a range of age associated predispositions to
developing disease. So if you look at for example,
by people generally have a poor response to viral infection like
we saw during the COVID pandemic or how people respond really
poorly to influenza infection. These are generally elicited
through defects in in T cell production and potentially also
B cell production and functionality.
And I think it's highly likely that the defects there are not
related to hematopoietic stem cells.
I think that also if we think about some age associated
hematologic malignancies that relate more to the lymphoid
branch of hematopoiesis, they're the likely cell of origin
probably isn't a hematopoietic stem cell.
So these are kind of examples of things that have evolved
independent of the hematopoietic system.
So actually we've been carrying out a number of studies in the
laboratory mouse where it's relatively straightforward to
measure multiple different hematopoietic metrics from the
same mouse. So for example, we would
transplant hematopoietic stem cells, but also in the same
individual, look at anemia, look at the level of peripheral blood
cells, look at the, the, the, the gene expression programs,
the different cell types. And the amazing thing to me is
that actually we see huge diversity there, but we see a
very poor correlation between stem cell dysfunction in that
individual as measured by what the stem cell does when we
transplant it into a recipient and the actual heap
hematopoietic phenotypes in the primary animal.
That doesn't seem to be a good correlation which would be
predicted in the literature. And in fact, after we've
transplanted the stem cells and these cells have regenerated
hematopoiesis in the recipient animal, we see a poor
correlation in blood cell parameters between the donor and
the recipient, which you wouldn't predict if the stem
cells were actually driving what was happening in the primary
mouse. Why is is there this difference?
What else is driving aging in this mice?
Yeah, So this is the $1,000,000 question.
What's the mechanistic driver? So again, I'd I'd revert back to
one of my original comments that I don't think aging is one
thing. I think aging is multiple
different things. And therefore I think it's
highly likely that there are different mechanisms that are
driving the evolution of this phenomena.
So we can see alterations in niche, niche composition.
This is also something that we've studied and found a kind
of lack of correlation between this and what's happening in
terms of the blood cell compartmentalization.
And, and actually at the moment, we're really struggling to find
anything that correlates particularly well with the
phenotypes that we're observing in the mice, even when we look
at things that have been previously published in the
literature. So actually my own pets favorite
theory for for what drives aging is that I'm a big fan of this
entropy model of aging. And basically what this relates
to is this idea that a cell or a system goes from an ordered to a
disordered state. And we believe that one of the
major drivers of this is cell division.
So for example, on a very basic level, we know that when you
replicate your genome, it's very challenging to replicate it
perfectly. I think the same thing holds
true, for example, when we try to replicate the epigenome
status of a daughter cell compared to the parent cell.
So you end up with a diversification and the more
cell divisions, the more you differ from the original cell.
So this we think is potentially A mechanism through which
hematopoietic stem cells achieve diversification.
And this diversification can also drive an evolutionary
process. So this kind of creates a system
of clonal competition, outgrowth of clones with, for example,
favorable growth characteristics and then potentially also
disordered functionality afterwards.
So this is attractive to me, but that's extremely difficult to
study because most of our computational analysis methods
tend to focus on what's coherently changing rather than
to what degree do we see diversification.
So your work has shown that inflammatory stress, even early
in life can accelerate HSE ageing.
What can you tell us about this? Yeah.
So we were interested in inflammation and aging for quite
a long period of time. So actually I used to work in
the the field of inherited bone marrow failure, specifically
looking at Franconi anemia. And it was very clear from the
literature that there was this link between inflammation and
bone marrow failure in that setting.
And so this kind of piqued my interest and I was working on
this in the setting of Franconi anemia.
And it really was kind of one of these Eureka moments when I
started working in Heidelberg and saw the work of Andreas
Trump, who showed that these pro inflammatory cytokines can push
stem cells from this long term quiescent or dormant state into
active cell cycle. So now this idea that cell
division is something that drives loss of functionality, it
kind of made sense to me that potentially the inflammation was
making the stem cells divide. And the more inflammation you
would be exposed to, the more those cells would diversify away
from the original cells that you'd got in there.
So in that context, we start to carry out studies.
We had some very elegant mouse models that have been developed
by Andreas Trump and and her and Marika S, as a former postdoc in
his laboratory, is now also a group leader and works in the
next office to me. And these mouse models allowed
you in vivo to pull apart the stem cells that didn't divide so
much with the passage of time. You can even see dormant cells
that barely divide during the lifetime of a mouse.
And actually, interestingly, these cells retain a young
phenotype. And then the stem cells that
have divided more, and now you can expose to inflammation.
And the interesting thing is that even though all these stem
cells are exposed to inflammation, it's the ones that
divide that lose the functional potency.
And the ones that can still stay dormant, they still retain their
functional potency. So importantly, this kind of
brings into question this concept of self renewal, this
idea that a stem cell can make a perfect stem cell door to cell.
And I think one of the take home messages from our work is stem
cells can divide to make more stem cells, but very, very
rarely do those stem cells have the same functional potency as
the parent. So you end up in a situation
where each round of inflammation draws some of the stem cell pool
into cycle, it loses functional potency and it never gets
regained by those cells. So it's irreversible.
And what that means is that now later on week, a month, a year
later, if you have another, another stimulus that draws more
of the stem cell pool into cycle and they lose their functional
potency, you can now have an additive or cumulative depletion
of the stem cell pool. And this to me is a really
attractive mechanism to a kind of explain clonal succession
with aging, but also clonal contraction during aging.
But this is happening in the HSC cells, so it's been driven by
the environment of an inflammation.
How much of this increased vulnerability comes from the?
Yeah. So what I was talking about
there was really with the focus on the hematopoietic stem cell
compartment. So trying to enumerate the
number of hematopoietic stem cells actually in these mice
that we've exposed to multiple rounds of inflammation where
we've depleted the stem cell pool.
Actually, hematopoiesis looks relatively normal in that
setting. And I think that's also what you
would predict based on what we know of how things work in
humans. Yeah, so we do.
We are exposed to multiple rounds of infection, sometimes
pretty severe infection, and we always kind of bounce back to
these levels where we're able to maintain homeostatic production
of blood cells. And interestingly, there are
studies of very old humans, so centenarians who've had the a
massive contraction of their stem cell pool.
Maybe they've got one or two stem cells that are supporting
hematopoiesis, but they're still able to maintain normal levels
of peripheral blood cells. And I think that's kind of an
important concept because although the stem cell pool
contracts, we still have a system that that has evolved in
order to be able to sustain blood production during life.
So these mice generally their blood cell systems look pretty
normal. I think that what's interesting
is when you start to dial in things like these mutations that
you see in in clonal hematopoiesis.
So for example, the group of Grand Chalon and Catherine King
have done very elegant studies looking at DNMT 3, a loss of
function and then driving, adding on top of that bacterial
infection. And you can see this expansion
of the mutant clones in that particular setting.
And in the mice, I don't think that there's a strong phenotype
illustrated at the level that the mature blood cells.
Yeah, and maybe that relates to, you know, missing ingredients in
terms of our mouse models that are important in humans.
So most of the time our mice are kept in specified pathogen free
conditions where they're not readily changed, challenged by
pathogens. Maybe if we depleted the bloods,
the stem cell pool sufficiently, then added on top some kind of
infection, perhaps those mice would have a shorter lifespan or
not be able to respond so much to those challenges.
But yeah, in, in, in that setting, again, we've been very
much focused on the stem cell pool rather than any age
associated phenotypes in terms of mature blood cells.
You mentioned clonal hematopoiesis.
How does inflammation influence the clonal expansion?
Yeah. Again, I think that that's a
really interesting and important question.
I, I think that we're only now starting to delve into that to
some extent. So I mentioned before the work
of people like Grant Challon and Catherine King.
I think there's also been very exciting data recently from the
likes of her Parish Bias and John Dick looking at human
samples, where indeed it does look like exposures to
inflammatory stimuli and maybe infectious stimuli provide a
selection advantage for for example DNMT 3A mutant clones.
So I think it isn't 100% clear why that is the case, but I
think it data does seem to indicate that with each exposure
to inflammation and infection, you program the epigenome
somewhat along the lines of trained immunity where if you
execute a specific transcriptional program over and
over again, there's a residual memory of this in the stem
cells. And I guess the idea is that if
you now go in again with the same kind of stimulus like an
infection that the cells will be able to more rapidly respond or
be able to respond with a a greater magnitude effect that
same stimulus or something similar.
Or perhaps there's a little bit of a cost towards this because
hematopoietic stem cells have to be good all rounders that are
able to produce multiple different cell types and carry
different functions. So maybe if you program them in
a particular direction, then maybe they don't perform so well
as a stem cell. Now if you look at the DNNT 3A
setting, I think what's clear is that now these cells have less
of this priming effect when you give the inflammatory stemics.
So they have less of a epigenetic memory of that
exposure. And it's tempting to speculate
that that might actually facilitate these cells still
maintaining their stem cell attributes.
And maybe being able to be resistant had this inflammatory
challenge. So I think it's a little bit
different the the idea that, for example, a stem cell would get a
pro proliferative mutation and now this mutation would give a
positive selection advantage and allow it to expand more rapidly
than the rest of the stem cell pool.
But rather this idea that there's a constant ongoing
attrition of the stem cell compartment and maybe things
like the DNMT 3A mutations, T mutations might make the cells
more resistant to that. So they're fitter in that
context. So do you think any of these
features can be targeted for delaying or mitigating?
Aging, yeah, potentially. I mean, I think that I'm not a
big fan of this idea of rejuvenation.
I mean, it would be nice, yeah. But I think it's kind of hard to
think about exactly how that would work.
So even if you look in these extreme settings where people
formally demonstrate this. So I'm talking about things like
if you put reprogramming factors into cells that you've taken
from an elderly Organism, or actually if you generate A
transgenic mouse where you can transiently induce the
reprogramming factors. And now you partially reset the
epigenome and the mice by and large look younger and actually
have improved health metrics. So first of all, it it's
obviously very difficult to think about exactly how you're
going to facilitate that in the setting of a human.
But even when we start to think about fundamental mechanisms
that are taking place there, I don't think you're completely
resetting the clock on the changes that occurred during
aging. So obvious example, the somatic
mutations that have been acquired, they're still going to
be there. So I refer back now to the
comment that I made towards the beginning of the podcast where I
was talking about aging probably being multiple different things
and multiple different destinations.
Now if you ask me, do I think you can correct some of these
clinically relevant phenotypes, the answer to that will be yes.
And I think that it's not going to be some kind of panacea for
all aging phenotypes, but maybe in a more targeted fashion we
could think about addressing things like immune dysfunction,
so compromised adaptive immune system.
There are some of these hand hematopoietic rejuvenation
strategies that have been put out there.
So things like dietary restriction would be one of
them. Mtor inhibition, this idea of
depleting myeloid biased aged stem cells.
These are all things that have been put forward.
I think it'll be interesting to see how robustly, robustly those
kind of findings can be recapitulated across broad
different animal models. I think that they're clearly
benefits to things like dietary restriction, but rejuvenation?
I'm not so sure that that's a reality, but I will be very
happy to be proved wrong. Is there anything else that you
would like to add for the audience?
So I think that one of the things that's important if you
want to do research in this area is, is to really kind of take
take notice of the literature that's out there, but really
kind of take a step back and think about broadly, if we're
looking at aging, if we if we kind of think about what we
know, what's obvious about kind of human aging now that people
develop very kind of vastly different phenotypes at
different rates. That's kind of an important
thing, I think. And to purely study aging in the
context of old versus young. But this idea that we'll be able
to identify mechanisms that define what happens to every
individual, that seems kind of unlikely.
Maybe we need to carry out the entire analysis and design our
experiments in in slightly different ways to try and
somehow understand this diversification process.
Because I think if we can try to understand the basic mechanism
that underlies this collapse of the system, then we can actually
do meaningful research to think about whether it is possible to
delay that or reverse some of the features, or whether that
doesn't make any sense at all. And we need to think about
things like cell replacement therapies.
Is the opportunity to keep the system functioning for as long
as we need it to? So if I understand well, there's
this diversity that we knew already.
We know that, you know, during a lifetime very different things
happen, one person compared to another and that causes aging.
But you're saying that there's also this huge diversity in the
internal regular processes in the cells.
So the diversity comes from everywhere in the aging process,
not only from outside of the body, but also from our
biological processes. They're different from one
person to the other. So it's really hard to tackle.
Yeah, process. Although I mean, one of the
things that we often kind of debate within the group is we're
spending a lot of time and effort and trying to
characterize this stochasticity in terms of the diversification
of the function of the hematopoietic system.
And there I think the, the really exciting thing is not
just kind of characterize the level of an entire system, but
be able to dial into individual cells and clonal systems that
occur within the hematopoietic compartment to try to understand
what's happening there. And so, yes, that there is this
kind of really complex pattern of diversification, but the
debate that we have a lot in the laboratory is whether some kind
of extrinsic pressure can actually drive you towards a
more coherent system or whether it will actually, just as you
were saying, make the diversification even broader.
So I think that this is kind of next set of experiments that
we'd like to approach. But yeah, the problem is
studying aging. It takes a long time.
Well, thank you very much for this fascinating conversation.
Thank you for being with us today.
Thank you, I've enjoyed it. Thank you to the audience for
listening. If you enjoyed this episode,
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Stay tuned for more episodes of EHM Blog.