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Reversing Aging
Rapidly
with Short-Term Calorie Restriction
Continued
from...
L.E.: Might this explain why there is an increased inflammatory
response with aging and why calorie restriction tends to reverse
that?
S.S.: I don't know what that inflammatory response is due
to, it's very intriguing. Is it a physiological inflammation,
or is it inappropriate changes in the regulators of those
inflammatory genes that are not really related to true inflammation?
L.E.: In other words, perhaps the body thinks that there
is an enemy that doesn't really exist.
S.S.: Or is there real inflammation that they're responding
to, and if so, what's the inducer? It's a very interesting
and complex question, and something that's going to be exciting
as more people begin to work on it and try to deduce what's
going on.
L.E.: Well, we certainly know from the proponents of the
glycation hypothesis of aging that macrophages (inflammatory
cells) will attack glycated myelin and so forth because of
the molecular change involved in glycation. There could also
be other, analogous changes that would accumulate simply by
failure of turnover of the proteins involved.
S.S.: We actually made sections and had them examined by
the Pathology Laboratory at UCLA. We didn't see any signs
of increased macrophage activity in the calorie-restricted
livers, or in the old livers versus the younger livers. But
those studies were just preliminary and were just quick looks.
I think there's a lot more work to be done to investigate
that phenomenon.
L.E.: In comparing changes that you have seen and other people
have seen in gene expression from tissue to tissue, can you
draw any conclusions about the nature of aging in general?
S.S.: Well, so far, based on aging in brain and muscle and
liver, a generalization is that aging seems to involve an
increase in inflammatory gene expression and an increase in
what's broadly categorized as stress gene expression. Caloric
restriction seems to reverse most of that. I think that's
our major consistency right now.
L.E.: The stress proteins, meaning certain proteins that
stabilize other proteins against environmental stresses, were
one of the major protein classes that were suggested to rise
with aging in the first Weindruch and Prolla gene profiling
experiment. Much was made of that observation.
S.S.: Well before the Weindruch and Prolla papers came out,
we were publishing papers that showed that these stress proteins,
or "chaperones," go down with caloric restriction.
L.E.: Quite right, and that they go up with aging.
S.S.: Yes. Heat shock proteins are chaperones. Chaperones
respond to stress. You have to understand the purpose of chaperones
to understand why a calorie restriction mediated decrease
in chaperone levels may be extremely important.
Normal proteins have to have a certain shape in order to
work, and stress may cause "unfolding" of proteins so that
they lose their proper shape. Chaperones are required at a
certain level to assist with or correct folding of proteins.
They also go around and rescue proteins that have become improperly
folded and refold them properly. If they can't be refolded,
the chaperones tag them with ubiquitin so they can be degraded
and eliminated from the cell.
When you have a stress, like, for instance, exposure to radiation,
the cells that are damaged have to make a decision. Are they
going to repair themselves and, if they do, has the repair
been successful? Or has the damage been too severe, such that
the cell, when it repairs itself, is still damaged and may
become a cancer cell? Or might the cell secrete destructive
local hormones to the cells around it? In such cases, the
cell needs to make the appropriate decision to commit suicide
and be eliminated from the body and replaced by a healthy
cell.
These kinds of molecular decisions are being made all the
time, not just after a dose of radiation. As part of the normal
process of living, for example, there is damage to our DNA
that has to be repaired, and molecular decisions have to be
made about how to institute and evaluate the repair process.
Chaperones are also involved in the decision about whether
a cell will commit suicide. Chaperones are part of the machinery
for regulating gene expression in some key instances. For
instance, high chaperone levels inhibit apoptosis.
L.E.: Apoptosis being cell suicide or the elimination of
defective cells such as pre-cancerous cells.
S.S.: That's right. Some chaperones bind to some pro-apoptotic
factors and prevent apoptosis, and if you lower the levels
of those chaperones, then you encourage more apoptosis.
So, if you have high chaperone levels with age, that tends
to make cells less apt to commit suicide and more apt to continue
to exist, even when they're severely damaged and may be secreting
harmful cytokines to the tissues around them, or possibly
converting to a cancer cell. So, when calorie restriction
lowers those chaperone levels, it releases some of those factors
slightly more, so the decision is slightly more likely to
be made to commit suicide and kill those damaged cells that
might otherwise survive.
Therefore, calorie restriction is anti-cancer. That's well
established. Calorie restriction is also pro-apoptotic. It
promotes cell suicide of damaged cells and we think the reason
it's pro-apoptotic is because it lowers chaperone levels.
As more and more data are coming out, I think that's becoming
a stronger and better- supported conclusion. So, that's just
one of the surprising things that we found. You might think
that over-expressing chaperones would be a positive, but actually
because of this pro-cancer effect, it can be a negative.
L.E.: I suppose one might imagine it could be positive, say
in a post-mitotic tissue, in which dead cells can't be replaced.
But then again, you have to balance cell loss against the
probability of dying very rapidly from cancer.
S.S.: That's right, and those are the kinds of complex and
critical decisions that cells are making in our bodies all
the time.
L.E.: The inflammatory proteins that you saw going up are
kind of a motley crew are they not? And a lot of inflammatory
proteins that might be most informative about what's going
on, don't seem to be there.
Dr. Spindler identifies
where regulatory proteins bind to a specific gene.
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S.S.: That may be partly a function of which genes were on
the chip and partly a function of the subtleties of how proteins
work together. If the level of one of the components of a
group of proteins changes, whether that has an effect on overall
activity and whether that will influence other specific proteins
may not be obvious. I'll just give you an example. One of
the chaperones, HSP-90, does a lot of things. It binds some
steroid hormone receptors and keeps them out of the nucleus
and inactive. When the hormone that interacts with the receptor
shows up, it disassociates the receptor from the chaperone
and the receptor now becomes active. That same HSP-90 also
binds two pro-apoptosis factors.
L.E.: So there can be multiple effects of a given interaction.
S.S.: Yes. HSP-90 also is only one of a group of proteins
with a relationship to the steroid hormone receptor or with
the pro-apoptotic factors. So, there's a great deal left to
be found out about how all of these specific gene changes
affect physiology.
L.E.: Yes, it's very complicated.
S.S.: I hope the leads that we're getting will attract people
to investigate these kinds of questions.
L.E.: Yes. Basically, you're trying to understand the changes
that take place over time in a system that nobody even understands
to start with.
S.S.: It's an immensely complicated system, but not infinitely
complicated. I'm confident that we'll be able to understand
it. It's just going to take time and work.
L.E.: And in fact you've already identified a lot of pathways
that have implications for the control of disease, so you're
certainly making rapid progress. But progress can sometimes
bring confusion, too. For example, your data and a lot of
other observations indicate that calorie restriction reduces
growth hormone function, thyroid hormone function and cell
proliferation, and yet we need these functions in order to
live. Can you make anything out of that, yet, at this point
in the game?
S.S.: There's more complexity, but the functions that we
need to procreate our species are not always the same as the
functions we need to survive a long time. There are hormonal
systems at work that want to speed us to fertility and fecundity
and ensure that we'll reproduce. There are also imperatives
to ensure that we'll produce offspring that will be aggressive
for men, or that will be nurturing for women. Those are a
different set of priorities than living a long time. In fact,
calorie restricted animals are not very good at procreating,
so it may be that some of these effects that we're seeing
seem to be counter-intuitive because we're not keeping in
mind what it is they're trying to accomplish.
L.E.: There may be important changes where a 50 percent increase
or decrease would really make a major effect. Do you have
any sense as to what's going on at levels of change less than
1.7 fold?
S.S.: That's a difficult question. It's one that, with the
number of animals we have and with the technology we're using,
we don't feel confident talking about. We feel very confident
talking about changes of 1.7 fold and above.
L.E.: It seems that several genes whose expression changed
the most with aging were not affected by either short-term
or long-term calorie restriction.
S.S.: Right, and that's not to say that those changes with
aging are not important, because of course calorie restriction
does not stop aging. It just slows it or reverses it to an
extent.
L.E.: Indeed. Do you have any plans to go beyond calorie
restriction and CR mimetics to attack those aspects of aging
that persist in the face of calorie restriction?
S.S.: Not anytime soon. The question of finding out what
causes calorie restriction to extend life span is challenging
enough for now.
L.E.: Dr. Spindler, thank you very much for your interview.
S.S.: Thank you.
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