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Flies and worms aren't amenable to stem cell therapy, among other things.
Most senior gerontologists forget this and assume that everything must be
easier in flies and worms than in mice. This makes them reluctant to believe
that reversing aging in mice is foreseeable, since it can't "even" be done in
these simpler organisms. That means they don't support grant applications
to try to develop reversal of aging, and that means such work doesn't get
done. This is one of my more recent attempts to change that.
The following is a slightly (only slightly, I'm afraid) tidied-up
version of something I wrote a few days ago to Tom Johnson, a very
prominent and well-known biogerontologist who discovered the first
life-extending mutation in any animal, the nematode mutation age-1.
That was about 15 years ago, and Tom had an extremely hard time getting
his colleagues to believe his result, even though he was as thoroughly
trained as any geneticist and had obtained very solid data. He hasn't
forgotten this, so his attitude to my rather analogous current battle
to get biogerontology to take seriously the idea of reversing
aging is one of sympathy and support, even though he is very skeptical
of the possibility of such a thing. Because of this he has initiated
a dialogue with me to give me a chance to convince him of my view. I
have found this dialogue very useful in sharpening up my reasoning for
why reversing aging is not only possible but foreseeable.
By way of background, readers should first familiarise themselves (if
they don't know about it already) with the outline of my proposal for
reversing mammalian (eventually human) aging. I have a website about
my work here, and the seven
key components of my approach are summarised
here, with links
to more detailed descriptions. In my letter to Tom, I seek to clarify
exactly why it is appropriate to call these approaches "aging-reversal"
interventions. The conclusion of my reasoning is that reversing aging
in flies or worms is actually really hard, a lot harder than in mice,
largely because (to cut a long story short) flies and worms aren't
amenable to stem cell therapy. Its not just stem cell therapy, either:
there are a few other fundamental components of aging that are probably
no easier (though no harder either) to reverse in these so-called
"simple" animals than in mammals. This is an extremely surprising
conclusion to any mainstream gerontologist, accustomed to thinking of
small invertebrates as much simpler than a mammal and thus much easier
to manipulate -- and, indeed, on the face of it the achievements of
gerontology so far are in opposition to my view, since worm lifespan
has been increased by a factor of six and mouse lifespan only by much
less than a factor of two. I don't yet know what Tom thinks of my
argument, but I will report his reply here in due course.
The importance of all this to non-scientists is that people like Tom
hold the key to the rate of progress in curing aging. While senior
biogerontologists think reversing aging is impossible, however wrong
their reasons for thinking that, they will not support the spending
of significant sums on trying to do it. And because nearly all money
for research is targeted by a system of expert peer review, the lack
of their support is decisive.
Tom asked in his latest communication whether there was any evidence
for a treatment in any species making that individual or population of
individuals 20% younger. He said that this is the sort of definitive
criterion that it would take to convince a skeptical public. Here's
my reply.
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Hi Tom,
I agree absolutely. Here is a clear-cut statement of my position:
1) Health being so hard to measure, the only persuasive measure of
"physiological age" that is available to us today is remaining life
expectancy in the absence of any (hypothetical) future anti-aging
technologies.
2) Thus, an intervention can only properly be described as an "aging
reversal" therapy if its one-off delivery to an organism a fair
way through its natural life expectancy considerably increases
its remaining life expectancy.
3) Even a therapy that meets this criterion can be argued not quite
to be an aging-reversal therapy but instead a really good aging
retardation therapy. Certainly if the remaining lifespan following
the therapy is longer than the total lifespan without the therapy,
we must clearly conclude that retardation has occurred (though
reversal may have occurred too).
4) On the other hand, the idea that the therapy must be one-off,
rather than periodic or continuous, is perhaps over-restrictive:
a modest aging-reversal therapy applied once might give results
than fell short of statistical significance, whereas repeated
therapy would do better.
5) Hence, what I mean by an aging-reversal therapy is one that (a)
substantially increases remaining life expectancy when applied
late-onset, whether once or often, and (b) causes a reduction of
some set of quantifiable parameters that increase progressively
throughout aging and that we have some reason to believe make a
contribution to pathology once they reach sufficient abundance.
This is the central message of my work over the past few years. I
claim that there are only seven major classes of parameter fitting
the above description that are not already known to be entirely the
result of the changes in other such parameters (though in many cases
the pecking order of which parameters affect which others the most
is of course not known). I further claim that fixing (reducing the
abundance of) *all* such parameters will necessarily have the effect
of extending remaining lifespan, simply because the reason why a
40-year-old dies sooner than a 20-year-old is necessarily embodied
in the differences between those two people's physical composition.
[Note, however, that this does not precisely constitute moving the
organism back to an earlier time of life, because it means leaving
the accumulating changes that are *not* eventually pathogenic (such
as distaste for contemporary popular music) alone.] Conversely, a
treatment that reverses some set of promising-looking parameters but
does not greatly increase lifespan is not an aging-reversal therapy,
because the fact that lifespan is not increased means that something
that needs to be reversed (i.e., that does contribute to pathology
eventually) is not being reversed, nor even greatly retarded.
So, that means that I agree 100% with the mainstream biogerontology
consensus that we do not yet have an aging-reversal intervention (by
the above definition) in any animal. However, the shortness of
the list of things we seem to need to fix as components of such an
intervention is encouraging, and the availability of detailed and
entirely feasible strategies for fixing all seven of them is more
encouraging still.
I have a feeling that you think the fact that we can't yet do this
in worms or flies is a reason to presume it'll be many decades till
we can do it in mice. I don't agree, simply because of the nature
of the seven targets. Extracellular crosslinks and intracellular
aggregates probably matter in worms and flies and are no easier to
fix in them than in mice. Ditto mitochondrial mutations (if they
matter at all). Extracellular junk (amyloid) and senescent or
otherwise toxic cells are probably not an issue in flies and worms
so that makes things easier, but on the other hand, since flies and
worms don't get cancer, their nuclear mutation rate may also be a
limiter, and since they're so very postmitotic, stem cell therapy
is impossible. So in fact, worms and flies are probably a good deal
harder to age-reverse than humans!
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