Current Research Into Telomeres III

Aubrey de Grey ag24 at mole.bio.cam.ac.uk
Sat Sep 5 08:46:26 EST 1998


Tom Matthews wrote:

> we can (and
> should) divide all of the various theories of aging into those which are
> secondary or "derivative" and those which are primary or "ultimate".

Absolutely.  That's the only way to develop a proper "theory of theories
of aging", in my view.  I think it's cleaner to classify the changes than
the theories, though.  A "theory of aging", in the sense you're using the
term, is basically a statement that a particular age-related change is a
dominant determinant of the rate of most (or all) other changes (and of
itself), so it's equivalent to classify changes rather than theories, but
less open to misinterpretation.

> Furthermore, it appears
> that research is at the stage where there is good evidence that certain
> derivative aging changes are implicated in specific aging pathologies,
> but the evidence for implication of any ulimate aging changes is weaker
> (although there clearly *must* be "ultimate" causes).

Exactly.

> Among those which are derivative would be free radical damage and AGE
> accumulation.

That's not quite safe.  When they affect un-recycled material (such as
extracellular elastin, etc), they're in the "ultimate" category.

> Among those which are ultimate are mtDNA damage/change (in
> non-dividing cells only and DNA damage/change (whether due to telomere
> shortening or otherwise) in both dividing and non-dividing cells (can
> there be anything else which is "ultimate"?).

Yes, plenty.  We must include anything that isn't recycled, whether or
not it formally could be.

> list which of the various aging theories are in which categories

Anything that is not recycled, and is thus increasingly damaged during
life, is potentially an ultimate cause of age-related pathologies.  That includes:

- nuclear DNA of non-dividing cells
- mitochondrial DNA of non-dividing cells (but only because turnover
  of mitochondria in such cells quixotically amplifies damaged mtDNA)
- lipofuscin
- AGE and other (eg oxidative) damage to elastin, crystallin etc (though
  maybe not to most collagen, which appears to be slowly turned over
  -- see eg Rucklidge et al, Biochim Biophys Acta 1992; 1156:57-61)
- nuclear DNA of stem cells (particularly telomere shortening and
  dysdifferentiation from loss of methylation and histone acetylation)
- glands which shrink with age due to slower cell division than death

I don't claim that the above list is exhaustive, but I think it covers
the major categories.  I also don't claim that these are all significant
determinants of the rate of aging -- only that they have the potential
to be (see below).

> and furthermore which primary theory (or theories) the
> various secondary theories are derivative of.  

[ I'll stick with "ultimate" and "derivative" rather than "primary" and
  "secondary", since the latter have connotations of how important the
  process is, as opposed to where it fits in the causal chain. ]

This brings us back to a question that William raised a few weeks ago,
and to the "no cell is an island" point.  There is so much interplay
between different biological processes, including the degenerative ones
that we're discussing, that we can now say with some confidence that
all the derivative changes are driven by all the ultimate ones -- and
moreover, that the ultimate ones are also all accelerated by each other,
largely via the derivative ones.  What we don't know is which one (or
ones) of the ultimate changes injects the greatest impetus into this
causal network, or whether it's the same one for all cell types.  My
guess is that most of the ultimate ones are harmless, because they in
fact inject only an infinitesimal impetus during a normal lifespan,
and that any ultimate change that injects a strong impetus anywhere
injects it everywhere.  That's what I've called "the overinterpretable
pleiotropy of human aging" -- aging may be far simpler than it looks.

Aubrey de Grey



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