Current Research Into Telomeres III

Tom Matthews tmatth at netcom.ca
Sat Sep 5 20:16:25 EST 1998


Aubrey de Grey wrote:

> > 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.

My mistake. I thought that except for DNA, *all* other molecules where
*eventually* recycled. If they are not, it seems to me that causing such
should be easier than gene therapy to effect DNA aging changes.

> > 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

Isn't this last one really "derivative" of whatever is causign the
"slower cell division than death"? which in turn would likely have a DNA
cause. 

> [ 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. ]

I understand and agree.

> 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

Just too clarify, I assume you mean that "each" of the derivative
changes are driven by *all* the ultimate ones. ie each of the ultimate
ones is among that causes of any (and every) derivative one.

> -- 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.

Let us hope so, and that we can soon discover and modify those ultimate
aging causes which are currently essential.


--Tom 
Tom Matthews
 
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