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Current Research Into Telomeres III

Brian Rowley browley at GALAXY.UCR.EDU
Sat Sep 5 12:29:15 EST 1998

At 01:44 PM 9/5/98 GMT, you wrote:
>I may have been unclear.  What I meant was: Starting from the strong
>evidence that CR extends lifespan largely by reducing free radical

There are other, equally viable hypotheses. For example, CR downregulates
insulin-stimulated metabolic pathways by chronically lowering blood glucose.
By antagonizing insulin-related pathways, gene expression of many enzymes is
changed. These big changes in gene expression might explain the longevity
benefit of CR.

Is there evidence that inhibiting the insulin pathway confers longevity?
Well, temperature-sensitive daf-2 mutations double the life span of C.
elegans. Daf-2 encodes a receptor that is homologous to the mammalian
insulin receptor. By knocking out an element in an insulin-related pathway,
you double life span. That's even better than the 50% increase in life span
achieved by CR, and more specific.

Ah, but does inhibition of the insulin pathway simply reduce mitochondrial
metabolism in such a way that fewer damaging free radicals are generated?
Apparently not. Certain temperature-sensitive Age-1 gene mutations double
the life span of C. elegans while *increasing* oxygen consumption and rate
of metabolism. Age-1 is part of the same metabolic chain as daf-2 -- it acts
on daf-2 as its direct precursor in fact. The effect kicks in at maturity,
at which time the worms become hypermetabolic. They continue to be
hypermetabolic for twice the life span of their non-mutant counterpoints! No
reduction in mitochondrial metabolism here. Neither is a reduction in
metabolism observed over the doubled life span of daf-2 mutants. The
consistent link between longevity-enhancing CR and longevity-enhancing
daf-2/ Age-1 mutations may be an inhibition of insulin signaling, not
reduction in metabolism or free radicals. In fact, reduction in metabolism
is entirely optional, as we seen in the case of daf-2 and Age-1 mutations.
All that might be needed is a reduction in the expression of select genes
turned on by insulin. Drugs can affect gene expression... Or, perhaps a
specific, partial antagonist to the insulin receptor can be injected etc.
Mere speculation, but my point is that the free radical explanation is not
the only good explanation for the longevity benefit of CR. Not by half.

Reduced blood glucose also reduces irreversible glycation damage to
crystallin (e.g., Walford and Weindruch paper on spectrophotometric analysis
of changes in eye proteins CR vs. ad lib rodents) and elastin, as you later
point out.

The above is my rendition of readings of recent publications by Stephen R.
Spindler of the University of California, Riverside. Similar information can
be found in his most recent publications, which I highly recommend. Regards,

Brian Rowley

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