Re: mitochondrial aging

From: Robert J. Bradbury (
Date: Wed Oct 17 2001 - 06:01:38 MDT

Rafal wrote:

> The most quickly dividing cells (as in the small bowel, or the
> hematopoietic system) are not most limiting for survival -
> this seems to be most affected by postmitotic cell attrition, in the
> brain, skeletal muscle, and myocardium, as well as problems with the
> nuclear genome (leading to cancer).

I think the tissues with rapidly dividing cells *do* contribute
to some aspects of aging. As an increasing fraction of the cells
shut down due to telomere shortening they would accumulate in the
scenescent state. Presumably they then begin to accumulate waste
products (lipofuscin that is normally diluted out in cells that
divide) and mutations (because you don't go through the DNA repair
cycle that occurs when you replicate the DNA). This does show
up in things like poor nutrient absorption in the gut, a decline
in the immune system and decreasing ability of the skin to
resist injuries or heal.

Postmitotic cell attrition in the brain *will* be a problem but
it probably doesn't become significant until 200+ years. We
will have to develop methods of spuring the neuronal stem
cells to replace those lost and/or inducing greater plasticity
for those remaining.

In the skeletal muscle and myocardium its partially a cell loss
problem (apoptosis, perhaps induced by mitochondrial loss),
partially a neuronal problem (the signals don't propagate
as well to the muscle cells), and partially an accumulation
of waste products (e.g. lipofuscin) that diminish cell function.

We know nuclear mutations occur in dividing cells that lead to cancer.
What we don't have a good handle on is how mutations in non-dividing
cells effect their function. Do they cause the cells to commit
apoptosis? Do they cause dedifferentation of the cell so it
simply doesn't perform its natural function as well? It isn't
clear at this point though work is being done in mice to determine
the mutation rates and types in non-dividing tissues. So we
should have some ideas about this in the not-to-distant future.

There are at least 2 solutions for mitochondrial aging:
(a) to finish the job nature has been doing of moving the mitochondrial
genome into the nucleus where it is better protected (Aubrey has proposed
methods of doing this); (b) to develop a more robust DNA repair system
for the mitochondria (presumably similar to that found in the nucleus).
I think there is a fairly active debate about whether the mitochondria
have no DNA repair system (as used to be thought) or one that is
simply fairly poor.


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