mitochondrial aging

From: Smigrodzki, Rafal (SmigrodzkiR@MSX.UPMC.EDU)
Date: Thu Oct 18 2001 - 10:18:51 MDT

Robert J. Bradbury" <> wrote:

I think the tissues with rapidly dividing cells *do* contribute
to some aspects of aging.

### I agree.
  As an increasing fraction of the cells
shut down due to telomere shortening they would accumulate in the
scenescent state.

### In human skin there is an accumulation of cells with poor ability to
divide but I do not know if this has ever been conclusively shown to be due
to telomere shortening. References?


  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).

### Lipofuscin accumulation can be explained by a diminished ability to
process protein and lipids, secondary to low ATP levels. Mutations actually
accumulate primarily during cell division, despite the repair system.
Quiescent cells are much less prone to mutating, AFAIK.

  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.

### Yes, you are right that these phenomena contribute to aging and death. But is there a proof that they are caused by telomere shortening?


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.

#### Here I have to disagree - the frequency of clinically significant cognitive dysfunction (and reduction of neuron number) at age 85 and above is in some populations as high as 50% (although there are very wide variations in the reported numbers).


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.

### I do not think that lipofuscin is a cause of problems - more likely it is just a side-effect of aging, while the important factors limiting function are, for example, the inability to synthesize and process sufficient amounts of proteins, including stress-response proteins like chaperonins, which leads to accumulation of inactive, denatured proteins and results in reduced concentration of active enzymes. ----

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.

### You are right - we need more data here. But it is quite clear that mtDNA mutations do accumulate in quiescent cells, at a rate dependent on the energy output of the cell. This is due to the constant replication and removal of mtDNA, independently of cell division.


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.

### There was an article published by Dr Turnbull's group on the targeting of oligos to the mitochondrial compartment using covalently bound peptide import sequences. Such oligos could be used to specifically inhibit the replication of defective copies of mtDNA, giving an advantage to the normal ones. This could allow the treatment of conditions with a defined mutation, like MERRF, MELAS, LHON, but unfortunately would be most likely not feasible for aging, where the mutations are multiple and very varied. Maybe we'll just have to upload to eacape this problem.

Rafal Smigrodzki, MD-PhD

This archive was generated by hypermail 2b30 : Sat May 11 2002 - 17:44:14 MDT