RE: Open-minded skepticism (was: RE: Choose how long you live)

From: Rafal Smigrodzki (rms2g@virginia.edu)
Date: Fri Jul 26 2002 - 15:12:19 MDT


Joao Magalhaes wrote:

My approach toward all theories of aging is open-minded skepticism. mtDNA
being at the origin of aging is an interesting hypothesis, although since
nuclear DNA is more central it's more likely to be the key regulatory
aspect of aging.

### I am also open-mindedly skeptical but with a bias towards mtDNA as the
final common pathway of aging in general (whatever the specific causes act
upstream), with the exception of carcinogenesis (due to nuclear damage) and
autoimmunity (I have no idea about its cause). But, this is just an educated
guess, and we'll have to wait a few years for the answer. May our mitos or
whatever, hold out long enough.
-------

>Rafal ( writing this after crunching through about 5 megabases of human
>mtDNA today, and everyday for the last two weeks, planning to sequence a
>grand total of 10,000 megabases over the next year or so)

Really?

### Well, oops. Writing bleary-eyed after a whole day of sequence editing
made me slip up by couple orders of magnitude. I do only 150 kilobase a day,
and plan to have 20 megabase total in my project.

-------

 I normally ask three questions to any theory of aging: 1) How to
explain Werner's syndrome?

### Werner's syndrome is one of many syndromes somewhat resembling aging.
Its cause, a mutation in a helicase, seems to yield support to the idea that
nuclear DNA is the source of at least some aspects of aging beside cancer.
To my knowledge (an OVID) search there is no research on the function of
mitos in Werner's syndrome but I bet you 10$ it will turn out to be
abnormal, too. But see below.

----
 2) How to guarantee the theory -- in this case
mtDNA mutation accumulation -- isn't just an effect of aging, rather than a
cause?
### I assume you are asking whether a phenomenon is actively involved in
causing the loss of function that *is* aging, or if the phenomenon is just
something that accompanies aging. Well, in the case of mtDNA mutations,
there is a mechanistic explanation - the loss of energy-producing
organelles, verified by polarography, confocal imaging, and analysis of
cybrids. That such a loss is causing death of cells by apoptosis and
diminished ability to perform their functions is also quite convincingly
demonstrated.
-------
 3) How to explain differences in the rate of aging between different
animals? Perhaps you can answer me question 3) based on the mitochondria
theory of aging?
### There can be a number of possibilities. MtDNA repair can be more or less
efficient (regulated by both mitochondrial and nuclear genes). The amount of
metabolic strain on mitochondria could vary, with high metabolic demand
accelerating mtDNA loss. The efficiency of the electron transfer chain could
vary, with different amounts of ROS produced. I could imagine some more
mechanisms but I am not well-enough versed in comparative biochemistry to
choose one of them and support it with references.
-----
 Why mice age a lot faster than humans? Have there been any
mtDNA genes mapped in humans that protect our mtDNA? In fact, how different
is mtDNA between different species?
### See here
http://megasun.bch.umontreal.ca/ogmp/projects/other/mt_list.html. There are
406 genomes listed here, and enough variation between them to keep
researchers occupied for years. I do not know about any detailed
explanations of differences in aging rate in terms of mtDNA causes. However,
as I said before, the rate of aging could be under nuclear control, even if
the final common pathway for the aging-associated function loss is indeed
mtDNA dysfunction.
Rafal


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