From: Robert J. Bradbury (bradbury@aeiveos.com)
Date: Sun Dec 08 2002 - 13:29:53 MST
Hi again Joao,
On Sun, 8 Dec 2002, Joao Magalhaes wrote:
> First of all, thanks for your opinions. I appreciate it. As for your
> thoughts, I don't think our theories are that far apart. Basically, you
> focus on mutations while I prefer more subtle changes in the DNA.
No, clearly not far apart. I could easily accept the Guarante/Sir2
acetylation/deacetylation involvement with a bit more evidence.
Aging is clearly not going to be one single explanation as much as
humans would like to reduce it to that.
> I'm not just talking about mutations that alter the genome. When I refer to
> DNA damage, I'm including telomere shortening, chromatin structure--certain
> 3D-formations alter transcription and allow for cancer, and perhaps, I
> speculate, aging too--, methylation, etc.
Agreed. One has to "imprint" a function on the chromatin. Maintaining
that over 100 years has to be pretty tricky (given that you have to recycle
the proteins). But tortoises and whales seem to show one can do it for
longer than humans do.
> I'm not sure I understand what you're trying to say. Are you suggesting
> that yeast are better tuned than human cells to deal with stress?
I'm not so sure you can compare yeast and human cells (and reach good
conclusions). Yeast cells are designed primarily to divide. Human
cells are designed to divide then for the most part to go into
"maintenance" mode. As much as I like and respect Michael Fossil,
I think he may have done aging research a disservice by focusing
too much attention on dividing cells (and telomeres) in "Reversing
Human Aging".
Dividing yeast cells may be better tuned than dividing human cells
to deal with the stresses that they face (Deinococcus certainly
is -- see other recent ExI discussions). There may be very large
differences in genomes tuned towards "self" survival vs. genomes
tuned towards "organismal" survival.
> I understand cancer is one problem absent from yeast. Yet Drosophila and C.
> elegans, as far as I know, don't have cancer and still age. How do you
> explain them?
I'd put much of "aging" on the shoulders of incomplete genetic programs
in cells that do not replicate. So we are back to dysdifferentation,
mitochondrial aging, lipofuscin accumulation, etc.
Humans may have the luxury of saying "if this cell is pre-cancerous then
lets delete it" hoping that a stem cell of the right type may move in
to replace it. I doubt such programs are active in Drosophila and
C. elegans. The fact that they may not be active indefinately in
humans may be part of aging. (The question being can stem cells always
provide a replacement for a defective/deleted cell.)
The lifespans of Drosophila and C. elegans are so short that the cancer
risk is low. But as one evolves to a larger and longer lived organism
the cancer risk increases significantly. So as the cancer risk increases
so to must the genomic defenses against it. So in the evolution of genomic
programs that are long-lived, one also has to evolve programs that manage
to deal with one cell that can turn against the collective body. It is
a consequence of the larger number of cells and their longer lifetimes
(in which to accumulate mutations) that makes cancer a problem in
larger organisms. You are always up against the wall -- how does one
extend lifespan while at the time reducing cancer?
Robert
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