Re: AGING: Accumulation of DNA damage

From: Joao Pedro de Magalhaes (joao.magalhaes@fundp.ac.be)
Date: Tue Jun 27 2000 - 11:31:53 MDT


Hi!

Robert Bradbury wrote:
>As I've stated for may years (since my comments in the early
>'90's on sci.life-extension and bionet.molbio.ageing),
>DNA damage accumulation *should* be part of aging.
>I base this entirely on the observation that mutations
>are known to accumulate and in single cells that get
>amplified lead to cancer. We have little idea what the
>mutations may be in non oncogene/tumor-suppressor genes
>with the exception of some work done in the HPRT
>gene (R. Albertini comes to mind) and some work
>that I believe has been done in blood group genes
>though the details slip my mind at the moment.

That DNA mutations accumulate with age has long been known (I can give you
several refs on that). The question is whether this affects or not the
aging process (upstream or downstream?). Studies done in the 60's and 70's
using ionizing radiation, UV, chemical mutagens, etc. in mice and flies
showed that the mutations caused by these agents are not a part of the
aging process. Perhaps other forms of DNA damage are involved (the
telomeres?) but there is no conclusive evidence on that.

>It does however in my mind provide a significant amount of gravity
>for the DNA Damage theory as being a factor in the aging process.
>The developmental genes in an adult can accumulate mutations and
>you will never know it. But if you try to grow a new adult using
>those genes with accumulated mutations, then the results detailed
>above are a likely result.

I asked this in a previous post, I ask it again, why then do clones made
from young cells (taken from foetus, not young adults) show the exact same
problems? Until you can answer me this I will not be convinced.

>This makes sense -- why would you want to expend resources repairing
>genes that the average cell will never use again?

I never liked Kirkwood's disposable soma theory and this reminds me of it.
Here's my problem: if you overexpress telomerase in mitotic cells they will
overcome aging without any noticeable loss of resources. So, even assuming
the telomeres as an anti-cancer mechanisms, cells can very cheaply overcome
senescence, contradicting Kirkwood's theory. Many species showing
vegetative reproduction are other examples refuting these theories. In
addition, studies done in biotechnology show that cells can overexpress
large amounts of trangenic genes without any noticeable deleterious effect
(unless a toxic product is involved, of course).

>In looking at this it seems to me that nature will have tuned
>repair mechanisms (you don't think running ECC checks on 3x10^9 BP/cell
>that are receiving thousands+ mutations/day is cheap do you???)
>to match the requirements -- "frequently used programs" ==
>"highly active repair", "less used programs" == "less active repair",
>"never used programs" == "very rare repair".

I must say that although your ideas are logical I'm not convinced. For
instance, wouldn't it be cheaper to just repair everything instead of
creating and powering a whole mechanism just to determine what is useful
and what isn't. Besides, I am not aware of any experimental evidence
supporting these ideas (unless you know something I don't; for example, has
DNA repair the same efficiency in introns and exons?). And let's face it,
there are already dozens of logical theoretical framworks to explain aging.

Best wishes.

UnitÚ de Biologie et Biochimie Cellulaire
FacultÚs Universitaires Notre-Dame de la Paix
61, rue de Bruxelles
B-5000 Namur
Belgique
tel : 32-81-724321
fax : 32-81-724135



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