Re : AGING: Accumulation of DNA damage

From: Joao Pedro de Magalhaes (
Date: Mon Jul 10 2000 - 08:57:26 MDT


>What would be interesting is to study the effects of long-term low-dose
>exposure to mutagens/radiation.

Some of the studies I read were done at long periods of time. In fact, some
mice and flies exposed to low doses of radiation actually lived longer
(perhaps a form of hormetics?). See Strehler's book, around page 275.

>Also interesting would be using
>mutagens/radiation to attempt to induce aging in non-aging organisms.

Obviously to induce aging in a non-aging organism would be tremendous. In a
perfect world you would irradiate or knok-out some genes from some lobsters
(or whatever) and get a beutiful Gompertz mortality curve, exponential
increases in the incidence of dozens of diseases, etc. However, you would
probably get increased mortality due to cancer or a few pathologies
increasing with age, but not a coherent phenotype ressembling mammalian
aging. I mean, if many gerontologists don't consider Werner's syndrome
accelerated aging, why would they consider whatever deleterious phenotype
you could give to lobsters as aging?

>Do you have studies that cite the clone failure rate and developmental
>abnormalities are the same with foetal cells *and* adults?

[Hill et al., 2000]

They took cells from an old steer and made a clone. Then they took cells
from the clone in the foetal stage and made a new clone; they got viable
calfs in both experiments with similar results regarding abnormal calfs and
abortions. West's latest experiment concerned young cells and cells aged in
vitro and the results were the same. Finally, there was a Korean team that
also used in vitro aged cells and found that they were better for cloning.
Of course that you can argue that in vitro aged cells are not the same thing
as in vivo and that the cells in the foetus are not that different from the
adult steer's. But still ...

>I would not have expected that people would have done these studies yet,
>certainly not in replicated work that you can make strong claims about.

No, they're not conclusive experiments but make one think.

>It sounds like you are mixing apples and oranges. Mitotic cells in
>my mind cannot be classed as "soma".

Really? Don't tell that to Kirkwood cause his research is largely based on
that assumption.

>My brain cells typically don't
>divide and that is the "soma" that when disposed of causes the problems.

So you think post-mitotic cells are the pacemakers of aging? If so, how do
they spread aging throughout the body? Hormones?

>In the long run even the bodies of Sequoia trees are disposable!
>Certainly in bacteria or endlessly self-cloning plants there is
>no "soma" to dispose of. The entire organism is "reproductive".
>There *is* aging however in that some fraction of those reproductive
>cells are likely to be sterile.

I don't get it. Bacteria are sterile because of aging!? Also, some tissues
from plants with vegetative reproduction cannot be used for reproduction and
yet don't show aging (I'm thinking about leaves).

>Guarante's work in budding yeast
>shows that cellular aging does occur and it is caused by what is
>effectively DNA damage.

Although the basic principles of life are the same for all organisms, there
is no reason to believe yeast senescence has anything to do with human
aging. In addition, as you should know, the "DNA damage" presumably causing
S.cerevisiae to age is completely different from the DNA mutations generally
quoted as causing human aging.

>> 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).
>I'm not sure that I see how this applies.

I was pointing that expressing a few more genes is not deleterious to cells
and therefore cellular senescence should not be regarded as the outcome of
shifting "energy" from repair to other functions. At least in proliferative

>you want to harvest a nonsecretable protein, you don't much care
>whether the cell is sterile, you simply care what its yield was.

It's just a minor detail, but when you want cells to produce some protein,
you want them to reproduce as quick as possible. So you should to care
whether they're sterile or not.

>I'm fairly sure there is a difference in repair rates between transcribed and
>untranscribed genes. Think about it for a minute -- how do you even *do*
>repair for the genes that are switched "off" in cells? Shouldn't those
>genes be wrapped up in condensed DNA and unavailable to the repair enzymes?
>If so (or if the repair simply proceeds at a rate below the damage
>accumulation rate), then you are going to get an accumulation of defective

Although large sections of chromosomes can be non-coding regions, small
introns and exons can often alternate. And it can also depend on the type of
error (if you have a break in the DNA it is repaired no matter its place).
One thing that has always troubled me is: if non-coding regions are so easy
to mutate and lose, how come they exist in such large amounts? I don't
recall in detail my classes on the subject but I don't remember studying DNA
repair mechanisms specific of coding regions. Perhaps they exist but, until
further evidence, I cannot accept them.

>The genes that are "forever" turned off are only needed if you want to
>make a clone from the cell and so only show up as defective if you
>try to do that. I have a hard time linking DNA damage with aging
>in active cells, where, in theory, the active genes should be repaired.
>But I could see something like a slow accumulation of iron or copper
>in the nucleus accelerating the rates at which DNA damage occurs
>such that the cell can't maintain a functional set of undamaged
>genes, leading to an eventual decline in cell function (e.g. aging).
>Note that I'm primarily discussing post-mitotic cells here, though
>this could be applied to some degree in infrequently dividing
>stem cells.

Let's admit you're right, how do you think non-aging species cope with this?
Unknown repair mechanisms?

Best wishes.

Joao Pedro de Magalhaes
The University of Namur (FUNDP)
Unit of Cellular Biochemistry & Biology
Rue de Bruxelles, 61
B-5000 Namur BELGIUM

Fax: + 32 81 724135
Phone: + 32 81 724133
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