[extropy-chat] AGING: New Theory

Robert J. Bradbury bradbury at aeiveos.com
Fri Apr 16 15:51:19 UTC 2004

On Fri, 16 Apr 2004, Joao Magalhaes wrote:

> What I'm saying is that although oxidative damage to the DNA accumulates
> with age in some tissues, it is not proven this is a cause rather an effect
> of ageing. And the cited experiments suggest this is an effect of ageing.

Well (Van Remmen, 2003 [1]) is interesting in that free radicals seem to
to be contributing to cancer but not to ageing.  Though the standard
caveat should be added that this is research in mice and not in humans.

In this case the entire somatic mutation approach may need to be modified
such that it is only involved in cancer -- which is the cause of death
for ~30% of people.

> As for the rest of your theory, Robert, I agree with the view that changes
> in DNA over time play a role in ageing. This could even be the case in stem
> cell stocks, as suggested by Van Zant's work. Yet I have some reservations
> on the idea that only one type of DNA damage causes ageing. At a first
> glance, it just doesn't seem right. Like I wrote previously on the
> mechanisms of CR, your idea is theoretically sound but there is no direct
> evidence in support of it. Can you think of one or two experiments that can
> prove or disprove your theory?

As Aubrey pointed out to me the theory as described ignores possible
epigenetic changes.  Which in light of the difference between the
progeria gene and the W.S. gene functions may be of significant concern.
[See [2] for example when causes/symptoms of the two may be difficult
to separate.]

I'm perfectly willing to accept that stem cell depletion may play an
important role in aging -- that would sound like one needs an experiment
to measure apoptosis (human cells are very intolerant of double strand
breaks and might undergo apoptosis at a higher rate than mice) and
replacement by stem cells with age.  The recent report by (Li, 2004 [3])
suggests that you cannot separate Werner's Syndrome type aging from
a direct involvement with double strand breaks (which is what PARP
is involved in dealing with).  It sounds like we need some kind of
complex pulse-chase experiment with long-lived radioisotopes to
measure cell death and stem cell replacement rates.

Now, with regard to the double strand break problem itself -- the
problem in my mind is *where* do the breaks occur?  I think you can
get at this problem with high amplification PCR.  If you assume the
breaks are taking place at random places in the genome (but perhaps
with some bias with respect to junk DNA, regulatory DNA and expressed
DNA) then if you have enough cells and simply amplify various regions
of the genome you should be able to gather statistical evidence
with respect to where breaks are taking place and how they may
impact gene expression.  This may feedback into the actual structure
of DNA in the nucleus and the whole LAMIN/progeria/epigenetic story.

If the DSB somatic mutation theory is correct you should be able
to pull out the locations where breaks (and microdeletions) have
taken place by differences in the length of the PCR amplification
products.  Vijg's (and others) work suggests that the deletions
are taking place but to the best of my knowledge nobody has tried
to do a statistical analysis of where they occur directly.

Finally, one needs mutant mice knockouts in at least the W.S.
gene as well as the Artemis gene (perhaps heterozygous) to see
if that impacts the frequency of microdeletions significantly.


1. Van Remmen H, Ikeno Y, Hamilton M, Pahlavani M, Wolf N, Thorpe SR,
Alderson NL, Baynes JW, Epstein CJ, Huang TT, Nelson J, Strong R, Richardson A.
Physiol Genomics. 2003 Dec 16;16(1):29-37.
Life-long reduction in MnSOD activity results in increased DNA damage and
higher incidence of cancer but does not accelerate aging. mutations in atypical Werner's syndrome.

2. Chen L, Lee L, Kudlow BA, Dos Santos HG, Sletvold O, Shafeghati Y,
Botha EG, Garg A, Hanson NB, Martin GM, Mian IS, Kennedy BK, Oshima J.
LMNA mutations in atypical Werner's syndrome.
Lancet. 2003 Aug 9;362(9382):440-5

3. Li B, Navarro S, Kasahara N, Comai L.
J Biol Chem. 2004 Apr 2;279(14):13659-67. Epub 2004 Jan 20.
Identification and biochemical characterization of a Werner's syndrome protein
complex with Ku70/80 and poly(ADP-ribose) polymerase-1.

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