X-Message-Number: 25821
Date: Fri, 18 Mar 2005 18:42:58 -0800 (PST)
From: Doug Skrecky <>
Subject: aging is not slowed by increased DNA repair

[It has been a tenet of faith for some scientists that DNA damage and
repair processes MUST drive aging. The danger of such uncritical
assumptions is that progress in gerontology is stalled until these
road blocks of complacency are destroyed. The destruction of one such
road block was announced by this 2001 abstract.]

Ann N Y Acad Sci. 2001 Apr;928:132-40.
Health span and life span in transgenic mice with modulated DNA
repair.
   One way to better understand the contribution of DNA repair,
DNA damage, and mutagenesis in aging would be to enhance DNA
repair activity, lower DNA damage, and lower mutagenesis.
Because the repair protein O6-methylguanine-DNA methyltransferase
(MGMT) acts alone and stoichiometrically, the human MGMT (hMGMT)
cDNA was selected to test the feasibility of enhancing DNA repair
activity in transgenic mice. MGMT activity is largely responsible
for ameliorating the deleterious effects of O6-methylguanine
(O6mG) lesions in DNA in a direct reversal mechanism. A transgene
was constructed consisting of a portion of the human transferrin
(TF) promoter and hMGMT cDNA such that hMGMT is expressed in
transgenic mouse brain and liver. Expression of hMGMT was
associated with a significant reduction in the occurrence of an
age-related hepatocellular carcinoma in male mice at 15 months
of age. Longitudinal and cross-sectional studies were initiated
to determine whether the reduced incidence of hepatocellular
carcinoma would impact median or maximum life span. The
cross-sectional study performed on 15-month-old male animals
confirmed the reduced occurrence of spontaneous hepatocellular
carcinoma. At 30 months of age, however, the occurrence of
hepatocellular carcinoma in at least one transgenic line was
similar to that for nontransgenic animals. The longitudinal
study is ongoing; however, at present no significant differences
in life span have been detected. Tissues expressing the MGMT
transgene also displayed greater resistance to alkylation-induced
tumor formation. These results suggest that transgenes can be
used to direct enhanced DNA repair gene expression and that
enhanced expression can protect animals from certain spontaneous
and induced tumors.

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