Apoptosis, genome maintenance, and aging
Y. Suh
The University of Texas Health Science Center at San Antonio, Department of Physiology, Barshop Institute for Longevity and Aging Studies, 15355 Lambda Drive, San Antonio, TX 78245, USA
Unrepaired or misrepaired DNA damage has been implicated as a causal
factor in cancer and aging. Apoptosis in response to DNA damage, a
major tumor suppressor mechanism, is antagonistically pleiotropic,
promoting the development of specific ageing phenotypes as well as
suppressing the development of cancer. This is illustrated by reduced
spontaneous tumor formation and premature appearance of other
aging-related phenotypes in several mouse mutants harboring genetic
defects in genome maintenance. Here we studied one of these mutants,
the XpdTTD mutant mouse model, harboring a defect in both nucleotide
excision repair (NER) and general transcription. We observed a dramatic
age-related increase in apoptosis in the liver as compared to control
mice. The increase in apoptosis may contribute to the accelerated aging
phenotypes and the reduced incidence of cancer observed in these
mutants. To gain further insight into the molecular basis for the
up-regulation of apoptosis and its relation to the mutant-specific
manifestation of age-related phenotypes, gene expression profiles of
mutant and control mouse liver were compared with normal aging. The
results indicate that genes involved in lipid metabolism and immune
response are significantly down-regulated in mutant liver compared to
wild type liver. Comparison of expression profiles with normal liver
aging indicated similar changes in lipid metabolism, but increased
expression levels of genes involved in immune response and other
responses to stresses. We conclude that the premature aging phenotype
associated with the XpdTTD defect in repair and transcription causes an
imbalance of normal patterns of growth and metabolism that is both
similar and distinct from alterations during normal liver aging.
Key words:
apoptosis, genome, aging, ageing phenotype
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