Article,
DNA damage as the primary cause of aging
The Quarterly Review of Biology, 56 (3): 279--303 (September 1981)PMID: 7031747.
Abstract
DNA damage appears to be ubiquitous in the
biological world, as judged by the variety of organisms
which have evolved DNA-repair systems. Previously, it
was proposed that germ-line DNA of multicellular
organisms may be protected from damage, and
consequently from aging, by efficient recombinational
repair during meiosis. The somatic line, however, may
be vulnerable to the accumulation of DNA damage, and
hence undergo aging, owing to relatively less repair.
Although the DNA lesions most important in aging are
not known yet, there is evidence for serveral types of
endogenous damage. DNA lesions have been shown to
interfere with transcription and replication, and so
lead to loss of cell function and death. In mammals,
there is a progressive decline of function in many
different tissues with increasing age. Deterioration of
central nervous system functions appears to be a
critical part of the aging process. This may be due to
the low DNA repair capacity which is found in
postmitotic brain tissue, and which could result in the
accumulation of DNA lesions in this tissue. Also
reviewed is evidence that species longevity is directly
related to tissue DNA-repair capacity and that aging
may be accelerated by treatment with DNA-damaging
agents, or in individuals with genetically defective
repair. Although it has been frequently postulated that
somatic mutation may be cause of aging, current
evidence suggests that it is probably less important
than DNA damage. A prominent theory on the evolution
of aging, which attributes special importance to genes
that are advantagous in youth but are deleterious later
on, is discussed in terms of regulatory genes that
reduce DNA repair as cells differentiate to the
postmitotic state. Finally, we hypothesize that the
factors which determine maximum longevity of
individuals in a population are the rate of occurrence
of DNA damage, the rate of DNA repair, the degree
of cellular redundancy, and the extent of exposure to
stress.
