Theories of Biological Aging: DNA Damage
The idea that DNA damage may be a major factor in aging has been popular since 1974, when Ronald Hart and Richard Setlow demonstrated a direct correlation between life span and capacity for DNA repair. The idea is still largely unproven, although much data supporting it have been obtained. DNA damage includes altered bases, mismatched base pairs, strand cross-linking, and both single- and double-strand breaks. The three main repair pathways are nucleotide excision repair, base excision repair, and direct reversal of damage. As the molecular mechanisms of DNA repair pathways became clearer during the 1980s and 1990s, it became possible to study this question with greater sophistication, but the importance of DNA damage and repair in aging remains unclear.
The possible role of DNA damage in an error-catastrophe scenario is discussed in the next essay, Theories of Biological Aging: Error Catastrophe. As pointed out there, studies to document age-related changes in the fidelity of DNA polymerases have not provided convincing support for either theory, even though DNA polymerase β, the main polymerase involved in DNA repair, is relatively error-prone. The major DNA polymerase in mammalian cells, DNA polymerase α, copies DNA with very high fidelity, and early reports of decreasing fidelity of this enzyme with increasing age have not held up.
Early work on DNA repair focused mainly on the repair of pyrimidine dimers in DNA. Pyrimidine dimers are produced by the cross-linking of two adjacent pyrimidine bases (thymine or cytosine) when DNA is exposed to ultraviolet light. In the 1980s it became clear that such dimers may not be the most abundant DNA lesion in vivo, as few cells are actually exposed to ultraviolet light. It is now recognized that altered bases due to oxidative stress occur much more frequently than dimers, and it has been estimated that as many as 100,000 oxidized bases may be generated in DNA per cell, per day. Such damage is repaired by a pathway known as base excision repair, which begins by removal of the damaged base, followed by DNA breakage at the site of the missing base, removal of the remaining damage, and replacement of the missing nucleotide(s) by DNA polymerase β. This enzyme is absolutely essential for mammalian viability, although cells lacking it can be grown in culture. This suggests that a certain amount of DNA damage can be tolerated in single cells grown in culture, but that the combined effect of many damaged cells in one or more critical tissues is not tolerable.
Much of the early—and generally inconclusive—work on this theory focused on looking for changes in the levels of DNA repair enzymes as a function of age. Work in the late 1990s used transgenic mice and focused on looking at the level and nature of spontaneous mutations as a function of age. The general results from these experiments include: (1) mutation frequency does increase with age, (2) mutations tend to be greater in proliferating tissues than in nonproliferating tissues, and (3) the nature of the mutations varies with age and tissue examined. Both point mutations (single base-pair change) and chromosomal rearrangements accumulate with age in most examined tissues, and it is assumed that the latter has more serious implications for the aging individual. It is certainly clear that DNA rearrangements are closely associated with cancer induction.
The belief that DNA damage may contribute to aging is bolstered by the discovery that the protein coded for by the gene for Werner’s syndrome (which simulates accelerated human aging), possesses two enzyme activities known to be involved in DNA metabolism. Both of these activities could play an essential role in DNA repair, with the obvious inference that a DNA repair deficiency may be a cause of premature aging. Cells from Werner’s syndrome patients do show an increase in mutations and chromosome alterations, although these two enzyme activities could also be required for DNA replication, transcription, or recombination.
Finally, mutations in mitochondrial DNA also increase with age, particularly in the form of deletions. The level of these deletions increases exponentially with age in human tissues, but it is not clear what role this plays in aging, as most human cells have hundreds of mitochondria and the level of any given deletion rarely reaches more than a few percent of all mitochondrial genomes. The deletion frequencies are highest in mitochondria from postmitotic tissues such as muscle, heart, and brain, but different brain regions may exhibit widely varying deletion frequencies.
It is generally assumed that both nuclear and mitochondrial mutations are largely the result of oxidative stress, and that this stress is greater in the mitochondria than in the nucleus. What is still generally lacking are results that unequivocally relate oxidative stress, mutation induction, and aging.
HUBER R. WARNER
See also ACCELARATED AGING: ANIMAL MODELS; ACCELERATED AGING: HUMAN PROGEROID SYNDROMES; CELLULAR AGING; GENETICS; LIFE SPAN EXPANSION; MUTATION; THEORIES OF BIOLOGICAL AGING: ERROR CATASTROPHE.
OSHIMA, J. ‘‘The Werner Syndrome Protein: An Update.’’ Bioessays 22 (2000): 894–901.
VIJG, J., and KNOOK, D. L. ‘‘DNA Repair in Relation to the Aging Process.’’ Journal of the American Geriatrics Society 35 (1987): 532–541.
WARNER, H. R., and JOHNSON, T. E. ‘‘Parsing Age, Mutations and Time.’’ Nature Genetics 17 (1997): 368–370.
- Theories of Biological Aging: Error Catastrophe
- Theories of Biological Aging: Disposable Soma
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