Arguing DNA Damage as a Cause of Aging

A stochastic accumulation of nuclear DNA damage progresses throughout life. This is definitely a cause of increased cancer risk, one of the reasons why cancer is predominantly a disease of the old, but is it also a contributing cause of degenerative aging in general? This is an arguable proposition, with some researchers suggesting that DNA damage doesn't meaningfully impact aging over the length of a human life span, while others consider it the most important cause of aging.

Here is a review paper on the subject. It is always pleasant to see researchers openly discuss increasing life span through biotechnology, even if I don't necessarily agree with the likely effectiveness of the research path they choose. It is still the case that many scientists will not talk openly about the goal of extending human life.

Genome instability has long been implicated as the main causal factor in aging. Somatic cells are continuously exposed to various sources of DNA damage, from reactive oxygen species to UV radiation to environmental mutagens.

To cope with the tens of thousands of chemical lesions introduced into the genome of a typical cell each day, a complex network of genome maintenance systems acts to remove damage and restore the correct base pair sequence. Occasionally, however, repair is erroneous, and such errors, as well as the occasional failure to correctly replicate the genome during cell division, are the basis for mutations and epimutations. There is now ample evidence that mutations accumulate in various organs and tissues of higher animals, including humans, mice, and flies. What is not known, however, is whether the frequency of these random changes is sufficient to cause the phenotypic effects generally associated with aging. The exception is cancer, an age-related disease caused by the accumulation of mutations and epimutations.

Here, we first review current concepts regarding the relationship between DNA damage, repair, and mutation, as well as the data regarding genome alterations as a function of age. We then describe a model for how randomly induced DNA sequence and epigenomic variants in the somatic genomes of animals can result in functional decline and disease in old age. Finally, we discuss the genetics of genome instability in relation to longevity to address the importance of alterations in the somatic genome as a causal factor in aging and to underscore the opportunities provided by genetic approaches to develop interventions that attenuate genome instability, reduce disease risk, and increase life span.



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