Mutation and catastrophe in the aging genome.

Mutation and catastrophe in the aging genome. Exp Gerontol. 2017 Mar 02;: Authors: Milholland B, Suh Y, Vijg J Abstract In the 1960s, Leslie Orgel proposed what is now known as the error catastrophe theory of aging, arguing that errors in protein translation that reduce the fidelity of the protein-translating enzymes would lead to a feedback loop of increasingly inaccurate protein synthesis, terminating in the death of the organism. This mechanism of aging would be consistent with the exponential increase of mortality observed in humans, but the error catastrophe theory of aging has been generally disregarded by researchers due to a lack of evidence for an age-related increase in protein errors. Another theory of aging, proposed at roughly the same time, is Leo Szilard's two-hit model of somatic mutation accumulation, which assumed a linear increase in mutations over time but explained the nonlinear pattern of human mortality through a mechanism of genetic and cellular redundancy which kept mortality low until the redundancy was exhausted, at which point mortality rapidly rose. Here, we synthesize the two theories, along with the latest advances in genomics research. We propose a new catastrophe theory of aging, this time with somatic mutations as the primary agent of the feedback loop. Similar to protein errors affecting translation itself, somatic mutations in genes involved in DNA replication and repair would lead to a feedback lo...
Source: Experimental Gerontology - Category: Geriatrics Authors: Tags: Exp Gerontol Source Type: research