More on DNA damage and the somatotroph axis

Yesterday we discussed a paper that described short-lived DNA repair-deficient mutants undergoing physiological changes strongly reminiscent of long-lived genetic dwarf or calorie restricted (CR) animals.

Here is another paper that addresses the issue, Niedernhofer et al.:

XPF-ERCC1 endonuclease is required for repair of helix-distorting DNA lesions and cytotoxic DNA interstrand crosslinks. Mild mutations in XPF cause the cancer-prone syndrome xeroderma pigmentosum. A patient presented with a severe XPF mutation leading to profound crosslink sensitivity and dramatic progeroid symptoms. It is not known how unrepaired DNA damage accelerates ageing or its relevance to natural ageing. Here we show a highly significant correlation between the liver transcriptome of old mice and a mouse model of this progeroid syndrome. Expression data from XPF-ERCC1-deficient mice indicate increased cell death and anti-oxidant defences, a shift towards anabolism and reduced growth hormone/insulin-like growth factor 1 (IGF1) signalling, a known regulator of lifespan. Similar changes are seen in wild-type mice in response to chronic genotoxic stress, caloric restriction, or with ageing. We conclude that unrepaired cytotoxic DNA damage induces a highly conserved metabolic response mediated by the IGF1/insulin pathway, which re-allocates resources from growth to somatic preservation and life extension. This highlights a causal contribution of DNA damage to ageing and demonstrates that ageing and end-of-life fitness are determined both by stochastic damage, which is the cause of functional decline, and genetics, which determines the rates of damage accumulation and decline.

The authors of this paper add to the evidence that chronic DNA damage can induce the same metabolic changes as life-extending mutations or treatments. Furthermore, they expand the story by demonstrating a strong correlation between the transcriptome of progeroid DNA repair mutants and aged wildtype mice — arguing, in effect, that the syndrome exhibited by the mutant is a good model of aging. (This last bit is an important piece of the puzzle, sincemany types of mutations can shorten lifespan without actually accelerating the aging process per se.)