Editors' ChoiceLONGEVITY

Gonad–Life-Span Coupling

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Sci. Signal.  18 Dec 2012:
Vol. 5, Issue 255, pp. ec324
DOI: 10.1126/scisignal.2003880

Elimination of the germ line increases life span in model organisms, such as flies and nematodes. In the nematode Caenorhabditis elegans, the increase in life span induced by removal of the germ line requires the presence of the somatic components of the gonad (somatic gonad). The bile acid–like dafachronic acid (DA) steroids have been identified as life-extending signals from the somatic gonad, but the germline factors that antagonize these signals have not been identified. C. elegans hermaphrodites lacking the gene glp-1 have no germ line and show an extended life span relative to wild-type (WT) worms. Shen et al. found that DA production increased during the fourth larval (L4) and adult stages in glp-1 mutants compared with WT animals but was the same as WT during earlier developmental stages. The microRNAs (miRNAs) mir-84 and mir-241 are direct transcriptional targets of the DA receptor DAF-12, and production of both these miRNAs was stimulated during the L2–L3 developmental transition in WT animals and continued through the L4 stage. Compared with the abundance in WT animals of the same stage, the abundance of these miRNAs was increased in glp-1 L4s and peaked at three- to fourfold greater amounts in mutant adults. The observed up-regulation of these miRNAs in glp-1 mutants depended upon DA signaling, and both miRNAs were required for the life-extending effects of germline stem cell removal by laser ablation or by glp-1 mutation. Genetic experiments indicated that mir-84 and mir-241 promoted nuclear localization and activity of the transcription factor DAF-16, a homolog of vertebrate FOXO that accumulates in intestinal cell nuclei in animals lacking a germ line. Signaling through the kinase Akt inhibits DAF-16, and the authors determined that akt-1 was a target of mir-84– and mir-241–mediated transcriptional inhibition. Knocking down akt-1 expression by RNA interference extended life span in WT, glp-1 animals, mir-84;mir-241;glp-1 triple mutants. The authors also identified the L1–L2 transition regulator lin-14 as a target of mir-84 and mir-241 repression. These results suggest a model in which a developmental timing program that normally controls transitions between larval stages is redeployed in the absence of the germ line to increase life span. The signals that connect germline loss or the absence of germline stem cell proliferation to increased DA production remain unidentified.

Y. Shen, J. Wollam, D. Magner, O. Karalay, A. Antebi, A steroid receptor–microRNA switch regulates life span in response to signals from the gonad. Science 338, 1472–1476 (2012). [Abstract] [Full Text]

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