Signaling Control of Life-Span

Science's STKE  30 Mar 2004:
Vol. 2004, Issue 226, pp. tw116-TW116
DOI: 10.1126/stke.2262004TW116

Life-span control in the nematode Caenorhabditis elegans depends on the protein Sir2 and its interaction with Daf-16, a member of the Foxo family of transcription factors. Daf-16 participates in an insulin-like signaling pathway, and inhibition of signaling through this pathway extends life-span. Brunet et al. studied the mammalian homolog of Sir2 known as SIRT1. SIRT1 is a nicotinamide adenine dinucleotide-dependent histone deacetylase that directly interacts with the mammalian Foxo family transcription factor FOXO3 and contributes to its deacetylation. This interaction may enhance or decrease FOXO-dependent transcription, depending on the target gene analyzed. Furthermore, expression of SIRT appears to enhance the effects of FOXO3 in promoting resistance to oxidative stress, but to inhibit FOXO-mediated signaling that promotes cell death. This enhanced stress tolerance and avoidance of cell death could provide a mechanism to increase longevity.

A. Brunet, L. B. Sweeney, J. F. Sturgill, K. F. Chua, P. L. Greer, Y. Lin, H. Tran, S. E. Ross, R. Mostoslavsky, H. Y. Cohen, L. S. Hu, H.-L. Cheng, M. P. Jedrychowski, S. P. Gygi, D. A. Sinclair, F. W. Alt, M. E. Greenberg, Stress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase. Science 303, 2011-2015 (2004). [Abstract] [Full Text]