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Aging was thought to be a haphazard process, which was not driven by any defined mechanisms. Recently, it has been reported that changing in single gene expression can extend lifespan. Many mutations that extend lifespan are involved in endocrine signaling. The mechanisms of longevity by such mutations are conserved among various species ranging from yeast to mice. One of the most important pathways underlying the regulation of longevity is the insulin signal pathway. In this review, we will describe long-lived animals that have mutations in this pathway and discuss the relationship between insulin signaling, diabetes, and longevity.

The yeast silent information regulator 2 (Sir2) is an NAD-dependent histone deacetylase and silences transcription at the mating type loci, telomeres and the ribosomal DNA. Over-expression of Sir2 extends the life span of yeast and C. elegans, while Sir2 knockout shortened yeast life span to about 50%. Mammalian cells also express several Sir2 homologues. However, most of physiological functions of Sir2 homologues seem to be unknown. We found that Sir2 alpha (SIRT1) was highly expressed during embryogenesis. In the adult mouse brain, ependymal cells and some cells of subventricular zone expressed Sir2 alpha. To identify proliferating neural cells in the adult brain, BrdU was administered in the drinking water for 2 weeks. BrdU-positive and nestin-positive cells expressed Sir2 alpha. Furthermore, neurosphere cultured from E14 mouse striatum expressed Sir2 alpha. The expression of Sir2 alpha in neurosphere disappeared after differentiation. Nicotinamide, splitomicin and sirtinol, potent inhibitors of Sir2 alpha, inhibited the growth of neurosphere. FACS analysis showed that sirtinol did not increase sub-G1 population of cells. Differentiation of neurosphere into neuron and oligodendrocyte was inhibited by the addition of nicotinamide, splitomicin or sirtinol in the differentiation medium. These results suggest that Sir2 alpha has a pivotal role in the proliferation and differentiation of neural stem cells.