Institute for Aging Research

Sirtuins in Aging

One of the most promising lines of investigation in the biology of aging is the ability of the sirtuin family of NAD-dependent histone deacetylases to enhance life span in yeast 48, flies49, and nematodes (Guarente, Helfand). Furthermore resveratrol, the mammalian SIRT1 activator50, increased the life span of high fat fed animals51, and healthy life span52 in normal fed animals (Sinclair). Transgenic Sirt1 animals show improved insulin action (Accili)53 that may work acutely through the hypothalamus (Knight, Barzilai), and chronically through changes in mitochondrial biogenesis (Nair) in models and humans (Hawkins, Crandall). Other sirtuins54 also have a role in glucose metabolism (Haigis), and sirtuin genetics in humans (Suh) are under investigation.

  1. Sinclair, D. A., Lin, S. J. & Guarente, L. Life-span extension in yeast. Science 312, 5771:195-197; author reply 195-197, doi:312/5771/195d [pii]10.1126/science.312.5771.195d (2006).
  2. Rogina, B. & Helfand, S. L. Sir2 mediates longevity in the fly through a pathway related to calorie restriction. Proc Natl Acad Sci U S A 101, 45:15998-16003, doi:0404184101 [pii]10.1073/pnas.0404184101 (2004).
  3. Milne, J. C., Lambert, P. D., Schenk, S., Carney, D. P., Smith, J. J., Gagne, D. J. et al. Small molecule activators of SIRT1 as therapeutics for the treatment of type 2 diabetes. Nature 450, 7170:712-716, doi:nature06261 [pii]10.1038/nature06261 (2007).
  4. Baur, J. A., Pearson, K. J., Price, N. L., Jamieson, H. A., Lerin, C., Kalra, A. et al. Resveratrol improves health and survival of mice on a high-calorie diet. Nature 444, 7117:337-342, doi:nature05354 [pii]10.1038/nature05354 (2006).
  5. Pearson, K. J., Baur, J. A., Lewis, K. N., Peshkin, L., Price, N. L., Labinskyy, N. et al. Resveratrol delays age-related deterioration and mimics transcriptional aspects of dietary restriction without extending life span. Cell Metab 8, 2:157-168, doi:S1550-4131(08)00182-4 [pii]10.1016/j.cmet.2008.06.011 (2008).
  6. Banks, A. S., Kon, N., Knight, C., Matsumoto, M., Gutierrez-Juarez, R., Rossetti, L. et al. SirT1 gain of function increases energy efficiency and prevents diabetes in mice. Cell Metab 8, 4:333-341, doi:S1550-4131(08)00255-6 [pii]10.1016/j.cmet.2008.08.014 (2008).
  7. Haigis, M. C., Mostoslavsky, R., Haigis, K. M., Fahie, K., Christodoulou, D. C., Murphy, A. J. et al. SIRT4 inhibits glutamate dehydrogenase and opposes the effects of calorie restriction in pancreatic beta cells. Cell 126, 5:941-954, doi:S0092-8674(06)01020-8 [pii]10.1016/j.cell.2006.06.057 (2006).
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