Understanding how biochemical signals influence aging just got a bit more complicated. The histone deacetylase encoded by the Sir2 gene in yeast enhances replicative life span, that is, life span measured as the total number of daughter cells one mother cell can produce. Another way to measure aging is to measure the time that cells survive in a nonmitotic state--chronological life span. Fabrizio et al. report that loss of Sir2 alone had no effect on chronological life span. However, an unexpected pro-aging effect of Sir2 was revealed when analyzed in the context of two yeast mutants that extend chronological life span. Lack of the yeast homolog of the protein kinase Akt or caloric restriction both extend chronological lifetime in yeast. Under these conditions, loss of Sir2 led to further increases in life span. Fabrizio et al. explored several possible explanations for these effects. In nutrient-depleted cells, loss of Sir2 caused a decrease in the rate of accumulation of age-dependent DNA mutations. Stress resistance of the Sir2-depleted cells was also enhanced when they were exposed to oxidative stress or heat shock. Loss of Sir2 also led to an increase in the amount of alcohol dehydrogenase 2 and its activity. The authors propose that alcohol (produced and excreted as yeast during fermentation but also used as a carbon source when nutrients are depleted) is a key signal to yeast cells reflecting their metabolic state and that its depletion leads to a program that extends chronological aging. The authors, and Kennedy in commentary on the paper, discuss the implications of the findings for understanding aging in mammals as well, and how regulatory pathways that control and respond to metabolism may converge to regulate longevity.
P. Fabrizio, C. Gattazzo, L. Battistella, M. Wei,C. Cheng, K. McGrew,V. D. Longo, Sir2 blocks extreme life-span extension. Cell 123, 655-667 (2005). [PubMed]
B. K. Kennedy, The enigmatic role of Sir2 in aging. Cell 123, 548-550 (2005). [PubMed]