Chunk #24 — Epigenetics-Relevant Consequences of Oxidative Alcohol Metabolism — Increases in NADH/NAD+ Ratio and Their Consequences — Modulation of Gene Expression
The Sir2 protein links cellular metabolism and transcriptional silencing through its NAD+-dependent HDAC activity (Imai et al. 2000). This activity is essential for Sir2 functions, including gene silencing, regulation of the circadian clock, and its role in obesity and longevity (Rutter et al. 2001). The extraordinary requirement of NAD+ in the deacetylation reaction suggests that Sir2 may function as a sensor for the energy status of cells, linking the energy level represented by available NAD+ to the silencing of gene expression. The mammalian orthologue of Sir2, known as SIRT1, also is a NAD+-dependent deacetylase (Imai et al. 2000) whose substrates include histones and the transcription factor p53 (Vaziri et al. 2001). NAD+ activates Sir2 during CR, which not only extends the life span in a wide variety of organisms, but also reduces the incidence of age-related diseases such as diabetes, cancer, immune deficiencies, and cardiovascular disorders (Bordone and Guarente 2005).
