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Hypoxia-inducible factors HIF-1α and HIF-2α are homologous transcription factors that activate an adaptive response in mammalian cells to low concentrations of environmental oxygen (1, 2). HIF-activated genes protect against damaging reactive oxygen molecules generated by mitochondria in response to hypoxia, and also stimulate erythrocyte proliferation and blood vessel formation to enhance organism survival. Under normal oxygen conditions, HIF-1α and HIF-2α are hydroxylated on key prolines, which promotes their degradation. However, under hypoxic conditions, the HIF proteins are stabilized and accumulate in cells. On page 1289 of this issue, Dioum et al. show that during hypoxia, HIF-2α is deacetylated and thereby activated by SIRT1, a nicotinamide adenine dinucleotide (NAD)–dependent deacetylase (3). This finding extends the reach of SIRT1 as a cell and tissue maintenance and anti-aging factor to include resistance to hypoxic stress. SIRT1 has already been shown to protect against metabolic, genotoxic, and heat stress by deacetylating other key transcription factors that respond to those stressors (4–8) (see the figure).