The Sir2 deacetylase modulates organismal life-span in various species. However, the molecular mechanisms by which Sir2 increases longevity are largely unknown. We show that in mammalian cells, the Sir2 homolog SIRT1 appears to control the cellular response to stress by regulating the FOXO family of Forkhead transcription factors, a family of proteins that function as sensors of the insulin signaling pathway and as regulators of organismal longevity. SIRT1 and the FOXO transcription factor FOXO3 formed a complex in cells in response to oxidative stress, and SIRT1 deacetylated FOXO3 in vitro and within cells. SIRT1 had a dual effect on FOXO3 function: SIRT1 increased FOXO3's ability to induce cell cycle arrest and resistance to oxidative stress but inhibited FOXO3's ability to induce cell death. Thus, one way in which members of the Sir2 family of proteins may increase organismal longevity is by tipping FOXO-dependent responses away from apoptosis and toward stress resistance.

SUMMARY Olfactory cortex pyramidal cells integrate sensory input from olfactory bulb mitral and tufted (M/T) cells and project axons back to the bulb. However, the impact of cortical feedback projections on olfactory bulb circuits is unclear. Here, we selectively express channelrhodopsin-2 in olfactory cortex pyramidal cells and show that cortical feedback projections excite diverse populations of bulb interneurons. Activation of cortical fibers directly excites GABAergic granule cells, which in turn inhibit M/T cells. However, we show that cortical inputs preferentially target short axon cells that drive feedforward inhibition of granule cells. In vivo, activation of olfactory cortex that only weakly affects spontaneous M/T cell firing strongly gates odor-evoked M/T cell responses: cortical activity suppresses odor-evoked excitation and enhances odor-evoked inhibition. Together, these results indicate that although cortical projections have diverse actions on olfactory bulb microcircuits, the net effect of cortical feedback on M/T cells is an amplification of odor-evoked inhibition.

Growth factor suppression of apoptosis correlates with the phosphorylation and inactivation of multiple proapoptotic proteins, including the BCL-2 family member BAD. However, the physiological events required for growth factors to block cell death are not well characterized. To assess the contribution of BAD inactivation to cell survival, we generated mice with point mutations in the BAD gene that abolish BAD phosphorylation at specific sites. We show that BAD phosphorylation protects cells from the deleterious effects of apoptotic stimuli and attenuates death pathway signaling by raising the threshold at which mitochondria release cytochrome c to induce cell death. These findings establish a function for endogenous BAD phosphorylation, and elucidate a mechanism by which survival kinases block apoptosis in vivo.