Sirt1: def-eating senescence?

Abstract

Sirt1, the closest mammalian homolog of the Sir2 yeast longevity protein, has been extensively investigated in the last few years as an avenue to understand the connection linking nutrients and energy metabolism with aging and related diseases. From this research effort the picture has emerged of an enzyme at the hub of a complex array of molecular interactions whereby nutrient-triggered signals are translated into several levels of adaptive cell responses, the failure of which underlies diseases as diverse as diabetes, neurodegeneration and cancer. Sirt1 thus connects moderate calorie intake to "healthspan," and a decline of Sirt-centered protective circuits over time may explain the "catastrophic" nature of aging.

Figure 1. Role of Sirt1 in mammalian aging. Mammalian aging is the time-dependent loss of health with increased occurrence of chronic degenerative, neoplastic and inflammatory diseases. These fundamental pathologic processes are profoundly affected by nutrients and their metabolism. Current evidence points to a major role for the protein deacetylase Sirt1 as a metabolic sensor that translates nutrient availability into largely protective cell responses, thus prolonging healthspan. Molecular interactions whereby Sirt1 exerts this role are in the focus of the present article. Protein lysine deacetylation by Sirt1 involves hydrolysis of NAD+ into nicotinamide (NAM), itself an inhibitor of the enzyme activity, and yields O-acetyl-ADP-ribose (not shown) and the deacetylated substrate. The dependence on NAD links Sirt1 activity to the energy status of the cell via the cellular NAD:NADH ratio and the absolute levels of NAD.

Figure 2. Mondrian’s style synopsis of the upstream regulators and molecular targets of Sirt1, discussed in detail in the article. Regulation occurs at the level of Sirt1 mRNA (transcriptional and post-transcriptional) and protein (expression level and activity). Some of the transcriptional regulators of Sirt1 are also targets of the sirtuin (not shown).

Figure 3. Sirt1 roles in the hypoxic response through HIF1α. Sirt1 may dictate distinct cell responses under different conditions of reduced oxygen availability. Two situations relevant to human pathology are depicted: hypoxia (i.e., reduced oxygen transport with normal blood flow and nutrient supply) and ischemia (decrease or block of perfusion, with reduced supply of oxygen and nutrients). In the former condition, accumulation of NADH inhibits Sirt1, thus promoting acetylation of HIF1α by p300 and transcription of HIF targets like the vascular endothelial growth factor (VEGF). Conversely, under ischemia, limited nutrient supply activates Sirt1, leading to deacetylation and Inhibition of HIF1α. This model, in part speculative, is based on reference and does not include Sirt1-dependent activation of HIF2α, as described in reference .

Figure 4. Nutrient sensing through the cAMP cascade and CREB/Sirt1. Fasting-induced hormones raise intracellular cAMP, leading to PKA-dependent phosphorylation and activation of both CREB and Sirt1. A parallel cascade triggered by cAMP through the adaptor Epac and CaMKII results in AMPK activation, increased NAD+/NADH ratio and metabolic activation of the sirtuin1. Sirt1 and CREB form a complex on cAMP responsive promoters and Sirt1 promotes CREB transcriptional activity, in part through deacetylation of the co-activator CRTC/TORC1. Sirt1 is also transcriptionally induced by CREB, thus creating a positive feedback loop. Calorie restriction and its mimic Resveratrol impinge at multiple levels on this complex circuitry. Note that some important interactions have been omitted for simplicity; for instance, in liver, Sirt1 inhibits CREB-dependent transcription of gluconeogenic enzymes by deacetylating TORC2 or directly CREB.