2.3 Sirtuin Pathway
SIRT1 is the most studied family member of the mammalian sirtuins 1-7, which are class III histone deacetylases that utilize NAD+, a coenzyme involved in many biological reactions, to improve longevity. Many have reported that sirtuins are major nutrient-sensing proteins that promote health span from yeast to mice, and its activity seems to explain the beneficial effect of CR 57, 58. Moreover, the life-extending effects of CR are abrogated when sirtuins are deleted in various animal models 57. Induced overexpression of SIRT1 has been shown to suppress malignancies partly via p53 signaling. SIRT1 and AMPK share many downstream targets, including PGC1α, FOXO, and eNOS 59, 60. They also induce similar biological actions such as stimulating the mitochondrial biogenesis and attenuating inflammation. Specifically, SIRT1 can deacetylase FOXO3 and induce ROS detoxification to ameliorate oxidative stress 61. SIRT1 also deacetylases FOXO4 and increases its transactivation capacity. Furthermore, deacetylation of p65 by SIRT1 inhibits NF-kB signaling, resulting in an anti-inflammatory effect50.
As mentioned above, SIRT1 is a downstream target of AMPK. However, SIRT1 can also activate AMPK, forming a positive feedback loop. AMPK can activate SIRT1 by raising cellular NAD+ levels, raising NAD+:NADH ratio, and enhancing the transcription of Nicotinamide phosphoribosyltransferase (NAmPRTase or Nampt), a regulator of the intracellular NAD pool 62; in turn, SIRT1 activates AMPK by deacetylating and triggering the liver kinase B1 (LKB1). LKB1 can also be triggered by energy stress to activate AMPK and several related kinases 63 .