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 .