Mitochondrial SIRT3 and nuclear SIRT6 repress the use of carbon from carbohydrates through glycolysis, by inhibiting the function of HIF-1α [60, 103]. Similarly, mitochondrial SIRT4 regulates the use carbon from amino acids by repressing glutamate dehydrogenase [104]. Thus, SIRT3, SIRT4, and SIRT6 all repress the Warburg effect, in which deregulation of glycolysis and glutaminolysis occurs in many human tumors and supports tumor growth. Accordingly, the loss of SIRT3 [103] or SIRT6 [105] induces glycolysis, and loss of SIRT4 induces glutaminolysis [104]. Finally, loss of each of these three sirtuins has been found in many human tumors, with loss of up to 40% in breast and ovarian cancer for SIRT3, and 20% of all cancers for SIRT6 [104, 105, 106].

SIRT1 activity can be regulated post-transcriptionally by several mechanisms, including phosphorylation [107, 108], interactions with other proteins such as DBC1 (deleted in breast cancer 1) [109, 110], or changes in NAD+ levels [111]. Importantly, AMPK activates expression of the NAD biosynthetic enzyme NAMPT, linking the activity of these two crucial energy-sensing pathways [79]. Moreover, it appears likely that NAD+ levels decline with aging, which would lead to a reduction in sirtuin activity and also blunt the effects of resveratrol and other STACs. It is not clear whether this decline in NAD+ is severe enough to affect metabolic enzymes that bind it tightly as a cofactor. The decline in NAD+ was first noticed in transgenic mice overexpressing SIRT1 in pancreatic beta cells [112]. These mice show enhanced glucose-stimulated insulin secretion when they are young, but lose this phenotype when they become old (18–24 months). Importantly, administration of the NAD+ precursor, nicotinamide mononucleotide (NMN), can restore the metabolic phenotype in old transgenic mice. This finding suggests that a decrease in NAD+ with aging was responsible for the blunting of the phenotype in pancreatic beta cells of SIRT1 transgenic mice. More recently, supplementation with NAD precursors has been shown to restore NAD+ levels and prevent diet- or aging-induced diabetes in wild-type mice [113, 114]. Another recent paper suggests that a metabolite derived from the NAD+ precursor nicotinamide, 1-methyl nicotinamide, may have beneficial effects in worms [115].

An aging-induced decline in NAD+ levels has also been linked to an aging-dependent activation of poly-ADP-ribose polymerase (PARP) [54]. This enzyme responds to DNA damage and ADP-ribosylates proteins at sites of DNA breaks by cleaving NAD+. This finding is complementary to an earlier study showing that PARP-1 inhibition in mice increased NAD+ content and upregulated SIRT1 [116]. Thus, one can imagine that aging is associated with chronic DNA damage leading to NAD+ depletion and sirtuin inactivation. Indeed, a decrease in the activity of SIR-2.1 in worms or SIRT1 in mammals also leads to mitochondrial dysfunction, possibly related to increased acetylation of FOXO and PGC-1α [54]. Thus, one can trace an aging-dependent mechanism connecting the nucleus and mitochondria resulting from NAD+ deficiency.

Lastly, the circadian clock also regulates NAD+ levels via the enzyme NAMPT [117, 118]. This connection was recently shown to lead to circadian cycles of SIRT3 activation, mitochondrial protein deacetylation, and oxidative metabolism [119]. In mice mutant for the circadian clock, SIRT3 function is thus defective and oxidative metabolism becomes dysfunctional. Importantly, NAD+ supplementation of the mutant mice via NMN can help to correct this metabolic defect.

Almost 14 years ago, yeast SIR2 and its mammalian ortholog SIRT1 were recognized as NAD+-dependent deacetylases, which immediately inspired research into the roles of sirtuins in metabolic regulation. Now it is well accepted that sirtuins play important roles in a broad spectrum of biological processes, although questions still remain (Box 1). Sirtuins function to slow aging and various disorders associated with aging, including metabolic diseases, cancer, and neurodegenerative conditions. Sirtuins respond to the energy availability provided by the diet to determine the acetylation status of histones, key transcription factors, and metabolic enzymes. This coordinated response helps deliver the benefits of CR on health and physiology. Indeed, STACs have been shown to target SIRT1 directly [48, 120], and present a promising strategy to ameliorate age-related diseases. Novel drugs for other sirtuins may also become available and offer additional benefits. And finally, NAD+ supplementation in combination with STACs may offer a synergetic strategy to promote healthy aging.

We apologize to researchers whose work was not cited due to space limitations. This work was supported by grants from the NIH and the Glenn Foundation for Medical Research to L.G. H-C.C. is an Ellison Medical Foundation Fellow of the Life Science Research Foundation. L.G. consults for GSK, Chronos, Elysiumhealth, and Inside Tracker.

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