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].

The emerging role of NAD+ in aging

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.

Concluding remarks and future perspectives

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.

Outstanding questions

Acknowledgments

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.

References

1 Imai, S. et al. (2000) Transcriptional silencing and longevity protein sir2 is an NAD-dependent histone deacetylase. Nature 403, 795–800
2 Klar, A.J. et al. (1979) Mar1-a regulator of the hma and hmalpha loci in Saccharomyces cerevisiae. Genetics 93, 37–50
3 Sinclair, D.A. and Guarente, L. (1997) Extrachromosomal rdna circles–a cause of aging in yeast. Cell 91, 1033–1042
4 Kaeberlein, M. et al. (1999) The sir2/3/4 complex and sir2 alone promote longevity in Saccharomyces cerevisiae by two different mechanisms. Genes Dev. 13, 2570–2580
5 Tissenbaum, H.A. and Guarente, L. (2001) Increased dosage of a sir-2 gene extends lifespan in caenorhabditis elegans. Nature 410, 227–230
6 Viswanathan, M. and Guarente, L. (2011) Regulation of caenorhabditis elegans lifespan by sir-2.1 transgenes. Nature 477, E1–E2
7 Rogina, B. and Helfand, S.L. (2004) Sir2 mediates longevity in the fly through a pathway related to calorie restriction. Proc. Natl. Acad. Sci. U.S.A. 101, 15998–16003
8 Lin, S.J. et al. (2000) Requirement of NAD and sir2 for life-span extension by calorie restriction in Saccharomyces cerevisiae. Science 289, 2126–2128
9 Lin, S.J. et al. (2002) Calorie restriction extends Saccharomyces cerevisiae lifespan by increasing respiration. Nature 418, 344–348
10 Anderson, R.M. et al. (2003) Yeast life-span extension by calorie restriction is independent of nad fluctuation. Science 302, 2124–2126
11 Burnett, C. et al. (2011) Absence of effects of sir2 overexpression on lifespan in C. elegans and drosophila. Nature 477, 482–485
12 Kanfi, Y. et al. (2012) The sirtuin sirt6 regulates lifespan in male mice. Nature 483, 218–221
13 Satoh, A. et al. (2013) Sirt1 extends life span and delays aging in mice through the regulation of nk2 homeobox 1 in the dmh and lh. Cell Metab. 18, 416–430
14 Guarente, L. (2013) Calorie restriction and sirtuins revisited. Genes Dev. 27, 2072–2085
15 Dryden, S.C. et al. (2003) Role for human sirt2 NAD-dependent deacetylase activity in control of mitotic exit in the cell cycle. Mol. Cell. Biol. 23, 3173–3185
16 Vaquero, A. et al. (2006) Sirt2 is a histone deacetylase with preference for histone h4 lys 16 during mitosis. Genes Dev. 20, 1256–1261
17 Serrano, L. et al. (2013) The tumor suppressor sirt2 regulates cell cycle progression and genome stability by modulating the mitotic deposition of h4k20 methylation. Genes Dev. 27, 639–653
18 Verdin, E. et al. (2010) Sirtuin regulation of mitochondria: energy production, apoptosis, and signaling. Trends Biochem. Sci. 35, 669–675
19 Chalkiadaki, A. and Guarente, L. (2012) Sirtuins mediate mammalian metabolic responses to nutrient availability. Nat. Rev. Endocrinol. 8, 287–296
20 Kaeberlein, M. et al. (2004) Saccharomyces cerevisiae ssd1-v confers longevity by a sir2p-independent mechanism. Genetics 166, 1661–1672
21 Bishop, N.A. and Guarente, L. (2007) Two neurons mediate dietrestriction-induced longevity in C. elegans. Nature 447, 545–549
22 Kenyon, C. (2010) A pathway that links reproductive status to lifespan in Caenorhabditis elegans. Ann. N. Y. Acad. Sci. 1204, 156–162
23 Johnson, S.C. et al. (2013) mTOR is a key modulator of ageing and agerelated disease. Nature 493, 338–345
24 Kahn, B.B. et al. (2005) Amp-activated protein kinase: ancient energy gauge provides clues to modern understanding of metabolism. Cell Metab. 1, 15–25
25 Cohen, H.Y. et al. (2004) Calorie restriction promotes mammalian cell survival by inducing the sirt1 deacetylase. Science 305, 390–392
26 Lombard, D.B. et al. (2007) Mammalian sir2 homolog sirt3 regulates global mitochondrial lysine acetylation. Mol. Cell. Biol. 27, 8807– 8814
27 Nakagawa, T. et al. (2009) Sirt5 deacetylates carbamoyl phosphate synthetase 1 and regulates the urea cycle. Cell 137, 560–570
28 Civitarese, A.E. et al. (2007) Calorie restriction increases muscle mitochondrial biogenesis in healthy humans. PLoS Med. 4, e76
29 Chalkiadaki, A. and Guarente, L. (2012) High-fat diet triggers inflammation-induced cleavage of sirt1 in adipose tissue to promote metabolic dysfunction. Cell Metab. 16, 180–188
30 Pedersen, S.B. et al. (2008) Low sirt1 expression, which is upregulated by fasting, in human adipose tissue from obese women. Int. J. Obes. 32, 1250–1255
31 Costa Cdos, S. et al. (2010) Sirt1 transcription is decreased in visceral adipose tissue of morbidly obese patients with severe hepatic steatosis. Obes. Surg. 20, 633–639
32 Chen, D. et al. (2005) Increase in activity during calorie restriction requires sirt1. Science 310, 1641
33 Cohen, D.E. et al. (2009) Neuronal sirt1 regulates endocrine and behavioral responses to calorie restriction. Genes Dev. 23, 2812–2817
34 Boily, G. et al. (2008) Sirt1 regulates energy metabolism and response to caloric restriction in mice. PLoS ONE 3, e1759
35 Mercken, E.M. et al. (2013) Sirt1 but not its increased expression is essential for lifespan extension in caloric restricted mice. Aging Cell http://dx.doi.org/10.1111/acel.12151
36 Someya, S. (2010) Sirt3 mediates reduction of oxidative damage and prevention of age-related hearing loss under caloric restriction. Cell 143, 802–812
37 Hallows, W.C. et al. (2011) Sirt3 promotes the urea cycle and fatty acid oxidation during dietary restriction. Mol. Cell 41, 139–149
38 Baur, J.A. et al. (2006) Resveratrol improves health and survival of mice on a high-calorie diet. Nature 444, 337–342
39 Lagouge, M. et al. (2006) Resveratrol improves mitochondrial function and protects against metabolic disease by activating sirt1 and pgc- 1alpha. Cell 127, 1109–1122
40 Bordone, L. et al. (2007) Sirt1 transgenic mice show phenotypes resembling calorie restriction. Aging Cell 6, 759–767
41 Pfluger, P.T. et al. (2008) Sirt1 protects against high-fat diet-induced metabolic damage. Proc. Natl. Acad. Sci. U.S.A. 105, 9793–9798
42 Herranz, D. et al. (2010) Sirt1 improves healthy ageing and protects from metabolic syndrome-associated cancer. Nat. Commun. 1, 3
43 Biason-Lauber, A. et al. (2013) Identification of a sirt1 mutation in a family with type 1 diabetes. Cell Metab. 17, 448–455
44 Howitz, K.T. et al. (2003) Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature 425, 191–196
45 Milne, J.C. et al. (2007) Small molecule activators of sirt1 as therapeutics for the treatment oftype 2 diabetes. Nature 450, 712–716
46 Lam, Y.Y. et al. (2013) Resveratrol vs. calorie restriction: data from rodents to humans. Exp. Gerontol. 48, 1018–1024
47 Barger, J.L. et al. (2008) A low dose of dietary resveratrol partially mimics caloric restriction and retards aging parameters in mice. PLoS ONE 3, e2264
48 Hubbard, B.P. et al. (2013) Evidence for a common mechanism of sirt1 regulation by allosteric activators. Science 339, 1216–1219
49 Wood, J.G. et al. (2004) Sirtuin activators mimic caloric restriction and delay ageing in metazoans. Nature 430, 686–689
50 Berdichevsky, A. et al. (2006) C. elegans sir-2.1 interacts with 14-3-3 proteins to activate daf-16 and extend life span. Cell 125, 1165–1177
51 Rizki, G. et al. (2011) The evolutionarily conserved longevity determinants hcf-1 and sir-2.1/sirt1 collaborate to regulate daf-16/ foxo. PLoS Genet. 7, e1002235
52 Stumpferl, S.W. et al. (2012) Natural genetic variation in yeast longevity. Genome Res. 22, 1963–1973
53 Ludewig, A.H. et al. (2013) Pheromone sensing regulates caenorhabditis elegans lifespan and stress resistance via the deacetylase sir-2.1. Proc. Natl. Acad. Sci. U.S.A. 110, 5522–5527
54 Mouchiroud, L. et al. (2013) The NAD(+)/sirtuin pathway modulates longevity through activation of mitochondrial upr and foxo signaling. Cell 154, 430–441 
55 Banerjee, K.K. et al. (2012) Dsir2 in the adult fat body, but not in muscles, regulates life span in a diet-dependent manner. Cell Rep. 2, 1485–1491
56 Liu, Y. et al. (2008) A fasting inducible switch modulates gluconeogenesis via activator/coactivator exchange. Nature 456, 269–273
57 Rodgers, J.T. et al. (2005) Nutrient control of glucose homeostasis through a complex of pgc-1alpha and sirt1. Nature 434, 113–118
58 Purushotham, A. et al. (2009) Hepatocyte-specific deletion of sirt1 alters fatty acid metabolism and results in hepatic steatosis and inflammation. Cell Metab. 9, 327–338
59 Hallows, W.C. et al. (2012) Regulation of glycolytic enzyme phosphoglycerate mutase-1 by sirt1 protein-mediated deacetylation. J. Biol. Chem. 287, 3850–3858
60 Zhong, L. et al. (2010) The histone deacetylase sirt6 regulates glucose homeostasis via hif1alpha. Cell 140, 280–293
61 Kim, H.S. et al. (2010) Hepatic-specific disruption of sirt6 in mice results in fatty liver formation due to enhanced glycolysis and triglyceride synthesis. Cell Metab. 12, 224–236
62 Horton, J.D. et al. (2002) SREBPS: activators of the complete program of cholesterol and fatty acid synthesis in the liver. J. Clin. Invest. 109, 1125–1131
63 Walker, A.K. et al. (2010) Conserved role of sirt1 orthologs in fastingdependent inhibition of the lipid/cholesterol regulator srebp. Genes Dev. 24, 1403–1417
64 Li, X. et al. (2007) Sirt1 deacetylates and positively regulates the nuclear receptor lxr. Mol. Cell 28, 91–106
65 Kemper, J.K. et al. (2009) Fxr acetylation is normally dynamically regulated by p300 and sirt1 but constitutively elevated in metabolic disease states. Cell Metab. 10, 392–404
66 Lee, J. et al. (2010) A pathway involving farnesoid x receptor and small heterodimer partner positively regulates hepatic sirtuin 1 levels via microrna-34a inhibition. J. Biol. Chem. 285, 12604–12611
67 Tao, R. et al. (2013) Hepatic srebp-2 and cholesterol biosynthesis are regulated by foxo3 and sirt6. J. Lipid Res. 54, 2745–2753
68 Elhanati, S. et al. (2013) Multiple regulatory layers of srebp1/2 by sirt6. Cell Rep. 4, 905–912
69 Asher, G. et al. (2008) Sirt1 regulates circadian clock gene expression through per2 deacetylation. Cell 134, 317–328
70 Nakahata, Y. et al. (2008) The NAD+-dependent deacetylase sirt1 modulates clock-mediated chromatin remodeling and circadian control. Cell 134, 329–340
71 Hirschey, M.D. et al. (2010) Sirt3 regulates mitochondrial fatty-acid oxidation by reversible enzyme deacetylation. Nature 464, 121–125
72 Shimazu, T. et al. (2010) Sirt3 deacetylates mitochondrial 3-hydroxy- 3-methylglutaryl coa synthase 2 and regulates ketone body production. Cell Metab. 12, 654–661
73 Nasrin, N. et al. (2010) Sirt4 regulates fatty acid oxidation and mitochondrial gene expression in liver and muscle cells. J. Biol. Chem. 285, 31995–32002
74 Laurent, G. et al. (2013) Sirt4 represses peroxisome proliferatoractivated receptor a activity to suppress hepatic fat oxidation. Mol. Cell. Biol. 33, 4552–4561
75 Gerhart-Hines, Z. et al. (2007) Metabolic control of muscle mitochondrial function and fatty acid oxidation through sirt1/pgc- 1alpha. EMBO J. 26, 1913–1923
76 Hardie, D.G. et al. (2012) Ampk: a nutrient and energy sensor that maintains energy homeostasis. Nat. Rev. Mol. Cell Biol. 13, 251–262
77 Jager, S. et al. (2007) Amp-activated protein kinase (ampk) action in skeletal muscle via direct phosphorylation of pgc-1alpha. Proc. Natl. Acad. Sci. U.S.A. 104, 12017–12022
78 Fulco, M. et al. (2008) Glucose restriction inhibits skeletal myoblast differentiation by activating sirt1 through ampk-mediated regulation of nampt. Dev. Cell 14, 661–673
79 Canto, C. et al. (2009) AMPK regulates energy expenditure by modulating nad+ metabolism and sirt1 activity. Nature 458, 10561060
80 Lan, F. et al. (2008) Sirt1 modulation of the acetylation status, cytosolic localization, and activity of lkb1. Possible role in AMPactivated protein kinase activation. J. Biol. Chem. 283, 27628–27635
81 Jing, E. et al. (2013) Sirt3 regulates metabolic flexibility of skeletal muscle through reversible enzymatic deacetylation. Diabetes 62, 3404–3417
82 Iwabu, M. et al. (2010) Adiponectin and adipor1 regulate pgc-1alpha and mitochondria by ca(2+) and ampk/sirt1. Nature 464, 1313–1319
83 Picard, F. et al. (2004) Sirt1 promotes fat mobilization in white adipocytes by repressing ppar-gamma. Nature 429, 771–776
84 Qiang, L. et al. (2012) Brown remodeling of white adipose tissue by sirt1-dependent deacetylation of ppargamma. Cell 150, 620–632
85 Mattagajasingh, I. et al. (2007) Sirt1 promotes endotheliumdependent vascular relaxation by activating endothelial nitric oxide synthase. Proc. Natl. Acad. Sci. U.S.A. 104, 14855–14860
86 Shinmura, K. et al. (2008) Impact of 6-mo caloric restriction on myocardial ischemic tolerance: possible involvement of nitric oxidedependent increase in nuclear sirt1. Am. J. Physiol. Heart Circ. Physiol. 295, H2348–H2355
87 Planavila, A. et al. (2011) Sirt1 acts in association with pparalpha to protect the heart from hypertrophy, metabolic dysregulation, and inflammation. Cardiovasc. Res. 90, 276–284
88 Alcendor, R.R. et al. (2007) Sirt1 regulates aging and resistance to oxidative stress in the heart. Circ. Res. 100, 1512–1521
89 Pillai, V.B. et al. (2010) Exogenous nad blocks cardiac hypertrophic response via activation of the sirt3-lkb1-amp-activated kinase pathway. J. Biol. Chem. 285, 3133–3144
90 Sundaresan, N.R. et al. (2012) The sirtuin sirt6 blocks igf-akt signaling and development of cardiac hypertrophy by targeting cjun. Nat. Med. 18, 1643–1650
91 Vakhrusheva, O. et al. (2008) Sirt7 increases stress resistance of cardiomyocytes and prevents apoptosis and inflammatory cardiomyopathy in mice. Circ. Res. 102, 703–710
92 Ramadori, G. et al. (2008) Brain sirt1: Anatomical distribution and regulation by energy availability. J. Neurosci. 28, 9989–9996
93 Satoh, A. et al. (2010) Sirt1 promotes the central adaptive response to diet restriction through activation of the dorsomedial and lateral nuclei of the hypothalamus. J. Neurosci. 30, 10220–10232
94 Ramadori, G. et al. (2010) Sirt1 deacetylase in pomc neurons is required for homeostatic defenses against diet-induced obesity. Cell Metab. 12, 78–87
95 Ramadori, G. et al. (2011) Sirt1 deacetylase in sf1 neurons protects against metabolic imbalance. Cell Metab. 14, 301–312
96 Sasaki, T. et al. (2010) Induction of hypothalamic sirt1 leads to cessation of feeding via agouti-related peptide. Endocrinology 151, 2556–2566
97 Velasquez, D.A. et al. (2011) The central sirtuin 1/p53 pathway is essential for the orexigenic action of ghrelin. Diabetes 60, 1177– 1185
98 Lu, M. et al. (2013) Neuronal sirt1 deficiency increases insulin sensitivity in both brain and peripheral tissues. J. Biol. Chem. 288, 10722–10735
99 Chang, H.C. and Guarente, L. (2013) Sirt1 mediates central circadian control in the scn by a mechanism that decays with aging. Cell 153, 1448–1460
100 Firestein, R. et al. (2008) The sirt1 deacetylase suppresses intestinal tumorigenesis and colon cancer growth. PLoS ONE 3, e2020
101 Wang, R.H. et al. (2008) Impaired DNA damage response, genome instability, and tumorigenesis in sirt1 mutant mice. Cancer Cell 14, 312–323
102 Kim, H.S. et al. (2011) Sirt2 maintains genome integrity and suppresses tumorigenesis through regulating apc/c activity. Cancer Cell 20, 487–499
103 Finley, L.W. et al. (2011) Sirt3 opposes reprogramming of cancer cell metabolism through hif1alpha destabilization. Cancer Cell 19, 416– 428
104 Jeong, S.M. et al. (2013) Sirt4 has tumor-suppressive activity and regulates the cellular metabolic response to DNA damage by inhibiting mitochondrial glutamine metabolism. Cancer Cell 23, 450–463
105 Sebastian, C. et al. (2012) The histone deacetylase sirt6 is a tumor suppressor that controls cancer metabolism. Cell 151, 1185–1199
106 Kim, H.S. et al. (2010) Sirt3 is a mitochondria-localized tumor suppressor required for maintenance of mitochondrial integrity and metabolism during stress. Cancer Cell 17, 41–52
107 Guo, X. et al. (2010) Dyrk1a and dyrk3 promote cell survival through phosphorylation and activation of sirt1. J. Biol. Chem. 285, 13223– 13232
108 Gerhart-Hines, Z. et al. (2011) The camp/pka pathway rapidly activates sirt1 to promote fatty acid oxidation independently of changes in NAD(+). Mol. Cell 44, 851–863
109 Kim, J.E. et al. (2008) Dbc1 is a negative regulator of sirt1. Nature 451, 583–586 110 Escande, C. et al. (2010) Deleted in breast cancer-1 regulates sirt1 activity and contributes to high-fat diet-induced liver steatosis in mice. J. Clin. Invest. 120, 545–558
111 Lin, S.J. et al. (2004) Calorie restriction extends yeast life span by lowering the level of NADH. Genes Dev. 18, 12–16
112 Ramsey, K.M. et al. (2008) Age-associated loss of sirt1-mediated enhancement of glucose-stimulated insulin secretion in beta cellspecific sirt1-overexpressing (besto) mice. Aging Cell 7, 78–88
113 Yoshino, J. et al. (2011) Nicotinamide mononucleotide, a key NAD(+) intermediate, treats the pathophysiology of diet- and age-induced diabetes in mice. Cell Metab. 14, 528–536
114 Canto, C. et al. (2012) The NAD(+) precursor nicotinamide riboside enhances oxidative metabolism and protects against high-fat dietinduced obesity. Cell Metab. 15, 838–847
115 Schmeisser, K. et al. (2013) Role of sirtuins in lifespan regulation is linked to methylation of nicotinamide. Nat. Chem. Biol. 9, 693–700
116 Bai, P. et al. (2011) Parp-1 inhibition increases mitochondrial metabolism through sirt1 activation. Cell Metab. 13, 461–468
117 Ramsey, K.M. et al. (2009) Circadian clock feedback cycle through nampt-mediated nad+ biosynthesis. Science 324, 651–654
118 Nakahata, Y. et al. (2009) Circadian control of the nad+ salvage pathway by clock-sirt1. Science 324, 654–657
119 Peek, C.B. et al. (2013) Circadian clock NAD+ cycle drives mitochondrial oxidative metabolism in mice. Science 342, 1243417
120 Dai, H. et al. (2010) Sirt1 activation by small molecules: Kinetic and biophysical evidence for direct interaction of enzyme and activator. J. Biol. Chem. 285, 32695–32703