Sirtuins as regulators of metabolism and healthspan

Key Points

  • Sirtuins regulate protein function by NAD+-dependent post-translational modification, thereby representing a metabolic sensor.

  • Compounds activating sirtuins could be used to treat age-associated mitochondrial diseases.

  • Activation of SIRT1 improves metabolism and global health in organisms ranging from Caenorhabditis elegans to humans.

  • The role of sirtuins in natural longevity is debated, but it is widely accepted that sirtuins have a role in the maintenance of metabolic health.

Abstract

Since the beginning of the century, the mammalian sirtuin protein family (comprising SIRT1–SIRT7) has received much attention for its regulatory role, mainly in metabolism and ageing. Sirtuins act in different cellular compartments: they deacetylate histones and several transcriptional regulators in the nucleus, but also specific proteins in other cellular compartments, such as in the cytoplasm and in mitochondria. As a consequence, sirtuins regulate fat and glucose metabolism in response to physiological changes in energy levels, thereby acting as crucial regulators of the network that controls energy homeostasis and as such determines healthspan.

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Figure 1: Regulation of sirtuin expression and activity.
Figure 2: Sirtuins mediate metabolic responses in several tissues during different physiological challenges.
Figure 3: Overview of the role of sirtuins in the regulation of pathways involved in glucose metabolism.
Figure 4: Overview of the role of sirtuins in the regulation of lipid metabolism.

References

  1. 1

    Zoncu, R., Efeyan, A. & Sabatini, D. M. mTOR: from growth signal integration to cancer, diabetes and ageing. Nature Rev. Mol. Cell Biol. 12, 21–35 (2011).

  2. 2

    Cantó, C. & Auwerx, J. AMP-activated protein kinase and its downstream transcriptional pathways. Cell. Mol. Life Sci. 67, 3407–3423 (2010).

  3. 3

    Houtkooper, R. H., Williams, R. W. & Auwerx, J. Metabolic networks of longevity. Cell 142, 9–14 (2010).

  4. 4

    Fontana, L., Partridge, L. & Longo, V. D. Extending healthy life span — from yeast to humans. Science 328, 321–326 (2010).

  5. 5

    Haigis, M. C. & Sinclair, D. A. Mammalian sirtuins: biological insights and disease relevance. Annu. Rev. Pathol. 5, 253–295 (2010).

  6. 6

    Guarente, L. Franklin & H. Epstein lecture: sirtuins, aging, and medicine. N. Engl. J. Med. 364, 2235–2244 (2011).

  7. 7

    Kaeberlein, M., McVey, M. & Guarente, L. The SIR2/3/4 complex and SIR2 alone promote longevity in Saccharomyces cerevisiae by two different mechanisms. Genes Dev. 13, 2570–2580 (1999).

  8. 8

    Imai, S., Armstrong, C. M., Kaeberlein, M. & Guarente, L. Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase. Nature 403, 795–800 (2000). This study describes the NAD dependence of yeast Sir2.

  9. 9

    Howitz, K. T. et al. Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature 425, 191–196 (2003). This report describes the first small molecule screen for sirtuin activators, identifying resveratrol as a caloric restriction mimetic.

  10. 10

    Frye, R. A. Phylogenetic classification of prokaryotic and eukaryotic Sir2-like proteins. Biochem. Biophys. Res. Commun. 273, 793–798 (2000).

  11. 11

    Tanno, M., Sakamoto, J., Miura, T., Shimamoto, K. & Horio, Y. Nucleocytoplasmic shuttling of the NAD+-dependent histone deacetylase SIRT1. J. Biol. Chem. 282, 6823–6832 (2007).

  12. 12

    Vaquero, A. et al. SirT2 is a histone deacetylase with preference for histone H4 Lys 16 during mitosis. Genes Dev. 20, 1256–1261 (2006).

  13. 13

    Huang, J. Y., Hirschey, M. D., Shimazu, T., Ho, L. & Verdin, E. Mitochondrial sirtuins. Biochim. Biophys. Acta 1804, 1645–1651 (2010).

  14. 14

    Mostoslavsky, R. et al. Genomic instability and aging-like phenotype in the absence of mammalian SIRT6. Cell 124, 315–329 (2006).

  15. 15

    Ford, E. et al. Mammalian Sir2 homolog SIRT7 is an activator of RNA polymerase I transcription. Genes Dev. 20, 1075–1080 (2006).

  16. 16

    Braunstein, M., Sobel, R. E., Allis, C. D., Turner, B. M. & Broach, J. R. Efficient transcriptional silencing in Saccharomyces cerevisiae requires a heterochromatin histone acetylation pattern. Mol. Cell. Biol. 16, 4349–4356 (1996).

  17. 17

    Haigis, M. C. et al. SIRT4 inhibits glutamate dehydrogenase and opposes the effects of calorie restriction in pancreatic β-cells. Cell 126, 941–954 (2006).

  18. 18

    Liszt, G., Ford, E., Kurtev, M. & Guarente, L. Mouse Sir2 homolog SIRT6 is a nuclear ADP-ribosyltransferase. J. Biol. Chem. 280, 21313–21320 (2005).

  19. 19

    Michishita, E. et al. SIRT6 is a histone H3 lysine 9 deacetylase that modulates telomeric chromatin. Nature 452, 492–496 (2008).

  20. 20

    Zhong, L. et al. The histone deacetylase Sirt6 regulates glucose homeostasis via Hif1α. Cell 140, 280–293 (2010).

  21. 21

    Nakagawa, T., Lomb, D. J., Haigis, M. C. & Guarente, L. SIRT5 deacetylates carbamoyl phosphate synthetase 1 and regulates the urea cycle. Cell 137, 560–570 (2009).

  22. 22

    Peng, C. et al. The first identification of lysine malonylation substrates and its regulatory enzyme. Mol. Cell. Proteomics 9 Sep 2011 (doi:10.1074/mcp.M111.012658).

  23. 23

    Du, J. et al. Sirt5 is an NAD-dependent protein lysine demalonylase and desuccinylase. Science 334, 806–809 (2011). References 22 and 23 describe desuccinylation and demalonylation as a novel function for SIRT5. Reference 23 identifies CPS1 as a desuccinylated target.

  24. 24

    Houtkooper, R. H., Cantó, C., Wanders, R. J. & Auwerx, J. The secret life of NAD+: an old metabolite controlling new metabolic signaling pathways. Endocr. Rev. 31, 194–223 (2010).

  25. 25

    Bitterman, K. J., Anderson, R. M., Cohen, H. Y., Latorre-Esteves, M. & Sinclair, D. A. Inhibition of silencing and accelerated aging by nicotinamide, a putative negative regulator of yeast sir2 and human SIRT1. J. Biol. Chem. 277, 45099–45107 (2002).

  26. 26

    Anderson, R. M., Bitterman, K. J., Wood, J. G., Medvedik, O. & Sinclair, D. A. Nicotinamide and PNC1 govern lifespan extension by calorie restriction in Saccharomyces cerevisiae. Nature 423, 181–185 (2003).

  27. 27

    Kustatscher, G., Hothorn, M., Pugieux, C., Scheffzek, K. & Ladurner, A. G. Splicing regulates NAD metabolite binding to histone macroH2A. Nature Struct. Mol. Biol. 12, 624–625 (2005).

  28. 28

    Liou, G. G., Tanny, J. C., Kruger, R. G., Walz, T. & Moazed, D. Assembly of the SIR complex and its regulation by O-acetyl-ADP-ribose, a product of NAD-dependent histone deacetylation. Cell 121, 515–527 (2005).

  29. 29

    Tong, L. & Denu, J. M. Function and metabolism of sirtuin metabolite O-acetyl-ADP-ribose. Biochim. Biophys. Acta 1804, 1617–1625 (2010).

  30. 30

    Feige, J. N. & Auwerx, J. Transcriptional targets of sirtuins in the coordination of mammalian physiology. Curr. Opin. Cell Biol. 20, 303–309 (2008).

  31. 31

    Cantó, C. & Auwerx, J. Targeting sirtuin 1 to improve metabolism: all you need is NAD+? Pharmacol. Rev. 64, 166–187 (2011).

  32. 32

    Vaziri, H. et al. hSIR2(SIRT1) functions as an NAD-dependent p53 deacetylase. Cell 107, 149–159 (2001).

  33. 33

    Luo, J. et al. Negative control of p53 by Sir2α promotes cell survival under stress. Cell 107, 137–148 (2001).

  34. 34

    Herranz, D. & Serrano, M. SIRT1: recent lessons from mouse models. Nature Rev. Cancer 10, 819–823 (2010).

  35. 35

    Lerin, C. et al. GCN5 acetyltransferase complex controls glucose metabolism through transcriptional repression of PGC-1α. Cell Metab. 3, 429–438 (2006).

  36. 36

    Rodgers, J. T. et al. Nutrient control of glucose homeostasis through a complex of PGC-1α and SIRT1. Nature 434, 113–118 (2005). This article provides the mechanistic link between SIRT1 activity and PGC1α acetylation.

  37. 37

    Minor, R. K. et al. SRT1720 improves survival and healthspan of obese mice. Sci. Rep. 1, 70 (2011).

  38. 38

    Cantó, C. et al. Interdependence of AMPK and SIRT1 for metabolic adaptation to fasting and exercise in skeletal muscle. Cell Metab. 11, 213–219 (2010).

  39. 39

    Cantó, C. et al. AMPK regulates energy expenditure by modulating NAD+ metabolism and SIRT1 activity. Nature 458, 1056–1060 (2009). This paper describes how NAD+ levels link AMPK and SIRT1 activity.

  40. 40

    Feige, J. N. et al. Specific SIRT1 activation mimics low energy levels and protects against diet-induced metabolic disorders by enhancing fat oxidation. Cell Metab. 8, 347–358 (2008).

  41. 41

    Lagouge, M. et al. Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1α. Cell 127, 1109–1122 (2006).

  42. 42

    Baur, J. A. et al. Resveratrol improves health and survival of mice on a high-calorie diet. Nature 444, 337–342 (2006). References 41 and 42 describe the beneficial effects of resveratrol treatment in mice, showing improved metabolic profile.

  43. 43

    Brunet, A. et al. Stress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase. Science 303, 2011–2015 (2004).

  44. 44

    Motta, M. C. et al. Mammalian SIRT1 represses forkhead transcription factors. Cell 116, 551–563 (2004).

  45. 45

    van der Horst, A. et al. FOXO4 is acetylated upon peroxide stress and deacetylated by the longevity protein hSir2(SIRT1). J. Biol. Chem. 279, 28873–28879 (2004).

  46. 46

    Zhong, L. & Mostoslavsky, R. Fine tuning our cellular factories: sirtuins in mitochondrial biology. Cell Metab. 13, 621–626 (2011).

  47. 47

    Verdin, E., Hirschey, M. D., Finley, L. W. & Haigis, M. C. Sirtuin regulation of mitochondria: energy production, apoptosis, and signaling. Trends Biochem. Sci. 35, 669–675 (2010).

  48. 48

    Lombard, D. B. et al. Mammalian Sir2 homolog SIRT3 regulates global mitochondrial lysine acetylation. Mol. Cell. Biol. 27, 8807–8814 (2007).

  49. 49

    Hirschey, M. D. et al. SIRT3 regulates mitochondrial fatty-acid oxidation by reversible enzyme deacetylation. Nature 464, 121–125 (2010). This study describes the fatty acid oxidation enzyme LCAD as a SIRT3 target and its role during fasting.

  50. 50

    Hirschey, M. D. et al. SIRT3 deficiency and mitochondrial protein hyperacetylation accelerate the development of the metabolic syndrome. Mol. Cell 21, 177–190 (2011).

  51. 51

    Shimazu, T. et al. SIRT3 deacetylates mitochondrial 3-hydroxy-3-methylglutaryl CoA synthase 2 and regulates ketone body production. Cell Metab. 12, 654–661 (2010).

  52. 52

    Someya, S. et al. Sirt3 mediates reduction of oxidative damage and prevention of age-related hearing loss under caloric restriction. Cell 143, 802–812 (2010). This article shows how SIRT3 regulates IDH2 activity and oxidative stress defence and thereby mediates the effects of caloric restriction on age-related hearing loss.

  53. 53

    Ahn, B. H. et al. A role for the mitochondrial deacetylase Sirt3 in regulating energy homeostasis. Proc. Natl Acad. Sci. USA 105, 14447–14452 (2008).

  54. 54

    Finley, L. W. et al. Succinate dehydrogenase is a direct target of sirtuin 3 deacetylase activity. PLoS ONE 6, e23295 (2011).

  55. 55

    Jing, E. et al. Sirtuin-3 (Sirt3) regulates skeletal muscle metabolism and insulin signaling via altered mitochondrial oxidation and reactive oxygen species production. Proc. Natl Acad. Sci. USA 108, 14608–14613 (2011).

  56. 56

    Qiu, X., Brown, K., Hirschey, M. D., Verdin, E. & Chen, D. Calorie restriction reduces oxidative stress by SIRT3-mediated SOD2 activation. Cell Metab. 12, 662–667 (2010).

  57. 57

    Schlicker, C. et al. Substrates and regulation mechanisms for the human mitochondrial sirtuins Sirt3 and Sirt5. J. Mol. Biol. 382, 790–801 (2008).

  58. 58

    North, B. J., Marshall, B. L., Borra, M. T., Denu, J. M. & Verdin, E. The human Sir2 ortholog, SIRT2, is an NAD+-dependent tubulin deacetylase. Mol. Cell 11, 437–444 (2003).

  59. 59

    Beirowski, B. et al. Sir-two-homolog 2 (Sirt2) modulates peripheral myelination through polarity protein Par-3/atypical protein kinase C (aPKC) signaling. Proc. Natl Acad. Sci. USA 108, E952–E961 (2011).

  60. 60

    Jiang, W. et al. Acetylation regulates gluconeogenesis by promoting PEPCK1 degradation via recruiting the UBR5 ubiquitin ligase. Mol. Cell 43, 33–44 (2011).

  61. 61

    Jing, E., Gesta, S. & Kahn, C. R. SIRT2 regulates adipocyte differentiation through FoxO1 acetylation/deacetylation. Cell Metab. 6, 105–114 (2007).

  62. 62

    Nasrin, N. et al. SIRT4 regulates fatty acid oxidation and mitochondrial gene expression in liver and muscle cells. J. Biol. Chem. 285, 31995–32002 (2010).

  63. 63

    Schwer, B. et al. Neural sirtuin 6 (Sirt6) ablation attenuates somatic growth and causes obesity. Proc. Natl Acad. Sci. USA 107, 21790–21794 (2010).

  64. 64

    Vakhrusheva, O. et al. Sirt7 increases stress resistance of cardiomyocytes and prevents apoptosis and inflammatory cardiomyopathy in mice. Circ. Res. 102, 703–710 (2008).

  65. 65

    Nemoto, S., Fergusson, M. M. & Finkel, T. Nutrient availability regulates SIRT1 through a forkhead-dependent pathway. Science 306, 2105–2108 (2004).

  66. 66

    Coste, A. et al. The genetic ablation of SRC-3 protects against obesity and improves insulin sensitivity by reducing the acetylation of PGC-1α. Proc. Natl Acad. Sci. USA 105, 17187–17192 (2008).

  67. 67

    Noriega, L. G. et al. CREB and ChREBP oppositely regulate SIRT1 expression in response to energy availability. EMBO Rep. 12, 1069–1076 (2011).

  68. 68

    Hayashida, S. et al. Fasting promotes the expression of SIRT1, an NAD+-dependent protein deacetylase, via activation of PPARα in mice. Mol. Cell. Biochem. 339, 285–292 (2010).

  69. 69

    Han, L. et al. SIRT1 is regulated by a PPARγ–SIRT1 negative feedback loop associated with senescence. Nucleic Acids Res. 38, 7458–7471 (2010).

  70. 70

    Okazaki, M. et al. PPARβ/δ regulates the human SIRT1 gene transcription via Sp1. Endocr. J. 57, 403–413 (2010).

  71. 71

    Chen, W. Y. et al. Tumor suppressor HIC1 directly regulates SIRT1 to modulate p53-dependent DNA-damage responses. Cell 123, 437–448 (2005).

  72. 72

    Zhang, Q. et al. Metabolic regulation of SIRT1 transcription via a HIC1:CtBP corepressor complex. Proc. Natl Acad. Sci. USA 104, 829–833 (2007).

  73. 73

    Bai, P. et al. PARP-2 regulates SIRT1 expression and whole-body energy expenditure. Cell Metab. 13, 450–460 (2011).

  74. 74

    Yamakuchi, M., Ferlito, M. & Lowenstein, C. J. miR-34a repression of SIRT1 regulates apoptosis. Proc. Natl Acad. Sci. USA 105, 13421–13426, (2008).

  75. 75

    Lee, J. et al. 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 (2010).

  76. 76

    Rane, S. et al. Downregulation of miR-199a derepresses hypoxia-inducible factor-1α and sirtuin 1 and recapitulates hypoxia preconditioning in cardiac myocytes. Circ. Res. 104, 879–886 (2009).

  77. 77

    Giralt, A. et al. Peroxisome proliferator-activated receptor-γ coactivator-1α controls transcription of the Sirt3 gene, an essential component of the thermogenic brown adipocyte phenotype. J. Biol. Chem. 286, 16958–16966 (2011).

  78. 78

    Sasaki, T. et al. Phosphorylation regulates SIRT1 function. PLoS ONE 3, e4020, (2008).

  79. 79

    Nasrin, N. et al. JNK1 phosphorylates SIRT1 and promotes its enzymatic activity. PLoS ONE 4, e8414 (2009).

  80. 80

    Guo, X., Williams, J. G., Schug, T. T. & Li, X. DYRK1A and DYRK3 promote cell survival through phosphorylation and activation of SIRT1. J. Biol. Chem. 285, 13223–13232 (2010).

  81. 81

    Yang, Y. et al. SIRT1 sumoylation regulates its deacetylase activity and cellular response to genotoxic stress. Nature Cell Biol. 9, 1253–1262 (2007).

  82. 82

    Bai, P. et al. PARP-1 inhibition increases mitochondrial metabolism through SIRT1 activation. Cell Metab. 13, 461–468 (2011). This report demonstrates how the interplay between different NAD+ consumers can regulate SIRT1 activity.

  83. 83

    Kim, E. J., Kho, J. H., Kang, M. R. & Um, S. J. Active regulator of SIRT1 cooperates with SIRT1 and facilitates suppression of p53 activity. Mol. Cell 28, 277–290 (2007).

  84. 84

    Picard, F. et al. Sirt1 promotes fat mobilization in white adipocytes by repressing PPAR-γ. Nature 429, 771–776 (2004).

  85. 85

    Kim, J. E., Chen, J. & Lou, Z. DBC1 is a negative regulator of SIRT1. Nature 451, 583–586 (2008).

  86. 86

    Zhao, W. et al. Negative regulation of the deacetylase SIRT1 by DBC1. Nature 451, 587–590 (2008).

  87. 87

    Escande, C. et al. 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 (2010).

  88. 88

    Mulligan, P. et al. A SIRT1–LSD1 corepressor complex regulates Notch target gene expression and development. Mol. Cell 42, 689–699 (2011).

  89. 89

    Chen, D. et al. Tissue-specific regulation of SIRT1 by calorie restriction. Genes Dev. 22, 1753–1757 (2008).

  90. 90

    Kim, H. J. et al. Metabolomic analysis of livers and serum from high-fat diet induced obese mice. J. Proteome Res. 10, 722–731 (2011).

  91. 91

    Collins, P. B. & Chaykin, S. The management of nicotinamide and nicotinic acid in the mouse. J. Biol. Chem. 247, 778–783 (1972).

  92. 92

    Bieganowski, P. & Brenner, C. Discoveries of nicotinamide riboside as a nutrient and conserved NRK genes establish a Preiss–Handler independent route to NAD+ in fungi and humans. Cell 117, 495–502 (2004).

  93. 93

    Yoshino, J., Mills, K. F., Yoon, M. J. & Imai, S. Nicotinamide mononucleotide, a key NAD+ intermediate, treats the pathophysiology of diet- and age-induced diabetes in mice. Cell Metab. 14, 528–536 (2011).

  94. 94

    Schreiber, V., Dantzer, F., Ame, J. C. & de Murcia, G. Poly(ADP-ribose): novel functions for an old molecule. Nature Rev. Mol. Cell Biol. 7, 517–528 (2006).

  95. 95

    Krishnakumar, R. & Kraus, W. L. The PARP side of the nucleus: molecular actions, physiological outcomes, and clinical targets. Mol. Cell 39, 8–24 (2010).

  96. 96

    Barbosa, M. T. et al. The enzyme CD38 (a NAD glycohydrolase, EC 3.2.2.5) is necessary for the development of diet-induced obesity. FASEB J. 21, 3629–3639 (2007).

  97. 97

    Dong, M. et al. Design, synthesis and biological characterization of novel inhibitors of CD38. Org. Biomol. Chem. 9, 3246–3257 (2011).

  98. 98

    Lavu, S., Boss, O., Elliott, P. J. & Lambert, P. D. Sirtuins — novel therapeutic targets to treat age-associated diseases. Nature Rev. Drug Discov. 7, 841–853 (2008).

  99. 99

    Pearson, K. J. et al. Resveratrol delays age-related deterioration and mimics transcriptional aspects of dietary restriction without extending life span. Cell Metab. 8, 157–168 (2008).

  100. 100

    Timmers, S. et al. Calorie restriction-like effects of 30 days of resveratrol supplementation on energy metabolism and metabolic profile in obese humans. Cell Metab. 14, 612–622 (2011). This paper is the first description of resveratrol treatment in humans, mimicking the effects of caloric restriction by showing improved (mitochondrial) metabolism in obese subjects.

  101. 101

    Milne, J. C. et al. Small molecule activators of SIRT1 as therapeutics for the treatment of type 2 diabetes. Nature 450, 712–716 (2007).

  102. 102

    Pacholec, M. et al. SRT1720, SRT2183, SRT1460, and resveratrol are not direct activators of SIRT1. J. Biol. Chem. 285, 8340–8351 (2010).

  103. 103

    Beher, D. et al. Resveratrol is not a direct activator of SIRT1 enzyme activity. Chem. Biol. Drug Des. 74, 619–624 (2009).

  104. 104

    Um, J. H. et al. AMP-activated protein kinase-deficient mice are resistant to the metabolic effects of resveratrol. Diabetes 59, 554–563 (2010).

  105. 105

    Hawley, S. A. et al. Use of cells expressing γ-subunit variants to identify diverse mechanisms of AMPK activation. Cell Metab. 11, 554–565 (2010).

  106. 106

    Zheng, J. & Ramirez, V. D. Inhibition of mitochondrial proton F0F1-ATPase/ATP synthase by polyphenolic phytochemicals. Br. J. Pharmacol. 130, 1115–1123 (2000).

  107. 107

    Bouche, C., Serdy, S., Kahn, C. R. & Goldfine, A. B. The cellular fate of glucose and its relevance in type 2 diabetes. Endocr. Rev. 25, 807–830 (2004).

  108. 108

    Liu, Y. et al. A fasting inducible switch modulates gluconeogenesis via activator/coactivator exchange. Nature 456, 269–273 (2008). This study describes how SIRT1, CRTC2 and FOXO1 are temporally regulated during fasting.

  109. 109

    Frescas, D., Valenti, L. & Accili, D. Nuclear trapping of the forkhead transcription factor FoxO1 via Sirt-dependent deacetylation promotes expression of glucogenetic genes. J. Biol. Chem. 280, 20589–20595 (2005).

  110. 110

    Herzog, B., Hall, R. K., Wang, X. L., Waltner-Law, M. & Granner, D. K. Peroxisome proliferator-activated receptor-γ coactivator-1α, as a transcription amplifier, is not essential for basal and hormone-induced phosphoenolpyruvate carboxykinase gene expression. Mol. Endocrinol. 18, 807–819 (2004).

  111. 111

    Bordone, L. et al. SIRT1 transgenic mice show phenotypes resembling calorie restriction. Aging Cell 6, 759–767 (2007).

  112. 112

    Rutanen, J. et al. SIRT1 mRNA expression may be associated with energy expenditure and insulin sensitivity. Diabetes 59, 829–835 (2010).

  113. 113

    Wang, R. H. et al. Hepatic Sirt1 deficiency in mice impairs mTorc2/Akt signaling and results in hyperglycemia, oxidative damage, and insulin resistance. J. Clin. Invest. 121, 4477–4490 (2011). This article demonstrates that hepatic SIRT1 deficiency causes whole-body insulin resistance owing to hyperglycaemia-induced oxidative stress.

  114. 114

    Purushotham, A. et al. Hepatocyte-specific deletion of SIRT1 alters fatty acid metabolism and results in hepatic steatosis and inflammation. Cell Metab. 9, 327–338 (2009). This study shows that hepatic SIRT1 deletion increases susceptibility to hepatic steatosis and body weight gain upon high-fat feeding.

  115. 115

    Rodgers, J. T. & Puigserver, P. Fasting-dependent glucose and lipid metabolic response through hepatic sirtuin 1. Proc. Natl Acad. Sci. USA 104, 12861–12866 (2007).

  116. 116

    Kim, J. W., Tchernyshyov, I., Semenza, G. L. & Dang, C. V. HIF-1-mediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adaptation to hypoxia. Cell Metab. 3, 177–185 (2006).

  117. 117

    Lim, J. H. et al. Sirtuin 1 modulates cellular responses to hypoxia by deacetylating hypoxia-inducible factor 1α. Mol. Cell 38, 864–878 (2010).

  118. 118

    Finley, L. W. et al. SIRT3 opposes reprogramming of cancer cell metabolism through HIF1α destabilization. Cancer Cell 19, 416–428 (2011).

  119. 119

    Muoio, D. M. & Newgard, C. B. Mechanisms of disease: molecular and metabolic mechanisms of insulin resistance and β-cell failure in type 2 diabetes. Nature Rev. Mol. Cell Biol. 9, 193–205 (2008).

  120. 120

    Moynihan, K. A. et al. Increased dosage of mammalian Sir2 in pancreatic β-cells enhances glucose-stimulated insulin secretion in mice. Cell Metab. 2, 105–117 (2005).

  121. 121

    Bordone, L. et al. Sirt1 regulates insulin secretion by repressing UCP2 in pancreatic β-cells. PLoS Biol. 4, e31 (2006).

  122. 122

    Ahuja, N. et al. Regulation of insulin secretion by SIRT4, a mitochondrial ADP-ribosyltransferase. J. Biol. Chem. 282, 33583–33592 (2007).

  123. 123

    Schug, T. T. & Li, X. Sirtuin 1 in lipid metabolism and obesity. Ann. Med. 43, 198–211 (2011).

  124. 124

    Strable, M. S. & Ntambi, J. M. Genetic control of de novo lipogenesis: role in diet-induced obesity. Crit. Rev. Biochem. Mol. Biol. 45, 199–214 (2010).

  125. 125

    Horton, J. D., Goldstein, J. L. & Brown, M. S. SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver. J. Clin. Invest. 109, 1125–1131 (2002).

  126. 126

    Li, X. et al. SIRT1 deacetylates and positively regulates the nuclear receptor LXR. Mol. Cell 28, 91–106 (2007).

  127. 127

    Ponugoti, B. et al. SIRT1 deacetylates and inhibits SREBP-1C activity in regulation of hepatic lipid metabolism. J. Biol. Chem. 285, 33959–33970 (2010).

  128. 128

    Walker, A. K. et al. Conserved role of SIRT1 orthologs in fasting-dependent inhibition of the lipid/cholesterol regulator SREBP. Genes Dev. 24, 1403–1417 (2010).

  129. 129

    Pfluger, P. T., Herranz, D., Velasco-Miguel, S., Serrano, M. & Tschop, M. H. Sirt1 protects against high-fat diet-induced metabolic damage. Proc. Natl Acad. Sci. USA 105, 9793–9798 (2008).

  130. 130

    Wang, R. H., Li, C. & Deng, C. X. Liver steatosis and increased ChREBP expression in mice carrying a liver specific SIRT1 null mutation under a normal feeding condition. Int. J. Biol. Sci. 6, 682–690 (2010).

  131. 131

    Kim, H. S. et al. Hepatic-specific disruption of SIRT6 in mice results in fatty liver formation due to enhanced glycolysis and triglyceride synthesis. Cell Metab. 12, 224–236 (2010).

  132. 132

    Wang, P., Mariman, E., Renes, J. & Keijer, J. The secretory function of adipocytes in the physiology of white adipose tissue. J. Cell Physiol. 216, 3–13 (2008).

  133. 133

    Heikkinen, S., Auwerx, J. & Argmann, C. A. PPARγ in human and mouse physiology. Biochim. Biophys. Acta 1771, 999–1013 (2007).

  134. 134

    Wang, F. & Tong, Q. SIRT2 suppresses adipocyte differentiation by deacetylating FOXO1 and enhancing FOXO1's repressive interaction with PPARγ Mol. Biol. Cell 20, 801–808 (2009).

  135. 135

    Schreurs, M., Kuipers, F. & van der Leij, F. R. Regulatory enzymes of mitochondrial β-oxidation as targets for treatment of the metabolic syndrome. Obes. Rev. 11, 380–388 (2010).

  136. 136

    Xu, F. et al. Lack of SIRT1 (mammalian sirtuin 1) activity leads to liver steatosis in the SIRT1± mice: a role of lipid mobilization and inflammation. Endocrinology 151, 2504–2514 (2010).

  137. 137

    Li, Y. et al. Hepatic overexpression of SIRT1 in mice attenuates endoplasmic reticulum stress and insulin resistance in the liver. FASEB J. 25, 1664–1679 (2011).

  138. 138

    Ajmo, J. M., Liang, X., Rogers, C. Q., Pennock, B. & You, M. Resveratrol alleviates alcoholic fatty liver in mice. Am. J. Physiol. Gastrointest. Liver Physiol. 295, 833–842 (2008).

  139. 139

    Yamazaki, Y. et al. Treatment with SRT1720, a SIRT1 activator, ameliorates fatty liver with reduced expression of lipogenic enzymes in MSG mice. Am. J. Physiol. Endocrinol. Metab. 297, 1179–1186 (2009).

  140. 140

    Yamamoto, H. et al. NCoR1 is a conserved physiological modulator of muscle mass and oxidative function. Cell 147, 827–839 (2011). This paper shows that reduced co-repressor activity can improve metabolism similarly to enhanced co-activator activity.

  141. 141

    Handschin, C. & Spiegelman, B. M. Peroxisome proliferator-activated receptor-γ coactivator 1 coactivators, energy homeostasis, and metabolism. Endocr. Rev. 27, 728–735 (2006).

  142. 142

    Fernandez-Marcos, P. J. & Auwerx, J. Regulation of PGC-1α, a nodal regulator of mitochondrial biogenesis. Am. J. Clin. Nutr. 93, 884S–890S (2011).

  143. 143

    Jager, S., Handschin, C., St- Pierre, J. & Spiegelman, B. M. AMP-activated protein kinase (AMPK) action in skeletal muscle via direct phosphorylation of PGC-1α. Proc. Natl Acad. Sci. USA 104, 12017–12022 (2007).

  144. 144

    Gonzalez, A. A., Kumar, R., Mulligan, J. D., Davis, A. J. & Saupe, K. W. Effects of aging on cardiac and skeletal muscle AMPK activity: basal activity, allosteric activation, and response to in vivo hypoxemia in mice. Am. J. Physiol. Regul. Integr. Comp. Physiol. 287, R1270–R1275 (2004).

  145. 145

    Schenk, S. et al. Sirt1 enhances skeletal muscle insulin sensitivity in mice during caloric restriction. J. Clin. Invest. 121, 4281–4288 (2011). This paper demonstrates that caloric restriction-induced insulin sensitivity is mediated by SIRT1 in skeletal muscle in mice.

  146. 146

    Palacios, O. M. et al. Diet and exercise signals regulate SIRT3 and activate AMPK and PGC-1α in skeletal muscle. Aging 1, 771–783 (2009).

  147. 147

    Philp, A. et al. Sirtuin 1 (SIRT1) deacetylase activity is not required for mitochondrial biogenesis or peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) deacetylation following endurance exercise. J. Biol. Chem. 286, 30561–30570 (2011).

  148. 148

    Cantó, C. & Auwerx, J. PGC-1α, SIRT1 and AMPK, an energy sensing network that controls energy expenditure. Curr. Opin. Lipidol. 20, 98–105 (2009).

  149. 149

    Tissenbaum, H. A. & Guarente, L. Increased dosage of a sir-2 gene extends lifespan in Caenorhabditis elegans. Nature 410, 227–230 (2001).

  150. 150

    Rogina, B. & Helfand, S. L. Sir2 mediates longevity in the fly through a pathway related to calorie restriction. Proc. Natl Acad. Sci. USA 101, 15998–16003 (2004).

  151. 151

    Bass, T. M., Weinkove, D., Houthoofd, K., Gems, D. & Partridge, L. Effects of resveratrol on lifespan in Drosophila melanogaster and Caenorhabditis elegans. Mech. Ageing Dev. 128, 546–552 (2007).

  152. 152

    Kaeberlein, M. & Powers, R. W. Sir2 and calorie restriction in yeast: a skeptical perspective. Ageing Res. Rev. 6, 128–140 (2007).

  153. 153

    Burnett, C. et al. Absence of effects of Sir2 overexpression on lifespan in C. elegans and Drosophila. Nature 477, 482–485 (2011). This study shows that Sir2 and sir-2.1 overexpression is not sufficient to extend lifespan in flies and worms, respectively.

  154. 154

    Viswanathan, M. & Guarente, L. Regulation of Caenorhabditis elegans lifespan by sir-2.1 transgenes. Nature 477, 1–2 (2011).

  155. 155

    Li, Y., Xu, W., McBurney, M. W. & Longo, V. D. SirT1 inhibition reduces IGF-I/IRS-2/Ras/ERK1/2 signaling and protects neurons. Cell Metab. 8, 38–48 (2008).

  156. 156

    Herranz, D. et al. Sirt1 improves healthy ageing and protects from metabolic syndrome-associated cancer. Nature Commun. 1, 3 (2010). This report demonstates that SIRT1 overexpression in mice improves healthy ageing but does not extend lifespan.

  157. 157

    Flachsbart, F. et al. Sirtuin 1 (SIRT1) sequence variation is not associated with exceptional human longevity. Exp. Gerontol. 41, 98–102 (2006).

  158. 158

    Bastin, J., Lopes-Costa, A. & Djouadi, F. Exposure to resveratrol triggers pharmacological correction of fatty acid utilization in human fatty acid oxidation-deficient fibroblasts. Hum. Mol. Genet. 20, 2048–2057 (2011).

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Acknowledgements

The authors apologize to colleagues whose original work could not be cited owing to space limitations. The authors thank team members of the Auwerx laboratory for discussions. R.H.H. is supported by a Rubicon fellowship of the Netherlands Organization for Scientific Research (NWO), and E.P. is funded by the Academy of Finland and the Finnish Cultural Foundation. The work in the Auwerx laboratory is supported by grants of the École Polytechnique Fédérale de Lausanne, Faculty of Life Science, the European Union Ideas programme (ERC-2008-AdG-23118), the Velux Stiftung and the Swiss National Science Foundation (31003A-124713 and 31003A-125487).

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Glossary

Caloric restriction

A reduction of caloric intake (typically 20–50% less than average) that has been shown to increase lifespan in a variety of organisms.

Nutriceutical

A food product that provides health benefits.

ADP-ribosyltransferases

Enzymes that transfer an ADP-ribose group on a protein target.

Demalonylate

The act of removing a malonyl group from a specific Lys residue of a target protein.

Desuccinylate

The act of removing a succinyl group from a specific Lys residue of a target protein.

Ketone bodies

Metabolic energy units derived from fat breakdown. Ketone bodies serve to fuel the brain in times of low blood glucose concentrations.

Tricarboxylic acid cycle

(TCA cycle). Also known as Krebs cycle. Acetyl-CoA derived from glucose or fat breakdown is further metabolized to offer reduced energy equivalents that are used by mitochondrial oxidative phosphorylation to generate ATP.

Oxidative phosphorylation

(OXPHOS). Mitochondrial enzymatic chain of events by which ATP is generated.

Reactive oxygen species

(ROS). Oxygen radicals that are produced as by-products of oxidative phosphorylation in mitochondria. In excess, they can cause intracellular and mitochondrial damage, which promotes cell death.

Steatosis

A condition characterized by abnormal accumulation of lipids within the cell.

K m

(Michaelis constant). Enzymatic property describing the substrate concentration at which the enzyme works at half-maximal capacity.

Hyperinsulinaemia

A condition that occurs when there is excess insulin in the circulation.

Fasting hypoglycaemia

A condition during fasting that occurs when circulating glucose levels are abnormally low.

Insulinoma cells

Tumour cells derived from pancreatic β-cells that secrete insulin.

Single-nucleotide polymorphisms

Naturally occurring single nucleotide variations in a DNA sequence. The most common type of genetic polymorphism.

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Houtkooper, R., Pirinen, E. & Auwerx, J. Sirtuins as regulators of metabolism and healthspan. Nat Rev Mol Cell Biol 13, 225–238 (2012). https://doi.org/10.1038/nrm3293

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