Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

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.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

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.

Similar content being viewed by others

References

  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).

    Article  CAS  Google Scholar 

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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  PubMed  CAS  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  Google Scholar 

  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).

    Article  CAS  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  Google Scholar 

  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).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

Download references

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).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Johan Auwerx.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

Related links

FURTHER INFORMATION

Auwerx laboratory homepage

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.

Rights and permissions

Reprints and permissions

About this article

Cite this article

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

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrm3293

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing