Sirtuins are a critical component of evolutionarily conserved longevity pathways. Sirtuins are nicotinamide adenine dinucleotide (NAD+)-dependent lysine deacylases that promote longevity and healthy ageing.
Sirtuin-activating compounds (STACs) bind to and allosterically modulate the affinity of SIRT1 for NAD+ and protein substrates, resulting in increased activity.
Increasing NAD+ levels through various strategies can enhance the activity of all sirtuins and improve metabolic function and increase longevity.
Sirtuin overexpression and treatment with naturally occurring and synthetic STACs improves metabolic function and increases longevity in mice.
More than 50 clinical trials are currently evaluating the safety and physiological activity of naturally occurring and synthetic STACs for treating human disease.
The sirtuins (SIRT1–7) are a family of nicotinamide adenine dinucleotide (NAD+)-dependent deacylases with remarkable abilities to prevent diseases and even reverse aspects of ageing. Mice engineered to express additional copies of SIRT1 or SIRT6, or treated with sirtuin-activating compounds (STACs) such as resveratrol and SRT2104 or with NAD+ precursors, have improved organ function, physical endurance, disease resistance and longevity. Trials in non-human primates and in humans have indicated that STACs may be safe and effective in treating inflammatory and metabolic disorders, among others. These advances have demonstrated that it is possible to rationally design molecules that can alleviate multiple diseases and possibly extend lifespan in humans.
This is a preview of subscription content, access via your institution
Open Access articles citing this article.
Smooth muscle liver kinase B1 inhibits foam cell formation and atherosclerosis via direct phosphorylation and activation of SIRT6
Cell Death & Disease Open Access 22 August 2023
Nature Communications Open Access 17 June 2023
Signal Transduction and Targeted Therapy Open Access 14 March 2023
Subscribe to this journal
Receive 12 print issues and online access
$189.00 per year
only $15.75 per issue
Rent or buy this article
Prices vary by article type
Prices may be subject to local taxes which are calculated during checkout
Robine, J. M. et al. The joint action on healthy life years (JA: EHLEIS). Arch. Public Health 71, 2 (2013).
McCay, C. M., Crowell, M. F. & Maynard, L. A. The effect of retarded growth upon the length of life span and upon the ultimate body size. 1935. Nutrition 5, 155–171 (1989). A pioneering study reporting that reduced calorie intake and reduced body size leads to extended longevity.
Anderson, R. M. & Weindruch, R. The caloric restriction paradigm: implications for healthy human aging. Am. J. Hum. Biol. 24, 101–106 (2012). An important review outlining what lessons have been learnt from calorie restriction studies and how they can be applied to human ageing.
Sinclair, D. A. Toward a unified theory of caloric restriction and longevity regulation. Mech. Ageing Dev. 126, 987–1002 (2005).
Kenyon, C. J. The genetics of ageing. Nature 464, 504–512 (2010).
Lopez-Otin, C., Blasco, M. A., Partridge, L., Serrano, M. & Kroemer, G. The hallmarks of aging. Cell 153, 1194–1217 (2013).
Miller, R. A. et al. Rapamycin-mediated lifespan increase in mice is dose and sex dependent and metabolically distinct from dietary restriction. Aging Cell 13, 468–477 (2014).
Martin-Montalvo, A. et al. Metformin improves healthspan and lifespan in mice. Nat. Commun. 4, 2192 (2013).
Mercken, E. M., Carboneau, B. A., Krzysik-Walker, S. M. & de Cabo, R. Of mice and men: the benefits of caloric restriction, exercise, and mimetics. Ageing Res. Rev. 11, 390–398 (2012).
Spindler, S. R. Caloric restriction: from soup to nuts. Ageing Res. Rev. 9, 324–353 (2010).
Phung, O. J., Sobieraj, D. M., Engel, S. S. & Rajpathak, S. N. Early combination therapy for the treatment of type 2 diabetes mellitus: systematic review and meta-analysis. Diabetes Obes. Metab. 16, 410–417 (2014).
Check-Hayden, E. Anti-ageing pill pushed as bona fide drug. Nature 522, 265–266 (2015).
Friedman, D. B. & Johnson, T. E. Three mutants that extend both mean and maximum life span of the nematode, Caenorhabditis elegans, define the age-1 gene. J. Gerontol. 43, B102–B109 (1988). Arguably the first evidence to indicate that genes may control longevity in worms.
Friedman, D. B. & Johnson, T. E. A mutation in the age-1 gene in Caenorhabditis elegans lengthens life and reduces hermaphrodite fertility. Genetics 118, 75–86 (1988).
Kennedy, B. K., Austriaco, N. R. Jr, Zhang, J. & Guarente, L. Mutation in the silencing gene SIR4 can delay aging in S. cerevisiae. Cell 80, 485–496 (1995). The first study to show that sirtuins are involved in controlling yeast longevity.
Kenyon, C., Chang, J., Gensch, E., Rudner, A. & Tabtiang, R. A. C. elegans mutant that lives twice as long as wild type. Nature 366, 461–464 (1993). These findings provided undisputed evidence that a single gene mutation can robustly extend longevity in the worm C. elegans.
Pacholec, M. et al. SRT1720, SRT2183, SRT1460, and resveratrol are not direct activators of SIRT1. J. Biol. Chem. 285, 8340–8351 (2010).
Burnett, C. et al. Absence of effects of Sir2 overexpression on lifespan in C. elegans and Drosophila. Nature 477, 482–485 (2011).
Rine, J. & Herskowitz, I. Four genes responsible for a position effect on expression from HML and HMR in Saccharomyces cerevisiae. Genetics 116, 9–22 (1987).
Kennedy, B. K. et al. Redistribution of silencing proteins from telomeres to the nucleolus is associated with extension of life span in S. cerevisiae. Cell 89, 381–391 (1997).
Sinclair, D. A. & Guarente, L. Extrachromosomal rDNA circles — a cause of aging in yeast. Cell 91, 1033–1042 (1997). The first study to show that replicative lifespan is mediated by the accumulation of ERCs.
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).
Stumpferl, S. W. et al. Natural genetic variation in yeast longevity. Genome Res. 22, 1963–1973 (2012).
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). The first study to determine the mechanism for Sir2 was a NAD-dependent histone deacetylase.
Landry, J. et al. The silencing protein SIR2 and its homologs are NAD-dependent protein deacetylases. Proc. Natl Acad. Sci. USA 97, 5807–5811 (2000).
Frye, R. A. Phylogenetic classification of prokaryotic and eukaryotic Sir2-like proteins. Biochem. Biophys. Res. Commun. 273, 793–798 (2000).
Tissenbaum, H. A. & Guarente, L. Increased dosage of a sir-2 gene extends lifespan in Caenorhabditis elegans. Nature 410, 227–230 (2001).
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).
Rizki, G. et al. The evolutionarily conserved longevity determinants HCF-1 and SIR-2.1/SIRT1 collaborate to regulate DAF-16/FOXO. PLoS Genet. 7, e1002235 (2011).
Schmeisser, K. et al. Role of sirtuins in lifespan regulation is linked to methylation of nicotinamide. Nat. Chem. Biol. 9, 693–700 (2013).
Moroz, N. et al. Dietary restriction involves NAD+-dependent mechanisms and a shift toward oxidative metabolism. Aging Cell 13, 1075–1085 (2014).
Banerjee, K. K. et al. dSir2 in the adult fat body, but not in muscles, regulates life span in a diet-dependent manner. Cell Rep. 2, 1485–1491 (2012).
Whitaker, R. et al. Increased expression of Drosophila Sir2 extends life span in a dose-dependent manner. Aging (Albany, NY) 5, 682–691 (2013).
Houtkooper, R. H., Pirinen, E. & Auwerx, J. Sirtuins as regulators of metabolism and healthspan. Nat. Rev. Mol. Cell Biol. 13, 225–238 (2012).
Oberdoerffer, P. et al. SIRT1 redistribution on chromatin promotes genomic stability but alters gene expression during aging. Cell 135, 907–918 (2008).
Sinclair, D. A., Mills, K. & Guarente, L. Molecular mechanisms of yeast aging. Trends Biochem. Sci. 23, 131–134 (1998).
Fernandez-Marcos, P. J. & Auwerx, J. Regulation of PGC-1α, a nodal regulator of mitochondrial biogenesis. Am. J. Clin. Nutr. 93, 884S–890S (2011).
Toiber, D., Sebastian, C. & Mostoslavsky, R. Characterization of nuclear sirtuins: molecular mechanisms and physiological relevance. Handb. Exp. Pharmacol. 206, 189–224 (2011).
Haigis, M. C. & Sinclair, D. A. Mammalian sirtuins: biological insights and disease relevance. Annu. Rev. Pathol. 5, 253–295 (2010). A thorough review of the various biological mechanisms of sirtuin function in mammalian systems and physiology.
Chang, H. C. & Guarente, L. SIRT1 and other sirtuins in metabolism. Trends Endocrinol. Metab. 25, 138–145 (2014).
Nakagawa, T. & Guarente, L. SnapShot: sirtuins, NAD, and aging. Cell Metab. 20, 192 (2014). Lists the many sirtuin signalling protein targets.
Luo, J. et al. Negative control of p53 by Sir2α promotes cell survival under stress. Cell 107, 137–148 (2001).
Vaziri, H. et al. hSIR2SIRT1 functions as an NAD-dependent p53 deacetylase. Cell 107, 149–159 (2001).
Yeung, F. et al. Modulation of NF-κB-dependent transcription and cell survival by the SIRT1 deacetylase. EMBO J. 23, 2369–2380 (2004).
Rodgers, J. T. et al. Nutrient control of glucose homeostasis through a complex of PGC-1α and SIRT1. Nature 434, 113–118 (2005).
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).
Cohen, H. Y. et al. Calorie restriction promotes mammalian cell survival by inducing the SIRT1 deacetylase. Science 305, 390–392 (2004).
Cohen, H. Y. et al. Acetylation of the C terminus of Ku70 by CBP and PCAF controls Bax-mediated apoptosis. Mol. Cell 13, 627–638 (2004).
Pillai, J. B., Isbatan, A., Imai, S. & Gupta, M. P. Poly(ADP-ribose) polymerase-1-dependent cardiac myocyte cell death during heart failure is mediated by NAD+ depletion and reduced Sir2α deacetylase activity. J. Biol. Chem. 280, 43121–43130 (2005).
Vaitiekunaite, R. et al. Expression and localization of Werner syndrome protein is modulated by SIRT1 and PML. Mech. Ageing Dev. 128, 650–661 (2007).
Li, K. et al. Regulation of WRN protein cellular localization and enzymatic activities by SIRT1-mediated deacetylation. J. Biol. Chem. 283, 7590–7598 (2008).
Peng, C. et al. The first identification of lysine malonylation substrates and its regulatory enzyme. Mol. Cell Proteomics 10, M111.012658 (2011).
Du, J. et al. Sirt5 is a NAD-dependent protein lysine demalonylase and desuccinylase. Science 334, 806–809 (2011).
Haigis, M. C. et al. SIRT4 inhibits glutamate dehydrogenase and opposes the effects of calorie restriction in pancreatic beta cells. Cell 126, 941–954 (2006).
Feldman, J. L. et al. Kinetic and structural basis for acyl-group selectivity and NAD dependence in sirtuin-catalyzed deacylation. Biochemistry 54, 3037–3050 (2015).
Feldman, J. L., Baeza, J. & Denu, J. M. Activation of the protein deacetylase SIRT6 by long-chain fatty acids and widespread deacylation by mammalian sirtuins. J. Biol. Chem. 288, 31350–31356 (2013).
Tanner, K. G., Landry, J., Sternglanz, R. & Denu, J. M. Silent information regulator 2 family of NAD- dependent histone/protein deacetylases generates a unique product, 1-O-acetyl-ADP-ribose. Proc. Natl Acad. Sci. USA 97, 14178–14182 (2000).
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).
Landry, J., Slama, J. T. & Sternglanz, R. Role of NAD+ in the deacetylase activity of the SIR2-like proteins. Biochem. Biophys. Res. Commun. 278, 685–690 (2000).
Kraus, D. et al. Nicotinamide N-methyltransferase knockdown protects against diet-induced obesity. Nature 508, 258–262 (2014).
Hong, S. et al. Nicotinamide N-methyltransferase regulates hepatic nutrient metabolism through Sirt1 protein stabilization. Nat. Med. 21, 887–894 (2015).
Wang, Y., Liang, Y. & Vanhoutte, P. M. SIRT1 and AMPK in regulating mammalian senescence: a critical review and a working model. FEBS Lett. 585, 986–994 (2011).
Gerhart-Hines, Z. et al. The cAMP/PKA pathway rapidly activates SIRT1 to promote fatty acid oxidation independently of changes in NAD+. Mol. Cell 44, 851–863 (2011).
Armour, S. M. et al. Inhibition of mammalian S6 kinase by resveratrol suppresses autophagy. Aging (Albany, NY) 1, 515–528 (2009). These findings provided an interesting link between mammalian sirtuins and mTOR signalling.
Ghosh, H. S., McBurney, M. & Robbins, P. D. SIRT1 negatively regulates the mammalian target of rapamycin. PLoS ONE 5, e9199 (2010).
Liu, M. et al. Resveratrol inhibits mTOR signaling by promoting the interaction between mTOR and DEPTOR. J. Biol. Chem. 285, 36387–36394 (2010).
Mouchiroud, L. et al. The NAD+/sirtuin pathway modulates longevity through activation of mitochondrial UPR and FOXO signaling. Cell 154, 430–441 (2013).
Longo, V. D. Linking sirtuins, IGF-I signaling, and starvation. Exp. Gerontol. 44, 70–74 (2009). This paper provides a strong link between calorie restriction, IGF1 signalling and sirtuins.
Bordone, L. et al. SIRT1 transgenic mice show phenotypes resembling calorie restriction. Aging Cell 6, 759–767 (2007).
Banks, A. S. et al. SirT1 gain of function increases energy efficiency and prevents diabetes in mice. Cell Metab. 8, 333–341 (2008).
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).
Satoh, A. et al. 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 (2013).
Kanfi, Y. et al. The sirtuin SIRT6 regulates lifespan in male mice. Nature 483, 218–221 (2012).
Kanfi, Y. et al. SIRT6 protects against pathological damage caused by diet-induced obesity. Aging Cell 9, 162–173 (2010).
Kugel, S. et al. SIRT6 suppresses pancreatic cancer through control of Lin28b. Cell 165, 1401–1415 (2016).
Chalkiadaki, A. & Guarente, L. The multifaceted functions of sirtuins in cancer. Nat. Rev. Cancer 15, 608–624 (2015).
Howitz, K. T. et al. Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature 425, 191–196 (2003).
Milne, J. C. et al. Small molecule activators of SIRT1 as therapeutics for the treatment of type 2 diabetes. Nature 450, 712–716 (2007).
Dai, H. et al. SIRT1 activation by small molecules: kinetic and biophysical evidence for direct interaction of enzyme and activator. J. Biol. Chem. 285, 32695–32703 (2010).
Hubbard, B. P. & Sinclair, D. A. Small molecule SIRT1 activators for the treatment of aging and age-related diseases. Trends Pharmacol. Sci. 35, 146–154 (2014).
Mao, Z. et al. SIRT6 promotes DNA repair under stress by activating PARP1. Science 332, 1443–1446 (2011).
Van, M. M. et al. SIRT6 represses LINE1 retrotransposons by ribosylating KAP1 but this repression fails with stress and age. Nat. Commun. 5, 5011 (2014).
Xu, Z. et al. SIRT6 rescues the age related decline in base excision repair in a PARP1-dependent manner. Cell Cycle 14, 269–276 (2015).
Sebastian, C. et al. The histone deacetylase SIRT6 is a tumor suppressor that controls cancer metabolism. Cell 151, 1185–1199 (2012).
Borra, M. T., Langer, M. R., Slama, J. T. & Denu, J. M. Substrate specificity and kinetic mechanism of the Sir2 family of NAD+-dependent histone/protein deacetylases. Biochemistry 43, 9877–9887 (2004).
Kaeberlein, M. et al. Substrate-specific activation of sirtuins by resveratrol. J. Biol. Chem. 280, 17038–17045 (2005).
Chen, Y. et al. Quantitative acetylome analysis reveals the roles of SIRT1 in regulating diverse substrates and cellular pathways. Mol. Cell Proteomics 11, 1048–1062 (2012).
Lakshminarasimhan, M., Rauh, D., Schutkowski, M. & Steegborn, C. Sirt1 activation by resveratrol is substrate sequence-selective. Aging (Albany, NY) 5, 151–154 (2013).
Hubbard, B. P. et al. Evidence for a common mechanism of SIRT1 regulation by allosteric activators. Science 339, 1216–1219 (2013). A report of a sirtuin amino acid peptide screen that revealed the essential amino acid required for STAC binding to SIRT1.
Zorn, J. A. & Wells, J. A. Turning enzymes ON with small molecules. Nat. Chem. Biol. 6, 179–188 (2010).
Dai, H. et al. Crystallographic structure of a small molecule SIRT1 activator–enzyme complex. Nat. Commun. 6, 7645 (2015). The determination of the crystal structure for a truncated SIRT1 bound to the activator STAC-1.
Ghisays, F. et al. The N-terminal domain of SIRT1 is a positive regulator of endogenous SIRT1-dependent deacetylation and transcriptional outputs. Cell Rep. 10, 1665–1673 (2015).
Cuperus, G., Shafaatian, R. & Shore, D. Locus specificity determinants in the multifunctional yeast silencing protein Sir2. EMBO J. 19, 2641–2651 (2000).
Howitz, K. T. & Sinclair, D. A. Xenohormesis: sensing the chemical cues of other species. Cell 133, 387–391 (2008).
Fulco, M. et al. Glucose restriction inhibits skeletal myoblast differentiation by activating SIRT1 through AMPK-mediated regulation of Nampt. Dev. Cell 14, 661–673 (2008).
Canto, C. et al. AMPK regulates energy expenditure by modulating NAD+ metabolism and SIRT1 activity. Nature 458, 1056–1060 (2009).
Park, S. J. et al. Resveratrol ameliorates aging-related metabolic phenotypes by inhibiting cAMP phosphodiesterases. Cell 148, 421–433 (2012).
Gledhill, J. R., Montgomery, M. G., Leslie, A. G. & Walker, J. E. Mechanism of inhibition of bovine F1-ATPase by resveratrol and related polyphenols. Proc. Natl Acad. Sci. USA 104, 13632–13637 (2007).
Zini, R., Morin, C., Bertelli, A., Bertelli, A. A. & Tillement, J. P. Effects of resveratrol on the rat brain respiratory chain. Drugs Exp. Clin. Res. 25, 87–97 (1999).
Sajish, M. & Schimmel, P. A human tRNA synthetase is a potent PARP1-activating effector target for resveratrol. Nature 519, 370–373 (2015).
Gerdts, J., Brace, E. J., Sasaki, Y., DiAntonio, A. & Milbrandt, J. Neurobiology. SARM1 activation triggers axon degeneration locally via NAD+ destruction. Science 348, 453–457 (2015).
Hou, X. et al. SIRT1 regulates hepatocyte lipid metabolism through activating AMP-activated protein kinase. J. Biol. Chem. 283, 20015–20026 (2008).
Ivanov, V. N. et al. Resveratrol sensitizes melanomas to TRAIL through modulation of antiapoptotic gene expression. Exp. Cell Res. 314, 1163–1176 (2008).
Lan, F., Cacicedo, J. M., Ruderman, N. & Ido, Y. SIRT1 modulation of the acetylation status, cytosolic localization, and activity of LKB1. Possible role in AMP-activated protein kinase activation. J. Biol. Chem. 283, 27628–27635 (2008).
Price, N. L. et al. SIRT1 is required for AMPK activation and the beneficial effects of resveratrol on mitochondrial function. Cell Metab. 15, 675–690 (2012).
Tome-Carneiro, J. et al. Resveratrol and clinical trials: the crossroad from in vitro studies to human evidence. Curr. Pharm. Des. 19, 6064–6093 (2013). A meta-analysis of the effects of resveratrol in clinical trials.
Walsh, G. P. Does diet or alcohol explain the French paradox. Lancet 345, 528 (1995).
Semba, R. D. et al. Resveratrol levels and all-cause mortality in older community-dwelling adults. JAMA Intern. Med. 174, 1077–1084 (2014).
Jimenez-Gomez, Y. et al. Resveratrol improves adipose insulin signaling and reduces the inflammatory response in adipose tissue of rhesus monkeys on high-fat, high-sugar diet. Cell Metab. 18, 533–545 (2013).
Mattison, J. A. et al. Resveratrol prevents high fat/sucrose diet-induced central arterial wall inflammation and stiffening in nonhuman primates. Cell Metab. 20, 183–190 (2014).
Fiori, J. L. et al. Resveratrol prevents β-cell dedifferentiation in nonhuman primates given a high-fat/high-sugar diet. Diabetes 62, 3500–3513 (2013).
AlGhatrif, M. et al. Longitudinal trajectories of arterial stiffness and the role of blood pressure: the Baltimore Longitudinal Study of Aging. Hypertension 62, 934–941 (2013).
Bhatt, J. K., Thomas, S. & Nanjan, M. J. Resveratrol supplementation improves glycemic control in type 2 diabetes mellitus. Nutr. Res. 32, 537–541 (2012).
Crandall, J. P. et al. Pilot study of resveratrol in older adults with impaired glucose tolerance. J. Gerontol. A Biol. Sci. Med. Sci. 67, 1307–1312 (2012).
Wong, R. H. et al. Acute resveratrol supplementation improves flow-mediated dilatation in overweight/obese individuals with mildly elevated blood pressure. Nutr. Metab. Cardiovasc. Dis. 21, 851–856 (2011).
Magyar, K. et al. Cardioprotection by resveratrol: a human clinical trial in patients with stable coronary artery disease. Clin. Hemorheol. Microcirc. 50, 179–187 (2012).
Poulsen, M. M. et al. High-dose resveratrol supplementation in obese men: an investigator-initiated, randomized, placebo-controlled clinical trial of substrate metabolism, insulin sensitivity, and body composition. Diabetes 62, 1186–1195 (2013).
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).
Turner, R. S. et al. A randomized, double-blind, placebo-controlled trial of resveratrol for Alzheimer disease. Neurology 85, 1383–1391 (2015).
Kim, D. et al. SIRT1 deacetylase protects against neurodegeneration in models for Alzheimer's disease and amyotrophic lateral sclerosis. EMBO J. 26, 3169–3179 (2007).
Hausenblas, H. A., Schoulda, J. A. & Smoliga, J. M. Resveratrol treatment as an adjunct to pharmacological management in type 2 diabetes mellitus — systematic review and meta-analysis. Mol. Nutr. Food Res. 59, 147–159 (2015).
Cote, C. D. et al. Resveratrol activates duodenal Sirt1 to reverse insulin resistance in rats through a neuronal network. Nat. Med. 21, 498–505 (2015).
Minor, R. K. et al. SRT1720 improves survival and healthspan of obese mice. Sci. Rep. 1, 70 (2011).
Mitchell, S. J. et al. The SIRT1 activator SRT1720 extends lifespan and improves health of mice fed a standard diet. Cell Rep. 6, 836–843 (2014). Describes the effects of feeding the STAC SRT1720 on healthspan and lifespan.
Mercken, E. M. et al. SRT2104 extends survival of male mice on a standard diet and preserves bone and muscle mass. Aging Cell 13, 787–796 (2014). Long-term administration of STAC SRT2104 extends healthspan and longevity.
Graff, J. et al. A dietary regimen of caloric restriction or pharmacological activation of SIRT1 to delay the onset of neurodegeneration. J. Neurosci. 33, 8951–8960 (2013).
Miranda, M. X. et al. The Sirt1 activator SRT3025 provides atheroprotection in Apoe−/− mice by reducing hepatic Pcsk9 secretion and enhancing Ldlr expression. Eur. Heart J. 36, 51–59 (2015).
Hoffmann, E. et al. Pharmacokinetics and tolerability of SRT2104, a first-in-class small molecule activator of SIRT1, after single and repeated oral administration in man. Br. J. Clin. Pharmacol. 75, 186–196 (2013).
Libri, V. et al. A pilot randomized, placebo controlled, double blind phase I trial of the novel SIRT1 activator SRT2104 in elderly volunteers. PLoS ONE 7, e51395 (2012).
Venkatasubramanian, S. et al. Cardiovascular effects of a novel SIRT1 activator, SRT2104, in otherwise healthy cigarette smokers. J. Am. Heart Assoc. 2, e000042 (2013).
Krueger, J. G. et al. A randomized, placebo-controlled study of SRT2104, a SIRT1 activator, in patients with moderate to severe psoriasis. PLoS ONE 10, e0142081 (2015).
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).
Anderson, R. M. et al. Manipulation of a nuclear NAD+ salvage pathway delays aging without altering steady-state NAD+ levels. J. Biol. Chem. 277, 18881–18890 (2002).
Malavasi, F. et al. Evolution and function of the ADP ribosyl cyclase/CD38 gene family in physiology and pathology. Physiol. Rev. 88, 841–886 (2008).
Camacho-Pereira, J. et al. CD38 dictates age-related NAD decline and mitochondrial dysfunction through an SIRT3-dependent mechanism. Cell Metab. 23, 1127–1139 (2016).
Braidy, N. et al. Age related changes in NAD+ metabolism oxidative stress and Sirt1 activity in Wistar rats. PLoS ONE 6, e19194 (2011).
Gomes, A. P. et al. Declining NAD+ induces a pseudohypoxic state disrupting nuclear-mitochondrial communication during aging. Cell 155, 1624–1638 (2013).
Ramsey, K. M., Mills, K. F., Satoh, A. & Imai, S. Age-associated loss of Sirt1-mediated enhancement of glucose-stimulated insulin secretion in β cell-specific Sirt1-overexpressing (BESTO) mice. Aging Cell 7, 78–88 (2008).
Chang, H. C. & Guarente, L. SIRT1 mediates central circadian control in the SCN by a mechanism that decays with aging. Cell 153, 1448–1460 (2013).
Gong, B. et al. Nicotinamide riboside restores cognition through an upregulation of proliferator-activated receptor-gamma coactivator 1α regulated beta-secretase 1 degradation and mitochondrial gene expression in Alzheimer's mouse models. Neurobiol. Aging 34, 1581–1588 (2013).
Zhang, H. et al. NAD+ repletion improves mitochondrial and stem cell function and enhances life span in mice. Science 352, 1436–1443 (2016).
Escande, C. et al. Flavonoid apigenin is an inhibitor of the NAD+ase CD38: implications for cellular NAD+ metabolism, protein acetylation, and treatment of metabolic syndrome. Diabetes 62, 1084–1093 (2013).
Haffner, C. D. et al. Discovery, synthesis, and biological evaluation of thiazoloquin(az)olin(on)es as potent CD38 inhibitors. J. Med. Chem. 58, 3548–3571 (2015).
Mouchiroud, L., Houtkooper, R. H. & Auwerx, J. NAD+ metabolism: a therapeutic target for age-related metabolic disease. Crit. Rev. Biochem. Mol. Biol. 48, 397–408 (2013). A thorough review outlining the potential mechanisms and roles of NAD in metabolism and disease.
Canto, C. et al. The NAD+ precursor nicotinamide riboside enhances oxidative metabolism and protects against high-fat diet-induced obesity. Cell Metab. 15, 838–847 (2012).
Khan, N. A. et al. Effective treatment of mitochondrial myopathy by nicotinamide riboside, a vitamin B3 . EMBO Mol. Med. 6, 721–731 (2014).
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).
Tummala, K. S. et al. Inhibition of de novo NAD+ synthesis by oncogenic URI causes liver tumorigenesis through DNA damage. Cancer Cell 26, 826–839 (2014).
Scheibye-Knudsen, M. et al. A high-fat diet and NAD+ activate Sirt1 to rescue premature aging in cockayne syndrome. Cell Metab. 20, 840–855 (2014).
Brown, K. D. et al. Activation of SIRT3 by the NAD+ precursor nicotinamide riboside protects from noise-induced hearing loss. Cell Metab. 20, 1059–1068 (2014).
Xu, W. et al. Lethal cardiomyopathy in mice lacking transferrin receptor in the heart. Cell Rep. 13, 533–545 (2015).
Wang, G. et al. P7C3 neuroprotective chemicals function by activating the rate-limiting enzyme in NAD salvage. Cell 158, 1324–1334 (2014).
Yoon, M. J. et al. SIRT1-mediated eNAMPT secretion from adipose tissue regulates hypothalamic NAD+ and function in mice. Cell Metab. 21, 706–717 (2015).
Jarolim, S. et al. A novel assay for replicative lifespan in Saccharomyces cerevisiae. FEMS Yeast Res. 5, 169–177 (2004).
Yang, H. et al. Nutrient-sensitive mitochondrial NAD+ levels dictate cell survival. Cell 130, 1095–1107 (2007).
Morselli, E. et al. Autophagy mediates pharmacological lifespan extension by spermidine and resveratrol. Aging (Albany, NY) 1, 961–970 (2009).
Viswanathan, M., Kim, S. K., Berdichevsky, A. & Guarente, L. A role for SIR-2.1 regulation of ER stress response genes in determining C. elegans life span. Dev. Cell 9, 605–615 (2005).
Zarse, K. et al. Differential effects of resveratrol and SRT1720 on lifespan of adult Caenorhabditis elegans. Horm. Metab. Res. 42, 837–839 (2010).
Wood, J. G. et al. Sirtuin activators mimic caloric restriction and delay ageing in metazoans. Nature 430, 686–689 (2004).
Bauer, J. H., Goupil, S., Garber, G. B. & Helfand, S. L. An accelerated assay for the identification of lifespan-extending interventions in Drosophila melanogaster. Proc. Natl Acad. Sci. USA 101, 12980–12985 (2004).
Bauer, J. H. et al. dSir2 and Dmp53 interact to mediate aspects of CR-dependent lifespan extension in D. melanogaster. Aging (Albany, NY) 1, 38–48 (2009).
Genade, T. & Lang, D. M. Resveratrol extends lifespan and preserves glia but not neurons of the Nothobranchius guentheri optic tectum. Exp. Gerontol. 48, 202–212 (2013).
Liu, T. et al. Resveratrol attenuates oxidative stress and extends lifespan in the annual fish Nothobranchius guentheri. Rejuven. Res. 18, 225–233 (2015).
Valenzano, D. R. & Cellerino, A. Resveratrol and the pharmacology of aging: a new vertebrate model to validate an old molecule. Cell Cycle 5, 1027–1032 (2006).
Yu, X. & Li, G. Effects of resveratrol on longevity, cognitive ability and aging-related histological markers in the annual fish Nothobranchius guentheri. Exp. Gerontol. 47, 940–949 (2012).
Rascon, B., Hubbard, B. P., Sinclair, D. A. & Amdam, G. V. The lifespan extension effects of resveratrol are conserved in the honey bee and may be driven by a mechanism related to caloric restriction. Aging (Albany, NY) 4, 499–508 (2012).
Baur, J. A. et al. Resveratrol improves health and survival of mice on a high-calorie diet. Nature 444, 337–342 (2006). The first evidence to indicate that resveratrol could reverse many of the detriments of feeding a high-fat diet in mice and extend longevity.
Barger, J. L., Kayo, T., Pugh, T. D., Prolla, T. A. & Weindruch, R. Short-term consumption of a resveratrol-containing nutraceutical mixture mimics gene expression of long-term caloric restriction in mouse heart. Exp. Gerontol. 43, 859–866 (2008).
Barger, J. L. et al. A low dose of dietary resveratrol partially mimics caloric restriction and retards aging parameters in mice. PLoS ONE 3, e2264 (2008).
Park, S. K. et al. Gene expression profiling of aging in multiple mouse strains: identification of aging biomarkers and impact of dietary antioxidants. Aging Cell 8, 484–495 (2009).
Lagouge, M. et al. Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1α. Cell 127, 1109–1122 (2006).
Nakata, A. et al. Potent SIRT1 enzyme-stimulating and anti-glycation activities of polymethoxyflavonoids from Kaempferia parviflora. Nat. Prod. Commun. 9, 1291–1294 (2014).
Nayagam, V. M. et al. SIRT1 modulating compounds from high-throughput screening as anti-inflammatory and insulin-sensitizing agents. J. Biomol. Screen. 11, 959–967 (2006).
Lamming, D. W., Sabatini, D. M. & Baur, J. A. Pharmacologic means of extending lifespan. J. Clin. Exp. Pathol. (Suppl. 4), 7327 (2012).
Boily, G., He, X. H., Pearce, B., Jardine, K. & McBurney, M. W. Sirt1-null mice develop tumors at normal rates but are poorly protected by resveratrol. Oncogene 28, 2882–2893 (2009).
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).
Garavaglia, S. et al. The high-resolution crystal structure of periplasmic Haemophilus influenzae NAD nucleotidase reveals a novel enzymatic function of human CD73 related to NAD metabolism. Biochem. J. 441, 131–141 (2012).
Grozio, A. et al. CD73 protein as a source of extracellular precursors for sustained NAD+ biosynthesis in FK866-treated tumor cells. J. Biol. Chem. 288, 25938–25949 (2013).
Carafa, V. et al. Sirtuin functions and modulation: from chemistry to the clinic. Clin. Epigenetics 8, 61 (2016). An in-depth review discussing sirtuin inhibition as a potential therapeutic target.
Lin, S. J., Defossez, P. A. & Guarente, L. Requirement of NAD and SIR2 for life-span extension by calorie restriction in Saccharomyces cerevisiae. Science 289, 2126–2128 (2000).
Lamming, D. W. et al. HST2 mediates SIR2-independent life-span extension by calorie restriction. Science 309, 1861–1864 (2005).
Kaeberlein, M., Kirkland, K. T., Fields, S. & Kennedy, B. K. Sir2-independent life span extension by calorie restriction in yeast. PLoS Biol. 2, E296 (2004).
Tsuchiya, M. et al. Sirtuin-independent effects of nicotinamide on lifespan extension from calorie restriction in yeast. Aging Cell 5, 505–514 (2006).
Mei, S. C. & Brenner, C. Calorie restriction-mediated replicative lifespan extension in yeast is non-cell autonomous. PLoS Biol. 13, e1002048 (2015).
Evans, C. et al. NAD+ metabolite levels as a function of vitamins and calorie restriction: evidence for different mechanisms of longevity. BMC Chem. Biol. 10, 2 (2010).
Wang, Y. & Tissenbaum, H. A. Overlapping and distinct functions for a Caenorhabditis elegans SIR2 and DAF-16/FOXO. Mech. Ageing Dev. 127, 48–56 (2006).
van der Horst, A., Schavemaker, J. M., Pellis-van, B. W. & Burgering, B. M. The Caenorhabditis elegans nicotinamidase PNC-1 enhances survival. Mech. Ageing Dev. 128, 346–349 (2007).
Viswanathan, M. & Guarente, L. Regulation of Caenorhabditis elegans lifespan by sir-2.1 transgenes. Nature 477, E1–E2 (2011).
Gruber, J., Tang, S. Y. & Halliwell, B. Evidence for a trade-off between survival and fitness caused by resveratrol treatment of Caenorhabditis elegans. Ann. NY Acad. Sci. 1100, 530–542 (2007).
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).
Greer, E. L. & Brunet, A. Different dietary restriction regimens extend lifespan by both independent and overlapping genetic pathways in C. elegans. Aging Cell 8, 113–127 (2009).
Mair, W., Panowski, S. H., Shaw, R. J. & Dillin, A. Optimizing dietary restriction for genetic epistasis analysis and gene discovery in C. elegans. PLoS ONE 4, e4535 (2009).
Astrom, S. U., Cline, T. W. & Rine, J. The Drosophila melanogaster sir2+ gene is nonessential and has only minor effects on position-effect variegation. Genetics 163, 931–937 (2003).
Newman, B. L., Lundblad, J. R., Chen, Y. & Smolik, S. M. A. Drosophila homologue of Sir2 modifies position-effect variegation but does not affect life span. Genetics 162, 1675–1685 (2002).
Pallos, J. et al. Inhibition of specific HDACs and sirtuins suppresses pathogenesis in a Drosophila model of Huntington's disease. Hum. Mol. Genet. 17, 3767–3775 (2008).
Hoffmann, J., Romey, R., Fink, C., Yong, L. & Roeder, T. Overexpression of Sir2 in the adult fat body is sufficient to extend lifespan of male and female Drosophila. Aging (Albany, NY) 5, 315–327 (2013).
Parashar, V. & Rogina, B. dSir2 mediates the increased spontaneous physical activity in flies on calorie restriction. Aging (Albany, NY) 1, 529–541 (2009).
McBurney, M. W. et al. The mammalian SIR2α protein has a role in embryogenesis and gametogenesis. Mol. Cell. Biol. 23, 38–54 (2003).
Boily, G. et al. SirT1 regulates energy metabolism and response to caloric restriction in mice. PLoS ONE 3, e1759 (2008).
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).
The authors thank M. B. Schultz for suggestions and edits and are grateful for financial support from the National Institute on Aging, the National Institutes of Health, the Paul F. Glenn Foundation for Medical Research, Edward Schulak, and Ovaxon.
D.A.S. is a consultant to and/or inventor on patents licensed to GlaxoSmithKline, Ovascience, MetroBiotech, Arc Bio, and Liberty BioSecurity. M.S.B. is a consultant for Ovascience.
- Replicative ageing
In yeast, the number of daughter cells produced by a mother cell before senescence.
- Redox reactions
Oxidation–reduction (redox) reactions involving the transfer of electrons between two chemical species.
- Hepatic steatosis
Also known as fatty liver, is a term used to describe the accumulation of fat in the liver cells.
- Allosteric activation
Activation of an enzyme by binding of a ligand, which enhances the binding of substrates at other binding sites.
- K m
Michaelis constant, which reflects the affinity of an enzyme for its substrate. The Km is measured as the substrate concentration at which the reaction rate is half of its maximum rate.
- K-type allosteric activation
Refers to the major type of allosteric activation, in which the main feature that is altered is the Michaelis constant (Km).
- HOMA index
The homeostatic model assessment (HOMA) index is a clinical measure used to predict the function of pancreatic β-cells and insulin resistance.
The degree and rate at which a substance is absorbed and is made available at the site of physiological activity.
The concentration of substrate that elicits a half-maximal enzymatic response.
- Plaque-type psoriasis
The most common form of the disease, which is manifested as raised, red patches covered with a silvery white build-up of dead skin cells or scale.
About this article
Cite this article
Bonkowski, M., Sinclair, D. Slowing ageing by design: the rise of NAD+ and sirtuin-activating compounds. Nat Rev Mol Cell Biol 17, 679–690 (2016). https://doi.org/10.1038/nrm.2016.93
This article is cited by
Journal of Translational Medicine (2023)
Journal of Translational Medicine (2023)
Nature Reviews Immunology (2023)
Acta Pharmacologica Sinica (2023)
Signal Transduction and Targeted Therapy (2023)