Numerous theories of how and why aging occurs have been postulated but a definitive comprehensive explanation remains elusive. Attempts to unravel genetic details of aging resulted in the identification of a yeast gene known as Sir2 as a modulator of life span. Identification and characterization of mammalian Sir2 homologs followed and has catapulted aging research to exciting new levels. This review begins with basic definitions of aging and then describes some of the most common theories of the aging process. The review presents information related to the initial discovery of the Sirtuins and summarizes some of the recent advances in defining roles for Sirtuin family members. SIRT6 is discussed in greater detail because it is one of the best characterized of the mammalian Sirtuins and seems to be one of the most important in the aging process and metabolic regulation.
S. E. Artandi, “Telomeres, Telomerase, and Human Disease,” New England Journal of Medicine, Vol. 355, No. 12, 2006, pp. 1195-1197. doi:10.1056/NEJMp068187
H. Vaziri and S. Benchimol, “Reconstitution of Telomerase Activity in Normal Human Cells Leads to Elongation of Telomeres and Extended Replicative Life Span,” Current Biology, Vol. 8, No. 5, 1998, pp. 279-282. doi:10.1016/S0960-9822(98)70109-5
A. Salminen, J. Huuskonen, J. Ojala, A. Kauppinen, K. Kaarniranta and T. Suuronen, “Activation of Innate Immunity System during Aging: NF-kB Signaling Is the Molecular Culprit of Inflamm-Aging,” Ageing Research Reviews, Vol. 7, No. 2, 2008, pp. 83-105. doi:10.1016/j.arr.2007.09.002
D. C. Allis, T. Jenuwein, D. Reinberg and M.-L. Caparros, “Epigenetics,” Cold Spring Harbor Laboratories Press, New York, 2007.
C. M. McCay, L. A. Maynard, G. Sperling and L. L. Barnes, “Retarded Growth, Lifespan, Ultimate Body Size and Age Changes in the Albino Rat after Feeding Diets Restricted in Calories,” Journal of Nutrition, Vol. 18, 1939, pp. 1-13.
D. Harman, “Free Radical Theory of Aging: Effect of Free Radical Reaction Inhibitors on the Mortality Rate of Male LAF Mice,” Journal of Gerontology, Vol. 23, No. 4, 1968, pp. 476-482. doi:10.1093/geronj/23.4.476
D. Harman, “Free Radical Theory of Aging: An Update,” Annual of the New York Academy of Science, Vol. 1067, 2006, pp. 10-21. doi:10.1196/annals.1354.003
E. R. Miller III, R. Pastor-Barriuso, D. Dalal, R. A. Riemersma, L. J. Appel and E. Guallar, “Meta-Analysis: HighDosage Vitamin E Supplementation May Increase Allcause Mortality,” Annals of Internal Medicine, Vol. 142, No. 1, 2005, pp. 37-46. doi:10.7326/0003-4819-142-1-200501040-00110
G. Bjelakovic, D. Nikolova, L. L. Gluud, R. G. Simonetti and C. Gluud, “Mortality in Randomized Trials of Antioxidant Supplements for Primary and Secondary Prevention: Systematic Review and Meta-Analysis,” The Journal of American Medical Association, Vol. 297, No. 8, 2007, pp. 842-857. doi:10.1001/jama.297.8.842
V. I. Perez, R. H. Van, A. Bokov, C. J. Epstein, J. Vijg and A. Richardson, “The Overexpression of Major Antioxidant Enzymes Does Not Extend the Lifespan of Mice,” Aging Cell, Vol. 8, No. 1, 2009, pp. 73-75. doi:10.1111/j.1474-9726.2008.00449.x
A. Mitsui, J. Hamuro, H. Nakamura, N. Kondo, Y. Hirabayashi, S. Ishizaki-Koizumi, T. Hirakawa, T. Inoue and J. Yodoi, “Overexpression of Human Thioredoxin in Transgenic Mice Controls Oxidative Stress and Life Span,” Antioxidants and Redox Signaling, Vol. 4, No. 4, 2004, pp. 693-696. doi:10.1089/15230860260220201
S. E. Schriner, N. J. Linford, G. M. Martin, P. Treuting, C. E. Ogburn, M. Emond, P. E. Coskun, W. Ladiges, N. Wolf, H. Van Remmen, D. C. Wallace and P. S. Rabinovitch, “Extension of Murine Lifespan by Overexpression of Catalase Targeted to Mitochondria,” Science, Vol. 308, No. 5730, 2005, pp. 1909-1911. doi:10.1126/science.1106653
S. K. Powers and M. J. Jackson, “Exercise-Induced Oxidative Stress: Cellular Mechanisms and Impact on Muscle Force Production,” Physiological Reviews, Vol. 88, No. 4, 2008, pp. 1243-1276. doi:10.1152/physrev.00031.2007
E. Nakamura, T. Moritani and A. Kanetaka, “Effects of Habitual Physical Exercise on Physiological Age in Men Aged 20 85 Years as Estimated Using Principal Component Analysis,” European Journal of Applied Physiology and Occupational Physiology, Vol. 73, No. 5, 1996, pp. 410-418. doi:10.1007/BF00334417
A. Navarro, C. Gomez, J. M. Lopez-Cepero and A. Boveris, “Beneficial Effects of Moderate Exercise on Mice Aging: Survival, Behavior, Oxidative Stress, and Mitochondrial Electron Transfer,” American Journal of Physiology Regulatory, Integrative and Comparative Physiology, Vol. 286, No. 3, 2004, pp. R505-R511. doi:10.1152/ajpregu.00208.2003
J. O. Holloszy, E. K. Smith, M. Vining and S. Adams, “Effect of Voluntary Exercise on Longevity of Rats,” Journal of Applied Physiology, Vol. 59, No. 3, 1985, pp. 826831.
J. M. Ivy, A. J. Klar and J. B. Hicks, “Cloning and Characterization of Four SIR Genes of Saccharomyces Cerevisiae,” Molecular and Cellular Biology, Vol. 6, No. 2, 1986, pp. 688-702.
J. Rine and I. Herskowitz, “Four Genes Responsible for a Position Effect on Expression from HML and HMR in Saccharomyces Cerevisiae,” Genetics, Vol. 116, No. 1, 1987, pp. 9-22.
M. Kaeberlein, M. McVey and L. Guarente, “The SIR2/3/ 4 Complex and SIR2 Alone Promote Longevity in Saccharomyces Cerevisiae by Two Different Mechanisms,” Genes Development, Vol. 13, No. 19, 1999, pp. 25702580. doi:10.1101/gad.13.19.2570
S. J. Lin, P. A. Defossez and L. Guarente, “Requirement of NAD and SIR2 for Life-Span Extension by Calorie Restriction in Saccharomyces Cerevisiae,” Science, Vol. 289, No. 5487, 2000, pp. 2126-2128. doi:10.1126/science.289.5487.2126
Taylor, et al., “Biological and Potential Therapeutic Roles of Sirtuin Deacetylases,” Cellular and Molecular Life Sciences, Vol. 65, No. 24, 2008, pp. 4000-4018. doi:10.1007/s00018-008-8357-y
S. Imai, C. M. Armstrong, M. Kaeberlein and L. Guarente, “Transcriptional Silencing and Longevity Protein Sir2 Is an NAD-Dependent Histone Deacetylase,” Nature, Vol. 403, No. 6771, 2000, pp. 795-800. doi:10.1038/35001622
W. C. Hallows, S. Lee and J. M. Denu, “Sirtuins Deacetylate and Activate Mammalian Acetyl-CoA Synthetases,” Proceedings of National Academy Science of the USA, Vol. 103, No. 27, 2006, pp. 10230-10235. doi:10.1073/pnas.0604392103
J. T. Rodgers, C. Lerin, W. Haas, S. P. Gygi, B. M. Spiegelman and P. Puigserver, “Nutrient Control of Glucose Homeostasis through a Complex of PGC-1alpha and SIRT1,” Nature, Vol. 434, No. 7029, 2005, pp. 113-118. doi:10.1038/nature03354
A. Brunet, L. B. Sweeney, J. F. Sturgill, K. F. Chua, P. L. Greer, Y. Lin, H. Tran, S. E. Ross, R. Mostoslavsky, et al., “Stress-Dependent Regulation of FOXO Transcription Factors by the SIRT1 Deacetylase,” Science, Vol. 303, No. 5666, 2004, pp. 2011-2015. doi:10.1126/science.1094637
F. Yeung, J. Hoberg, C. Ramsey, M. Keller, D. Jones, R. Frye and M. Mayo, “Modulation of NF-kappaB-Dependent Transcription and Cell Survival by the SIRT1 Deacetylase,” EMBO Journal, Vol. 23, No. 12, 2004, pp. 23692380. doi:10.1038/sj.emboj.7600244
J. M. Davis, E. A. Murphy, M. D. Carmichael and B. Davis, “Quercetin Increases Brain and Muscle Mitochondrial Biogenesis and Exercise Tolerance,” American Journal Physiology (Regulation and Integration of Comparative Physiology), Vol. 296, No. 4, 2009, pp. R1071R1077.
M. Knutson and C. Leeuwenburgh, “Resveratrol and Novel Potent Activators of SIRT1: Effects on Aging and Age-Related Diseases,” Nutrition Reviews, Vol. 66, No. 10, 2008, pp. 591-596. doi:10.1111/j.1753-4887.2008.00109.x
Metoyer and Pruitt, “The Role of Sirtuin Proteins in Obesity,” Pathophysiology, Vol. 15, No. 2, 2008, pp. 103-108. doi:10.1016/j.pathophys.2008.04.002
M. B. Scher, A. Vaquero and D. Reinberg, “SirT3 Is a Nuclear NAD+-Dependent Histone Deacetylase That Translocates to the Mitochondria upon Cellular Stress,” Genes Development, Vol. 21, No. 8, 2007, pp. 920-928. doi:10.1101/gad.1527307
Ahn, et al., “A Role for the Mitochondrial Deacetylase sirt3 in Regulating Energy Homeostasis,” Proceedings National Academy of Sciences, Vol. 105, No. 38, 2008, pp. 14447-14452. doi:10.1073/pnas.0803790105
I. Lanza, D. Short, K. Short, S. Raghavakaimal, R. Basu, M. Joyner, J. McConnel and K. S. Nair, “Endurance Exercise as a Countermeasure for Aging,” Diabetes, Vol. 57, No. 11, 2008, pp. 2933-2942. doi:10.2337/db08-0349
S. Zhao, W. Xu, W. Jiang, W. Yu, Y. Lin, T. Zhang, J. Yao, L. Zhou, Y. Zeng, H. Li, Y. Li, J. Shi, W. An, S. M. Hancock, F. He, L. Qin, J. Chin, P. Yang, X. Chen, Q. Lei, Y. Xiong and K. L. Guan, “Regulation of Cellular Metabolism by Protein Lysine Acetylation,” Science, Vol. 327, No. 3968, 2010, pp. 1000-1004. doi:10.1126/science.1179689
S. C. Kim, R. Sprung, Y. Chen, Y. Xu, H. Ball, J. Pei, T. Cheng, Y. Kho, H. Xiao, L. Xiao, N. V. Grishin, M. White, X. J. Yang and Y. Zhao, “Substrate and Functional Diversity of Lysine Acetylation Revealed by a Proteomics Survey,” Molecular Cell, Vol. 23, No. 4, 2006, pp. 607-618. doi:10.1016/j.molcel.2006.06.026
D. B. Lombard, F. W. Alt, H. L. Cheng, J. Bunkenborg, R. S. Streeper, R. Mostoslavsky, J. Kim, G. Yancopoulos, D. Valenzuela, A. Murphy, et al., “Mammalian Sir2 Homolog SIRT3 Regulates Global Mitochondrial Lysine Acetylation,” Molecular and Cellular Biology, Vol. 27, No. 24, 2007, pp. 88078814. doi:10.1128/MCB.01636-07
A. A. Kendrick, M. Choudhury, S. M. Rahman, C. E. McCurdy, M. Friederich, J. L. K. Van Hove, P. A. Watson, N. Birdsey, J. Bao, D. Gius, M. N. Sack, E. Jing, C. R. Kahn, J. E. Friedman and K. R. Jonscher, “Fatty Liver Is Associated with Reduced SIRT3 Activity and Mitochondrial Protein Hyperacetylation,” Biochemical Journal, Vol. 433, No. 3, 2011, pp. 505-514. doi:10.1042/BJ20100791
R. M. Anderson, D. Shanmuganayagan and R. Weindruch, “Caloric Restriction and Aging: Studies in Mice and Monkeys,” Toxicologic Pathology, Vol. 37, No. 1, 2008, pp. 47-51. doi:10.1177/0192623308329476
O. M. Palacios, J. J. Carmona, S. Michan, K. Y. Chen, Y. Manabe, J. L. Ward 3rd, L. J. Goodyear and Q. Tong, “Diet and Exercise Signals Regulate SIRT3 and Activate AMPK and PGC-1alpha in Skeletal Muscle,” Aging (Albany NY), Vol. 1, No. 9, 2009, pp. 771-783.
V. B. Pillai, N. R. Sundaresan, G. Kim, M. Gupta, S. B. Rajamohan, J. B. Pillai, S. Samant, P. V. Ravindra, A. Isbatan and M. P. Gupta, “Exogenous NAD Blocks Cardiac Hypertrophic Response via Activation of the SIRT3LKB1-AMP-Activated Kinase Pathway,” The Journal of Biological Chemistry, Vol. 285, No. 5, 2010, pp. 31333144. doi:10.1074/jbc.M109.077271
T. Shi, F. Wang, E. Stieren and Q. Tong, “SIRT3, a Mitochondrial Sirtuin Deacetylase, Regulates Mitochondrial Function and Thermogenesis in Brown Adipocytes,” The Journal of Biological Chemistry, Vol. 280, No. 14, 2005, pp. 13560-13567. doi:10.1074/jbc.M414670200
X. Kong, R. Wang, Y. Xue, X. Liu, H. Zhang, Y. Chen, F. Fang and Y. Chang, “ Sirtuin 3, a New Target of PGC1alpha, Plays an Important Role in the Suppression of ROS and Mitochondrial Biogenesis,” PLoS ONE, Vol. 5, No. 7, 2010, Article ID: e11707. doi:10.1371/journal.pone.0011707
N. Ahuja, B. Schwer, S. Carobbio, D. Waltregny, B. J. North, V. Castronovo, P. Maechler and E. Verdin, “Regulation of Insulin Secretion by SIRT4, a Mitochondrial ADP-Ribosyltransferase,” The Journal of Biological Chemistry, Vol. 282, No. 46, 2007, pp. 33583-33592. doi:10.1074/jbc.M705488200
M. C. Haigis, R. Mostoslavsky, K. M. Haigis, K. Fahie, D. C. Christodoulou, A. J. Murphy, D. M. Valenzuela, G. D. Yancopoulos, M. Karow, G. Blander, C. Wolberger, T. A. Prolla, R. Weindruch, F. W. Alt and L. Guarente, “SIRT4 Inhibits Glutamate Dehydrogenase and Opposes the Effects of Calorie Restriction in Pancreatic Beta Cells,” Cell, Vol. 126, No. 5, 2006, pp. 941-954. doi:10.1016/j.cell.2006.06.057
N. Nasrin, X. Wu, E. Fortier, Y. Feng, O. C. Bare, S. Chen, X. Ren, Z. Wu, R. S. Streeper and L. Bordone, “SIRT4 Regulates Fatty Acid Oxidation and Mitochondrial Gene Expression in Liver and Muscle Cells,” The Journal of Biological Chemistry, Vol. 285, No. 42, 2010, pp. 31995-32002. doi:10.1074/jbc.M110.124164
T. Nakagawa, D. J. Lomb, M. C. Haigis and L. Guarente, “SIRT5 Deacetylates Carbamoyl Phosphate Synthetase1 and Regulates the Urea Cycle,” Cell, Vol. 137, No. 3, 2009, pp. 560-570. doi:10.1016/j.cell.2009.02.026
B. Schwer, M. Eckersdorff, Y. Li, J. C. Silva, D. Fermin, M. V. Kurtev, C. Giallourakis, M. J. Comb, F. W. Alt and D. B. Lombard, “Calorie Restriction Alters Mitochondrial Protein Acetylation,” Aging Cell, Vol. 8, No. 5, 2009, pp. 604-606. doi:10.1111/j.1474-9726.2009.00503.x
J. C. Black, A. Mosley, T. Kitada, M. Washburn and M. Carey, “The SIRT2 Deacetylase Regulates Autoacetylation of p300,” Molecular Cell, Vol. 32, No. 3, 2008, pp. 449-455. doi:10.1016/j.molcel.2008.09.018
C. Schlicker, M. Gertz, P. Papatheodorou, B. Kachholz, C. F. Becker and C. Steegborn, “Substrates and Regulation Mechanisms for the Human Mitochondrial Sirtuins Sirt3 and Sirt5,” Journal Molecular Biology, Vol. 382, No. 3, 2008, pp. 790-801. doi:10.1016/j.jmb.2008.07.048
E. Michishita, et al., “SIRT6 Is a Histone H3 Lysine 9 Deacetylase That Modulates Telomeric Chromatin,” Nature, Vol. 452, No. 7186, 2008, pp. 492-496. doi:10.1038/nature06736
B. McClintock, “The Stability of Broken Ends of Chromosomes in Zea mays,” Genetics, Vol. 26, No. 2, 1941, pp. 234-282.
D. Gisselsson, et al., “Telomere Dysfunction Triggers Extensive DNA Fragmentation and Evolution of Complex Chromosome Abnormalities in Human Malignant Tumors,” Proceedings of the National Academy of Sciences of the United State of America, Vol. 98, No. 22, 2001, pp. 12683-12688. doi:10.1073/pnas.211357798
A. K. Meeker, et al., “Telomere Length Abnormalities Occur Early in the Initiation of Epithelial Carcinogenesis,” Clinical Cancer Research, Vol. 10, No. 10, 2004, pp. 3317-3326. doi:10.1158/1078-0432.CCR-0984-03
A. S. Multani and S. Chang, “WRN at Telomeres: Implications for Aging and Cancer,” Journal of Cell Science, Vol. 120, No. 5, 2007, pp. 713-721. doi:10.1242/jcs.03397
E. Michishita, et al., “ Cell Cycle-Dependent Deacetylation of Telomeric Histone H3 Lysine K56 by Human SIRT6,” Cell Cycle, Vol. 8, No. 16, 2009, pp. 2664-2666. doi:10.4161/cc.8.16.9367
R. Mostoslavsky, K. F. Chua, D. B. Lombard, W. W. Pang, M. R. Fischer, L. Gellon, P. Liu, G. Mostoslavsky, S. Franco, M. M. Murphy, K. D. Mills, P. Patel, J. T. Hsu, A. L. Hong, E. Ford, H. L. Cheng, C. Kennedy, N. Nunez, R. Bronson, D. Frendewey, W. Auerbach, D. Valenzuela, M. Karow, M. O. Hottiger, S. Hursting, J. C. Barrett, L. Guarente, R. Mulligan, B. Demple, G. D. Yancopoulos and F. W. Alt, “Genomic Instability and Aging-Like Phenotype in the Absence of Mammalian SIRT6,” Cell, Vol. 124, No. 2, 2006, pp. 315-329. doi:10.1016/j.cell.2005.11.044
R. A. McCord, et al., “SIRT6 Stabilizes DNA-Dependent Protein Kinase at Chromatin for DNA Double-Strand Break Repair,” Aging (Albany NY), Vol. 1, No. 1, 2009, pp. 109-121
Z. Mao, et al., “SIRT6 Promotes DNA Repair under Stress by Activating PARP1,” Science, Vol. 332, No. 6036, 2011, pp. 1443-1446. doi:10.1126/science.1202723
L. Zho, A. D’Urso, D. Toiber, C. Sebastian, R. E. Henry, D. D. Vadysirisack, A. Guimaraes, B. Marinelli, J. D. Wikstrom, T. Nir, C. B. Clish, B. Vaitheesvaran, O. Iliopoulos, I. Kurland, Y. Dor, R. Weissleder, O. S. Shirihai, L. W. Ellisen, J. M. Espinosa and R. Mostoslavsky, “The Histone Deacetylase Sirt6 regUlates Glucose Homeostasis via Hif1α,” Cell, Vol. 140, No. 2, 2010, pp. 280-293. doi:10.1016/j.cell.2009.12.041
J. J. Lum, T. Bui, M. Gruber, J. D. Gordan, R. J. DeBerardinis, K. L. Covello, M. C. Simon and C. B. Thompson, “The Transcription Factor HIF-1alpha Plays a Critical Role in the Growth Factor-Dependent Regulation of Both Aerobic and Anaerobic Glycolysis,” Genes Development, Vol. 21, No. 9, 2007, pp. 1037-1049. doi:10.1101/gad.1529107
T. N. Seagroves, H. E. Ryan, H. Lu, B. G. Wouters, M. Knapp, P. Thibault, K. Laderoute and R. S. Johnson, “Transcription Factor HIF-1 Is a Necessary Mediator of the Pasteur Effect in Mammalian Cells,” Molecular and Cellular Biology, Vol. 21, No. 10, 2001, pp. 3436-3444. doi:10.1128/MCB.21.10.3436-3444.2001
Y. Kanfi, S. Naiman, G. Amir, V. Peshti, G. Zinman, L. Nahum, Z. Bar-Joseph and H. Y. Cohen, “The Sirtuin SIRT6 Regulates Lifespan in Male Mice,” Nature, Vol. 483, No. 7388, 2012, pp. 218-221. doi:10.1038/nature10815
P. D. Lee, L. C. Giudice, C. A. Conover and D. R. Powell, “Insulin-Like Growth Factor Binding Protein-1: Recent Findings and New Directions,” Proceedings of the Society for Experimental Biology and Medicine, Vol. 216, No. 3, 1997, pp. 319-357.
C. J. Kenyon, “The Genetics of Ageing,” Nature, Vol. 464, No. 7288, 2010, pp. 504-512. doi:10.1038/nature08980
M. Holzenberger, et al., “IGF-1 Receptor Regulates Lifespan and Resistance to Oxidative Stress in Mice,” Nature, Vol. 421, No. 6919, 2003, pp. 182-187. doi:10.1038/nature01298
Y. Kanfi, V. Peshti, R. Gil, et al., “SIRT6 Protects against Pathological Damage Caused by Diet-Induced Obesity,” Aging Cell, Vol. 9, No. 2, 2010, pp. 162-173.
K. Yoshida, T. Shimizugawa, M. Ono and H. Furukawa, “Angiopoietinlike Protein 4 Is a Potent HyperlipidemiaInducing Factor in Mice and Inhibitor of Lipoprotein Lipase,” Journal of Lipid Research, Vol. 43, No. 11, 2002, pp. 1770-1772. doi:10.1194/jlr.C200010-JLR200
S. Cases, S. J. Smith, Y. W. Zheng, H. M. Myers, S. R. Lear, E. Sande, S. Novak, C. Collins, C. B. Welch, A. J. Lusis, S. K. Erickson and R. V. Farese Jr., “Identification of a Gene Encoding an Acyl CoA: Diacylglycerol Acyltransferase, a Key Enzyme in Triacylglycerol Synthesis,” Proceedings of the National Academy of Sciences of the United State of America, Vol. 95, No. 22, 1998, pp. 13018-13023. doi:10.1073/pnas.95.22.13018
T. L. Kawahara, E. Michishita, A. S. Adler, M. Damian, E. Berber, M. Lin, R. A. McCord, K. C. Ongaigui, L. D. Boxer, H. Y. Chang and K. F. Chua, “SIRT6 Links Histone H3 Lysine 9 Deacetylation to NF-κB-Dependent gene Expression and Organismal Life Span,” Cell, Vol. 136, No. 1, 2009, pp. 62-74. doi:10.1016/j.cell.2008.10.052
G. Natoli, “When Sirtuins and NF-κB Collide,” Cell, Vol. 136, No. 1, 2009, pp. 19-21. doi:10.1016/j.cell.2008.12.034
T. L. A. Kawahara, N. A. Rapicavoli, A. R. Wu, K. Qu, S. R. Quake, et al., “Dynamic Chromatin Localization of Sirt6 Shapes Stressand Aging-Related Transcriptional Networks,” PLoS Genetics, Vol. 7, No. 6, 2011, Article ID: e1002153. doi:10.1371/journal.pgen.1002153