Nicotinamide and PNC1 govern lifespan extension by calorie restriction in Saccharomyces cerevisiae
Open accessAbstract
Calorie restriction extends lifespan in a broad range of organisms, from yeasts to mammals. Numerous hypotheses have been proposed to explain this phenomenon, including decreased oxidative damage and altered energy metabolism. In Saccharomyces cerevisiae, lifespan extension by calorie restriction requires the NAD+-dependent histone deacetylase, Sir2 (ref. 1). We have recently shown that Sir2 and its closest human homologue SIRT1, a p53 deacetylase, are strongly inhibited by the vitamin B3 precursor nicotinamide. Here we show that increased expression of PNC1 (pyrazinamidase/nicotinamidase 1), which encodes an enzyme that deaminates nicotinamide, is both necessary and sufficient for lifespan extension by calorie restriction and low-intensity stress. We also identify PNC1 as a longevity gene that is responsive to all stimuli that extend lifespan. We provide evidence that nicotinamide depletion is sufficient to activate Sir2 and that this is the mechanism by which PNC1 regulates longevity. We conclude that yeast lifespan extension by calorie restriction is the consequence of an active cellular response to a low-intensity stress and speculate that nicotinamide might regulate critical cellular processes in higher organisms.
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NAM is a well reported and widely used sirtuin inhibitor and has been recently shown to inhibit NAD+-consuming activities in vivo.
“NAM, in contrast, is a well reported and widely used sirtuin inhibitor31 and has been recently shown to inhibit NAD+-consuming activities in vivo24.”
From NRK1 controls nicotinamide mononucleotide and nicotinamide riboside metabolism in mammalian cells (2016) · cites this paper as [31]
In response to calorie restriction, the yeast NAD biosynthetic gene PNC1, which catalyses the first and rate-limiting step in NAD+ biosynthesis, is induced.
“In response to calorie restriction, the yeast NAD biosynthetic gene that catalyses the first and rate-limiting step in NAD+ biosynthesis, PNC1, is induced46.”
From Mitochondrial and metabolic dysfunction in ageing and age-related diseases (2022) · cites this paper as [46]
The resulting NAD+ availability increases SIR2 activity, which boosts mitochondrial respiration and suppresses recombinant DNA recombination, a known cause of ageing in yeast.
“The resulting availability of NAD+ increases SIR2 activity, which boosts mitochondrial respiration and suppresses recombinant DNA recombination11,46, a known cause of ageing in yeast47.”
From Mitochondrial and metabolic dysfunction in ageing and age-related diseases (2022) · cites this paper as [46]
Upregulation of the NAD salvage pathway extends lifespan and mimics caloric restriction in yeast cells.
“The upregulation of the NAD salvage pathway, which recycles NAD+ from nicotinamide, was first shown to extend lifespan and mimic caloric restriction in yeast cells46.”
From Mitochondrial and metabolic dysfunction in ageing and age-related diseases (2022) · cites this paper as [46]
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Cites
Genomic Expression Programs in the Response of Yeast Cells to Environmental Changes
Gasch, A. P., Spellman, P. T., Kao, C. M., Carmel-Harel, O., Eisen, M. B., Storz, G., Botstein, D., & Brown, P. O. (2000) · Molecular Biology of the Cell · doi:10.1091/mbc.11.12.4241 · Cited by 4,815 · see citing works
Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase
Imai, S.-I., Armstrong, C. M., Kaeberlein, M., & Guarente, L. (2000) · Nature · doi:10.1038/35001622 · Cited by 3,510 · see citing works
hSIR2SIRT1 Functions as an NAD-Dependent p53 Deacetylase
Vaziri, H., Dessain, S. K., Eaton, E. N., Imai, S., Frye, R. A., Pandita, T. K., Guarente, L., & Weinberg, R. A. (2001) · Cell · doi:10.1016/s0092-8674(01)00527-x · Cited by 2,653 · see citing works
Kaeberlein, M., McVey, M., & Guarente, L. (1999) · Genes & Development · doi:10.1101/gad.13.19.2570 · Cited by 2,253 · cited 1× · see citing works
“Cells with an additional copy of SIR2 live 30% longer than the wild type, whereas sir2Δ strains age prematurel”
BackgroundNegative Control of p53 by Sir2α Promotes Cell Survival under Stress
Luo, J., Nikolaev, A. Y., Imai, S.-I., Chen, D., Su, F., Shiloh, A., Guarente, L., & Gu, W. (2001) · Cell · doi:10.1016/s0092-8674(01)00524-4 · Cited by 2,081 · see citing works
Increased dosage of a sir-2 gene extends lifespan in Caenorhabditis elegans
Tissenbaum, H. A., & Guarente, L. (2001) · Nature · doi:10.1038/35065638 · Cited by 1,918 · see citing works
Lin, S.-J., Defossez, P.-A., & Guarente, L. (2000) · Science · doi:10.1126/science.289.5487.2126 · Cited by 1,775 · see citing works
Extrachromosomal rDNA circles—a cause of aging in yeast
Sinclair, D. A., & Guarente, L. (1997) · Cell · doi:10.1016/s0092-8674(00)80493-6 · Cited by 1,500 · see citing works
Self-citationThe Therapeutic Potential of Poly(ADP-Ribose) Polymerase Inhibitors
Virág, L., & Szabó, C. (2002) · Pharmacological Reviews · doi:10.1124/pr.54.3.375 · Cited by 1,373 · see citing works
Calorie restriction extends Saccharomyces cerevisiae lifespan by increasing respiration
Lin, S.-J., Kaeberlein, M., Andalis, A. A., Sturtz, L. A., Defossez, P.-A., Culotta, V. C., Fink, G. R., & Guarente, L. (2002) · Nature · doi:10.1038/nature00829 · Cited by 1,057 · see citing works
Bitterman, K. J., Anderson, R. M., Cohen, H. Y., Latorre-Esteves, M., & Sinclair, D. A. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m205670200 · Cited by 1,002 · see citing works
Self-citationThe silencing protein SIR2 and its homologs are NAD-dependent protein deacetylases
Landry, J., Sutton, A., Tafrov, S. T., Heller, R. C., Stebbins, J., Pillus, L., & Sternglanz, R. (2000) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.110148297 · Cited by 970 · see citing works
Smith, J. S., Brachmann, C. B., Celic, I., Kenna, M. A., Muhammad, S., Starai, V. J., Avalos, J. L., Escalante-Semerena, J. C., Grubmeyer, C., Wolberger, C., et al. (2000) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.97.12.6658 · Cited by 718 · see citing works
A public database for gene expression in human cancers.
Lal, A., Lash, A., Altschul, S. F., Velculescu, V. E., Zhang, L., McLendon, R. E., Marra, M. A., Prange, C. K., Morin, P. J., Polyák, K., et al. (1999) · PubMed · Cited by 414 · see citing works
An intervention resembling caloric restriction prolongs life span and retards aging in yeast
Jiang, J. C., Jaruga, E., Repnevskaya, M. V., & Jazwinski, S. M. (2000) · The FASEB Journal · doi:10.1096/fj.00-0242fje · Cited by 383 · see citing works
Aksoy, S., Szumlanski, C. L., & Weinshilboum, R. M. (1994) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(17)36700-5 · Cited by 295 · see citing works
Anderson, R. M., Bitterman, K. J., Wood, J. G., Medvedik, O., Cohen, H. Y., Lin, S., Manchester, J. K., Gordon, J. I., & Sinclair, D. A. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m111773200 · Cited by 295 · see citing works
Self-citationLongevity Regulation by Drosophila Rpd3 Deacetylase and Caloric Restriction
Rogina, B., Helfand, S. L., & Frankel, S. A. (2002) · Science · doi:10.1126/science.1078986 · Cited by 276 · see citing works
Role of NAD+ in the Deacetylase Activity of the SIR2-like Proteins
Landry, J. W., Slama, J. T., & Sternglanz, R. (2000) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.2000.3854 · Cited by 254 · see citing works
Tanny, J. C., & Moazed, D. (2000) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.98.2.415 · Cited by 242 · see citing works
S-Adenosylmethionine-dependent Methylation inSaccharomyces cerevisiae
Niewmierzycka, A., & Clarke, S. G. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.2.814 · Cited by 226 · see citing works
Lin, S., Manchester, J. K., & Gordon, J. I. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m103509200 · Cited by 188 · see citing works
Kaeberlein, M. R., Andalis, A. A., Fink, G. R., & Guarente, L. (2002) · Molecular and Cellular Biology · doi:10.1128/mcb.22.22.8056-8066.2002 · Cited by 144 · see citing works
Ghislain, M., Talla, E., & François, J. M. (2002) · Yeast · doi:10.1002/yea.810 · Cited by 130 · see citing works
Sandmeier, J. J., Celic, I., Boeke, J. D., & Smith, J. S. (2002) · Genetics · doi:10.1093/genetics/160.3.877 · Cited by 120 · see citing works
Grant, R., & Kapoor, V. (1998) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.1998.70041759.x · Cited by 91 · see citing works
Kassem, H. S., Sangar, V., Cowan, R. A., Clarke, N. W., & Margison, G. P. (2002) · International Journal of Cancer · doi:10.1002/ijc.10631 · Cited by 88 · see citing works
The role of peroxisomes in aging
P�richon, R., Bourre, J. M., Kelly, J. F., & Roth, G. S. (1998) · Cellular and Molecular Life Sciences · doi:10.1007/s000180050192 · Cited by 66 · see citing works
Tanny, J. C. (2000) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.031563798 · Cited by 34 · see citing works
Effect of stress on the life span of the yeast Saccharomyces cerevisiae.
Święciło, A., Krawiec, Z., Wawryn, J., Bartosz, G., & Biliński, T. (2000) · Acta Biochimica Polonica · doi:10.18388/abp.2000_4015 · Cited by 33 · see citing works
Ünkefer, C. J., & London, R. E. (1984) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(17)43354-0 · Cited by 27 · see citing works
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Baur, J. A., & Sinclair, D. A. (2006) · Nature Reviews Drug Discovery · doi:10.1038/nrd2060 · Cited by 3,958 · see citing works
Self-citationSmall molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan
Howitz, K. T., Bitterman, K. J., Cohen, H. Y., Lamming, D. W., Lavu, S., Wood, J. G., Zipkin, R. E., Chung, P., Kisielewski, A., Zhang, L.-L., et al. (2003) · Nature · doi:10.1038/nature01960 · Cited by 3,796 · see citing works
Self-citationStress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase
Brunet, A., Sweeney, L. B., Sturgill, J. F., Chua, K. F., Greer, P. L., Lin, Y., Tran, H., Ross, S. E., Mostoslavsky, R., Cohen, H. Y., et al. (2004) · Science · doi:10.1126/science.1094637 · Cited by 3,239 · see citing works
Self-citationBroken Limits to Life Expectancy
Oeppen, J., & Vaupel, J. W. (2002) · Science · doi:10.1126/science.1069675 · Cited by 2,819 · see citing works
Mammalian Sirtuins: Biological Insights and Disease Relevance
Haigis, M. C., & Sinclair, D. A. (2010) · Annual Review of Pathology: Mechanisms of Disease · doi:10.1146/annurev.pathol.4.110807.092250 · Cited by 2,085 · see citing works
Self-citationSirtuins as regulators of metabolism and healthspan
Houtkooper, R. H., Pirinen, E., & Auwerx, J. (2012) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3293 · Cited by 2,008 · see citing works
Calorie restriction promotes mammalian cell survival by inducing the SIRT1 deacetylase
Cohen, H. Y., Miller, C., Bitterman, K. J., Wall, N. R., Hekking, B., Kessler, B., Howitz, K. T., Gorospe, M., de Cabo, R., & Sinclair, D. A. (2004) · Science · doi:10.1126/science.1099196 · Cited by 1,924 · see citing works
Self-citationSirtuins in mammals: insights into their biological function
Michán, S., & Sinclair, D. A. (2007) · Biochemical Journal · doi:10.1042/bj20070140 · Cited by 1,719 · see citing works
Self-citationSmall molecule activators of SIRT1 as therapeutics for the treatment of type 2 diabetes
Milne, J. C., Lambert, P. D., Schenk, S., Carney, D. P., Smith, J. J., Gagne, D. J., Jin, L., Boss, O., Perni, R. B., Vu, C. B., et al. (2007) · Nature · doi:10.1038/nature06261 · Cited by 1,707 · see citing works
Self-citationCantó, C., Menzies, K. J., & Auwerx, J. (2015) · Cell Metabolism · doi:10.1016/j.cmet.2015.05.023 · Cited by 1,648 · see citing works
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Blander, G., & Guarente, L. (2004) · Annual Review of Biochemistry · doi:10.1146/annurev.biochem.73.011303.073651 · Cited by 1,496 · see citing works
Ying, W. (2008) · Antioxidants & Redox Signaling · doi:10.1089/ars.2007.1672 · Cited by 1,494 · see citing works
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Imai, S.-I., & Guarente, L. (2014) · Trends in Cell Biology · doi:10.1016/j.tcb.2014.04.002 · Cited by 1,481 · see citing works
Mammalian sirtuins—emerging roles in physiology, aging, and calorie restriction
Haigis, M. C., & Guarente, L. P. (2006) · Genes & Development · doi:10.1101/gad.1467506 · Cited by 1,295 · see citing works
Metabolic control of muscle mitochondrial function and fatty acid oxidation through SIRT1/PGC‐1α
Gerhart‐Hines, Z., Rodgers, J. T., Bare, O., Lerin, C., Kim, S., Mostoslavsky, R., Alt, F. W., Wu, Z., & Puigserver, P. (2007) · The EMBO Journal · doi:10.1038/sj.emboj.7601633 · Cited by 1,294 · see citing works
Pearson, K. J., Baur, J. A., Lewis, K. N., Peshkin, L., Price, N. L., Labinskyy, N., Swindell, W. R., Kamara, D., Minor, R. K., Perez, E., et al. (2008) · Cell Metabolism · doi:10.1016/j.cmet.2008.06.011 · Cited by 1,162 · see citing works
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Ramsey, K. M., Yoshino, J., Brace, C. S., Abrassart, D., Kobayashi, Y., Marcheva, B., Hong, H.-K., Chong, J. L., Buhr, E. D., Lee, C., et al. (2009) · Science · doi:10.1126/science.1171641 · Cited by 1,126 · see citing works
Calorie restriction promotes mitochondrial biogenesis by inducing the expression of eNOS
Nisoli, E., Tonello, C., Cardile, A., Cozzi, V., Bracale, R., Tedesco, L., Falcone, S., Valerio, A., Cantoni, O., Clementi, E., et al. (2005) · Science · doi:10.1126/science.1117728 · Cited by 1,107 · see citing works
Kim, D., Nguyen, M. D., Dobbin, M. M., Fischer, A., Sananbenesi, F., Rodgers, J. T., Delalle, I., Baur, J. A., Sui, G., Armour, S. M., et al. (2007) · The EMBO Journal · doi:10.1038/sj.emboj.7601758 · Cited by 1,074 · see citing works
Self-citationNAD+ metabolism: pathophysiologic mechanisms and therapeutic potential
Xie, N., Zhang, L., Gao, W. Q., Huang, C., Huber, P., Zhou, X., Li, C. L., Shen, G., & Zou, B. (2020) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-020-00311-7 · Cited by 1,076 · see citing works
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Masoro, E. J. (2005) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2005.03.012 · Cited by 1,054 · see citing works
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Nemoto, S., Fergusson, M. M., & Finkel, T. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m501485200 · Cited by 1,047 · see citing works
Revollo, J. R., Grimm, A. A., & Imai, S.-I. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m408388200 · Cited by 1,010 · see citing works
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Self-citationNAD+ metabolism in health and disease
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Yang, H., Yang, T., Baur, J. A., Perez, E., Matsui, T., Carmona, J. J., Lamming, D. W., Souza-Pinto, N. C., Bohr, V. A., Rosenzweig, A., et al. (2007) · Cell · doi:10.1016/j.cell.2007.07.035 · Cited by 950 · see citing works
Self-citationThe secret life of NAD+: an old metabolite controlling new metabolic signaling pathways
Houtkooper, R. H., Cantó, C., Wanders, R. J., & Auwerx, J. (2010) · Endocrine Reviews · doi:10.1210/er.2009-0026 · Cited by 899 · see citing works
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Rajman, L., Chwalek, K., & Sinclair, D. A. (2018) · Cell Metabolism · doi:10.1016/j.cmet.2018.02.011 · Cited by 865 · see citing works
Self-citationSlowing ageing by design: the rise of NAD+ and sirtuin-activating compounds
Bonkowski, M. S., & Sinclair, D. A. (2016) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm.2016.93 · Cited by 834 · see citing works
Self-citationFulco, M., Cen, Y., Zhao, P., Hoffman, E. P., McBurney, M. W., Sauve, A. A., & Sartorelli, V. (2008) · Developmental Cell · doi:10.1016/j.devcel.2008.02.004 · Cited by 821 · see citing works
Poly(ADP-ribosyl)ation by PARP-1: `PAR-laying' NAD + into a nuclear signalPreprint
Kim, M. Y., Zhang, T., & Kraus, W. L. (2005) · Genes & Development · doi:10.1101/gad.1331805 · Cited by 803 · see citing works
Calorie restriction–the SIR2 connection
Guarente, L., & Picard, F. (2005) · Cell · doi:10.1016/j.cell.2005.01.029 · Cited by 793 · see citing works
Sauve, A. A., Wolberger, C., Schramm, V. L., & Boeke, J. D. (2006) · Annual Review of Biochemistry · doi:10.1146/annurev.biochem.74.082803.133500 · Cited by 763 · see citing works
Bieganowski, P., & Brenner, C. (2004) · Cell · doi:10.1016/s0092-8674(04)00416-7 · Cited by 750 · see citing works
Sirtuin 1 and Sirtuin 3: Physiological Modulators of Metabolism
Nogueiras, R., Habegger, K. M., Chaudhary, N., Finan, B., Banks, A. S., Dietrich, M. O., Horváth, T. L., Sinclair, D. A., Pfluger, P. T., & Tschöp, M. H. (2012) · Physiological Reviews · doi:10.1152/physrev.00022.2011 · Cited by 712 · see citing works
Self-citationMolecular mechanisms of dietary restriction promoting health and longevity
Green, C. L., Lamming, D. W., & Fontana, L. (2022) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-021-00411-4 · Cited by 714 · see citing works
Bogan, K. L., & Brenner, C. (2008) · Annual Review of Nutrition · doi:10.1146/annurev.nutr.28.061807.155443 · Cited by 707 · see citing works
Schwer, B., Bunkenborg, J., Verdin, R. O., Andersen, J. S., & Verdin, E. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0603968103 · Cited by 705 · see citing works
Resveratrol as an anti-inflammatory and anti-aging agent: Mechanisms and clinical implications
Alarcón‐de‐la‐Lastra, C., & Villegas, I. (2005) · Molecular Nutrition & Food Research · doi:10.1002/mnfr.200500022 · Cited by 705 · see citing works
Metabolic Regulation of Epigenetics
Lu, C., & Thompson, C. B. (2012) · Cell Metabolism · doi:10.1016/j.cmet.2012.06.001 · Cited by 699 · see citing works
PARPs and ADP-ribosylation: recent advances linking molecular functions to biological outcomes
Gupte, R., Liu, Z., & Kraus, W. L. (2017) · Genes & Development · doi:10.1101/gad.291518.116 · Cited by 681 · see citing works
Regulation of SIRT1 in cellular functions: Role of polyphenols
Chung, S., Yao, H., Caito, S. W., Hwang, J., Arunachalam, G., & Rahman, I. (2010) · Archives of Biochemistry and Biophysics · doi:10.1016/j.abb.2010.05.003 · Cited by 651 · see citing works
Kume, S., Uzu, T., Horiike, K., Chin-Kanasaki, M., Isshiki, K., Araki, S.-I., Sugimoto, T., Haneda, M., Kashiwagi, A., & Koya, D. (2010) · Journal of Clinical Investigation · doi:10.1172/jci41376 · Cited by 640 · see citing works
Calorie restriction extends yeast life span by lowering the level of NADH
Lin, S.-J., Ford, E., Haigis, M., Liszt, G., & Guarente, L. (2004) · Genes & Development · doi:10.1101/gad.1164804 · Cited by 632 · see citing works
Moynihan, K. A., Grimm, A. A., Plueger, M. M., Bernal‐Mizrachi, E., Ford, E. L., CRAS-MÉNEUR, C. M. H., Permutt, M. A., & Imai, S. (2005) · Cell Metabolism · doi:10.1016/j.cmet.2005.07.001 · Cited by 630 · see citing works
Aging and Survival: The Genetics of Life Span Extension by Dietary Restriction
Mair, W. B., & Dillin, A. G. (2008) · Annual Review of Biochemistry · doi:10.1146/annurev.biochem.77.061206.171059 · Cited by 600 · see citing works
The neuroprotective properties of calorie restriction, the ketogenic diet, and ketone bodies
Maalouf, M., Rho, J. M., & Mattson, M. P. (2008) · Brain Research Reviews · doi:10.1016/j.brainresrev.2008.09.002 · Cited by 575 · see citing works
Small molecule SIRT1 activators for the treatment of aging and age-related diseases
Hubbard, B. P., & Sinclair, D. A. (2014) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2013.12.004 · Cited by 572 · see citing works
Self-citationToward a unified theory of caloric restriction and longevity regulation
Sinclair, D. A. (2005) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2005.03.019 · Cited by 561 · see citing works
Self-citationChong, Z. Z., Li, F., & Maiese, K. (2005) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2005.02.004 · Cited by 536 · see citing works
Rajendrasozhan, S., Yang, S.-R., Kinnula, V. L., & Rahman, I. (2008) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/rccm.200708-1269oc · Cited by 520 · see citing works
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Smith, J. J., & Aitchison, J. D. (2013) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3700 · Cited by 470 · see citing works
Sirtuins as potential targets for metabolic syndrome
Guarente, L. (2006) · Nature · doi:10.1038/nature05486 · Cited by 468 · see citing works
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Sirtuin activators and inhibitors: Promises, achievements, and challenges
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“Upregulation of the NAD+ salvage pathway extends lifespan in yeast and flies via a pathway that overlaps with CR (Anderson et al., 2003; Balan et al., 2008; Moroz et al., 2014).”
BackgroundSelf-citationAvalos, J. L., Bever, K. M., & Wolberger, C. (2005) · Molecular Cell · doi:10.1016/j.molcel.2005.02.022 · Cited by 462 · see citing works
Wei, M., Fabrizio, P., Hu, J. H., Ge, H., Cheng, C., Li, L., & Longo, V. D. (2008) · PLoS Genetics · doi:10.1371/journal.pgen.0040013 · Cited by 454 · see citing works
Interactions between E2F1 and SirT1 regulate apoptotic response to DNA damage
Wang, C., Chen, L., Hou, X., Li, Z., Kabra, N., Ma, Y., Nemoto, S., Finkel, T., Gu, W. J., Cress, W. D., et al. (2006) · Nature Cell Biology · doi:10.1038/ncb1468 · Cited by 447 · see citing works
Sir2-Independent Life Span Extension by Calorie Restriction in Yeast
Kaeberlein, M., Kirkland, K. T., Fields, S., & Kennedy, B. K. (2004) · PLoS Biology · doi:10.1371/journal.pbio.0020296 · Cited by 441 · see citing works
Sirtuin signaling in cellular senescence and aging
Lee, S.-H., Lee, J.-H., Lee, H., & Min, K. (2019) · BMB Reports · doi:10.5483/bmbrep.2019.52.1.290 · Cited by 438 · see citing works
Genome-Wide Analysis of the Biology of Stress Responses through Heat Shock Transcription Factor
Hahn, J., Hu, Z., Thiele, D. J., & Iyer, V. R. (2004) · Molecular and Cellular Biology · doi:10.1128/mcb.24.12.5249-5256.2004 · Cited by 430 · see citing works
Targeting Sirtuin 1 to Improve Metabolism: All You Need Is NAD+?
Cantó, C., & Auwerx, J. (2012) · Pharmacological Reviews · doi:10.1124/pr.110.003905 · Cited by 433 · see citing works
Genetic links between diet and lifespan: shared mechanisms from yeast to humans
Bishop, N. A., & Guarente, L. (2007) · Nature Reviews Genetics · doi:10.1038/nrg2188 · Cited by 421 · see citing works
Lessons on longevity from budding yeast
Kaeberlein, M. R. (2010) · Nature · doi:10.1038/nature08981 · Cited by 420 · see citing works
Conserved Metabolic Regulatory Functions of Sirtuins
Schwer, B., & Verdin, E. M. (2008) · Cell Metabolism · doi:10.1016/j.cmet.2007.11.006 · Cited by 415 · see citing works
Belenky, P., Racette, F. G., Bogan, K. L., McClure, J. M., Smith, J. S., & Brenner, C. (2007) · Cell · doi:10.1016/j.cell.2007.03.024 · Cited by 411 · see citing works
Green, K. N., Steffan, J. S., Martinez-Coria, H., Sun, X., Schreiber, S. S., Thompson, L. M., & LaFerla, F. M. (2008) · The Journal of Neuroscience · doi:10.1523/jneurosci.3203-08.2008 · Cited by 404 · see citing works
“The sirtuin family of deacetylases is implicated in cellular pathways that influence longevity in yeast, C. elegans, Drosophila, and mammals (Tissenbaum and Guarente, 2001; Anderson et al., 2003; Howitz et al., 2003; Wood et al., 2004; Baur et al., 2006).”
BackgroundSirtuins: The ‘ <i>magnificent seven</i> ’, function, metabolism and longevity
Dali‐Youcef, N., Lagouge, M., Froelich, S., Koehl, C., Schoonjans, K., & Auwerx, J. (2007) · Annals of Medicine · doi:10.1080/07853890701408194 · Cited by 402 · see citing works
Caloric restriction, SIRT1 and longevity
Cantó, C., & Auwerx, J. (2009) · Trends in Endocrinology & Metabolism · doi:10.1016/j.tem.2009.03.008 · Cited by 395 · see citing works
It takes two to tango: NAD(+) and sirtuins in aging/longevity control
Imai, S.-I., & Guarente, L. (2016) · npj Aging and Mechanisms of Disease · doi:10.1038/npjamd.2016.17 · Cited by 394 · see citing works
Sir2 Blocks Extreme Life-Span Extension
Fabrizio, P., Gattazzo, C., Battistella, L., Wei, M., Cheng, C., McGrew, K., & Longo, V. D. (2005) · Cell · doi:10.1016/j.cell.2005.08.042 · Cited by 390 · see citing works
Ten years of NAD-dependent SIR2 family deacetylases: implications for metabolic diseases
Imai, S., & Guarente, L. (2010) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2010.02.003 · Cited by 387 · see citing works
Inhibition of SIRT1 Reactivates Silenced Cancer Genes without Loss of Promoter DNA Hypermethylation
Pruitt, K., Zinn, R. L., Ohm, J. E., McGarvey, K. M., Kang, S.-H. L., Watkins, D. N., Herman, J. G., & Baylin, S. B. (2006) · PLoS Genetics · doi:10.1371/journal.pgen.0020040 · Cited by 387 · see citing works
Similar gene expression patterns characterize aging and oxidative stress in Drosophila melanogaster
Landis, G. N., Abdueva, D. A., Skvortsov, D., Yang, J., Rabin, B. E., Carrick, J., Tavaré, S., & Tower, J. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0307605101 · Cited by 384 · see citing works
NRK1 controls nicotinamide mononucleotide and nicotinamide riboside metabolism in mammalian cells
Ratajczak, J., Joffraud, M., Trammell, S. A. J., Ras, R., Canela, N., Boutant, M., Kulkarni, S. S., Rodrigues, M., Redpath, P., Migaud, M. E., et al. (2016) · Nature Communications · doi:10.1038/ncomms13103 · Cited by 378 · see citing works
Seven sirtuins for seven deadly diseases ofaging
Morris, B. J. (2012) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2012.10.525 · Cited by 380 · see citing works
Sirtuins in Aging and DiseasePreprint
Guarente, L. (2007) · Cold Spring Harbor Symposia on Quantitative Biology · doi:10.1101/sqb.2007.72.024 · Cited by 371 · see citing works
Lysine Acetylation Goes Global: From Epigenetics to Metabolism and Therapeutics
Ali, I., Conrad, R. J., Verdin, E. M., & Ott, M. (2018) · Chemical Reviews · doi:10.1021/acs.chemrev.7b00181 · Cited by 366 · see citing works
De novo NAD+ biosynthetic impairment in acute kidney injury in humans
Mehr, A. P., Tran, M. T., Ralto, K. M., Leaf, D. E., Washco, V., Messmer, J., Lerner, A., Kher, A., Kim, S. H., Khoury, C. C., et al. (2018) · Nature Medicine · doi:10.1038/s41591-018-0138-z · Cited by 370 · see citing works
Regulation of histone deacetylase activities
Sengupta, N., & Seto, E. (2004) · Journal of Cellular Biochemistry · doi:10.1002/jcb.20179 · Cited by 347 · see citing works
Dietary restriction and lifespan: lessons from invertebrate models
Kapahi, P., Kaeberlein, M., & Hansen, M. (2017) · Ageing Research Reviews · doi:10.1016/j.arr.2016.12.005 · Cited by 340 · see citing works
Cardiac Aging: From Molecular Mechanisms to Significance in Human Health and Disease
Dai, D.-F., Chen, T., Johnson, S. C., Szeto, H., & Rabinovitch, P. S. (2012) · Antioxidants & Redox Signaling · doi:10.1089/ars.2011.4179 · Cited by 334 · see citing works
Protein acetylation in metabolism – metabolites and cofactors
Menzies, K. J., Zhang, H., Katsyuba, E., & Auwerx, J. (2016) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2015.181 · Cited by 331 · see citing works
The Sir2 family of protein deacetylases
Denu, J. M. (2005) · Current Opinion in Chemical Biology · doi:10.1016/j.cbpa.2005.08.010 · Cited by 325 · see citing works
Extension of Human Cell Lifespan by Nicotinamide Phosphoribosyltransferase
van der Veer, E., Ho, C. S. W., O’Neil, C. H., Barbosa, N., Scott, R., Cregan, S. P., & Pickering, J. G. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.c700018200 · Cited by 325 · see citing works
de Barros, M. H., Bandy, B., Tahara, E. B., & Kowaltowski, A. J. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m408918200 · Cited by 323 · see citing works
Myeloid Deletion of SIRT1 Induces Inflammatory Signaling in Response to Environmental Stress
Schug, T. T., Xu, Q., Gao, H., Peres-da-Silva, A., Draper, D. W., Fessler, M. B., Purushotham, A., & Li, X. (2010) · Molecular and Cellular Biology · doi:10.1128/mcb.00657-10 · Cited by 324 · see citing works
Ramsey, K. M., Mills, K. F., Satoh, A., & Imai, S. (2008) · Aging Cell · doi:10.1111/j.1474-9726.2007.00355.x · Cited by 321 · see citing works
SIRT1 is critical regulator of FOXO-mediated transcription in response to oxidative stress
Kobayashi, Y., Furukawa‐Hibi, Y., Chen, C., Horio, Y., Isobe, K., Ikeda, K., & Motoyama, N. (2005) · International Journal of Molecular Medicine · doi:10.3892/ijmm.16.2.237 · Cited by 316 · see citing works
The regulation of nicotinamide adenine dinucleotide biosynthesis by Nampt/PBEF/visfatin in mammals
Revollo, J. R., Grimm, A. A., & Imai, S. (2007) · Current Opinion in Gastroenterology · doi:10.1097/mog.0b013e32801b3c8f · Cited by 311 · see citing works
Medvedik, O., Lamming, D. W., Kim, K. D., & Sinclair, D. A. (2007) · PLoS Biology · doi:10.1371/journal.pbio.0050261 · Cited by 311 · see citing works
Self-citationLin, Y.-Y., Lu, J., Zhang, J., Walter, W., Dang, W., Wan, J., Tao, S., Qian, J. X., Zhao, Y., Boeke, J. D., et al. (2009) · Cell · doi:10.1016/j.cell.2009.01.033 · Cited by 309 · see citing works
Zhang, T., & Kraus, W. L. (2009) · Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics · doi:10.1016/j.bbapap.2009.10.022 · Cited by 306 · see citing works
NAD+ and Vitamin B3: From Metabolism to Therapies
Sauve, A. A. (2007) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.107.120758 · Cited by 303 · see citing works
Cancer-Specific Functions of SIRT1 Enable Human Epithelial Cancer Cell Growth and Survival
Ford, J. R., Jiang, M., & Milner, J. (2005) · Cancer Research · doi:10.1158/0008-5472.can-05-1923 · Cited by 295 · see citing works
Targeting mitochondria for cardiovascular disorders: therapeutic potential and obstacles
Bonora, M., Wieckowski, M. R., Sinclair, D. A., Kroemer, G., Pinton, P., & Galluzzi, L. (2018) · Nature Reviews Cardiology · doi:10.1038/s41569-018-0074-0 · Cited by 299 · see citing works
Self-citation
- Authors
- Anderson, R. M., Bitterman, K. J., Wood, J. G., Medvedik, O., & Sinclair, D. A.
- Affiliations
- Harvard University (US)
- Corresponding author
- Sinclair, David A.
- Venue
- Nature
- Published
- 2003-05
- Volume
- 423
- Issue
- 6936
- Pages
- 181-185
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC4802858
- OpenAlex
- W2006806054
- Cited by
- 736
- References
- 30
- Citations by year
- 2026: 18 · 2025: 17 · 2024: 11 · 2023: 10 · 2022: 26 · 2021: 18 · 2020: 24 · 2019: 23 · 2018: 30 · 2017: 26 · 2016: 29 · 2015: 35 · 2014: 30 · 2013: 24 · 2012: 39
- FWCI
- 13.20
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Institute on Aging (R37AG028730, P01AG027916, R01AG028730, R01AG019719, R01AG019972)
- National Institute of General Medical Sciences (R01GM068072)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
- Keywords
- caloric restriction, lifespan extension, nicotinamide, Sir2, SIRT1, NAD+-dependent histone deacetylase, longevity genes, Saccharomyces cerevisiae, aging
- MeSH terms
- Cell Nucleus, Cytoplasm, Energy Metabolism, Histone Deacetylases, Longevity, NAD, Niacin, Nicotinamidase, Niacinamide, Saccharomyces cerevisiae, Gene Expression Regulation, Fungal, Heat-Shock Response, Gene Silencing, Saccharomyces cerevisiae Proteins, Caloric Restriction, Sirtuins, Silent Information Regulator Proteins, Saccharomyces cerevisiae, Sirtuin 2
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