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The SIR2/3/4 complex and SIR2 alone promote longevity in Saccharomyces cerevisiae by two different mechanisms
Open accessAbstract
The SIR genes are determinants of life span in yeast mother cells. Here we show that life span regulation by the Sir proteins is independent of their role in nonhomologous end joining. The short life span of a sir3 or sir4 mutant is due to the simultaneous expression of a and alpha mating-type information, which indirectly causes an increase in rDNA recombination and likely increases the production of extrachromosomal rDNA circles. The short life span of a sir2 mutant also reveals a direct failure to repress recombination generated by the Fob1p-mediated replication block in the rDNA. Sir2p is a limiting component in promoting yeast longevity, and increasing the gene dosage extends the life span in wild-type cells. A possible role of the conserved SIR2 in mammalian aging is discussed.
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“Loss of Sir2 increases rDNA recombination and shortens life span; whereas an extra genomic copy of Sir2, which increases rDNA stability, extends life span (Kaeberlein et al., 1999”
From DNA Repair, Genome Stability, and Aging (2005) · cites this paper as Kaeberlein et al., 1999
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“Loss of Sir2 increases rDNA recombination and shortens life span; whereas an extra genomic copy of Sir2, which increases rDNA stability, extends life span (Kaeberlein et al., 1999”
From DNA Repair, Genome Stability, and Aging (2005) · cites this paper as Kaeberlein et al., 1999
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“Furthermore, increasing the level of Sir2 in yeast increases lifespan (Kaeberlein et al., 1999).”
From The Aging Epigenome (2016) · cites this paper as Kaeberlein et al., 1999
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BackgroundSIRT1 redistribution on chromatin promotes genomic stability but alters gene expression during aging
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“The major genetic determinant of replicative life span a tin yeast to emerge from genetic studies is SIR2; lossof-function mutations shortened life span, and in- t Rcreased gene dosage extended it (Kaeberlein et al., 1999).”
BackgroundSIRT5 deacetylates carbamoyl phosphate synthetase 1 and regulates the urea cycle
Nakagawa, T., Lomb, D. J., Haigis, M. C., & Guarente, L. (2009) · Cell · doi:10.1016/j.cell.2009.02.026 · Cited by 787
“In yeast, C. elegans, and Drosophila, SIR2 orthologs slow aging and respond to metabolic conditions (Kaeberlein et al., 1999; Lin et al., 2002; Rogina and Helfand, 2004; Tissenbaum and Guarente, 2001; Wang et al., 2006).”
Self-citationHuman iPSC-based modeling of late-onset disease via progerin-induced aging
Miller, J. D., Ganat, Y. M., Kishinevsky, S., Bowman, R. L., Liu, B., Tu, E. Y., Mandal, P. K., Vera, E., Shim, J.-W., Kriks, S., et al. (2013) · Cell stem cell · doi:10.1016/j.stem.2013.11.006 · Cited by 777
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
Nucleocytoplasmic Shuttling of the NAD+-dependent Histone Deacetylase SIRT1*
Tanno, M., Sakamoto, J., Miura, T., Shimamoto, K., & Horio, Y. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m609554200 · Cited by 784
Substrate-specific activation of sirtuins by resveratrol
Kaeberlein, M., McDonagh, T., Heltweg, B., Hixon, J., Westman, E. A., Caldwell, S. D., Napper, A., Curtis, R., DiStefano, P. S., Fields, S., et al. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m500655200 · Cited by 745
Self-citationHuman Ageing Genomic Resources: new and updated databases
Tacutu, R., Thornton, D., Johnson, E., Budovsky, A., Barardo, D., Craig, T., Diana, E., Lehmann, G., Toren, D., Wang, J., et al. (2018) · Nucleic Acids Research · doi:10.1093/nar/gkx1042 · Cited by 738
Nicotinamide and PNC1 govern lifespan extension by calorie restriction in Saccharomyces cerevisiae
Anderson, R. M., Bitterman, K. J., Wood, J. G., Medvedik, O., & Sinclair, D. A. (2003) · Nature · doi:10.1038/nature01578 · Cited by 736
“Cells with an additional copy of SIR2 live 30% longer than the wild type, whereas sir2Δ strains age prematurel”
BackgroundResveratrol stimulates AMP kinase activity in neurons
Dasgupta, B., & Milbrandt, J. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0610068104 · Cited by 723
SIRT1 transgenic mice show phenotypes resembling calorie restriction
Bordone, L., Cohen, D., Robinson, A., Motta, M. C., Van Veen, E., Czopik, A., Steele, A. D., Crowe, H., Marmor, S., Luo, J., et al. (2007) · Aging Cell · doi:10.1111/j.1474-9726.2007.00335.x · Cited by 722
“…Journal compilation © Blackwell Publishing Ltd/Anatomical Society of Great Britain and Ireland 2007 764 Overexpression of Sir2 extends lifespan in yeast, C. elegans and Drosophila by a mechanism overlapping moderate CR (Kaeberlein et al., 1999; Tissenbaum & Guarente, 2001; Rogina & Helfand, 2004).”
BackgroundInfluentialSelf-citationThe Establishment, Inheritance, and Function of Silenced Chromatin in Saccharomyces cerevisiae
Rusché, L. N., Kirchmaier, A. L., & Rine, J. (2003) · Annual Review of Biochemistry · doi:10.1146/annurev.biochem.72.121801.161547 · Cited by 726
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 724
“In parallel with the work on calorie restriction, a genetic screen for long-lived mutants of Saccharomyces cerevisiae led to the discovery that the silent information regulation-2 (Sir2) gene could slow aging in this species (164, 306).”
BackgroundSchwer, 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
Sir2 links chromatin silencing, metabolism, and agingPreprint
Guarente, L. (2000) · Genes & Development · doi:10.1101/gad.14.9.1021 · Cited by 718
“These studies have led to the general conclusion that the silencing protein Sir2 is a limiting component of longevity; deletions of SIR2 shorten life span and an extra copy of this gene increases life span (Kaeberlein et al. 1999).”
BackgroundSelf-citationSirt1 Regulates Insulin Secretion by Repressing UCP2 in Pancreatic β Cells
Bordone, L., Motta, M. C., Picard, F., Robinson, A., Jhala, U. S., Apfeld, J., McDonagh, T., Lemieux, M., McBurney, M., Szilvasi, A., et al. (2005) · PLoS Biology · doi:10.1371/journal.pbio.0040031 · Cited by 715
“This gene regulates the life span in yeast [8] and Caenorhabditis elegans [9] as a longevity determinant.”
Self-citationShi, T., Wang, F., Stieren, E., & Tong, Q. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m414670200 · Cited by 712
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 713
“In yeast, the sirtuin (SIR)2 gene mediates the life-extending effects of calorie restriction by nutrient withdrawal [84], although the overproduction of SIR2 enzyme can prolong the life of yeast grown under normal nutrient conditions [85].”
BackgroundSIRT1 and aging related signaling pathways
Chen, C., Zhou, M., Ge, Y., & Wang, X. (2020) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2020.111215 · Cited by 714
Nutrient Availability Regulates SIRT1 Through a Forkhead-Dependent Pathway
Nemoto, S., Fergusson, M. M., & Finkel, T. (2004) · Science · doi:10.1126/science.1101731 · Cited by 671
Histone H4 lysine 16 acetylation regulates cellular lifespan
Dang, W., Steffen, K. K., Perry, R., Dorsey, J. A., Johnson, F. B., Shilatifard, A., Kaeberlein, M., Kennedy, B. K., & Berger, S. L. (2009) · Nature · doi:10.1038/nature08085 · Cited by 667
Self-citationLoss of epigenetic information as a cause of mammalian aging
Yang, J.-H., Hayano, M., Griffin, P. T., Amorim, J. A., Bonkowski, M. S., Apostolides, J. K., Salfati, E. L., Blanchette, M., Munding, E. M., Bhakta, M., et al. (2023) · Cell · doi:10.1016/j.cell.2022.12.027 · Cited by 643
Tumor Suppressor HIC1 Directly Regulates SIRT1 to Modulate p53-Dependent DNA-Damage Responses
Chen, W., Wang, D. H., Yen, R.-W. C., Luo, J., Gu, W. J., & Baylin, S. B. (2005) · Cell · doi:10.1016/j.cell.2005.08.011 · Cited by 663
“H S s s o r d f ( f a s f c L a o a e i a s w ( l IC1 Directly Regulates SIRT1 Transcription ince Sir2 expression level is critical in influencing life pan of yeast and worm (Kaeberlein et al., 1999; Tisenbaum and Guarente, 2001), homeostatic regulation f this protein would seem essential.”
BackgroundInfluentialNAD+ homeostasis in health and disease
Katsyuba, E., Romani, M., Hofer, D., & Auwerx, J. (2020) · Nature Metabolism · doi:10.1038/s42255-019-0161-5 · Cited by 627
Asymmetric Inheritance of Oxidatively Damaged Proteins During Cytokinesis
Aguilaniu, H., Gustafsson, L., Rigoulet, M., & Nyström, T. (2003) · Science · doi:10.1126/science.1080418 · Cited by 639
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
Self-citationEpigenetic regulation of ageing: linking environmental inputs to genomic stability
Benayoun, B. A., Pollina, E. A., & Brunet, A. (2015) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm4048 · Cited by 610
Sirtuins in aging and age-related disease
Longo, V. D., & Kennedy, B. K. (2006) · Cell · doi:10.1016/j.cell.2006.07.002 · Cited by 628
“In the absence of SIR2, the rate of ERC formation is enhanced and cells are short lived (Kaeberlein et al., 1999).”
BackgroundInfluentialMoynihan, 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 638
Mammalian Sir2 homolog SIRT7 is an activator of RNA polymerase I transcription
Ford, E., Voit, R., Liszt, G., Magin, C., Grummt, I., & Guarente, L. (2006) · Genes & Development · doi:10.1101/gad.1399706 · Cited by 629
“In yeast, Sir2p promotes longevity predominantly through its silencing role at the rDNA (Sinclair and Guarente 1997; Kaeberlein et al. 1999).”
BackgroundSelf-citationAbsence of effects of Sir2 overexpression on lifespan in C. elegans and Drosophila
Burnett, C., Valentini, S., Cabreiro, F., Goss, M., Somogyvári, M., Piper, M. D., Hoddinott, M., Sutphin, G. L., Leko, V., McElwee, J. J., et al. (2011) · Nature · doi:10.1038/nature10296 · Cited by 624
Self-citationThe Mammalian SIR2α Protein Has a Role in Embryogenesis and Gametogenesis
McBurney, M. W., Yang, X., Jardine, K., Hixon, M., Boekelheide, K., Webb, J. R., Lansdorp, P. M., & Lemieux, M. (2003) · Molecular and Cellular Biology · doi:10.1128/mcb.23.1.38-54.2003 · Cited by 611
“This effect of Sir2p is thought to be due to its ability to suppress recombination between tandem copies of the ribosomal genes, as aging mother cells show loss of ribosomal DNA, presumed to be due to recombinational excision from the genome (20).”
BackgroundDaitoku, H., Hatta, M., Matsuzaki, H., Aratani, S., Ohshima, T., Miyagishi, M., Nakajima, T., & Fukamizu, A. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0400593101 · Cited by 616
Metadata
- Authors
- Kaeberlein, M., McVey, M., & Guarente, L.
- Affiliations
- Massachusetts Institute of Technology (US)
- Venue
- Genes & Development
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 1999-10-01
- Volume
- 13
- Issue
- 19
- Pages
- 2570-2580
- ISSN
- 0890-9369 (ISSN-L)
- PMC
- PMC317077
- OpenAlex
- W2157649587
- Cited by
- 2,253
- References
- 52
- Citations by year
- 2026: 27 · 2025: 64 · 2024: 50 · 2023: 80 · 2022: 76 · 2021: 91 · 2020: 93 · 2019: 101 · 2018: 126 · 2017: 73 · 2016: 123 · 2015: 104 · 2014: 111 · 2013: 127 · 2012: 123
- Type
- posted content
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Genes & Development (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute of General Medical Sciences (T32GM07287, T32GM007287)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Telomeres, Telomerase, and Senescence
- Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
- Keywords
- Sir2p, Sir3p, longevity, lifespan regulation, Saccharomyces cerevisiae, non-homologous end joining, replication block, gene dosage, aging
- MeSH terms
- Mating Factor, DNA-Binding Proteins, DNA, Fungal, DNA, Ribosomal, Fungal Proteins, Histone Deacetylases, Peptides, Phenotype, Saccharomyces cerevisiae, Trans-Activators, Mutagenesis, Saccharomyces cerevisiae Proteins, Sirtuins, Silent Information Regulator Proteins, Saccharomyces cerevisiae, Sirtuin 2
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