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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
In the citing paper
“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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Mekhail, K., Seebacher, J., Gygi, S. P., & Moazed, D. (2008) · Nature · doi:10.1038/nature07460 · Cited by 233
Progressive loss of SIRT1 with cell cycle withdrawal
Sasaki, T., Maier, B., Bartke, A., & Scrable, H. J. (2006) · Aging Cell · doi:10.1111/j.1474-9726.2006.00235.x · Cited by 235
“Although first identified in yeast as a gene involved in mating type switching (Rine & Herskowitz, 1987), the SIR2 gene is highly conserved in organisms ranging from archea to humans (Brachmann et al ., 1995), where its role is much broader.”
BackgroundFree Radicals: Key to Brain Aging and Heme Oxygenase as a Cellular Response to Oxidative Stress
Poon, H. F., Calabrese, V., Scapagnini, G., & Butterfield, D. A. (2004) · The Journals of Gerontology Series A · doi:10.1093/gerona/59.5.m478 · Cited by 238
“It was also reported that inactive SIR2 mutants shorten the life span while over-expression of SIR2 extends it (227).”
BackgroundBitterman, K. J., Medvedik, O., & Sinclair, D. A. (2003) · Microbiology and Molecular Biology Reviews · doi:10.1128/mmbr.67.3.376-399.2003 · Cited by 240
“Although ERCs are so abundant in old cells that they can be visualized on an EtBr-stained gel, they are typically quantified by Southern blotting (6, 7, 36, 88, 114, 117, 152).”
BackgroundInfluentialBauer, J. H., Goupil, S., Garber, G. B., & Helfand, S. L. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0403493101 · Cited by 234
The Chronological Life Span of Saccharomyces cerevisiae
Fabrizio, P., & Longo, V. D. (2007) · Methods in molecular biology · doi:10.1007/978-1-59745-361-5_8 · Cited by 240
Obesity and aging: Molecular mechanisms and therapeutic approaches
Santos, A. L., & Sinha, S. (2021) · Ageing Research Reviews · doi:10.1016/j.arr.2021.101268 · Cited by 249
Mitochondrial Metabolism, Sirtuins, and AgingPreprint
Sack, M. N., & Finkel, T. (2012) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a013102 · Cited by 242
“Originally characterized in yeast as regulators of life span (Kaeberlein et al. 1999), the sirtuins are an evolutionarily conserved family of proteins that appear to exert a wide range of biological functions (Finkel et al.”
BackgroundThe sirtuin family’s role in aging and age-associated pathologies
Hall, J. A., Dominy, J. E., Lee, Y., & Puigserver, P. (2013) · Journal of Clinical Investigation · doi:10.1172/jci64094 · Cited by 240
“In 1999 it was reported that a sirtuin protein in brewer’s yeast, silent information regulator 2 (Sir2), could extend life span in S. cerevisiae (4).”
BackgroundMicroReview: Small molecules that regulate lifespan: evidence for xenohormesis
Lamming, D. W., Wood, J. G., & Sinclair, D. A. (2004) · Molecular Microbiology · doi:10.1111/j.1365-2958.2004.04209.x · Cited by 232
“SIR2 overexpression) ( Kaeberlein et al ., 1999; Bitterman et al ., 2003).”
InfluentialHuang, J., & Moazed, D. (2003) · Genes & Development · doi:10.1101/gad.1108403 · Cited by 232
“Accordingly, loss of silencing in sir2 cells results in an increased rate of Fob1-dependent recombination and ERC accumulation and reduces average life span, whereas increasing the dosage of SIR2 suppresses recombination and prolongs average life span (Kaeberlein et al. 1999).”
BackgroundResultInfluentialThe SirT3 Divining Rod Points to Oxidative Stress
Bell, E. L., & Guarente, L. (2011) · Molecular Cell · doi:10.1016/j.molcel.2011.05.008 · Cited by 235
“Starvation also induces the liver to synthesize ketones to help bridge energy deficits for the brain and SirT3 was also shown to deacetylate and activate 3-hydroxy-3-methylglutaryl CoA synthase 2 (HMGCS2), the rate-limiting enzyme for the synthesis of the ketone b-hydroxybuterate (Shimazu et al.,…”
BackgroundSelf-citationKobayashi, T. (2011) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-010-0613-2 · Cited by 235
“They reported that ‘‘pop-out’’ molecules (named extra-chromosomal rDNA circles, ERCs), derived from the rDNA by recombination, accumulated only in the mother cell, and they proposed that this ERC accumulation induced senescence.”
BackgroundInfluentialThe importance of NAMPT / NAD / SIRT1 in the systemic regulation of metabolism and ageing
Imai, S., & Yoshino, J. (2013) · Diabetes Obesity and Metabolism · doi:10.1111/dom.12171 · Cited by 240
“Indeed, in yeast, worms and flies, sirtuins have been shown to play an important role in the regulation of ageing and longevity [10–12].”
BackgroundKwon, H.-S., & Ott, M. (2008) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2008.08.001 · Cited by 233
Insulin/IGF-like signalling, the central nervous system and aging
Broughton, S., & Partridge, L. (2009) · Biochemical Journal · doi:10.1042/bj20082102 · Cited by 228
HST2 Mediates SIR2 -Independent Life-Span Extension by Calorie Restriction
Lamming, D. W., Latorre‐Esteves, M., Medvedik, O., Wong, S. N., Tsang, F. A., Wang, C., Lin, S.-J., & Sinclair, D. A. (2005) · Science · doi:10.1126/science.1113611 · Cited by 227
From sirtuin biology to human diseases: an update
Sebastián, C., Satterstrom, F. K., Haigis, M. C., & Mostoslavsky, R. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.r112.402768 · Cited by 201
“Originally described as a silencing factor in yeast (silencing information regulator), the protein Sir2 came out on top in a screen for modulators of yeast life span (2).”
BackgroundZhao, X., Allison, D., Condon, B., Zhang, F., Gheyi, T., Zhang, A., Ashok, S., Russell, M., MacEwan, I. J., Qian, Y., et al. (2013) · Journal of Medicinal Chemistry · doi:10.1021/jm301431y · Cited by 231
Dietrich, M. O., Antunes, C., Geliang, G., Liu, Z.-W., Borók, E., Nie, Y., Xu, A. W., Souza, D. O., Gao, Q., Diano, S., et al. (2010) · Journal of Neuroscience · doi:10.1523/jneurosci.2234-10.2010 · Cited by 229
“…the beneficial effects of calorie restriction, the only known physiological intervention that promotes a longer, healthier lifespan across species (Kaeberlein et al., 1999; Lin et al., 2000; Tissenbaum and Guarente, 2001; Cohen et al., 2004; Rogina and Helfand, 2004; Chen et al., 2005; Chen and…”
BackgroundSIRT3 regulates progression and development of diseases of aging
McDonnell, E., Peterson, B. S., Bomze, H. M., & Hirschey, M. D. (2015) · Trends in Endocrinology & Metabolism · doi:10.1016/j.tem.2015.06.001 · Cited by 217
“An additional SIR2 allele can increase lifespan by 30%, whereas ablation of SIR2 decreased lifespan in yeast [2].”
Small-Molecule Allosteric Activators of Sirtuins
Sinclair, D. A., & Guarente, L. (2011) · The Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev-pharmtox-010611-134657 · Cited by 226
“regulating replicative life span in budding yeast (8).”
BackgroundSelf-citationOxidative Stress and Epigenetic Regulation in Ageing and Age-Related Diseases
Cencioni, C., Spallotta, F., Martelli, F., Valente, S., Mai, A., Zeiher, A. M., & Gaetano, C. (2013) · International Journal of Molecular Sciences · doi:10.3390/ijms140917643 · Cited by 227
“Several miRNA clusters are up- or down-modulated in different tissues during ageing and are able to hit molecular targets that regulate lifespan, such as insulin-like growth factor 1 (IGF1)/insulin [45], forkhead box, sub-group O (FOXO) [46], SIRT1 [47] and cyclin-dependent kinase inhibitor 1A (p21) (Table 1) [48].”
BackgroundA Microarray-Based Genetic Screen for Yeast Chronological Aging Factors
Matecic, M., Smith, D. L., Pan, X., Maqani, N., Bekiranov, S., Boeke, J. D., & Smith, J. S. (2010) · PLoS Genetics · doi:10.1371/journal.pgen.1000921 · Cited by 233
“The budding yeast, Saccharomyces cerevisiae, has also been particularly useful, especially in characterizing the NAD-dependent protein deacetylase, Sir2, as a replicative lifespan (RLS) factor [4].”
BackgroundSirtuin deacetylases in neurodegenerative diseases of aging
Herskovits, A. Z., & Guarente, L. (2013) · Cell Research · doi:10.1038/cr.2013.70 · Cited by 230
Self-citationSIRT1 Deacetylates the DNA Methyltransferase 1 (DNMT1) Protein and Alters Its Activities
Peng, L., Yuan, Z., Ling, H., Fukasawa, K., Robertson, K. D., Olashaw, N., Koomen, J. M., Chen, J., Lane, W. S., & Seto, E. (2011) · Molecular and Cellular Biology · doi:10.1128/mcb.06147-11 · Cited by 230
Causal roles of mitochondrial dynamics in longevity and healthy aging
Sharma, A., Smith, H. J., Yao, P., & Mair, W. B. (2019) · EMBO Reports · doi:10.15252/embr.201948395 · Cited by 222
“Sirtuins act in response to changes in the NAD:NADH ratio and were first linked to longevity in yeast [98].”
Turning enzymes ON with small molecules
Zorn, J. A., & Wells, J. A. (2010) · Nature Chemical Biology · doi:10.1038/nchembio.318 · Cited by 222
“The founding member of the sirtuin family, yeast Sir2p (silent information regulator protein 2), was identified as an important determinant of yeast longevit”
BackgroundSIRT1 decreases Lox-1-mediated foam cell formation in atherogenesis
Stein, S., Lohmann, C., Schäfer, N., Hofmann, J., Rohrer, L., Besler, C., Rothgiesser, K. M., Becher, B., Hottiger, M. O., Borén, J., et al. (2010) · European Heart Journal · doi:10.1093/eurheartj/ehq107 · Cited by 188
“Sir2 is an NAD-dependent class III deacetylase that was found to increase lifespan in yeast.(2) Its mammalian orthologue SIRT1 senses”
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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