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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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BackgroundIt 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
Self-citationYang, S.-R., Wright, J., Bauter, M., Seweryniak, K., Kode, A., & Rahman, I. (2007) · American Journal of Physiology-Lung Cellular and Molecular Physiology · doi:10.1152/ajplung.00308.2006 · Cited by 391
“They are widely distributed in all the phyla of life and are implicated in aging, cell cycle regulation, apoptosis, metabolism, and inflammation (12, 16, 31, 32).”
BackgroundPillai, J. B., Isbatan, A., Imai, S., & Gupta, M. P. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m506162200 · Cited by 404
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 394
Self-citationSir2 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 396
“Increased dosage of Sir2 was shown to extend the yeast replicative life span ( Kaeberlein et al., 1999 ).”
BackgroundResultInfluentialDietary restriction in Drosophila
Partridge, L., Piper, M. D. W., & Mair, W. B. (2005) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2005.03.023 · Cited by 392
The first long-lived mutants: discovery of the insulin/IGF-1 pathway for ageing
Kenyon, C. (2011) · Philosophical Transactions of the Royal Society B: Biological Sciences · doi:10.1098/rstb.2010.0276 · Cited by 376
“In 1999, the Guarente laboratory discovered that Sir2, later shown to be an NADdependent protein deacetylase, can increase lifespan in yeast (Kaeberlein et al. 1999) [52], and the roles of sirtuins in ageing have been studied intensively ever since.”
BackgroundAre sirtuins viable targets for improving healthspan and lifespan?
Baur, J. A., Ungvari, Z. I., Minor, R. K., Couteur, D. G. L., & de Cabo, R. (2012) · Nature Reviews Drug Discovery · doi:10.1038/nrd3738 · Cited by 393
Structure of the histone deacetylase SIRT2.
Finnin, M. S., Donigian, J. R., & Pavletich, N. P. (2001) · Nature Structural Biology · doi:10.1038/89668 · Cited by 376
Protein homeostasis and aging in neurodegeneration
Douglas, P. M., & Dillin, A. G. (2010) · The Journal of Cell Biology · doi:10.1083/jcb.201005144 · Cited by 381
“The role of sirtuins in aging was first discovered in S. cerevisiae as depletion of Sir2 shortened replicative lifespan, whereas overexpression lengthened replicative lifespan (Kaeberlein et al., 1999).”
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 375
Bellizzi, D., Rose, G., Cavalcante, P., Covello, G., Dato, S., De Rango, F., Greco, V., Maggiolini, M., Feraco, E., Mari, V., et al. (2005) · Genomics · doi:10.1016/j.ygeno.2004.11.003 · Cited by 367
“In model organisms the expression levels of SIR2 modulate life span [9–11].”
BackgroundMitochondrial function in hypoxic ischemic injury and influence of aging
Ham, P. B., & Raju, R. P. (2016) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2016.06.006 · Cited by 374
Chromatin and beyond: the multitasking roles for SIRT6
Kugel, S., & Mostoslavsky, R. (2014) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2013.12.002 · Cited by 374
“Sir2, the yeast homologue and founding member of the sirtuins, has been implicated in lifespan extension [59, 60].”
BackgroundMammalian Sirt1: insights on its biological functions
Rahman, S., & Islam, R. (2011) · Cell Communication and Signaling · doi:10.1186/1478-811x-9-11 · Cited by 362
“Sirt1 and its ortholog appear to have a key role in determining lifespan of yeast, flies, and mice [34-36].”
BackgroundErjavec, N., Larsson, L., Grantham, J., & Nyström, T. (2007) · Genes & Development · doi:10.1101/gad.439307 · Cited by 368
“This dual role of Sir2p could explain why sir2 deletions have a negative effect on the yeast replicative life span (Kaeberlein et al. 1999), as well as the segregation of damaged proteins, in cells lacking Fob1p, in which formation of ERCs is blocked.”
BackgroundBouras, T., Fu, M., Sauve, A. A., Wang, F., Quong, A. A., Perkins, N. D., Hay, R. T., Gu, W. J., & Pestell, R. G. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m408748200 · Cited by 361
The interaction between FOXO and SIRT1: tipping the balance towards survival
Giannakou, M. E., & Partridge, L. (2004) · Trends in Cell Biology · doi:10.1016/j.tcb.2004.07.006 · Cited by 354
Sirtuins in Renal Health and Disease
Morigi, M., Perico, L., & Benigni, A. (2018) · Journal of the American Society of Nephrology · doi:10.1681/asn.2017111218 · Cited by 359
H3K9 methylation and RNA interference regulate nucleolar organization and repeated DNA stability
Peng, J. C., & Karpen, G. H. (2007) · Nature Cell Biology · doi:10.1038/ncb1514 · Cited by 375
A molecular mechanism of chronological aging in yeast
Burtner, C. R., Murakami, C. J., Kennedy, B. K., & Kaeberlein, M. R. (2009) · Cell Cycle · doi:10.4161/cc.8.8.8287 · Cited by 353
Self-citationEffect of resveratrol and pterostilbene on aging and longevity
Li, Y., Li, S., & Lin, C. (2017) · BioFactors · doi:10.1002/biof.1400 · Cited by 356
“This study found that extra copies of Sir2 increased yeast replicative lifespan by 30%, whereas ablation of the Sir2 gene causes opposite effects on reducing lifespan by 50% [135].”
BackgroundThe Search for Antiaging Interventions: From Elixirs to Fasting Regimens
de Cabo, R., Carmona-Gutierrez, D., Bernier, M., Hall, M. N., & Madeo, F. (2014) · Cell · doi:10.1016/j.cell.2014.05.031 · Cited by 345
Sirtuins mediate mammalian metabolic responses to nutrient availability
Chalkiadaki, A., & Guarente, L. (2012) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2011.225 · Cited by 344
Self-citationIdentification of a small molecule inhibitor of Sir2p
Bedalov, A., Gatbonton, T., Irvine, W. P., Gottschling, D. E., & Simon, J. A. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.261574398 · Cited by 344
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
Self-citationAnimal models of aging research: implications for human aging and age-related diseases
Mitchell, S. J., Scheibye-Knudsen, M., Longo, D. L., & de Cabo, R. (2015) · Annual Review of Animal Biosciences · doi:10.1146/annurev-animal-022114-110829 · Cited by 328
The Polarisome Is Required for Segregation and Retrograde Transport of Protein Aggregates
Liu, B., Larsson, L., Caballero, A., Hao, X., Öling, D., Grantham, J., & Nyström, T. (2010) · Cell · doi:10.1016/j.cell.2009.12.031 · Cited by 351
“These multiple roles of Sir2p could explain why sir2 deletions have a negative effect on yeast replicative life span in cells lacking Fob1p (Kaeberlein et al., 1999), in which formation of ERCs is drastically reduced, and suggest that Sir2p controls life span also in an ERC-independent manner.”
BackgroundLifespan extension in Caenorhabditis elegans by complete removal of food
Kaeberlein, T. L., Smith, E. D., Tsuchiya, M., Welton, K. L., Thomas, J. H., Fields, S., Kennedy, B. K., & Kaeberlein, M. R. (2006) · Aging Cell · doi:10.1111/j.1474-9726.2006.00238.x · Cited by 350
“One model that has been proposed as an evolutionarily conserved mechanism for lifespan extension by DR is activation of the Sir2-family protein deacetylases (sirtuins) (Guarente & Picard, 2005), based on observations that elevated expression of sirtuins increases lifespan in yeast (Kaeberlein et al., 1999), worms (Tis…”
BackgroundSelf-citationSirT1 inhibition reduces IGF-I/IRS-2/Ras/ERK1/2 signaling and protects neurons
Li, Y., Xu, W., McBurney, M. W., & Longo, V. D. (2008) · Cell Metabolism · doi:10.1016/j.cmet.2008.05.004 · Cited by 331
“Sir2 modulates aging and life span in yeast, C. elegans, and Drosophila (Fabrizio et al., 2005; Kaeberlein et al., 1999; Rogina and Helfand, 2004; Tissenbaum and Guarente, 2001).”
BackgroundEpigenetic factors in aging and longevity
Gravina, S., & Vijg, J. (2009) · Pflügers Archiv - European Journal of Physiology · doi:10.1007/s00424-009-0730-7 · Cited by 329
The role of epigenetics in aging and age-related diseases
Calvanese, V., Lara, E., Kahn, A., & Fraga, M. F. (2009) · Ageing Research Reviews · doi:10.1016/j.arr.2009.03.004 · Cited by 329
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
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
“…crucial for its ability to regulate life span because Sir2 suppresses homologous recombination and hence the formation and accumulation of toxic extrachromosomal rDNA circles, one of the primary causes of yeast aging (Gottlieb & Esposito, 1989; Sinclair & Guarente, 1997; Kaeberlein et al ., 1999).”
BackgroundGerhart‐Hines, Z., Dominy, J. E., Blättler, S. M., Jedrychowski, M. P., Banks, A. S., Lim, J.-H., Chim, H., Gygi, S. P., & Puigserver, P. (2011) · Molecular Cell · doi:10.1016/j.molcel.2011.12.005 · Cited by 336
“…Schwer and Verdin, 2008), DNA damage repair (Luo et al., 2001; Yuan et al., 2007), neuronal protection (Donmez et al., 2010), circadian patterning (Asher et al., 2008; Nakahata Molec et al., 2008), and longevity (Kaeberlein et al., 1999; Viswanathan et al., 2005; Viswanathan andGuarente, 2011).”
Background
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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