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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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Cites
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The role of declining adaptive homeostasis in ageing
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“The histone deacetylase SIR2 is a critical factor that slows down replicative aging (Kennedy et al., 1995; Kaeberlein et al., 1999), by repressing the recombination of repetitive ribosomal DNA (rDNA) and the subsequent formation of extrachromosomal rDNA circles (ERCs).”
BackgroundSmith, D. L., McClure, J. M., Matecic, M., & Smith, J. S. (2007) · Aging Cell · doi:10.1111/j.1474-9726.2007.00326.x · Cited by 225
“One of the most heavily studied examples, silent information regulator 2 ( SIR2 ) (Kaeberlein et al ., 1999), encodes an NAD + - dependent histone deacetylase that removes acetyl groups from specific lysine residues on the tails of histones H3 and H4 (Imai et al ., 2000; Landry et al ., 2000b;…”
BackgroundInfluentialLee, S. S., Vizcarra, I. A., Huberts, D. H. E. W., Lee, L. P., & Heinemann, M. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1113505109 · Cited by 219
“Consistent with data fromconventional dissection analysis (2, 7, 22), the lifespan of the SIR2 deletion mutant is significantly shorter than that of the wild-type strain (medianWT: 21 divisions vs.”
MethodKey proteins and pathways that regulate lifespan
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“Several potential mechanisms were implicated in the life extension observed by augmenting Sir2 activity including suppressing the formation of extrachromosomal rDNA circles (6), a known cause of yeast aging, as well as promoting asymmetric distribution of damaged proteins between mother and daughter cells (8).”
BackgroundFoxO1 Mediates an Autofeedback Loop Regulating SIRT1 Expression
Xiong, S., Salazar, G., Patrushev, N. A., & Alexander, R. W. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.163667 · Cited by 221
Sirtuins in glucose and lipid metabolism
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BackgroundKohlwein, S. D., Marten Veenhuis, A., & van der Klei, I. J. (2012) · Genetics · doi:10.1534/genetics.112.143362 · Cited by 213
“Nicotinamide 26 S. D. Kohlwein, M. Veenhuis, and I. J. van der Klei strongly inhibits Sir2, a protein important for life-span extension by calorie restriction (Kaeberlein et al. 1999), and, like Sir2, Pnc1 also functions in life-span extension (Anderson et al. 2003).”
BackgroundHistone deacetylase inhibitors as therapeutics for polyglutamine disorders
Butler, R. K., & Bates, G. P. (2006) · Nature reviews. Neuroscience · doi:10.1038/nrn1989 · Cited by 215
“SIR2 is related to ageing and longevity; overexpression of SIR2 extends the lifespan of budding yeast, whereas its knockout shortens the lifespan by ∼50% (Ref”
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“Silent information regulator 2 (SIR2) was first identified as a mediator of CR-induced lifespan extension in yeast [11]and subsequently has been shown to regulate this process in lower metazoans, such as Drosophila melanogaster and C.”
Jackson, M. D., & Denu, J. M. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m200671200 · Cited by 212
MYST-family histone acetyltransferases: beyond chromatin
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Mechanisms of Aging and the Preventive Effects of Resveratrol on Age-Related Diseases
Pyo, I. S., Yun, S., Yoon, Y. E., Choi, J. W., & Lee, S. (2020) · Molecules · doi:10.3390/molecules25204649 · Cited by 221
“In lower organisms, such as yeast, worms, and flies, SIRT-encoding genes are associated with lifespan extension [17,19,37].”
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Zhang, F., Wang, S., Gan, L., Vosler, P. S., Gao, Y., Zigmond, M. J., & Chen, J. (2011) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2011.09.001 · Cited by 211
Sirtuin/Sir2 Phylogeny, Evolutionary Considerations and Structural Conservation
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“In budding yeast, Sir2p action at ribosomal repeats is required to prevent illegitimate recombination leading to extrachomsomal ribosomal DNA circles, the accumulation of which is associated with aging (Gottlieb and Esposito, 1989; Kaeberlein et al., 1999; Sinclair and Guarente, 1997).”
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Nucleolar RNA polymerase II drives ribosome biogenesis
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An Age-Induced Switch to a Hyper-Recombinational State
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Linking chromatin function with metabolic networks: Sir2 family of NAD+-dependent deacetylases
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The coordination of nuclear and mitochondrial communication during aging and calorie restriction
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“Similarly, increased levels of Sir2 extend lifespan in worms and flies (Tissenbaum and Guarente, 2001; Rogina and Helfand, 2004).”
BackgroundInfluentialAn overview of Sirtuins as potential therapeutic target: Structure, function and modulators
Wang, Y., He, J., Liao, M., Hu, M., Li, W., Ouyang, H., Wang, X., Ye, T., Zhang, Y., & Ouyang, L. (2018) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2018.10.028 · Cited by 210
Bana, B., & Cabreiro, F. (2019) · Annual Review of Genetics · doi:10.1146/annurev-genet-112618-043650 · Cited by 212
Histone methylation makes its mark on longevity
Han, S., & Brunet, A. (2012) · Trends in Cell Biology · doi:10.1016/j.tcb.2011.11.001 · Cited by 204
Wu, M., Luo, Q., Nie, R., Yang, X., Tang, Z., & Chen, H. (2020) · Critical Reviews in Food Science and Nutrition · doi:10.1080/10408398.2020.1773390 · Cited by 208
“Extra copies of Sir2 increased yeast replicative lifespan by 30%, whereas ablation of the Sir2 gene caused opposite effects on lifespan reduction by 50% (Kaeberlein, McVey, and Guarente 1999).”
BackgroundSirtuins, Aging, and MetabolismPreprint
Guarente, L. (2011) · Cold Spring Harbor Symposia on Quantitative Biology · doi:10.1101/sqb.2011.76.010629 · Cited by 213
Self-citationTao, R., Vassilopoulos, A., Parisiadou, L., Yan, Y., & Gius, D. (2014) · Antioxidants & Redox Signaling · doi:10.1089/ars.2013.5482 · Cited by 194
“It has been proposed that loss of function and/or genetic mutation of these fidelity proteins create a cellular environment that is permissive for the development of disease, which can lead to human illnesses connected to aging such as carcinogenesis (40, 41, 83).”
BackgroundBudding yeast as a model organism to study the effects of age
Denoth‐Lippuner, A., Julou, T., & Barral, Y. (2014) · FEMS Microbiology Reviews · doi:10.1111/1574-6976.12060 · Cited by 211
“In these cells, the levels of ERCs are lower compared with wild-type, suggesting that, in cells containing fewer ERCs, deletion of SIR2 shortens lifespan in an ERC-independent manner (Kaeberlein et al., 1999).”
BackgroundSharples, A. P., Hughes, D. C., Deane, C. S., Saini, A. S., Selman, C., & Stewart, C. E. (2015) · Aging Cell · doi:10.1111/acel.12342 · Cited by 204
“The metazoan Sir2 proteins are recognized, somewhat controversially, for their role in regulating lifespan in yeast, worms and fruit flies (Kaeberlein et al., 1999; Burnett et al., 2011; Viswanathan & Guarente, 2011).”
BackgroundThe neurobiology of sirtuins and their role in neurodegeneration
Dönmez, G. (2012) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2012.05.007 · Cited by 199
Nicotinamide Clearance by Pnc1 Directly Regulates Sir2-Mediated Silencing and Longevity
Gallo, C. M., Smith, D. L., & Smith, J. S. (2004) · Molecular and Cellular Biology · doi:10.1128/mcb.24.3.1301-1312.2004 · Cited by 193
“cerevisiae life span (32), specifically in response to caloric restriction-like growth conditions (39).”
BackgroundInfluentialBranched-chain amino acids, mitochondrial biogenesis, and healthspan: an evolutionary perspective
Valerio, A., D'Antona, G., & Nisoli, E. (2011) · Aging · doi:10.18632/aging.100322 · Cited by 196
“The NAD-dependent histone deacetylase, Sir2, a well-characterized RLS factor [17], is required for yeast RLS extension by CR [14].”
BackgroundChromatin structure as a mediator of aging
Feser, J., & Tyler, J. K. (2010) · FEBS Letters · doi:10.1016/j.febslet.2010.11.016 · Cited by 206
“Deletion of SIR2 reduces the RLS, while introducing an extra genomic copy of SIR2 extends the RLS, indicating that Sir2 is a limiting factor during aging [15].”
BackgroundLifespan-regulating genes in C. elegans
Uno, M., & Nishida, E. (2016) · npj Aging and Mechanisms of Disease · doi:10.1038/npjamd.2016.10 · Cited by 202
Lindstrom, D. L., & Gottschling, D. E. (2009) · Genetics · doi:10.1534/genetics.109.106229 · Cited by 197
“…examine the relationship between RLS and viability in liquid culture, we constructed MEP strains deleted for either SIR2 (UCC8836) or FOB1 (UCC526), which are well characterized for their effects on yeast RLS (Defossez et al. 1999; Kaeberlein et al. 1999; reviewed in Steinkraus et al. 2008).”
MethodRole of selection in fixation of gene duplications
Kondrashov, F. A., & Kondrashov, A. S. (2006) · Journal of Theoretical Biology · doi:10.1016/j.jtbi.2005.08.033 · Cited by 195
Suwa, M., Nakano, H., Radak, Z. O., & Kumagai, S. (2008) · Metabolism · doi:10.1016/j.metabol.2008.02.017 · Cited by 198
“Silent information regulator 2 is an oxidized form of nicotinamide adenine dinucleotide (NAD)-dependent histone deacetylase that is required for longevity in Caenorhabditis elegans [18] and Saccharomyces cerevisiae [19] in response to energy restriction.”
BackgroundNAD + metabolism: A therapeutic target for age-related metabolic disease
Mouchiroud, L., Houtkooper, R. H., & Auwerx, J. (2013) · Critical Reviews in Biochemistry and Molecular Biology · doi:10.3109/10409238.2013.789479 · Cited by 193
“Thus, the increased dosage of SIR2 in yeast prevents the formation of extrachromosomal ribosomal DNA circles and prolongs lifespan, whereas its inhibition has the opposite effect, reducing the replicative lifespan by 50% (Kaeberlein et al., 1999).”
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“In addition to silencing, Sir2 activity is linked to lifespan extension in yeast (Kaeberlein et al., 1999), worms (Tissenbaum and Guarente, 2001) and flies (Rogina and Helfand, 2004), indicating that Sir2 has conserved its function throughout evolution.”
BackgroundMammalian Sirtuins and Energy Metabolism
Li, X., & Kazgan, N. (2011) · International Journal of Biological Sciences · doi:10.7150/ijbs.7.575 · Cited by 196
“cerevisiae, deletion of the Sir2 gene dramatically shortens lifespan, whereas an extra copy of the Sir2 extends lifespan by 40% (7).”
BackgroundGenetics of Aging in Caenorhabditis elegans
Antebi, A. (2007) · PLoS Genetics · doi:10.1371/journal.pgen.0030129 · Cited by 190
“Sirtuins are NAD+-dependent protein deacetylases whose increased dose augments longevity in yeast, worms, and flies [”
BackgroundWorming pathways to and from DAF-16/FOXO
Mukhopadhyay, A., Oh, S. W., & Tissenbaum, H. A. (2006) · Experimental Gerontology · doi:10.1016/j.exger.2006.05.020 · Cited by 198
McFaline-Figueroa, J. R., Vevea, J., Swayne, T. C., Zhou, C., Liu, C., Leung, G., Boldogh, I. R., & Pon, L. A. (2011) · Aging Cell · doi:10.1111/j.1474-9726.2011.00731.x · Cited by 194
“Sir2p, the founding member of the Sirtuin family of age-regulating proteins, is required for asymmetric distribution of aging determinants and mother–daughter age asymmetry (Kaeberlein et al., 1999; Aguilaniu et al., 2003; Erjavec et al., 2007).”
BackgroundFabrizio, P., Pletcher, S. D., Minois, N., Vaupel, J. W., & Longo, V. D. (2003) · FEBS Letters · doi:10.1016/s0014-5793(03)01462-5 · Cited by 197
Increased Life Span due to Calorie Restriction in Respiratory-Deficient Yeast
Kaeberlein, M. R., Hu, D., Kerr, E. O., Tsuchiya, M., Westman, E. A., Dang, N., Fields, S., & Kennedy, B. K. (2005) · PLoS Genetics · doi:10.1371/journal.pgen.0010069 · Cited by 193
“wild-type cells is most likely due to the hyperaccumulation of ERCs in cells lacking Sir2 activity [36,41].”
InfluentialSelf-citationATGL-Catalyzed Lipolysis Regulates SIRT1 to Control PGC-1α/PPAR-α Signaling
Khan, S. A., Sathyanarayan, A., Mashek, M. T., Ong, K. T., Wollaston‐Hayden, E. E., & Mashek, D. G. (2015) · Diabetes · doi:10.2337/db14-0325 · Cited by 189
“In addition, SIRT1 is a key signaling node in life span determination (6) and is required for the effects of calorie restriction on life span extension as observed in numerous species (7–9).”
BackgroundYamakuchi, M. (2012) · Frontiers in Physiology · doi:10.3389/fphys.2012.00068 · Cited by 196
“In yeast, Sir2 is recognized as a regulator of lifespan (Kaeberlein et al., 1999).”
BackgroundHuang, J., Gan, Q., Han, L., Li, J., Zhang, H., Sun, Y., Zhang, Z., & Tong, T. (2008) · PLoS ONE · doi:10.1371/journal.pone.0001710 · Cited by 189
“eukaryotes, including yeasts [3,4], worms [5] and flies [6].”
BackgroundRegulation of SIRT6 protein levels by nutrient availability
Kanfi, Y., Shalman, R., Peshti, V., Pilosof, S. N., Gozlan, Y. M., Pearson, K. J., Lerrer, B., Moazed, D., Marine, J., de Cabo, R., et al. (2008) · FEBS Letters · doi:10.1016/j.febslet.2008.01.019 · Cited by 187
“cerevisiae, Caenorhabditis elegans and Drosophila melanogaster through either genetic or chemical means, extends life-span by at least 30% [3–6].”
Epigenetic silencing mediates mitochondria stress-induced longevity
Schroeder, E. A., Raimundo, N., & Shadel, G. S. (2013) · Cell Metabolism · doi:10.1016/j.cmet.2013.04.003 · Cited by 186
“Yeast deficient in heterochromatin formation at these silenced loci exhibit decreased replicative lifespan (Dang et al., 2009; Kaeberlein et al., 1999), yet it is unknown how silencing at these regions influences chronological aging.”
InfluentialDiLoreto, R., & Murphy, C. T. (2015) · Molecular Biology of the Cell · doi:10.1091/mbc.e14-06-1084 · Cited by 192
“The sirtuins SIR3 and SIR4 are associated with lifespan and nuclear organization in Saccharomyces cerevisiae (Kaeberlein et al., 1999), regulating nucleolus fragmentation in aging yeast (Lewinska et al.”
BackgroundSIR2: a potential target for calorie restriction mimetics
Chen, D., & Guarente, L. (2007) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2006.12.004 · Cited by 187
Self-citationComing of age: molecular drivers of aging and therapeutic opportunities
Newgard, C. B., & Sharpless, N. E. (2013) · Journal of Clinical Investigation · doi:10.1172/jci68833 · Cited by 194
“discuss the possible role of the sirtuin family of enzymes in the control of aging (16), a field that had its origins with the report that overexpression of the yeast sirtuin Sir2 resulted in increased life span in that simple organism (17).”
BackgroundSIRT1 in the brain—connections with aging-associated disorders and lifespan
Ng, F. (2015) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2015.00064 · Cited by 192
“Its suppression of the formation of rDNA circles (Sinclair and Guarente, 1997) could play a role in extending yeast’s replicative, but not chronological lifespan (Kaeberlein et al., 1999; Fabrizio et al., 2005).”
BackgroundYang, T., Fu, M., Pestell, R. G., & Sauve, A. A. (2006) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2006.04.002 · Cited by 183
Energy metabolism and energy-sensing pathways in mammalian embryonic and adult stem cell fate
Rafalski, V. A., Mancini, E., & Brunet, A. (2012) · Journal of Cell Science · doi:10.1242/jcs.114827 · Cited by 181
“SIRT1 is the Sirtuin with the greatest homology to the yeast Sir2 deacetylase, which is known to extend the replicative lifespan of yeast (Kaeberlein et al., 1999).”
BackgroundMolecular and cellular pathways contributing to brain aging
Zia, A., Pourbagher‐Shahri, A. M., Farkhondeh, T., & Samarghandian, S. (2021) · Behavioral and Brain Functions · doi:10.1186/s12993-021-00179-9 · Cited by 195
Genes That Prolong Life: Relationships of Growth Hormone and Growth to Aging and Life Span
Bartke, A., Coschigano, K. T., Kopchick, J. J., Chandrashekar, V., Mattison, J. A., Kinney, B. A., & Hauck, S. (2001) · The Journals of Gerontology Series A · doi:10.1093/gerona/56.8.b340 · Cited by 180
FOXO transcription factors in ageing and cancer
Greer, E. L., & Brunet, A. (2007) · Acta Physiologica · doi:10.1111/j.1748-1716.2007.01780.x · Cited by 182
“The Sir2 family encodes class III deacetylases which extend longevity in invertebrates (Kaeberlein et al. 1999, Imai et al. 2000, Tissenbaum & Guarente 2001, Rogina & Helfand 2004, Wood et al. 2004).”
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Nucleolar Function in Lifespan Regulation
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Life Span Extension and Neuronal Cell Protection by Drosophila Nicotinamidase
Balan, V., Miller, G. S., Kaplun, L., Balan, K., Chong, Z.-Z., Li, F., Kaplun, A., VanBerkum, M. F. A., Arking, R., Freeman, D. C., et al. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m804681200 · Cited by 176
SIRT1 and AMPK in regulating mammalian senescence: A critical review and a working model
Wang, Y., Liang, Y. Q., & Vanhoutte, P. M. (2010) · FEBS Letters · doi:10.1016/j.febslet.2010.11.047 · Cited by 178
“The anti-ageing effects of Sir2 was firstly demonstrated by Kaeberlein et al, who showed that the integration of extra copies of Sir2 extended lifespan up to 30% in Saccharomyces cerevisiae [43].”
BackgroundResveratrol and novel potent activators of SIRT1: effects on aging and age-related diseases
Knutson, M. D., & Leeuwenburgh, C. (2008) · Nutrition Reviews · doi:10.1111/j.1753-4887.2008.00109.x · Cited by 178
Histone modifications and chromatin dynamics: a focus on filamentous fungi
Brosch, G., Loidl, P., & Graessle, S. (2008) · FEMS Microbiology Reviews · doi:10.1111/j.1574-6976.2007.00100.x · Cited by 180
“The latter are exclusively found in plants (Loidl, 2004) and will therefore not be discussed here.”
BackgroundSuppression of Homologous Recombination by the Saccharomyces cerevisiae Linker Histone
Downs, J. A., Kosmidou, E., Morgan, A., & Jackson, S. P. (2003) · Molecular Cell · doi:10.1016/s1097-2765(03)00197-7 · Cited by 174
Aging and reprogramming: a two-way street
Mahmoudi, S., & Brunet, A. (2012) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2012.10.004 · Cited by 171
SIRT1 Activation Confers Neuroprotection in Experimental Optic Neuritis
Shindler, K. S., Ventura, E. S., Rex, T. S., Elliott, P. J., & Rostami, A. M. (2007) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.07-0131 · Cited by 174
Genes determining yeast replicative life span in a long-lived genetic background
Kaeberlein, M. R., Kirkland, K. T., Fields, S., & Kennedy, B. K. (2005) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2004.10.007 · Cited by 170
“Consistent with prior reports (Kennedy et al., 1995; Kaeberlein et al., 1999), we found that deletion of either Sir3 or Sir4 modestly shortened life span (Table 3), although not significantly.”
BackgroundResultInfluentialSelf-citationPorcu, M., & Chiarugi, A. (2004) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2004.12.009 · Cited by 172
The Role of Mammalian Sirtuins in the Regulation of Metabolism, Aging, and Longevity
Satoh, A., Stein, L. R., & Imai, S. (2011) · Handbook of experimental pharmacology · doi:10.1007/978-3-642-21631-2_7 · Cited by 175
Vellai, T. (2008) · Cell Death and Differentiation · doi:10.1038/cdd.2008.126 · Cited by 173
A new role of the rDNA and nucleolus in the nucleus—rDNA instability maintains genome integrity
Kobayashi, T. (2008) · BioEssays · doi:10.1002/bies.20723 · Cited by 172
Cao, C., Lü, S., Kivlin, R., Wallin, B., Card, E., Bagdasarian, A., Tamakloe, T., Wang, W., Song, X., Chu, W., et al. (2008) · Journal of Cellular and Molecular Medicine · doi:10.1111/j.1582-4934.2008.00453.x · Cited by 171
“The best characterized of these genes is Saccharomyces cerevisiae SIR2, which is involved in silencing of mating type loci, telomere maintenance, DNA damage response and cell aging [1].”
BackgroundPaths of Convergence: Sirtuins in Aging and Neurodegeneration
Gan, L., & Mucke, L. (2008) · Neuron · doi:10.1016/j.neuron.2008.03.015 · Cited by 173
“However, under certain conditions, CR can also extend life span in S. cerevisiae in a Sir2-independent manner (Kaeberlein et al., 2004).”
BackgroundInfluentialNiederer, F., Ospelt, C., Brentano, F., Hottiger, M. O., Gay, R. E., Gay, S., Detmar, M. J., & Kyburz, D. (2011) · Annals of the Rheumatic Diseases · doi:10.1136/ard.2010.148957 · Cited by 172
“SIRT1 has emerged as a key anti-aging protein in different experimental models, such as in Sacharomyces cerevisiae, in sirt1-null mice as well as in various in vitro cell cultures.[11, 13, 14, 31-34] RASFs characteristically show a resistance to apoptosis.”
BackgroundLiu, M., Lei, H., Dong, P., Fu, X., Yang, Z., Yang, Y., Ma, J., Liu, X., Cao, Y., & Xiao, R. (2017) · Cell Transplantation · doi:10.1177/0963689717721221 · Cited by 173
“Using different model organisms, Sirt1 and Sirt2 have been implicated in life extension.(32) Our results indicate that hASCs from aged donors undergo a cellular senescence process, although some results did not show a significant difference.”
ResultSIRT1 suppresses the senescence-associated secretory phenotype through epigenetic gene regulation
Hayakawa, T., Iwai, M., Aoki, S., Takimoto, K., Maruyama, M., Maruyama, W., & Motoyama, N. (2015) · PLOS ONE · doi:10.1371/journal.pone.0116480 · Cited by 170
“Although previous studies reported that overexpression of the SIRT1 ortholog in the yeast, Caenorhabditis elegans, Drosophila melanogaster and mouse extended their lifespans, its effects on longevity per se remain controversial [22–26].”
BackgroundHigh Levels of SIRT1 Expression as a Protective Mechanism Against Disease-Related Conditions
Elibol, B., & Kilic, U. (2018) · Frontiers in Endocrinology · doi:10.3389/fendo.2018.00614 · Cited by 171
NAD metabolism and sirtuins: Metabolic regulation of protein deacetylation in stress and toxicity
Yang, T., & Sauve, A. A. (2006) · The AAPS Journal · doi:10.1208/aapsj080472 · Cited by 170
SIRT3 consolidates heterochromatin and counteracts senescence
Diao, Z., Ji, Q., Wu, Z., Zhang, W., Cai, Y., Wang, Z., Hu, J., Liu, Z., Wang, Q., Bi, S., et al. (2021) · Nucleic Acids Research · doi:10.1093/nar/gkab161 · Cited by 176
Kobayashi, T. (2003) · Molecular and Cellular Biology · doi:10.1128/mcb.23.24.9178-9188.2003 · Cited by 169
“As another aging gene, SIR2, whose gene product is a NAD-dependent histone deacetylase (20), is genetically downstream of FOB1 in the aging process, instability of the rDNA is probably an important component of this process (23).”
BackgroundZhang, Y., Tang, Z., Ren, Z., Qu, S.-L., Liu, M., Liu, L.-S., & Jiang, Z.-S. (2013) · Molecular and Cellular Biology · doi:10.1128/mcb.01215-12 · Cited by 167
Caloric restriction: From soup to nuts
Spindler, S. R. (2009) · Ageing Research Reviews · doi:10.1016/j.arr.2009.10.003 · Cited by 169
“Further, an additional copy of the orthologous gene can increase lifespan of yeast (Kaeberlein et al., 1999), C. elegans (Tissenbaum and Guarente, 2001), and Drosophila (Rogina and Helfand, 2004) by 18–50%.”
BackgroundPartridge, L. (2009) · Philosophical Transactions of the Royal Society B Biological Sciences · doi:10.1098/rstb.2009.0222 · Cited by 174
“Keywords: ageing; lifespan; ageing-related disease; geriatrics; preventative medicine; nutrient-sensing pathways”
BackgroundThe emerging role of alternative splicing in senescence and aging
Deschênes, M., & Chabot, B. (2017) · Aging Cell · doi:10.1111/acel.12646 · Cited by 172
“Sir2/SIRT1 activation extends lifespan in yeast, C. elegans, Drosophila, as well as in mice (Kaeberlein et al., 1999; Tissenbaum & Guarente, 2001; Whitaker et al., 2013; Mitchell et al., 2014).”
BackgroundThe African turquoise killifish: A research organism to study vertebrate aging and diapause
Hu, C., & Brunet, A. (2018) · Aging Cell · doi:10.1111/acel.12757 · Cited by 174
A therapeutic role for sirtuins in diseases of aging?
Westphal, C. H., Dipp, M., & Guarente, L. (2007) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2007.09.008 · Cited by 168
Self-citationMitochondrial-to-nuclear communication in aging: an epigenetic perspective
Zhu, D., Li, X., & Tian, Y. (2022) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2022.03.008 · Cited by 170
Ribosomal RNA gene repeats, their stability and cellular senescence
KOBAYASHI, T. (2014) · Proceedings of the Japan Academy, Series B · doi:10.2183/pjab.90.119 · Cited by 167
Vetterli, L., Brun, T., Giovannoni, L., Bosco, D., & Maechler, P. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.176842 · Cited by 170
Aging of mesenchymal stem cell: machinery, markers, and strategies of fighting
Al‐Azab, M., Safi, M., Idiiatullina, E., Al‐Shaebi, F., & Zaky, M. Y. (2022) · Cellular & Molecular Biology Letters · doi:10.1186/s11658-022-00366-0 · Cited by 178
Chromatin regulation and genome maintenance by mammalian SIRT6
Tennen, R. I., & Chua, K. F. (2010) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2010.07.009 · Cited by 167
Lifespan Control by Redox-Dependent Recruitment of Chaperones to Misfolded Proteins
Hanzén, S., Vielfort, K., Yang, J., Roger, F., Andersson, V., Zamarbide-Forés, S., Andersson, R., Malm, L., Palais, G., Biteau, B., et al. (2016) · Cell · doi:10.1016/j.cell.2016.05.006 · Cited by 166
Sirtuins and their Biological Relevance in Aging and Age-Related Diseases
Zhao, L., Cao, J., Hu, K., He, X., Dou, Y., Tong, T., & Han, L. (2020) · Aging and Disease · doi:10.14336/ad.2019.0820 · Cited by 178
“occurred in 1999 when it was reported that Sir2 overexpression could extend yeast lifespans by as much as 70% [3].”
BackgroundYamazaki, Y., Usui, I., Kanatani, Y., Matsuya, Y., Tsuneyama, K., Fujisaka, S., Bukhari, A., Suzuki, H., Senda, S., Imanishi, S., et al. (2009) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.90997.2008 · Cited by 137
The emerging and diverse roles of sirtuins in cancer: a clinical perspective
Chen, W., Yuan, H., & Su, L. (2013) · OncoTargets and Therapy · doi:10.2147/ott.s37750 · Cited by 169
Guo, W., Qian, L., Zhang, J., Zhang, W., Morrison, A., Hayes, P. D., Wilson, S., Chen, T., & Zhao, J. (2011) · Journal of Neuroscience Research · doi:10.1002/jnr.22725 · Cited by 163
“Key words: Alzheimer’s disease; amyloid; dendrites; neurotoxicity; phosphorylation Sirtuin 1 (Sirt1), the first identified nicotinamideadenine dinucleotide (NAD(1))-dependent histone deacetylase (HDAC; Kaeberlein et al., 1999), is the closest mammalian homologue of the yeast silent information regulator 2 (Sir2) that…”
BackgroundSIRT1 reduces endothelial activation without affecting vascular function in ApoE-/- mice
Stein, S., Schäfer, N., Breitenstein, A., Besler, C., Winnik, S. H., Lohmann, C., Heinrich, K., Brokopp, C. E., Handschin, C., Landmesser, U., et al. (2010) · Aging · doi:10.18632/aging.100162 · Cited by 164
“The NAD-dependent class III histone deacetylase Sir2 was found to increase lifespan in yeast [6].”
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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