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Increased dosage of a sir-2 gene extends lifespan in Caenorhabditis elegans
Abstract
In Caenorhabditis elegans, mutations that reduce the activity of an insulin-like receptor (daf-2) or a phosphatidylinositol-3-OH kinase (age-1) favour entry into the dauer state during larval development and extend lifespan in adults. Downregulation of this pathway activates a forkhead transcription factor (daf-16), which may regulate targets that promote dauer formation in larvae and stress resistance and longevity in adults. In yeast, the SIR2 gene determines the lifespan of mother cells, and adding an extra copy of SIR2 extends lifespan. Sir2 mediates chromatin silencing through a histone deacetylase activity that depends on NAD (nicotinamide adenine dinucleotide) as a cofactor. We have surveyed the lifespan of C. elegans strains containing duplications of chromosomal regions. Here we report that a duplication containing sir-2.1-the C. elegans gene most homologous to yeast SIR2-confers a lifespan that is extended by up to 50%. Genetic analysis indicates that the sir-2.1 transgene functions upstream of daf-16 in the insulin-like signalling pathway. Our findings suggest that Sir2 proteins may couple longevity to nutrient availability in many eukaryotic organisms.
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Enhanced expression of the worm sir-2.1 and fly dSir2 orthologs could extend lifespan in both invertebrate model systems.
“and subsequent reports indicated that enhanced expression of the worm (sir-2.1) and fly (dSir2) orthologs could extend lifespan in both invertebrate model systems (Rogina and Helfand, 2004; Tissenbaum and Guarente, 2001).”
From The Hallmarks of Aging (2013) · cites this paper as Tissenbaum and Guarente, 2001
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Redox regulation of mitochondrial function
Handy, D. E., & Loscalzo, J. (2012) · Antioxidants & Redox Signaling · doi:10.1089/ars.2011.4123 · Cited by 588
Evolutionary medicine: from dwarf model systems to healthy centenarians?
Longo, V. D., & Finch, C. E. (2003) · Science · doi:10.1126/science.1077991 · Cited by 575
Sir2-dependent activation of acetyl-CoA synthetase by deacetylation of active lysine
Starai, V. J., Celic, I., Cole, R. N., Boeke, J. D., & Escalante-Semerena, J. C. (2002) · Science · doi:10.1126/science.1077650 · Cited by 564
Aging as an event of proteostasis collapse
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Mouse Sir2 Homolog SIRT6 Is a Nuclear ADP-ribosyltransferase
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Self-citationThe updated biology of hypoxia-inducible factor
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Aging, Rejuvenation, and Epigenetic Reprogramming: Resetting the Aging Clock
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Cellular and molecular biology of aging endothelial cells
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Mitohormesis: Promoting Health and Lifespan by Increased Levels of Reactive Oxygen Species (ROS)
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Substrates and regulation mechanisms for the human mitochondrial sirtuins Sirt3 and Sirt5
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“Genetic manipulation of Sir2 orthologs was later demonstrated to affect lifespan in higher eukaryotes, such as nematodes [28, 29] and insects [30,31], even though the consistency and amplitude of this effect has been a matter of debate [32–34].”
BackgroundSirtuin activators and inhibitors: Promises, achievements, and challenges
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“, 2014) and live longer when sirtuins are overexpressed (Banerjee et al., 2012; Rizki et al., 2011; Rogina and Helfand, 2004; Tissenbaum and Guarente, 2001), although the magnitudes of the effects were challenged.”
BackgroundSirtuins, a promising target in slowing down the ageing process
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Sirtuins as potential targets for metabolic syndrome
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Self-citationCalorie restriction and sirtuins revisited
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Self-citationSir2-Independent Life Span Extension by Calorie Restriction in Yeast
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SirT1 Regulates Energy Metabolism and Response to Caloric Restriction in Mice
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Genetics and the Specificity of the Aging Process
Hekimi, S., & Guarente, L. (2003) · Science · doi:10.1126/science.1082358 · Cited by 434
Self-citationTargeting Sirtuin 1 to Improve Metabolism: All You Need Is NAD+?
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Regulation of Insulin Secretion by SIRT4, a Mitochondrial ADP-ribosyltransferase
Ahuja, N., Schwer, B., Carobbio, S., Waltregny, D., North, B. J., Castronovo, V., Maechler, P., & Verdin, E. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m705488200 · Cited by 422
Transcriptional outputs of the Caenorhabditis elegans forkhead protein DAF‐16
McElwee, J., Bubb, K., & Thomas, J. H. (2003) · Aging Cell · doi:10.1046/j.1474-9728.2003.00043.x · Cited by 416
Metadata
- Authors
- Tissenbaum, H. A., & Guarente, L.
- Venue
- Nature
- Published
- 2001-03
- Volume
- 410
- Issue
- 6825
- Pages
- 227-230
- ISSN
- 0028-0836
- 1476-4687
- Cited by
- 1,603
- References
- 4
- Language
- en
- Licence
- www.springer.com/tdm (tdm)
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