Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan
Abstract
In diverse organisms, calorie restriction slows the pace of ageing and increases maximum lifespan. In the budding yeast Saccharomyces cerevisiae, calorie restriction extends lifespan by increasing the activity of Sir2 (ref. 1), a member of the conserved sirtuin family of NAD(+)-dependent protein deacetylases. Included in this family are SIR-2.1, a Caenorhabditis elegans enzyme that regulates lifespan, and SIRT1, a human deacetylase that promotes cell survival by negatively regulating the p53 tumour suppressor. Here we report the discovery of three classes of small molecules that activate sirtuins. We show that the potent activator resveratrol, a polyphenol found in red wine, lowers the Michaelis constant of SIRT1 for both the acetylated substrate and NAD(+), and increases cell survival by stimulating SIRT1-dependent deacetylation of p53. In yeast, resveratrol mimics calorie restriction by stimulating Sir2, increasing DNA stability and extending lifespan by 70%. We discuss possible evolutionary origins of this phenomenon and suggest new lines of research into the therapeutic use of sirtuin activators.
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Resveratrol was identified as the most potent SIRT1 activator in an in vitro screen.
“Resveratrol, a natural polyphenolic compound present in various dietary components such as mulberries, peanuts, grapes and red wine, was identified as the most potent activator of SIRT1 (Howitz et al., 2003).”
From Calorie Restriction-like Effects of 30 Days of Resveratrol Supplementation on Energy Metabolism and Metabolic Profile in Obese Humans (2011) · cites this paper as Howitz et al., 2003
Experiments in animal models have shown that resveratrol significantly reduces body weight.
“Experiments in animal models have shown that resveratrol significantly reduces body weight [14].”
From The Role of Resveratrol Administration in Human Obesity (2021) · cites this paper as [14]
SIRT-1 is a human deacetylase that negatively regulates the p53 tumor suppressor gene and thus promotes cell survival.
“SIRT-1 is a human deacetylase that negatively regulates the p53 tumor suppressor gene, thus it promotes cell survival [14].”
From The Role of Resveratrol Administration in Human Obesity (2021) · cites this paper as [14]
Caloric restriction is an intervention capable of extending life span in many different organisms from yeast to mammals.
“an intervention capable of extending life span in many different organisms from yeast to mammals (Cohen et al., 2004; Howitz et al., 2003; Lin et al., 2000; Rogina and Helfand, 2004; Wood et al., 2004”
From DNA Repair, Genome Stability, and Aging (2005) · cites this paper as Howitz et al., 2003
Resveratrol extends lifespan in yeast, worms, and flies.
“resveratrol, a plant polyphenol commonly found in red wine that extends lifespan in yeast, worms and flies [143, 144].”
From PGC-1α in aging and anti-aging interventions (2009) · cites this paper as [143]
Quercetin activates AMPK and SIRT1.
“Indeed, this polyphenol has been reported to activate the AMPK and SIRT1 (Howitz et al., 2003; Hawley et al., 2010)”
From Mitochondrial (Dys)function and Insulin Resistance: From Pathophysiological Molecular Mechanisms to the Impact of Diet (2019) · cites this paper as Howitz et al., 2003
Resveratrol prolongs the life of flies, worms, and the replicative lifespan of yeast.
“Resveratrol prolongs the life of flies (Bauer et al., 2004), worms (Baur and Sinclair, 2006), and the replicative lifespan of yeast (Howitz et al., 2003), but not yeast’s chronological lifespan (our unpublished observations).”
From The Search for Antiaging Interventions: From Elixirs to Fasting Regimens (2014) · cites this paper as Howitz et al., 2003
Resveratrol has anti-aging effects in lower organisms, reduces signs of aging in mice, and extends survival.
“Resveratrol, an ingredient in red wines, is a polyphenolic SIRT1 activator that, like calorie restriction, has anti-aging effects in lower organisms (22, 143, 331), reduces signs of aging in mice (248), and extends survival (22).”
From Mitochondrial Dysfunction in Diabetes: From Molecular Mechanisms to Functional Significance and Therapeutic Opportunities (2010) · cites this paper as [143]
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- Authors
- Howitz, K. T., Bitterman, K. J., Cohen, H. Y., Lamming, D. W., Lavu, S., Wood, J. G., Zipkin, R. E., Chung, P., Kisielewski, A., Zhang, L.-L., Scherer, B., & Sinclair, D. A.
- Affiliations
- Harvard University (US)
- Corresponding author
- Sinclair, David A.
- Venue
- Nature
- Published
- 2003-08-24
- Volume
- 425
- Issue
- 6954
- Pages
- 191-196
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W2088381487
- Cited by
- 3,796
- References
- 30
- Citations by year
- 2026: 77 · 2025: 73 · 2024: 117 · 2023: 99 · 2022: 133 · 2021: 159 · 2020: 159 · 2019: 158 · 2018: 181 · 2017: 189 · 2016: 198 · 2015: 215 · 2014: 227 · 2013: 267 · 2012: 253
- FWCI
- 51.56
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Institute on Aging (R37AG028730, P01AG027916, R01AG028730, R01AG019719, R01AG019972, R13AG033466)
- National Institute of General Medical Sciences (R01GM068072)
- Topics
- Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Biochemical and Molecular Research
- Keywords
- sirtuins, Sir2, SIRT1, resveratrol, caloric restriction, lifespan extension, aging, Sir2p, p53 deacetylation, NAD+-dependent deacetylase, DNA stability, Saccharomyces cerevisiae, small molecule activators
- MeSH terms
- Resveratrol, Acetylation, Catalysis, Cell Line, Cell Survival, Flavonoids, Histone Deacetylases, Humans, Kinetics, Longevity, Phenols, Polymers, Recombination, Genetic, Saccharomyces cerevisiae, Stilbenes, Wine, Tumor Suppressor Protein p53, Cellular Senescence, Caloric Restriction, Sirtuins, Silent Information Regulator Proteins, Saccharomyces cerevisiae, Sirtuin 1, Sirtuin 2, Polyphenols
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