Sirt1 Regulates Aging and Resistance to Oxidative Stress in the Heart
Abstract
Silent information regulator (Sir)2, a class III histone deacetylase, mediates lifespan extension in model organisms and prevents apoptosis in mammalian cells. However, beneficial functions of Sir2 remain to be shown in mammals in vivo at the organ level, such as in the heart. We addressed this issue by using transgenic mice with heart-specific overexpression of Sirt1, a mammalian homolog of Sir2. Sirt1 was significantly upregulated (4- to 8-fold) in response to pressure overload and oxidative stress in nontransgenic adult mouse hearts. Low (2.5-fold) to moderate (7.5-fold) overexpression of Sirt1 in transgenic mouse hearts attenuated age-dependent increases in cardiac hypertrophy, apoptosis/fibrosis, cardiac dysfunction, and expression of senescence markers. In contrast, a high level (12.5-fold) of Sirt1 increased apoptosis and hypertrophy and decreased cardiac function, thereby stimulating the development of cardiomyopathy. Moderate overexpression of Sirt1 protected the heart from oxidative stress induced by paraquat, with increased expression of antioxidants, such as catalase, through forkhead box O (FoxO)-dependent mechanisms, whereas high levels of Sirt1 increased oxidative stress in the heart at baseline. Thus, mild to moderate expression of Sirt1 retards aging of the heart, whereas a high dose of Sirt1 induces cardiomyopathy. Furthermore, although high levels of Sirt1 increase oxidative stress, moderate expression of Sirt1 induces resistance to oxidative stress and apoptosis. These results suggest that Sirt1 could retard aging and confer stress resistance to the heart in vivo, but these beneficial effects can be observed only at low to moderate doses (up to 7.5-fold) of Sirt1.
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Sirtuin-1 plays an essential role in regulation of angiogenesis, a protective role against oxidative stress and cardiovascular disease, and higher expression levels of sirtuin-1 are associated with reducing disease.
“Sirtuin-1 plays an essential role in the regulation of angiogenesis, a protective role against oxidative stress and cardiovascular disease and higher expression levels of sirtuin-1 are associated with reducing disease (176–178).”
From A Critical Review of the Evidence That Metformin Is a Putative Anti-Aging Drug That Enhances Healthspan and Extends Lifespan (2021) · cites this paper as [176]
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Sedding, D., & Haendeler, J. (2007) · Circulation Research · doi:10.1161/01.res.0000269326.37165.3d · Cited by 21 · see citing works
- Authors
- Alcendor, R. R., Gao, S., Zhai, P., Zablocki, D., Holle, E., Yu, X., Tian, B., Wagner, T., Vatner, S. F., & Sadoshima, J.
- Affiliations
- Prisma Health (US)
- Venue
- Circulation Research
- Published
- 2007-05-25
- Volume
- 100
- Issue
- 10
- Pages
- 1512-1521
- ISSN
- 0009-7330 (ISSN-L)
- 1524-4571
- OpenAlex
- W2118204731
- Cited by
- 1,147
- References
- 54
- Citations by year
- 2026: 44 · 2025: 47 · 2024: 60 · 2023: 58 · 2022: 64 · 2021: 73 · 2020: 82 · 2019: 49 · 2018: 62 · 2017: 55 · 2016: 56 · 2015: 80 · 2014: 69 · 2013: 62 · 2012: 71
- FWCI
- 22.66
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Circulation Research (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute on Aging (AG28787, R01AG023039, AG023039, R01AG028787)
- National Heart, Lung, and Blood Institute (HL59139, R01HL067724, HL69020, HL-67724, P01HL059139, P01HL069020, R01HL091469)
- 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
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac electrophysiology and arrhythmias
- Keywords
- SIRT1, Sir2, cardiac aging, oxidative stress, cardiomyopathy, cardiac hypertrophy, apoptosis, myocardial fibrosis, FOXO, catalase, paraquat, transgenic mice, dose-dependent effects, cardiac dysfunction
- MeSH terms
- Forkhead Box Protein O1, Adenosine Triphosphate, Aging, Animals, Cells, Cultured, Echocardiography, Mice, Transgenic, Myocardium, NAD, Ventricular Function, Left, Rats, Wistar, Apoptosis, Oxidative Stress, Sirtuins, Mice, Rats, Forkhead Transcription Factors, Sirtuin 1
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