Cited by 182Sirtuins and Resveratrol in MedicineTelomeres, Telomerase, and SenescenceGenetics, Aging, and Longevity in Model Organisms

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Telomere Dysfunction Induces Sirtuin Repression that Drives Telomere-Dependent Disease

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Amano, Hisayuki, Chaudhury, Arindam, Rodriguez-Aguayo, Cristian, Lu, Lan, Akhanov, Viktor, Catic, Andre, Popov, Yury V., Verdin, Eric, Johnson, Hannah, Stossi, Fabio, Sinclair, David A., Nakamaru-Ogiso, Eiko, Lopez-Berestein, Gabriel, Chang, Jeffrey T., Neilson, Joel R., Meeker, Alan, Finegold, Milton, Baur, Joseph A., Sahin, Ergun·2019·Cell Metabolism

DOI 10.1016/j.cmet.2019.03.001PMC PMC6657508

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Abstract

Telomere shortening is associated with stem cell decline, fibrotic disorders, and premature aging through mechanisms that are incompletely understood. Here, we show that telomere shortening in livers of telomerase knockout mice leads to a p53-dependent repression of all seven sirtuins. P53 regulates non-mitochondrial sirtuins (Sirt1, 2, 6, and 7) post-transcriptionally through microRNAs (miR-34a, 26a, and 145), while the mitochondrial sirtuins (Sirt3, 4, and 5) are regulated in a peroxisome proliferator-activated receptor gamma co-activator 1 alpha-/beta-dependent manner at the transcriptional level. Administration of the NAD(+) precursor nicotinamide mononucleotide maintains telomere length, dampens the DNA damage response and p53, improves mitochondrial function, and, functionally, rescues liver fibrosis in a partially Sirt1-dependent manner. These studies establish sirtuins as downstream targets of dysfunctional telomeres and suggest that increasing Sirt1 activity alone or in combination with other sirtuins stabilizes telomeres and mitigates telomere-dependent disorders.

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Authors: Amano, H., Chaudhury, A., Rodriguez-Aguayo, C., Lu, L., Akhanov, V., Catic, A., Popov, Y. V., Verdin, E., Johnson, H., Stossi, F., Sinclair, D. A., Nakamaru-Ogiso, E., Lopez-Berestein, G., Chang, J. T., Neilson, J. R., Meeker, A., Finegold, M., Baur, J. A., & Sahin, E.
Affiliations: Baylor College of Medicine (US)
Philips (United States) (US)
Beth Israel Deaconess Medical Center (US)
Gladstone Institutes (US)
Harvard University (US)
The University of Texas Health Science Center at Houston (US)
Johns Hopkins University (US)
University of Pennsylvania (US)
ORCID: Chaudhury, Arindam
Lu, Lan
Akhanov, Viktor
Popov, Yury V.
Verdin, Eric
Johnson, Hannah
Stossi, Fabio
Sinclair, David A.
Chang, Jeffrey T.
Neilson, Joel R.
Meeker, Alan
Finegold, Milton
Baur, Joseph A.
Venue: Cell Metabolism
Publisher: Elsevier BV
Published: 2019-06
Volume: 29
Issue: 6
Pages: 1274-1290.e9
ISSN: 1550-4131 (ISSN-L)
DOI: 10.1016/j.cmet.2019.03.001
PMC: PMC6657508
OpenAlex: W2927492624
Cited by: 182
References: 51
Citations by year: 2026: 13 · 2025: 31 · 2024: 27 · 2023: 34 · 2022: 26 · 2021: 22 · 2020: 20 · 2019: 9
FWCI: 10.14
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
www.elsevier.com/open-access/userlicense/1.0/ (vor, 369 d)
Locations: Cell Metabolism (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
Funders: National Institutes of Health (AG043483, DK098656, CA125123, DK56338, FP00000019, R01DK115454)
National Institute on Aging (R01AG047924)
National Cancer Institute (CA190467)
American Cancer Society (RSG-15-088-01RMC)
Glenn Foundation for Medical Research (R01 DK100263, AG043483, R21 DE027490, R01 AG019719, DK098656, R37 AG028730)
Cancer Prevention and Research Institute of Texas (RP170719, RP150578)
Topics: Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Telomeres, Telomerase, and Senescence
Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
Keywords: telomere shortening, sirtuins, p53, liver fibrosis, microRNA, miR-34a, miR-26a, miR-145, SIRT1, nicotinamide mononucleotide, NAD+ precursors, DNA damage response, mitochondrial function, premature aging
MeSH terms: Animals, Cells, Cultured, Embryo, Mammalian, Female, Humans, Liver, Liver Cirrhosis, Male, Mice, Inbred C57BL, Mitochondria, Liver, Nicotinamide Mononucleotide, Down-Regulation, Gene Expression Regulation, Enzymologic, Mice, Knockout, Telomerase, Sirtuins, Mice, Sirtuin 1, HEK293 Cells, Telomere Homeostasis, Telomere Shortening

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Telomere Dysfunction Induces Sirtuin Repression that Drives Telomere-Dependent Disease

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