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Telomere Dysfunction Induces Sirtuin Repression that Drives Telomere-Dependent Disease
Open accessAbstract
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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“NMN promoted telomere lengthening in aged mice [36], pre-aging mice and humans [37•].”
From NAD+ Precursors Nicotinamide Mononucleotide (NMN) and Nicotinamide Riboside (NR): Potential Dietary Contribution to Health (2023) · cites this paper as [36]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Treatment with NMN (dissolved in 5-mM drinking water for 8 weeks) promoted telomere lengthening in generation 4 (G4) mice, dampened the DNA damage response and p53, functionally rescued liver fibrosis, and improved the mitochondrial biogenesis and function in a partially SIRT1-dependent manner [36].”
From NAD+ Precursors Nicotinamide Mononucleotide (NMN) and Nicotinamide Riboside (NR): Potential Dietary Contribution to Health (2023) · cites this paper as [36]
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In the citing paper
“The increased NAD+ levels in the liver tissue of NMN-treated G4 mice reversed the hyperacetylation of several sirtuin targets indicating the reinforcement of sirtuin activity [36].”
From NAD+ Precursors Nicotinamide Mononucleotide (NMN) and Nicotinamide Riboside (NR): Potential Dietary Contribution to Health (2023) · cites this paper as [36]
In the citing paper
“In addition, the concerted action of sirtuins has been found to stabilize telomers and alleviate telomere-associated disorders (Amano et al. 2019).”
From Reactive Oxygen Species, Toxicity, Oxidative Stress, and Antioxidants: Chronic Diseases and Aging (2023) · cites this paper as Amano et al. 2019
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Cites
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Cited by
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Reactive Oxygen Species, Toxicity, Oxidative Stress, and Antioxidants: Chronic Diseases and Aging
Jomova, K., Raptova, R., Alomar, S. Y., Alwasel, S. H., Nepovimova, E., Kuca, K., & Valko, M. (2023) · Archives of Toxicology · doi:10.1007/s00204-023-03562-9 · Cited by 2,638
Modulation of cellular processes by histone and non-histone protein acetylation
Shvedunova, M., & Akhtar, A. (2022) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-021-00441-y · Cited by 1,007
NAD+ in Brain Aging and Neurodegenerative Disorders
Lautrup, S., Sinclair, D. A., Mattson, M. P., & Fang, E. F. (2019) · Cell Metabolism · doi:10.1016/j.cmet.2019.09.001 · Cited by 790
Self-citationTelomeres: history, health, and hallmarks of aging
Chakravarti, D., LaBella, K. A., & DePinho, R. A. (2021) · Cell · doi:10.1016/j.cell.2020.12.028 · Cited by 637
NAD+ homeostasis in health and disease
Katsyuba, E., Romani, M., Hofer, D., & Auwerx, J. (2020) · Nature Metabolism · doi:10.1038/s42255-019-0161-5 · Cited by 627
Metadata
- 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
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2019-06
- Volume
- 29
- Issue
- 6
- Pages
- 1274-1290.e9
- ISSN
- 1550-4131 (ISSN-L)
- 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
- 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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