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Publication

Telomere Dysfunction Induces Sirtuin Repression that Drives Telomere-Dependent Disease.

Cell metabolism | 2019

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.

Pubmed ID: 30930169 RIS Download

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Associated grants

Agency: NCI NIH HHS, United States
Id: R01 CA190467
Agency: NIDCR NIH HHS, United States
Id: R21 DE027490
Agency: NIDDK NIH HHS, United States
Id: P30 DK056338
Agency: NIDDK NIH HHS, United States
Id: R01 DK100263
Agency: NIA NIH HHS, United States
Id: R01 AG019719
Agency: NIA NIH HHS, United States
Id: R01 AG043483
Agency: NIDDK NIH HHS, United States
Id: R01 DK098656
Agency: NCI NIH HHS, United States
Id: P30 CA016672
Agency: NCI NIH HHS, United States
Id: P30 CA125123
Agency: NIA NIH HHS, United States
Id: R01 AG047924
Agency: NIA NIH HHS, United States
Id: R37 AG028730
Agency: NIA NIH HHS, United States
Id: DP1 AG058605
Agency: NIDDK NIH HHS, United States
Id: R01 DK115454

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