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

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.

• Authors: Hisayuki Amano, Arindam Chaudhury, Cristian Rodriguez-Aguayo, Lan Lu, Viktor Akhanov, Andre Catic, Yury V Popov, Eric Verdin, Hannah Johnson, Fabio Stossi, David A Sinclair, Eiko Nakamaru-Ogiso, Gabriel Lopez-Berestein, Jeffrey T Chang, Joel R Neilson, Alan Meeker, Milton Finegold, Joseph A Baur, Ergun Sahin
• Journal: Cell metabolism (Cell Metab) Vol. 29 Issue 6 Pg. 1274-1290.e9 (06 04 2019) ISSN: 1932-7420 [Electronic] United States
• PMID: 30930169 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright © 2019 Elsevier Inc. All rights reserved.

Chemical References

• Nicotinamide Mononucleotide
• Telomerase
• Tert protein, mouse
• Sirtuin 1
• Sirtuins

Topics

• Animals
• Cells, Cultured
• Down-Regulation (drug effects, genetics)
• Embryo, Mammalian
• Female
• Gene Expression Regulation, Enzymologic (drug effects)
• HEK293 Cells
• Humans
• Liver (drug effects, metabolism, pathology)
• Liver Cirrhosis (genetics, pathology, prevention & control)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Mitochondria, Liver (drug effects, metabolism)
• Nicotinamide Mononucleotide (pharmacology)
• Sirtuin 1 (genetics, metabolism)
• Sirtuins (genetics, metabolism)
• Telomerase (genetics, metabolism)
• Telomere Homeostasis (drug effects, physiology)
• Telomere Shortening (drug effects, genetics, physiology)