Telomere Dysfunction Induces Sirtuin Repression that Drives Telomere-Dependent Disease
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, 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
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.
Keywords: liver disease; metabolism; p53; sirtuins; telomeres.
Conflict of interest statement
Declaration of Interests
J.A.B. is an inventor on a patent involving the use of NAD precursors to treat liver injuries. D.A.S. is a founder, equity owner, board member, advisor to, director of, consultant to, investor in and/or inventor on patents licensed to Vium, Jupiter Orphan Therapeutics, Cohbar, Galilei Biosciences, GlaxoSmithKline, OvaScience, EMD Millipore, Wellomics, Inside Tracker, Caudalie, Bayer Crop Science, Longwood Fund, Zymo Research, EdenRoc Sciences (and affiliates Arc-Bio, Dovetail Genomics, Claret Bioscience, Revere Biosensors, UpRNA and MetroBiotech, Liberty Biosecurity). Life Biosciences (and affiliates Selphagy, Senolytic Therapeutics, Spotlight Biosciences, Animal Biosciences, Iduna, Immetas, Prana, Continuum Biosciences, Jumpstart Fertility, and Lua. D.A.S. sits on the board of directors of both companies. DAS is an inventor on a patent application licensed to Elysium Health. His personal royalty share is directed to the Sinclair lab.
Copyright © 2019 Elsevier Inc. All rights reserved.
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Source: PubMed