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 Keith Meeker, Milton Finegold, Joseph A. Baur, Ergun Sahin

Research output: Contribution to journalArticle

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. Telomere dysfunction is implicated in the promotion of tissue damage and fibrosis through mechanisms that are incompletely understood. Amano et al. show that telomere dysfunction in liver tissue downregulates sirtuins through p53-dependent mechanisms. Increasing NAD(+) stabilizes telomeres, dampens DNA damage response, and improves telomere-dependent fibrosis in a partially Sirt1-dependent manner.

Original languageEnglish (US)
Pages (from-to)1274-1290.e9
JournalCell Metabolism
Volume29
Issue number6
DOIs
StatePublished - Jun 4 2019

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Keywords

  • liver disease
  • metabolism
  • p53
  • sirtuins
  • telomeres

ASJC Scopus subject areas

  • Physiology
  • Molecular Biology
  • Cell Biology

Cite this

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. K., Finegold, M., Baur, J. A., & Sahin, E. (2019). Telomere Dysfunction Induces Sirtuin Repression that Drives Telomere-Dependent Disease. Cell Metabolism, 29(6), 1274-1290.e9. https://doi.org/10.1016/j.cmet.2019.03.001