Format

Send to

Choose Destination
Cell Metab. 2019 Mar 20. pii: S1550-4131(19)30129-9. doi: 10.1016/j.cmet.2019.03.001. [Epub ahead of print]

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

Author information

1
Department of Physiology and Biophysics, Baylor College of Medicine, Houston, TX 77030, USA; Huffington Center on Aging, Baylor College of Medicine, Houston, TX 77030, USA.
2
Department of Physiology and Biophysics, Baylor College of Medicine, Houston, TX 77030, USA.
3
Department of Experimental Therapeutics & Center for RNA Interference and Non-Coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
4
Oncology Informatics & Genomics, Phillips Healthcare, Cambridge, MA 02141, USA.
5
Huffington Center on Aging, Baylor College of Medicine, Houston, TX 77030, USA.
6
Division of Gastroenterology and Hepatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA.
7
Gladstone Institute of Virology and Immunology, San Francisco, CA, USA; Department of Medicine, University of California, San Francisco, San Francisco, CA, USA; Buck Institute for Research on Aging, Novato, CA, USA.
8
Department of Molecular and Cellular Biology & Integrated Microscopy Core, Baylor College of Medicine, Boston, MA, USA.
9
Department of Genetics, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA.
10
Department of Biochemistry and Biophysics, School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
11
Department of Integrative Biology and Pharmacology, University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
12
Department of Pathology, Department of Oncology, Johns Hopkins Medical Institution, Baltimore, MD 21231, USA.
13
Department of Pathology, Baylor College of Medicine, Houston, TX 77030, USA.
14
Department of Physiology, Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania, Philadelphia, PA 19104, USA.
15
Department of Physiology and Biophysics, Baylor College of Medicine, Houston, TX 77030, USA; Huffington Center on Aging, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: esahin@bcm.edu.

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

PMID:
30930169
DOI:
10.1016/j.cmet.2019.03.001

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center