Journal
EMBO JOURNAL
Volume 39, Issue 21, Pages -Publisher
WILEY
DOI: 10.15252/embj.2019103420
Keywords
CD38NADase; mitochondrial impairment; NADmetabolism; replicative senescence; telomere biology disorders
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Funding
- Intramural Research Program of the National Institutes of Health, National Institute on Aging
- Division of Cancer Epidemiology and Genetics, National Cancer Institute
- NATIONAL INSTITUTE ON AGING [ZIAAG000698] Funding Source: NIH RePORTER
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Short telomeres are a principal defining feature of telomere biology disorders, such as dyskeratosis congenita (DC), for which there are no effective treatments. Here, we report that primary fibroblasts from DC patients and late generation telomerase knockout mice display lower nicotinamide adenine dinucleotide (NAD) levels, and an imbalance in the NAD metabolome that includes elevated CD38 NADase and reduced poly(ADP-ribose) polymerase and SIRT1 activities, respectively, affecting many associated biological pathways. Supplementation with the NAD precursor, nicotinamide riboside, and CD38 inhibition improved NAD homeostasis, thereby alleviating telomere damage, defective mitochondrial biosynthesis and clearance, cell growth retardation, and cellular senescence of DC fibroblasts. These findings reveal a direct, underlying role of NAD dysregulation when telomeres are short and underscore its relevance to the pathophysiology and interventions of human telomere-driven diseases.
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