Publication — IRIC

Re-equilibration of imbalanced NAD metabolism ameliorates the impact of telomere dysfunction.

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.

Publication date
septembre 16, 2020
Principal Investigators
Sun C, Wang K, Stock AJ, Gong Y, Demarest TG, Yang B, Giri N, Harrington L, Alter BP, Savage SA, Bohr VA, Liu Y
PubMed reference
EMBO J 2020:e103420
PubMed ID
32935380
Affiliation
Biomedical Research Center, National Institute on Aging/National Institutes of Health, Baltimore, MD, USA.