Boosting NAD ameliorates hematopoietic impairment linked to short telomeres in vivo

Short telomeres are a defining feature of telomere biology disorders (TBDs), including dyskeratosis congenita (DC), for which there is no effective general cure. Patients with TBDs often experience bone marrow failure. NAD, an essential metabolic coenzyme, is decreased in models of DC. Herein, using telomerase reverse transcriptase null (Tert(−/−)) mice with critically short telomeres, we investigated the effect of NAD supplementation with the NAD precursor, nicotinamide riboside (NR), on features of health span disrupted by telomere impairment. Our results revealed that NR ameliorated body weight loss in Tert(−/−) mice and improved telomere integrity and telomere dysfunction-induced systemic inflammation. NR supplementation also mitigated myeloid skewing of Tert(−/−) hematopoietic stem cells. Furthermore, NR alleviated villous atrophy and inflammation in the small intestine of Tert(−/−) transplant recipient mice. Altogether, our findings support NAD intervention as a potential therapeutic strategy to enhance aspects of health span compromised by telomere attrition. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s11357-023-00752-2.