Assessing therapeutic intervention of short telomere syndromes

National Institute On Aging

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Abstract

Telomere attrition is a defining feature of telomere biology disorders (TBDs), including dyskeratosis congenita (DC). Recently, we utilized the DC disease model and investigated the relationship between short telomeres/telomere dysfunction and the nicotinamide adenine dinucleotide (NAD) metabolome. Our studies have revealed that (i) primary cells derived from DC patients have lower NAD levels and display an imbalance in the NAD metabolome that includes elevated CD38, reduced PARP1 and SIRT1 expression and activities; and defective NAD-consuming enzyme-related signaling networks, including the NAD-SIRT1-PGC-1-mitochondria and the NAD-PARP-telomere DNA repair axis; and (ii) NAD supplementation and CD38 inhibition restore NAD levels and/or NAD-consuming PARP and SIRT activities, alleviate telomere dysfunction induced DNA damage response and mitochondrial impairment, and mostly importantly, delay the onset of replicative senescence in DC patient cells. Our results support the idea that telomere loss/dysfunction interferes with the NAD metabolism and related biological pathways, thereby contributing to TBD disease features. We have begun to investigate the NAD metabolome in the mouse model deficient in the key telomere maintenance enzyme, telomerase. The telomerase null mice gradually loss telomeres in successive generations, and late generation telomerase null mice with critically short telomeres have lower NAD levels and imbalanced NAD metabolome in brain tissues. We are currently investigating whether imbalanced NAD metabolome occurs in a cell- or tissue- dependent manner, especially hematopoietic lineage, in late generation telomerase null mice. Because patients with TBDs often experience bone marrow failure, for which there is no effective general cure, we have begun to study the effect of NAD supplementation with the NAD precursor, nicotinamide riboside (NR), on features of health-span disrupted by telomere impairment in vivo. Our preliminary results revealed that NR ameliorated body weight loss in telomerase null mice and improved telomere integrity. We will further examine if NR ameliorates telomere dysfunction-induced hematopoietic stem cell defects. Our studies pave the way for the development of therapeutic strategies for the treatment of telomere biology disorders as well as age-related disorders.