Assessing therapeutic intervention of short telomere syndromes

National Institute On Aging

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Abstract

We have previously 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 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. To investigate the impact of NAD implementation on aspects of health span compromised by telomere erosion, we used a mouse strain lacking in telomerase reverse transcriptase (Tert), which exhibits gradual loss of telomere length, fertility, and body weight in successive generations. In late-generation Tert null mice, oral supplementation with the NAD precursor, nicotinamide riboside (NR) resulted in a net increase in NAD levels and body weight, supporting the notion that boosting NAD levels has a beneficial effect. Despite the fact that late-generation Tert null mice had significant hematopoiesis impairments (a decreased lymphoid/myeloid ratio or myeloid skewing in their blood composition), NR improved telomere integrity and reduced myeloid skewing phenotype and systemic inflammation in a resting and/or BM transplant setting. In addition, our preliminary data showed that NR alleviated enteritis and enhances survival in late-generation Tert null mice. Our results shed light on the benefits of NAD supplementation in the context of telomere attrition/dysfunction and pave the way for the development of therapeutic strategies for the treatment of telomere biology disorders and possibly age-related disorders with telomere attrition. Currently, we are examining whether re-equilibration of imbalanced NAD metabolism enhances telomere loss/dysfunction-mediated pathophysiology in various tissues and, consequently, the overall fitness of late-generationTert null mice.