Assessing therapeutic intervention of short telomere syndromes

National Institute On Aging

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Abstract

We have utilized the DC disease model as well as late generation telomerase reverse transcriptase knockout (Tert-/-) mice to investigate the relationship between short telomeres/telomere dysfunction and the NAD metabolome. Our studies revealed several insights: (i) primary fibroblasts derived from DC patients and late generation Tert-/- mice with short telomere lengths have lower NAD levels and display an imbalance in the NAD metabolome that includes elevated CD38, and reduced PARP1 and SIRT1 expression and activities; (ii) DC fibroblasts are defective in the NAD-consuming enzyme-related signaling networks, including the NAD-SIRT1-PGC-1-mitochondria and the NAD-PARP-telomere DNA repair axis; and (iii) NR supplementation and CD38 inhibition restore NAD levels and/or NAD-consuming PARP and SIRT activities, alleviate p53 acetylation, telomere DNA damage, mitochondrial impairment including cellular and mitochondrial ROS, and mostly importantly, delay the onset of replicative senescence in DC fibroblasts. Our results support the idea that telomere loss/dysfunction interferes with the NAD metabolism and related biological pathways, thereby contributing to telomere and mitochondrial abnormalities and cellular senescence. Our studies pave the way for the development of therapeutic strategies for the treatment of short telomere syndromes as well as age-related disorders. We will continue to explore the following questions: a) The molecular pathways linking telomere dysfunction and CD38 hyperactivation, b) Is CD38 hyperactivation responsible for telomere loss/dysfunction-mediated pathophysiology in vivo, and c) Does re-equilibration of imbalanced NAD metabolism ameliorates telomere loss/dysfunction-mediated pathophysiology in vivo.