NAD+ Metabolism and Cellular Repair Processes

Rajman, L. et al. (2018)
"Therapeutic potential of NAD⁺ boosting molecules: the in vivo evidence"
📍 Cell Metabolism
🔗 https://pubmed.ncbi.nlm.nih.gov/29719225/

A Potent and Specific CD38 Inhibitor Ameliorates Age-Related Metabolic Dysfunction by Reversing Tissue NAD+ Decline

Mariana G Tarragó 1, Claudia C S Chini 1, Karina S Kanamori 1, Gina M Warner 1, Ariel Caride 1, Guilherme C de Oliveira 1, Micaela Rud 1, Adrienne Samani 2, Kyaw Z Hein 1, Runqing Huang 3, Diana Jurk 4, Dong Seong Cho 2, James J Boslett 5, Jordan D Miller 3, Jay L Zweier 5, João F Passos 4, Jason D Doles 2, David J Becherer 6, Eduardo N Chini 7Affiliations expand

• PMID: 29719225
• PMCID: PMC5935140
• DOI: 10.1016/j.cmet.2018.03.016

Abstract

Aging is characterized by the development of metabolic dysfunction and frailty. Recent studies show that a reduction in nicotinamide adenine dinucleotide (NAD+) is a key factor for the development of age-associated metabolic decline. We recently demonstrated that the NADase CD38 has a central role in age-related NAD+ decline. Here we show that a highly potent and specific thiazoloquin(az)olin(on)e CD38 inhibitor, 78c, reverses age-related NAD+ decline and improves several physiological and metabolic parameters of aging, including glucose tolerance, muscle function, exercise capacity, and cardiac function in mouse models of natural and accelerated aging. The physiological effects of 78c depend on tissue NAD+ levels and were reversed by inhibition of NAD+ synthesis. 78c increased NAD+ levels, resulting in activation of pro-longevity and health span-related factors, including sirtuins, AMPK, and PARPs. Furthermore, in animals treated with 78c we observed inhibition of pathways that negatively affect health span, such as mTOR-S6K and ERK, and attenuation of telomere-associated DNA damage, a marker of cellular aging. Together, our results detail a novel pharmacological strategy for prevention and/or reversal of age-related NAD+ decline and subsequent metabolic dysfunction.

Keywords: CD38; NAD(+); SIRTUINS; acetylation; aging; exercise capacity; glucose; progeroid; skeletal muscle.

Copyright © 2018 Elsevier Inc. All rights reserved.

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Conflict of interest statement

Declaration of interests: Dr. Chini holds a patent on the use of CD38 inhibitors for metabolic diseases.

Figures

Figure 1. Characterization of 78c as a…

Figure 2. 78c ameliorates metabolic dysfunction-associated features…

Figure 3. 78c promotes muscle functional improvement…

Figure 4. CD38 + cells regulate NAD …

Figure 5. 78c increases sirtuins and PARP…