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Cell Metab. 2018 May 1;27(5):1081-1095.e10. doi: 10.1016/j.cmet.2018.03.016.

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

Author information

1
Signal Transduction and Molecular Nutrition Laboratory, Kogod Aging Center, Department of Anesthesiology and Perioperative Medicine, Mayo Clinic College of Medicine, 222 3rd Avenue SW, Rochester, MN 55905, USA.
2
Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
3
Kogod Aging Center, Department of Surgery, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
4
Institute for Cell and Molecular Biosciences and Newcastle University Institute for Ageing, Newcastle University, Newcastle upon Tyne NE 4 5PL, UK.
5
Radiology and Biomedical Engineering, The Ohio State University, Columbus, OH 43210, USA.
6
Viamet Pharmaceuticals, Inc., 4505 Emperor Boulevard, Suite 300, Durham, NC 27703, USA.
7
Signal Transduction and Molecular Nutrition Laboratory, Kogod Aging Center, Department of Anesthesiology and Perioperative Medicine, Mayo Clinic College of Medicine, 222 3rd Avenue SW, Rochester, MN 55905, USA. Electronic address: chini.eduardo@mayo.edu.

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

PMID:
29719225
PMCID:
PMC5935140
[Available on 2019-05-01]
DOI:
10.1016/j.cmet.2018.03.016

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