Risks and rewards of targeting NAD+ homeostasis in the brain

Catherine Li; Lindsay E Wu

doi:10.1016/j.mad.2021.111545

Risks and rewards of targeting NAD⁺ homeostasis in the brain

Mech Ageing Dev. 2021 Sep:198:111545. doi: 10.1016/j.mad.2021.111545. Epub 2021 Jul 21.

Authors

Catherine Li¹, Lindsay E Wu²

Affiliations

¹ School of Medical Sciences, UNSW Sydney, NSW, 2052, Australia.
² School of Medical Sciences, UNSW Sydney, NSW, 2052, Australia. Electronic address: lindsay.wu@unsw.edu.au.

PMID: 34302821
DOI: 10.1016/j.mad.2021.111545

Abstract

Strategies to correct declining nicotinamide adenine dinucleotide (NAD⁺) levels in neurological disease and biological ageing are promising therapeutic candidates. These strategies include supplementing with NAD⁺ precursors, small molecule activation of NAD⁺ biosynthetic enzymes, and treatment with small molecule inhibitors of NAD⁺ consuming enzymes such as CD38, SARM1 or members of the PARP family. While these strategies have shown efficacy in animal models of neurological disease, each of these has the mechanistic potential for adverse events that could preclude their preclinical use. Here, we discuss the implications of these strategies for treating neurological diseases, including potential off-target effects that may be unique to the brain.

Keywords: CD38; Neurodegeneration; Nicotinamide adenine dinucleotide (NAD+); SARM1; Therapeutics.

Publication types

Research Support, Non-U.S. Gov't
Review

MeSH terms

Aging* / drug effects
Aging* / metabolism
Animals
Biosynthetic Pathways / drug effects
Biosynthetic Pathways / physiology
Humans
Molecular Targeted Therapy* / adverse effects
Molecular Targeted Therapy* / methods
NAD* / biosynthesis
NAD* / metabolism
Nervous System Diseases* / enzymology
Nervous System Diseases* / therapy
Risk Assessment

Substances

NAD