NAD+ in Aging: Molecular Mechanisms and Translational Implications

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Evandro F. Fang, Sofie Lautrup, Yujun Hou, Tyler G. Demarest, Deborah L. Croteau, Mark P. Mattson, Vilhelm A. Bohr

The coenzyme NAD+ is critical in cellular bioenergetics and adaptive stress responses. Its depletion has emerged as a fundamental feature of aging that may predispose to a wide range of chronic diseases. Maintenance of NAD+ levels is important for cells with high energy demands and for proficient neuronal function. NAD+ depletion is detected in major neurodegenerative diseases, such as Alzheimer's and Parkinson's diseases, cardiovascular disease and muscle atrophy. Emerging evidence suggests that NAD+ decrements occur in various tissues during aging, and that physiological and pharmacological interventions bolstering cellular NAD+ levels might retard aspects of aging and forestall some age-related diseases. Here, we discuss aspects of NAD+ biosynthesis, together with putative mechanisms of NAD+ action against aging, including recent preclinical and clinical trials. Recent discoveries have demonstrated an age-dependent decrease in cellular and/or tissue NAD+ levels in laboratory animal models. Moreover, NAD+ depletion has been linked to multiple hallmarks of aging. In premature aging animal models, NAD+ levels are decreased, while NAD+ replenishment can improve lifespan and healthspan through DNA repair and mitochondrial maintenance. Mitochondrial autophagy (mitophagy) has a major role in clearance of damaged and/or dysfunctional mitochondria, and compromised mitophagy has been linked to metabolic disorders, neurodegeneration [including Alzheimer's disease (AD) and Parkinson's disease (PD)] in addition to aging, and other age-related diseases. New evidence suggests that NAD+ precursors, such as nicotinamide and nicotinamide riboside, forestall pathology and cognitive decline in mouse models of AD. NAD+ supplementation can inhibit multiple aging features in animal models. This highlights essential roles for NAD+ in maintaining healthy aging, and suggests that NAD+ repletion may have broad benefits in humans.

Original languageEnglish
JournalTrends in Molecular Medicine
Volume23
Issue number10
Pages (from-to)899-916
Number of pages18
ISSN1471-4914
DOIs
Publication statusPublished - 2017

    Research areas

  • aging, autophagy, clinical application, DNA repair, metabolism, mitophagy, NAD, neurodegenerative disorder, stem cell

ID: 184772429