TY - JOUR

T1 - NAD+ in Aging

T2 - Molecular Mechanisms and Translational Implications

AU - Fang, Evandro F.

AU - Lautrup, Sofie

AU - Hou, Yujun

AU - Demarest, Tyler G.

AU - Croteau, Deborah L.

AU - Mattson, Mark P.

AU - Bohr, Vilhelm A.

PY - 2017

Y1 - 2017

N2 - 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.

AB - 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.

KW - aging

KW - autophagy

KW - clinical application

KW - DNA repair

KW - metabolism

KW - mitophagy

KW - NAD

KW - neurodegenerative disorder

KW - stem cell

U2 - 10.1016/j.molmed.2017.08.001

DO - 10.1016/j.molmed.2017.08.001

M3 - Review

C2 - 28899755

AN - SCOPUS:85028926903

VL - 23

SP - 899

EP - 916

JO - Trends in Molecular Medicine

JF - Trends in Molecular Medicine

SN - 1471-4914

IS - 10

ER -