NAD + in Aging: Molecular Mechanisms and Translational Implications

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. 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. 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. a model of AD. The mice express the human genes encoding Amyloid precursor protein (APP) and Presenilin 1 (PS1), similar to the APP/PS1 mouse, but also express human Tau. The mice show AD-like phenotypes, similar to APP/PS1 mice, including tau tangles and fibrils in the brain. formed from cleaved APP; Aβ aggregates to form large rafts of proteins that are toxic to neurons. a model of AD. Mice express the human genes encoding APP and PS1. The mice show severe Aβ plaque formation and neurodegeneration and/or cognitive impairments. a rare, untreatable, recessive inherited human disease characterized by severe neuromotor dysfunction, telangiectasia, sterility, cancer, and hypersensitivity to ionizing radiation. It is caused by mutations in the ATM gene, encoding ATM kinase, a regulator of the DNA damage response that is critical for genomic stability, telomere maintenance, and DNA double-strand break repair. evolutionarily conserved process where cytoplasmic substrates are engulfed in an autophagic vesicle, fused to lysosomes, followed by degradation and recycling. Autophagy is necessary for cellular homeostasis through a balance with apoptosis and inflammation. Compromised autophagy occurs in many age-related diseases. diet where the organism (e.g., mice) are not fed ad libitum. This restriction of food intake has been shown to increase lifespan. a rare premature aging disease with progressive neurodegeneration caused predominantly by mutations in genes encoding two DNA repair proteins: Cockayne syndrome group A (CSA) or Cockayne syndrome group B (CSB). pathway from which NAD+ is produced from tryptophan. the response of a cell to DNA damage. DNA damage activates a range of cellular processes, enabling the cell to survive and maintain genome integrity. a genetic disorder caused by the lack of dystrophin, which results in muscle weakness and degeneration. concepts or cellular and/or organismal processes all influencing and contributing to the process of aging. repair process of DSBs by the repair pathway HR. HR is dependent on the cell cycle. a model often used to study metabolic syndromes because it presents inherited glucose intolerance and insulin resistance, which result in hyperglycemia. KK/HlJ mice have a strong tendency to develop type 2 diabetes mellitus in response to certain dietary regimens (e.g., high-fat diet) and aging. a model of Duchenne’s muscle dystrophy with a phenotype resembling that of human patients, including muscle weakness and degeneration. a group of risk factors and pathologies, including heart disease, diabetes, obesity, stroke, among others. a specialized form of autophagy that regulates the turnover of damaged and dysfunctional mitochondria. mice that do not express NAMPT, a key protein in the NAD+ salvage pathway. They show embryonic lethality. a major coenzyme and/or compound in all human cells, exists in oxidized (NAD+) and reduced (NADH) forms. NAD+ has major roles in cellular energy metabolism, adaptive responses of cells to bioenergetic and oxidative stress, and aging. the only DSBR pathway in postreplicative cells, including neurons. a DNA repair pathway repairing bulky DNA adducts introduced in DNA by UV irradiation, environmental toxins, and certain antitumor agents. a E3 ubiquitin ligase; mutations in PARKIN, together with PINK1 (a serine/threonine kinase), are a leading cause of PD. PARKIN and PINK1 are also involved in mitophagy. post-translational modification performed by PARPs, mainly PARP1 in mammalian cells, via the use of NAD+. PARylation is also known as poly(ADP-ribosylation), pathway from which NAD+ is produced from nicotinic acid. rare diseases in which patients show aspects of aging at a very early age. primary pathway from which NAD+ is produced from NR, NMN, or NAM. rafts or aggregates of Tau proteins, often hyperphosphorylated, causing dysfunction and cell death of affected neurons. a rare autosomal-recessive disorder characterized by severe sun sensitivity and skin cancer. The etiology of XP is caused by mutation of genes encoding a group of DNA repair proteins, XP genes. foci that occur when the histone H2A variant H2AX is phosphorylated rapidly after a DSB induction in DNA. Given that the phosphorylation of H2AX occurs rapidly after the induction of DSBs and correlates well with DSBs, it is often used as a DSB marker.