A Conservative View of Targeting NAD+ Metabolism in Diseases of Aging

NAD+ metabolism in the context of aging and age-related disease is an area of some interest of late. NAD+ is involved in mitochondrial function, essential to cell and tissue function. The mechanisms of synthesizing and recycling NAD+ decline with age, and this might be an important contributing factor in the decline of mitochondrial function throughout the body. Certainly, the evidence in cells and animals suggests that mitochondrial function can be improved via restoration of youthful levels of NAD+.

Given that the available ways of manipulating NAD+ metabolism largely involve supplementation with vitamin B3 derivatives, such as niacin, nicotinamide riboside, and nicotinamide mononucleotide, much of this research in human patients is effectively a slightly more sophisticated extension of decades of clinical trials of high dose vitamin B3. As a recent review notes, the results to date have been hit and miss, as yet not that much better than can be obtained through exercise programs, but some degree of benefit to older individuals appears plausible.

Altered NAD+ homeostasis has been linked to multiple diseases affecting different organs, including the brain and nervous system, liver, heart and kidney. NAD+ depletion is a hallmark of ageing and numerous age-related disorders. Therefore, boosting NAD+ offers a promising option for enhancing resilient to aging or diseases, thereby extending a healthy lifespan. The NAD+ level can be elevated by dietary supplementation of NAD+ precursors, such as tryptophan, niacin (NA), nicotinamide mononucleotide (NMN), and nicotinamide riboside (NR), inhibition of NAD+-consuming enzymes, including PARP1 and CD38, management of the NAD+ biosynthesis via controlling NAD+-biosynthesis enzymes, or improving NAD+ bioavailability through exercise and caloric restriction.

NAD+ precursors can be used as a nutritional supplement to improve a broad spectrum of physiological functions and pathological processes. The therapeutic and preventive efficacy of NAD+ boosters, especially the soluble and orally bioavailable endogenous molecules NR, nicotinamide (NAM), and NA, have been assessed in a series of clinical trials in humans. Findings suggest that elevating NAD+ levels by administration of NAD+ precursors, including NMN, NR, NAM, and NA, is a rational therapeutic strategy to improve a healthy lifespan. Given that NAD+-depleting drugs exhibit anti-tumor potential due to their impact on DNA repair and inflammation, long-term boosting NAD+ might increase the risk of driving tumor growth. Moreover, the detrimental side effects of NAD+ and its intermediates may be caused by the NAD+-dependent sirtuins that have both oncogenic and tumor suppressive activity in different contexts. Consistent with this hypothesis, NMN treatment accelerates pancreatic cancer progression via creating an inflammatory environment. Thus, future clinical studies are necessary to assess the long-term safety of NAD+ precursors in human therapeutics.

The levels and compartmentalization of NAD+ dictate energy state that impinges on normal physiological and biological responses, as indicated by the regulatory role of NAD+ in proper redox homeostasis, genomic stability, gene expression, circadian clock, inflammation, metabolism, cellular bioenergetics, mitochondrial homeostasis, and adaptive stress responses. A healthy lifestyle and exercise are non-pharmacologic strategies to improve the body's resilience and extend healthy lifespan through enhancing NAD+ levels. NAD+ boosters can be applied for a broad spectrum of NAD+ deficiency related pathologies, such as infection, cancer, metabolic diseases, acute injury, aging, and aging-related neurodegenerative disorders. Conceivably, this could be achieved by boosting NAD+ via enhancing the NAD+ generation and diminishing NAD+ consumption.

Despite exciting and emerging strides in NAD+ biology, there are a variety of outstanding questions that warrant future systematic exploitation to accelerate the translation of remarkable bench work to effective clinical application in humans. The first interesting question is that the precise mechanisms executing the beneficial effects of NAD+ and its metabolites on pathologies and lifespan remain elusive. Further investigation understanding the landscape of NAD+ in response to diseases and identifying the specific effector molecules for each NAD+ precursors at different time points provide critical insights into development of effective interventions for various physiologies. Secondly, the systemic NAD+ metabolome is largely unexplored. Are there any tissue specificities for NAD+ boosting, such tissue preferences of distinct NAD+ precursors? What is the crosstalk with the NAD+ systems of each organ? What is the distinct NAD+ metabolome in each tissue? In spite of growing interest in the use of NAD+ precursors as a strategy for healthy aging, the in vivo pharmacokinetics remain poorly understood.

Link: https://doi.org/10.1038/s41392-020-00311-7

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