Therapeutic Potential of NAD-Boosting Molecules: The In Vivo Evidence

Abstract

Nicotinamide adenine dinucleotide (NAD), the cell's hydrogen carrier for redox enzymes, is well known for its role in redox reactions. More recently, it has emerged as a signaling molecule. By modulating NAD+-sensing enzymes, NAD+ controls hundreds of key processes from energy metabolism to cell survival, rising and falling depending on food intake, exercise, and the time of day. NAD+ levels steadily decline with age, resulting in altered metabolism and increased disease susceptibility. Restoration of NAD+ levels in old or diseased animals can promote health and extend lifespan, prompting a search for safe and efficacious NAD-boosting molecules that hold the promise of increasing the body's resilience, not just to one disease, but to many, thereby extending healthy human lifespan.

Keywords: CD38; PARP1; STAC; aging; cancer; cardiovascular disease; chromatin; epigenetics; inflammation; nicotinamide mononucleotide; nicotinamide riboside; sirtuins.

Copyright © 2018 Elsevier Inc. All rights reserved.

Figures

Figure 1. Primary pathways of NAD metabolism

There are two major pathways contributing to NAD synthesis: de novo synthesis and salvage from precursors. The de novo pathway of NAD synthesis converts tryptophan to quinolinic acid (QA) via the kynurenine pathway. The salvage pathways recycle nicotinamide mononuclotide (NMN), nicotinamide riboside (NR), nicotinamide (NAM) and nicotinic acid (NA) in various cellular compartments including the nucleus and mitochondria. These precursors are present in the extracellular milieu and may be transported across the plasma membrane where they are utilized. Extracellular NAD is cleaved by nucleotide phosphatases (CD73) or glycohydrolases (CD38 and CD157). Cleavage by CD73 yields NMN which CD73 can then re-cleave to yield NR. Cleavage by CD38 or CD157 yields NAM. NAM is also produced within cells by NAD+-consuming enzymes such as sirtuins, PARPS and SARM1. NAM and NR are converted to NMN by NAMPT and NRKs respectively. NMN and NAMN then are converted to NAD and NAAD respectively and NAAD is amidated by NADS to yield NAD. Cellular NAD levels may be boosted by activators of the salvage pathway (green) or by inhibitors of enzymes that consume NAD+ such as CD38, PARPs, and SARM1 (red).

Figure 2. Hallmarks of NAD homeostasis

NAD+ is not merely a redox co-factor, it is also a key signaling molecule that controls cell function and survival in response to environmental changes such as nutrient intake and cellular damage. Fluctuations in NAD impact mitochondrial function and metabolism, redox reactions, circadian rhythm, immune response and inflammation, DNA repair, cell division, protein-protein signaling, chromatin and epigenetics.

Figure 3. Physiological effects of NAD-boosting molecules

NAD+ levels steadily fall as we age, leading to a decline in the function of cells and organs. By raising NAD+, NAD+ boosters can have profound effects on the health and survival of mammals. Increases in NAD+ promote cognitive and sensory function, gluconeogenesis in liver, lipogenesis in adipose tissue, insulin secretion in pancreas, and insulin sensitivity in muscle. NAD+ also promotes endothelial cell proliferation and protects against cardio- and cerebrovascular disease. NAD regulates immune function and inflammation and, protects against acute injury in kidney. NAD promotes and extends fertility in both males and females, ostensibly by activation of sirtuins.

Figure 4. Potential impact of NAD+ boosters on human health via NAD+ signaling pathways

A decline in NAD+ during aging is believed to be a major cause of disease and disability, such as hearing and vision loss, as well as cognitive and motor dysfunction, immune deficiencies, auto-immunity and dysregulation of the inflammatory response leading to arthritis, metabolic dysfunction and cardiovascular disease. In mouse models, NAD+ boosters prevent or treat a variety of different diseases, prompting a search for NAD+ boosters that are safe and effective as drugs to treat both rare and common diseases, and potentially aging itself.