Today's open access paper provides an interesting view on the age-related reduction in cellular NAD+ levels, a topic of interest in the longevity community these past years. Nicotinamide adenine dinucleotide (NAD) is an important piece of molecular machinery in the function of the electron transport chain in mitochondria. The primary role of mitochondria is to generate the chemical energy store molecule adenosine triphosphate (ATP), used to power the cell. NAD cycles between NAD+ and NADH during this process, and lower levels of NAD imply a growing dysfunction in cellular energy metabolism.
Separately, researchers here show that lowered levels of NAD act to prime a cell for inflammatory activity. Mitochondrial dysfunction with age may affect levels of chronic inflammation in tissues via this mechanism. As we all know by now, chronic inflammation sustained over years provides a sizable contribution to degenerative aging, disrupting the normal processes of tissue maintenance, changing cell behavior for the worse, and accelerating many of the common age-related conditions.
Given this, it is interesting that fairly direct, compensatory restoration of NAD levels via the various approaches based on supplementation of vitamin B3 derivatives (niacin, nicotinamide riboside, nicotinamide mononucleotide, and so forth) perform so indifferently in clinical trials. They do not address deeper causes of this age-related decline, but do compensate in the production of more NAD. That said, exercise is better at restoring NAD levels in older people. Equally exercise produces numerous other beneficial effects on metabolism and cell function. The challenge in thinking about any newly considered mechanism of aging is, at the end of the day, whether or not it has a large effect size. The evidence for effect size is often indirect and dubious.
Intracellular nicotinamide adenine dinucleotide (NAD+) levels steadily decline with age in both rodents and humans. NAD+ is an essential electron acceptor in several redox reactions that maintain intracellular homeostasis. NAD+ also functions as a cofactor for non-redox NAD+-consuming enzymes, such as poly-ADP-ribose polymerases (PARPs) and sirtuins (SIRTs).
NAD+ is synthesized either from tryptophan in the de novo pathway or by recycling nicotinamide (NAM) in the salvage pathway. In mammals, the salvage pathway is the predominant source of NAD+ biosynthesis due to its high adaptability. Nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme for NAD+ biosynthesis in the salvage pathway, converts NAM to nicotinamide mononucleotide (NMN), which is subsequently converted into NAD+ by NMN adenyltransferase. Reduced NAMPT expression at both mRNA and protein levels has been observed in multiple tissues during aging and is primarily responsible for the aging-associated NAD+ decline.
NAD+ decline is implicated in the pathophysiology of various diseases, including metabolic, cardiovascular, and neurodegenerative diseases. The supplementation of NAD+ using NAD+ pathway intermediates attenuates these degenerative disorders. Thus, NAD+ biosynthesis can be a potent therapeutic target for many aging-associated diseases. However, it is unclear whether NAD+ depletion can trigger or promote chronic proinflammatory responses that are closely associated with increased susceptibility to aging-associated diseases. Of note, a previous study showed that NAD+ depletion inhibits lipopolysaccharide (LPS)-induced Toll-like receptor (TLR) signaling in human monocytes. Similarly, inhibition of NAMPT (using FK866, a NAMPT-specific inhibitor) modulated the proinflammatory responses in macrophages.
In this context, we assessed whether FK866-induced NAD+ decline can modulate pattern-recognition receptor (PRR)-mediated responses in myeloid cells. Consequently, we propose that NAD+ depletion can trigger NLRP3 activation in macrophages and induce in vitro and in vivo inflammasome activation in the presence of NLRP3-activating stimuli.