Targeting NAD+ Metabolism for the Treatment of Cardiovascular Disease

Nicotinamide adenine dinucleotide (NAD+) is important to mitochondrial function, the supply of chemical energy store molecules to power cellular processes, and thus to cell and tissue function. Levels of NAD+ decline with age, a part of the deterioration of mitochondrial function throughout the body:. Too little NAD+ is created, too little NAD+ is recycled after use. This downturn occurs for reasons in which the proximate causes are fairly clear, meaning which of the other molecules required for NAD+ synthesis and recycling come to be in short supply in old tissues, but a map of the deeper connections to the known root causes of aging is lacking.

Various vitamin B3 derived supplements have been shown to increase NAD+ levels in older individuals. Those that have undergone clinical trials were no better in this regard than the effects of structured exercise programs. It seems plausible that this performance can be improved upon, but will that produce better effects than exercise? That remains to be determined. As noted in this open access paper, there are plenty of age-related conditions in which loss of mitochondrial function is important, and either exercise or pharmacological approaches to produce NAD+ upregulation may produce benefits in older individuals by reducing this loss of function.

Nicotinamide adenine dinucleotide or NAD+, is one of the most essential small molecules in mammalian cells. NAD+ interacts with over 500 enzymes and plays important roles in almost every vital aspect in cell biology and human physiology. Dysregulation of NAD+ homeostasis is associated with a number of diseases including cardiovascular diseases (CVD). Particularly, modulation of NAD+ metabolism has been proposed to provide beneficial effects for CVD settings that are highly associated with sudden cardiac death (SCD), such as ischemia/reperfusion injury (I/R injury), heart failure, and arrhythmia.

The heart, along with the kidney and the liver has the highest level of NAD+ among all the organs. In mammalian cells, NAD+ is synthesized via two distinct pathways: the de novo pathway and the salvage pathway. The de novo pathway generates NAD+ from tryptophan through the kynurenine metabolic pathway, or nicotinic acid (NA) through the Preiss-Handler pathway. Nevertheless, most organs other than the liver, including the heart, use the salvage pathway as the main route to generate NAD+. Metabolic profiling of NAD+ biosynthetic routes in mouse tissues was established by measuring the in vitro activity of enzymes, the levels of substrates and products, and revealed that 99.3% of NAD+ in the heart is generated by the salvage pathway. On the other hand, enzymes involved in the de novo pathway are of low expression and low activity in the heart. The salvage pathway generates NAD+ from the NAD+ degradation product nicotinamide (NAM). NAM is converted into an intermediate product nicotinamide mononucleotide (NMN) via NAM phosphoribosyltransferase (NAMPT) - the rate limiting enzyme in the salvage pathway.

Both reductions in NAD+ biosynthesis and activation of NAD+-consuming enzymes can cause NAD+ depletion, which in turn may lead to dysregulation of numerous vital cellular functions. Chronic dysregulation of NAD+-dependent cell functions ultimately results in the development of CVD. An increasing number of studies, particularly in rodent models, have shown that boosting NAD+ is beneficial for CVD. Elevation of NAD+ levels can be achieved by supplementing NAD+, NAD+ precursors or modulating activities of enzymes responsible for NAD+ generation or degradation such as NAMPT, PARP, and CD38.

Human studies have shown that NAD+-boosting therapy can reduce mortality and provide moderate clinical benefits for patients with CAD. However, conflicting results on critical clinical outcomes such as incidence of composite mortality and major vascular events have raised the concern that whether NAD+-boosting therapy can ultimately become a primary treatment for CAD and other CVD. Several important aspects may help overcome these hurdles. First, it is critical to determine the effective dose of NAD+ boosters for each individual patient. Direct measurement for NAD+ level or NAD+ metabolome from accessible samples such as plasma should be considered. Second, the optimal time window for NAD+ booster supplementation remains to be established in human subjects. NAD+-boosting therapy should coordinate with the intrinsic circadian oscillation of NAD+ level in human body so that maximal beneficial effects can be achieved. With a more nuanced understanding of NAD+ biology in the heart and clinical studies designed with more sophistication, we anticipate that NAD+-boosting therapy would ultimately harness its potential for SCD-associated CVD.