What makes NAD⁺ so special is that its concentration in human tissues can be influenced both internally and externally, through the body’s own metabolic activity and through dietary supplementation. This makes it especially interesting in the context of aging and longevity, where maintaining or restoring NAD⁺ levels has become a widely discussed topic. In this article, we will try to answer whether NAD⁺ boosting can truly be considered safe and universally beneficial in the longevity context.
Several supplements that augment NAD⁺ levels or target NAD⁺-dependent metabolism are currently available. The best known are nicotinic acid (niacin) and its conjugates, nicotinamide riboside (NR), nicotinamide mononucleotide (NMN), nicotinamide, and even NAD⁺ itself. There is an ongoing discussion about which one is “better” or more effective. My view is that all of them can be biologically active, but their modes of action are different and depend on the molecule’s nature, dose, route of administration, and biological context. I will discuss different NAD⁺ supplements in one of my future articles.
One of the most interesting ideas in the longevity field today is that aging may not occur at the same rate in every organ, and therefore age-related NAD⁺ decline is also tissue specific. This implies that supplementation with NAD⁺ precursors should help slow aging by restoring NAD⁺ levels in tissues. The logic is understandable, but the evidence for humans is very limited. From animal studies, we know that NAD⁺ levels are indeed tissue specific and that their decline is not uniform across different tissues.
Now we return to NAD⁺ boosting in the context of longevity. The most commonly used compounds for this purpose are nicotinic acid, NR, and NMN. Here I want to specify that although all three lead to an increase in intracellular NAD⁺ as reflected in blood measurements, they are metabolized differently. Nicotinic acid is a basic form of vitamin B3 and is taken up by a selective transporter that is ubiquitously expressed across different cell types and tissues. NR and NMN are first processed by gut microbiota, which break them down and release nicotinic acid, making it available for use by the host, and only a minimal fraction of orally taken NR and NMN can be absorbed by the body as such.
So, if we assume that different tissues lose NAD⁺ at different rates, can we expect that each tissue will take only the amount of nicotinic acid needed to replenish NAD⁺ to its optimal physiological level? This is where the biology becomes more interesting. Cells do not “choose” whether to take up nicotinic acid or not; they take up all the nicotinic acid they encounter and convert it into the bioactive form of NAD⁺. That means oral supplementation is not a selective process targeted only to tissues that are currently deficient. One of the first compartments to respond to NAD⁺ boosting will be blood, for the obvious reason that it passes through the small intestine, where nutrient absorption takes place. As a result of supplementation, NAD⁺ levels will increase in all tissues at different rates, restoring levels in some of them and elevating them above the physiological range in others.
That raises an important question: what happens when NAD⁺ is increased in tissues that were functioning within their physiological range before supplementation? This is not just a theoretical concern. It has been shown that when NAD⁺ increases, the concentration of its degradation products also increases, and these metabolites have been associated with inflammation of blood vessels and with an increased risk of cardiovascular events. Our own data showed that an increase in NAD⁺ in healthy individuals triggered a metabolic signature of diabetes through yet unknown mechanisms. The first signs of altered glucose and lipid metabolism started to appear when blood NAD⁺ levels reached 50 µM on the way to saturation. In addition, long-term maintenance of elevated NAD⁺ levels may influence metabolic pathways in ways we still do not fully understand. That is especially important when the goal is healthy longevity, because interventions used for prevention should ideally not create new biological stress while trying to reduce old ones. My personal concern about chronically elevated NAD⁺ levels is the risk of triggering oncogenic transformation, as we know that cancer cells rely heavily on glycolysis, which is an NAD⁺-dependent process.
From experience, I know of only one example so far in which supplementation with high doses of niacin or NR for years did not result in any significant side effects. This is the case for patients with mitochondrial myopathy. Their skeletal muscles consume large amounts of NAD⁺, making them dependent on NAD⁺ precursors to match demand with intake. Even in these patients, however, the dose is maintained so that blood NAD⁺ levels do not reach saturation.
In conclusion, NAD⁺-boosting supplements are like a double-edged sword that must be used wisely. The benefits of NAD⁺ boosting in tissues will depend heavily on biological context. Even in cases where supplementation is necessary, it should be closely monitored to avoid the development of unwanted metabolic shifts of which we are already aware.
CSO Liliya Euro, PhD