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A Beginner’s Guide to NAD+

When it comes to pathways to extend longevity, NAD+ (Nicotinamide Adenine Dinucleotide), a critical metabolic compound, has attracted a lot of scientific and commercial attention in recent years. 

NAD+ is a cofactor (a non-protein chemical substance) that is required by enzymes to trigger chemical reactions essential in cellular metabolism. NAD+ is a necessary ingredient for energy metabolism both within the mitochondria (through oxidative phosphorylation) as well as outside of them (through glycolysis, the conversion of glucose into ATP). Additionally, NAD+ is required by enzymes that have been linked to longevity (i.e. PARPs, Sirtuins) as they are critical for DNA-repair processes and in chemical reactions necessary for immune system activation. 

The interesting fact about NAD+ is that its levels tend to fall as we age. The decline in NAD+ has been observed not only in humans, but in many other animal species as well. This depletion is attributed to a combination of factors including decreased synthesis, higher consumption due to increased age-related requirements (e.g., DNA-damage repair), and increased degradation of our internal NAD+ recycling capabilities (the body's predominant source of NAD+ is known as  the NAD+ salvage pathway, a process by which the byproducts of NAD+ consumption are recycled to create new NAD+ molecules).

NAD+ Oxidative Phosphorylation

NAD+ depletion is thought to make us more susceptible to age-related conditions such as neurodegeneration, cancer, and certain metabolic diseases. As such, NAD+ has been linked to a number of the hallmarks of aging (i.e., the cellular causes of aging), including mitochondrial dysfunction, DNA damage, nutrient-sensing dysregulation, and decreased autophagy. 

Specifically, as we age and accumulate more DNA damage, our cells require more repair. This implies the activation of a group of enzymes known as PARPs that require NAD+ to function. Increased PARP activity has been correlated with declines in normal NAD+ levels. This decline is in turn thought to depress the activity of other NAD+ consuming enzymes such as sirtuins, which are also involved in DNA repair, energy metabolism and circadian rhythms. Decreased sirtuin activity as a result of NAD+ depletion has also been observed with aging.

Conversely, lifestyle behaviors identified as being conducive to longer lifespan like calorie restriction and exercise have been shown to raise NAD+ levels. Many studies based on animal models (i.e., yeast, worms, and mice) have demonstrated that increasing NAD+ levels—either through diet or direct supplementation—contributes to the prevention and reversal of age-related diseases, and thus, increased lifespan. For example, increases in NAD+ levels as a result of fasting have been shown to stimulate the generation of new mitochondria. Additionally, scientists have observed that increasing levels of NAD+ in old mice helps to restore overall mitochondrial function.

NAD+ Research in Humans

Two companies in particular --Chromadex and Elysium-- are at the forefront when it comes to NAD+ and longevity research in humans. Both companies are focusing specifically on the potential of using Nicotinamide Riboside (NR), an NAD+ precursor, as a dietary supplement to increase NAD+ levels. NR occurs naturally in some food sources, but in practice getting the amount you’d need to impact your NAD+ levels from a normal diet would be quite difficult. This is where supplements gain their advantage by significantly driving up the amount of available precursors that can in turn increase production of NAD+.

  • ChromaDex has used its research on NR to develop a supplement called Tru Niagen. The company has tested this product across multiple randomized clinical trials to measure the effect of long-term NR supplementation on NAD+ levels, NAD+ metabolism, and mitochondrial function among other cardiometabolic parameters in humans. According to its most recently published research, a six-week Tru Niagen supplementation regime of 1000 mg/d is well-tolerated and sufficient to increase NAD+ metabolites, which can then enter the biochemical pathways needed to increase NAD+ levels in the cells. 
  • Elysium has also used research on NR to develop a supplement called Basis, which combines NR with the antioxidant, Pterostilbene. Elysium has published the results of a randomized clinical trial, in which the authors concluded that NAD+ levels responded to supplementation along a dose-response curve. Compared to participants who received a placebo, whole blood NAD+ levels increased 40% among participants who took the recommended dose of the supplement and 90% among participants who took twice the recommended dose after four weeks. Additionally, NAD+ levels remained high in both groups who received the supplement.

A note of caution

While preliminary research on increasing NAD+ levels in humans to combat aging is promising, additional research is required to determine the long-term effects of supplementation. For example, some cancer researchers argue that because cancer cells also use NAD+ for their metabolic processes, increasing NAD+ levels could potentially promote the growth of tumors by aiding in the repair of DNA damage in the cancerous cells. Other scientists argue the opposite, suggesting that an excess of NAD+ in the cells may boost mitochondrial energy metabolism and downregulate glycolysis, depriving cancer cells of the fuel they need to grow and spread. Both these scenarios seem plausible.  As can be expected, both Chromadex and Elysium have dismissed the claims that NAD+ supplementation may pose a cancer risk.

Another open question is how effectively is NR being taken up inside cells.  The studies conducted by Chromadex and Elysium show increased levels of NAD+ in blood.  It is much harder to determine if the same effect is seen inside cells (where you need the NAD+ levels to go up), since this is much harder to measure.  Similarly, it remains to be seen if the effect is uniform across organs, or localized to a few such as the liver.

Science is messy, and more often than not there are no black and white conclusions about the safety and efficacy of a supplement. While the evidence seems to bear out that adequate levels of NAD+ are important for sustaining processes that are key for longevity, one cannot be 100% certain that NR supplementation is effective.

Especially when it comes to longevity, given the innate difficulties in conducting clinical trials, we often find situations that call for making personal judgement calls (i.e. depending on your current age, waiting for the science to be definitive might take too long!).  In situations like this, we like to look at what the researchers advancing the science do for themselves.  

In the case of NAD+, one of the pioneers has been Dr. David Sinclair.  In his book Lifespan: Why We Age and Why We Don’t Have To, Sinclair shares that he takes a daily dose of 1 gram of NMN (an NAD+ precursor similar to NR, see below).  We’ve also heard Dr. Charles Brenner, who is credited with first discovering the NR molecule and is the Chief Scientific Advisor at Chromadex, share on Ben Greenfield’s podcast (see below) that he takes NR twice a day because the role the molecule plays in regulating the circadian rhythm. Again, none of these data points are conclusive.  They are just examples of well-informed people that have chosen to use NAD+ in their longevity protocols. 

As with all the topics that we cover, we highly recommend that any decision you make regarding NAD+ supplementation be made under the direct supervision of your doctor. 

Go Deeper: Here are some great additional resources we found on NAD+:

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