Replacing NMN to Raise NAD+: The Role of Quercetin & Niacinamide

Replacing NMN to Raise NAD+: The Role of Quercetin & Niacinamide

The pursuit of anti-aging strategies is an ongoing effort aimed at improving human health and lifespan. The scientific understanding of aging has advanced significantly in recent years, and researchers have identified several factors that contribute to the aging process, including genetic, environmental, and lifestyle factors. The search for anti-aging supplements aimed at maintaining health and vitality as we age continues, and there is a growing body of research suggesting that certain nutrients and compounds may have anti-aging effects.

One promising anti-aging supplement strategy being pursued is aimed at maintaining adequate levels of the coenzyme NAD+ (nicotinamide adenine dinucleotide) in the body which plays a role in promoting healthy aging and preventing the onset of age-related diseases. NAD+ has been shown to play a key role in regulating various cellular processes, including energy metabolism, DNA and mitochondria repair, and gene expression. As people age, NAD+ levels decrease, which is associated with reduced energy levels, DNA damage, cognitive impairments, and inflammatory conditions. One reason why NAD+ levels decline with age is that the enzymes involved in NAD+ biosynthesis become less efficient. This can lead to a reduction in NAD+ availability, which can in turn compromise cellular function and contribute to the aging process.

Several studies have suggested that increasing NAD+ levels through supplementation with precursors like NMN (nicotinamide mononucleotide) can help to mitigate some of the negative effects of aging and improve overall health. In preclinical studies, supplementation with NMN has been shown to improve a variety of health markers in aged mice, including metabolic function, exercise capacity, cognitive function, and can improve various age-related health markers, such as insulin sensitivity, blood glucose levels, and mitochondrial function. While the FDA had previously accepted NMN as a New Dietary Ingredient, on October 11, 2022, they revoked the NDI, so companies can no longer sell it in the United States. FDA stated that NMN has been authorized for investigation as a new drug” and “may not be marketed as a dietary supplement or as a food. With NMN’s fate as a dietary supplement in jeopardy, the search for other NAD+ boosters is on. A potential substitute for NMN that is strongly being pursued is the use of quercetin and niacinamide that have been shown to increase the levels of NAD+ in the body.

Studies have shown that quercetin can activate the SIRT1 enzyme, which in turn can increase NAD+ levels. SIRT1 is known to deacetylate proteins, including those involved in energy metabolism and DNA repair, and it requires NAD+ as a cofactor for its activity. Thus, by activating SIRT1, quercetin can indirectly increase NAD+ levels and promote cellular health. In addition, another mechanism is that quercetin inhibits the activity of the enzyme CD38, which is responsible for breaking down NAD+ in the body. By inhibiting CD38, quercetin may help to preserve NAD+ levels and promote cellular function. Other studies have suggested that quercetin may also indirectly increase NAD+ levels by promoting the activity of the NAD+-consuming enzyme PARP-1 (poly (ADP-ribose) polymerase-1). By increasing PARP-1 activity, quercetin may lead to the depletion of NAD+ levels in cells, which triggers the activation of NAD+ biosynthetic pathways to replenish cellular NAD+ stores. Also, quercetin may raise NAD+ levels by activating a key cellular energy sensor called AMP-activated protein kinase (AMPK). Activation of AMPK has been shown to increase NAD+ levels in cells, and quercetin has been found to activate AMPK, and improve markers of muscle function, exercise capacity, improved glucose tolerance and insulin sensitivity in various preclinical studies. 

In addition to quercetin, niacinamide is another promising anti-aging supplement that has been shown to have several beneficial effects on aging-related processes. It helps boost collagen production, improves skin barrier protection, and has anti-inflammatory activity. Niacinamide is also a precursor to the coenzyme and can increase NAD+ levels.  Niacinamide helps to raise NAD levels by being converted into nicotinamide adenine dinucleotide (NAD+) through a series of enzymatic reactions in the body via the salvage pathway. This pathway involves:

·      The conversion of niacinamide to nicotinamide mononucleotide (NMN) by an enzyme called nicotinamide phosphoribosyltransferase (NAMPT),

·      Followed by the conversion of NMN to NAD+ by another enzyme called NMN adenylyltransferase (NMNAT),

·      Therefore, supplementation with niacinamide can increase the availability of NMN, which can then be converted to NAD+ through the salvage pathway. 

In addition, niacinamide can increase NAD levels by acting as a substrate for the enzyme nicotinamide riboside kinase (NRK), which phosphorylates niacinamide to form nicotinamide riboside (NR). NR can then be converted to NMN by the enzyme NRK or by an alternative pathway involving nicotinamide riboside phosphoribosyl transferase (NRP). By acting as a substrate for NRK and NRP, niacinamide can increase the production of NMN, which can then be converted to NAD by NMNAT. This pathway is thought to be an important mechanism by which niacinamide can increase NAD levels in cells. Lastly, niacinamide can also indirectly increase NAD levels by inhibiting the activity of the enzyme CD38, which catalyzes the breakdown of NAD to nicotinamide and ADP-ribose. By inhibiting CD38, niacinamide can prevent the depletion of NAD and promote NAD accumulation in cells.

Overall, quercetin and niacinamide can increase NAD+ levels through different mechanisms, and both have been shown to have potential antiaging and health benefits. Unfortunately, the issue of attaining efficient accessibility to cells is challenging for both quercetin and niacinamide. Some data suggests that oral niacinamide has only around 40% bioavailability/absorption from the gut into the bloodstream. Additionally, the absolute bioavailability of quercetin is relatively low due to its poor solubility and extensive metabolism in the gut and liver. Studies have shown that oral quercetin supplementation typically results in plasma concentrations of less than 1 micromole/L, which is considered to be subtherapeutic for most of its biological effects. 

To address these issues, the scientists at Verdant Nature have employed their VN-SNEDDS™ (self emulsifying dietary delivery system) technology to the combination of Quercetin+Niacinamide called NADPro™. NADPro™ is a unique molecule consisting of both quercetin+niacinamide that was developed under the IP owned by Verdant Nature. NADPro™ is available in both emulsion or powder forms and is fully water dispersible, neutral tasting, and odorless making in applicable in a variety of dosage formats including gummies, beverages, lozenges, tablets, capsules, softgels, etc. For further information, I can be reached at carl@verdantnature.com.

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