Enhancing Longevity-Promoting Cocktails: Combining Micronutrients with NAD+ Precursors to Maximize Their Effects

Mixing nutraceutical molecules with nicotinamide adenine dinucleotide (NAD+) precursors may synergistically boost and maintain NAD+ levels while bolstering their longevity-promoting benefits.

(An aged individual’s hand alongside a younger person’s hand, each holding different types of supplement capsules |
By Bennett M. Sherman

Key Points:

  • Combining NAD+ precursors with other nutraceuticals like resveratrol may extend the number of disease-free years people live.
  • Adding micronutrients such as fisetin and quercetin to NAD+ precursor supplementation may aid in eliminating dysfunctional cells that emit inflammatory molecules — senescent cells — to enhance lifespan.

Cellular nicotinamide adenine dinucleotide (NAD+) levels decline as we grow older. Based on its role in a multitude of cellular processes, including energy generation and DNA repair, falling concentrations of this essential molecule correlate with the onset of age-related conditions like cardiovascular disease and metabolic disorders. Finding new ways to counteract lower NAD+ levels with NAD+ precursors has entered the scientific community’s spotlight, yet research is only beginning to examine whether there are additive or synergistic anti-aging benefits from combining multiple supplements.

Surveying some of the potential improvements from adding nutraceuticals like fisetin and quercetin to NAD+ precursor supplementation presents a novel approach to enhancing the benefits of these nutraceuticals. Furthermore, exploring data from human trials and rodent studies reveals the effectiveness of each molecule independently and in conjunction with NAD+ precursors, painting a clear picture of their combined potential efficacy. As such, the concept of combining nutraceuticals with NAD+ precursors could be pivotal in optimizing NAD+ levels and cellular functionality.

Lower NAD+ During Aging Impedes Crucial Metabolic, Immune, and DNA Repair Processes

Cellular NAD+ concentrations peak during our youthful years and steadily diminish over time, causing a dilemma. Cellular processes, such as energy production, metabolism, immunity, and DNA repair, rely on sufficient NAD+ levels to operate efficiently.

Along those lines, NAD+ is one of the principal molecules in the Krebs cycle — a series of energy-producing chemical reactions occurring within cells. In fact, the Krebs cycle utilizes NAD+ in three out of eight of its reactions. For this reason, age-related declines in NAD+ levels can limit the availability of cellular resources for energy production. Consequently, this limitation may contribute to the feelings of reduced vitality often associated with old age.

Sirtuins, key proteins involved in metabolism that also trigger pro-longevity cascades, require NAD+ for their activity. As such, age-related declines in NAD+ can inhibit the ability of sirtuins to promote longevity. One proposed method to combat aging and age-related diseases entails stimulating sirtuin function with NAD+ precursors or other nutraceuticals to enhance metabolism and activate pro-longevity proteins like FOXO.

Additionally, CD38 enzymes, crucial for modulating immunity and inflammation, require sufficient NAD+ to function. Interestingly, the concentration of CD38 enzymes increases with age. Along those same lines, CD38 is well-known as one of the primary NAD+-consuming proteins during aging. Suppressing CD38 has also been proposed as an interventional target to counteract aging and age-related diseases.

Other enzymes called PARPs require sufficient NAD+ to perform their cellular tasks of DNA maintenance and repair. As DNA damage accumulates during aging, PARP NAD+ consumption increases in concert. Thus, age-related NAD+ declines may hinder PARP function. Furthermore, PARPs activate in response to age-related DNA damage, further depleting NAD+ and contributing to its decline.

Adding Flavonoids, Stilbenes, and Carotenoids to NAD+ Precursors May Enhance Anti-Aging Benefits

Research has shown that supplementing with NAD+ precursors like nicotinamide mononucleotide (NMN) or nicotinamide riboside (NR) can counteract age-related NAD+ level reductions. Restoring NAD+ levels with the precursor NMN has been shown to enhance aging-associated parameters like muscle function and insulin sensitivity in aged humans. Along those lines, evidence supports that NAD+ precursor supplementation is a promising way to combat aging and age-related diseases.

The question arises: could the addition of nutraceuticals targeting NAD+ depletion and other aging-related pathways enhance the benefits of NAD+ precursors? To examine this idea, let’s examine some nutraceuticals that influence the activity of NAD+-consuming enzymes like sirtuins and CD38.

A group of these molecules are stilbenes, which are found in grape skins, peanuts, blueberries, and cranberries. The naturally-occurring molecules in this group are resveratrol and pterostilbene and these confer similar antioxidant and anti-inflammatory effects. However, these two molecules differ in their bioavailability — the proportion of the substance entering circulation following ingestion. While resveratrol shows 20% bioavailability, pterostilbene confers a whopping 80% bioavailability. Intriguingly, both of these molecules have been shown to have anti-diabetic and anticancer effects. Furthermore, resveratrol has been shown to significantly increase lifespan in mice fed a high-calorie diet.

(Baur et al., 2006 | Nature) Resveratrol extends lifespan in mice fed a high calorie diet. Compared to non-treated mice fed a high calorie diet (red line), those that consumed resveratrol showed a longer lifespan (blue line), comparable to healthy mice fed a standard diet (black line).

At the molecular level, stilbenes have been shown to stimulate the NAD+-dependent sirtuin SIRT1. Along those lines, supplementing with stilbenes may improve sirtuin function. In essence, increasing NAD+ with precursors like NMN or NR may serve as the fuel sirtuins need to function, while resveratrol may provide the stimulation needed to improve sirtuin activity. This circumstance may improve metabolism and antioxidant activation to alleviate age-related diseases and slow aging itself.

A study examining the combined effects of NMN and resveratrol showed that mixing these nutraceuticals increased NAD+ to levels higher than NMN alone in the brain, heart, kidney, and lungs of mice. Although supplementation with these molecules was found to increase NAD+ levels, the studies did not assess functional outcomes like ATP (energy) generation, cardiovascular protection, or muscle strength. This omission limits the applicability of the findings to merely understanding NAD+ elevation. and further research is needed to determine whether combining NAD+ precursors with stilbenes enhances physiological function outside of these outcomes.

Molecules Like CoQ10 and Betaine Promote Metabolism to Ward Off Age-Related Diseases

Coenzyme Q10 (CoQ10) is another molecule with potential anti-aging benefits that doesn’t neatly fit within any other nutraceutical compound categories. It participates in reactions within the cell’s powerhouse — the mitochondria — for cellular energy production. Low levels of CoQ10 are associated with numerous age-related diseases like neurodegenerative disorders, diabetes, cancer, scarring (fibrosis), and cardiovascular diseases.

However, supplementing with CoQ10 has been shown to have cardioprotective and antioxidant effects. In human trials, CoQ10 supplementation has been shown to alleviate high blood pressure (hypertension) and cellular stress from the buildup of unstable molecules (oxidative stress) along with lowering the risk of heart failure.

Combining CoQ10 with NAD+ precursor supplements may offer a means to counteract age-related diseases while improving energy levels. Despite the known individual benefits of supplementing with  NAD+ or CoQ10, there is a noticeable gap in knowledge exploring the combined effects of these compounds.

Another supplemental molecule falling outside of categorization with other compounds is the anti-inflammatory molecule betaine. Supplementing with betaine has been implicated in postponing aging-related cellular processes by promoting fat (lipid) and glucose (sugar) metabolism and inhibiting inflammation through gene activity. Supplementing with combined NAD+ precursors and betaine has been proposed to reverse age-related declines in betaine abundance; however, studies exploring the benefits of such a combination haven’t been performed.

Flavonoids Eliminate Dysfunctional Cells and Confer Anti-Inflammatory Effects

A group of molecules with the potential to add anti-aging benefits to NAD+ precursor supplementation are the flavonoids — plant-derived molecules giving fruits and vegetables their coloration. A number of flavonoids like fisetin and quercetin have senolytic properties, meaning they eliminate senescent cells, which are considered to be a hallmark of aging. These dysfunctional cells release proinflammatory molecules into the extracellular milieu. Thus, their elimination presents an exciting strategy to combat the effects of aging.

With the senolytic action of flavonoids, studies have shown that fisetin and quercetin confer anticancer benefits in human cancer cells. Furthermore, fisetin has been found to extend lifespan in mice. Currently, clinical trials are underway to determine whether fisetin’s senolytic benefits apply to humans. These trials are seeking to illuminate whether  fisetin can have tangible benefits, such as reduced inflammation and improved walking speed in elderly populations exhibiting signs of frailty (NCT03675724, NCT03430037).

Interestingly, fisetin has been found to stimulate the pro-longevity enzyme, sirtuin SIRT1. This leaves open the possibility that mixing the flavonoid fisetin with NAD+ precursors like NMN or NR may enhance metabolism. Further studies are needed to find what benefits combining fisetin with NAD+ precursors confers.

Another flavonoid, quercetin, has a strikingly similar molecular structure compared to fisetin. This molecule has been found to act as a senolytic with potential benefits for age-related cardiovascular disease, inflammation, oxidative stress, cancer, and diabetes. Quercetin has also been shown to protect against aging in cell models for premature aging.

Intriguingly, quercetin has been shown to inhibit the NAD+-consuming enzyme CD38, which protects against metabolic disorders. Similarly, supplementing NAD+ precursors with quercetin may amplify their NAD+-boosting effects. More studies are necessary to show whether combining quercetin with NAD+ precursors truly enhances metabolic and DNA-protecting benefits.

Anti-Inflammatory Carotenoids Activate SIRT1 and Enhance NAD+ Levels When Administered With NMN

Carotenoids are another group of molecules that have strong anti-inflammatory properties. This group includes the two molecules astaxanthin and lycopene.

Astaxanthin supports mitochondrial integrity and alleviates oxidative stress. Astaxanthin has also been shown to stimulate the sirtuin SIRT1 and protect the heart and reduce cardiac scarring (fibrosis) after injury in rats. Interestingly, a study showed that adding astaxanthin to NMN supplementation along with blood orange extract raised NAD+ levels higher than NR and astaxanthin or NR and pterostilbene in aging zebrafish. Thus, adding astaxanthin to NAD+ precursor supplements may provide a way to enhance NAD+ levels, all the while stimulating SIRT1.

Another carotenoid, lycopene, exhibits antioxidant and anti-inflammatory effects. Research indicates that lycopene can improve physical performance and skin aging in elderly individuals. Additionally, lycopene has been shown to activate the sirtuin SIRT1 to improve muscle generation, and combining lycopene with NMN has been shown to prevent cognitive impairment and reduce damage from oxidative stress in prematurely aged rats. For this reason, adding lycopene to NAD+ precursor supplements may be a promising way to increase anti-aging benefits.

Another molecule called epigallocatechin gallate (EGCG), found in green tea, has been proposed to confer neuroprotective, antioxidant, and anti-inflammatory effects. Along those lines, this molecule is currently under investigation as a way to treat age-related conditions ranging from brain inflammation to aging itself. EGCG has also been shown to extend lifespan in rats exposed to high levels of oxidative stress. Whether EGCG influences SIRT1 activation remains unclear. But with its antioxidant properties, adding EGCG to NAD+ precursor supplementation may be a way to enhance anti-aging benefits. More research is required, though, to find whether adding EGCG to NAD+ supplements enhances NAD+ levels and alleviates inflammation in aging individuals.

Curcumin, a molecule found in the spice turmeric, has been shown to act as a senolytic. At the molecular level, curcumin has been found to stimulate sirtuins, including SIRT1 and SIRT3. A human study found that six weeks of curcumin supplementation improved antioxidant and blood oxygen utilization in human runners. The connection between curcumin and sirtuin activation is clear, but whether adding curcumin to NAD+ precursor supplementation enhances anti-aging benefits needs further study.

Alpha ketoglutarate is another molecule involved in the Krebs cycle for the generation of cellular energy. Providing worms with alpha ketoglutarate extends their lifespan, so it’s possible that supplementing with this molecule may confer longevity-enhancing benefits. Currently, there is limited data exploring the effects of alpha-ketoglutarate on NAD+ levels or any NAD+-dependent proteins. As such, the benefits of adding alpha ketoglutarate to NAD+ precursor supplementation remains uncertain.

(Sharma et al., 2023 | Nutrients) The molecular structures of micronutrients that may enhance NAD+ precursors’ benefits when taken with them.

Finding Supplements with Multiple Anti-Aging Micronutrients

The longevity-stimulating benefits of multiple nutraceuticals aside from NAD+ precursors have been established. The next step for researchers is to confirm that combining them with NMN or NR further enhances NAD+ levels, possibly stimulates sirtuins, and/or inhibits the NAD+-consuming enzyme CD38 in a way superior to NAD+ precursors alone. Such actions from these molecules could further reduce inflammation and provide benefits against age-related cardiovascular, neurological, and metabolic diseases.

Some supplements available today already blend NAD+ precursors with additions like stilbenes and senolytic flavonoids. An intriguing question is whether incorporating carotenoids and other compounds like EGCG could further amplify these supplements’ prospective anti-aging benefits. While various molecules, including these, can be purchased as supplements, combining them with NAD+ precursors remains largely unexplored. Thus, any venture into such combinations should be approached with caution, given their untested status in enhancing the benefits of NAD+ precursor supplementation.

(Sharma et al., 2023 | Nutrients) Combining micronutrients with NAD+ precursors can enhance sirtuin activation, suppress enzyme CD38, increase NAD+ levels, and eliminate dysfunctional cells that emit inflammatory molecules (senescent cells). Stilbenes activate the sirtuin SIRT1 and increase NAD+ levels. Carotenoids, curcumin and flavonoids act as senolytics to eliminate senescent cells. Curcumin also stimulates sirtuin SIRT1, flavonoids inhibit CD38 and increase NAD+ levels, and carotenoids stimulate SIRT1 and increase NAD+ levels.
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