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NMN Combinations: How Resveratrol and Ginsenosides Help NMN Increase NAD+ in Specific Organs

You can increase the potential effectiveness of your nicotinamide mononucleotide (NMN) supplementation by combining it with other active compounds like resveratrol and ginsenosides.

But how exactly does this work? What’s the optimal dose? What are the potential benefits?

Today, we’ll dive deep into a fascinating animal study published in 2022 by Long-Bo Bai and colleagues to answer all of these questions. [1] 

But here’s the most important part if you’re pressed on time!

Compared to supplementation with NMN alone:

  • Resveratrol and NMN combinations increase NAD+ levels by 1.59 times in the heart and by 1.72 times in skeletal muscle.
  • NMN combinations with ginsenosides Rg3 & Rh2 increase NAD+ levels in the lungs by 1.97 times.

In practice, this could suggest that various NMN combinations may be used in the near future to fight off age-related issues in specific organs, preserving and improving their function as needed.

Let’s explore the details! But first, a quick memory refresh…

Increasing NAD+ in Specific Organs: What’s the Point?

Life as we know it is impossible without NAD+. In simple terms, it serves as an electron transporter in hundreds of chemical reactions in all cells of the body.

Here are just a few examples of the processes in your body that need NAD+:

  • Glycolysis, meaning breaking down of glucose (the body’s primary carbohydrate) for energy
  • Gluconeogenesis, the formation of glucose from non-carbohydrate sources, like proteins and fat
  • Energy metabolism through the oxidation of carbs, fats, and protein
  • Production of cholesterol, fatty acids, and steroids (including hormones like testosterone and estrogen)

And that’s just the tip of the iceberg.

So, you can probably imagine why the dramatic drop in NAD+ levels in aging living beings is a crucial matter. Restoring NAD+ has been shown to improve energy levels, overall health, and even slow down or reverse certain medical conditions.

But how can you increase NAD+ levels in specific organs?

After all, everyone ages differently. Some people have higher cardiovascular risk, others have stronger hearts but get respiratory issues more often. Can NAD+ therapy be organ-specific?

Looks like the answer is positive, thanks to NMN and various NMN combinations!

NAD+ Precursors, Delivered Just Where You Need Them

Supplementation with NAD+ directly is mostly ineffective due to the large size of the molecule. 

Your cells can’t absorb it effectively. Instead, NAD+ has to be created within the cells, and that’s where NAD+ precursors enter the stage.

Nicotinamide mono nucleotide (NMN) is one of the most effective, well-studied, and safest of them. It has been shown to significantly improve NAD levels without side effects, but this result is largely non-specific. In other words, it increases your NAD+ levels everywhere, in all organs and tissues in your body.

But what if you want or need an extra NAD+ boost in a specific organ? 

For example:

  • Lifelong athletes could enjoy their favorite sports and activities longer by increasing NAD+ in the skeletal muscles
  • People with a family history of heart disease could potentially decrease their risk by focusing on the NAD+ metabolism in their heart
  • Former or current smokers could significantly support their lungs by supplying them with some extra NAD+ to promote local regeneration

Scientists are looking for the best combinations to achieve these goals, and now we finally have some really encouraging data. In a nutshell, the answer could be in using NMN combinations with other active compounds like resveratrol and ginsenosides.

For the Liver, Kidneys, and (Maybe) Brain: Take NMN Alone

Yep, it turns out that some things work best on their own. 

Compared to the subjects who received NMN combinations with resveratrol or ginsenosides, the NMN-only group has been shown to have higher NAD+ levels in their brain, kidney, and liver cells. 

However, this effect was statistically significant (p < .001) only for the liver and kidneys. For the brain, the effect was noticeable but failed to reach statistical significance in this study.

For the Heart and Skeletal Muscle: Choose NMN Combinations With Resveratrol

Compared to supplementation with NMN alone, NMN combinations with resveratrol improved NAD+ levels in the heart by 1.59 times. According to the authors of the study, this would lead to the following benefits:

  • Blocking the symptoms of agonist-induced heart hypertrophy (growth)
  • Protecting the heart cells from ischemia-reperfusion injury. This peculiar type of damage happens when some of the heart’s arteries get blocked by a blood clot or atherosclerosis and local cells start dying due to low blood supply (ischemia). Sometimes, when the blood flow is restored (reperfusion) in this part of the heart, the local inflammation and oxidation gets worse due to more oxygen being delivered. The fresh oxygen ”feeds the fire” of inflammation, resulting in extensive damage.

As for skeletal muscle, supplying it with enough NMN (and the resulting NAD+)  could potentially improve performance and maybe even prevent or slow down age-related muscle loss.

For the Lungs: NMN Combinations With Ginsenosides Are Optimal

NMN combinations with ginsenosides improve NAD+ levels in the lungs by 1.97 times compared to supplementation with NMN alone.

But since ginsenosides are a huge group of active compounds (steroid-like saponins) found in all plants from the ginseng species… Does it matter which specific ginsenosides you take?

Well,  this study confirmed the synergistic action of ginsenosides Rg3 and Rh2. The richest source of Rg3 and Rh2 is Korean red ginseng (scientifically known as Panax ginseng C.A. Meyer), a special variety of processed ginseng. It has been used in Far East Asia as a natural medicine for many centuries. Conversely, ordinary unprocessed ginseng is relatively low in these ginsenosides.

This is explained by the fact that Korean red ginseng is produced through a meticulous process of steaming and drying, during which many natural ginsenosides like Rb1 and Rc are converted into Rg3. [2]

All of the above leads us to the main problem: true, high-quality, genuine Korean red ginseng is sort of rare and can get quite expensive. It’s also extremely hard to standardize in terms of ginsenoside content, as it can get very different from one batch to another, so keep that in mind.

As for the potential health benefits of this combination, it could be extremely useful for people living in heavily polluted areas, as well as current or former smokers to combat the premature aging of lung tissue caused by tobacco smoke or environmental pollution.

Why NMN Combinations With Resveratrol and Ginsenosides Work So? P53 Might Be the Answer

In many cases, it’s hard to pinpoint why synergistic combinations of active compounds work so well. However, in the case of NMN combinations with resveratrol and ginsenosides, we have a pretty good theory about the underlying mechanism of their success.

According to Long-Bo Bai and colleagues, the authors of our main study today, it all may boil down to p53.

P53 is a gene that encodes an essential protein that’s present in the nucleus of all cells of your body. Sometimes referred to as the ”tumor suppressor protein,” p53 helps to control cell growth, programmed death (apoptosis), and other processes. One of them appears to be NAD+ production.

Some studies reported that nicotinamide mononucleotide adenylyltransferase 2 (NMNAT2), a gene and enzyme that’s essential for NAD+ production, is apparently a downstream target for p53. [3] In other words, p53 appears to activate NMNAT2. 

So what do resveratrol and ginsenosides have to do with this? 

  • Resveratrol has been reported to activate p53. [4]
  • Ginsenosides have been reported to stabilize the binding of p53 with DNA, regulating the expression of resulting downstream proteins. [5]

To summarize, both resveratrol and ginsenosides help to activate p53 and improve its function, which leads to increased expression of the NMNAT2 enzyme. And since NMNAT2 makes NAD+ from NMN, that explains the higher levels of resulting NAD+ when using NMN combinations with resveratrol and ginsenosides!

Optimal Dosage and Safety Recommendations

Before we finish this review with some tips on dosage and safety, let’s go through a quick disclaimer first.

The paper we explored today is NOT a clinical study. It’s an animal study, on mice. Well-designed, meticulous as it may be, but it’s still an animal study. In other words, we cannot be 100% sure that all of the findings from this research will be identical in humans. But we can make an educated guess and take it from there, using the clinical data that we have from other sources.

Calculating the Human Equivalent Dose

In Long-Bo Bai’s study, these were the doses given to mice:

  • NMN: 500 mg/kg
  • Resveratrol: 50 mg/kg
  • Ginsenosides Rh2&Rg3: 50 mg/kg

This doesn’t mean that humans could expect identical results from the same doses. Larger beings have much slower metabolism rates and usually require smaller doses per unit of body weight. Pharmacologists and biochemists have known this for many decades and developed a few formulas to calculate human equivalent doses (HED) based on animal doses. [6]

After going through the calculations, here’s what we end up with:

  • NMN: 40.5 mg/kg
  • Resveratrol: 4.05 mg/kg
  • Ginsenosides Rh2&Rg3: 4.05 mg/kg

In other words, if you weigh 70 kg (or about 154 lb), for an equivalent dose to the one that mice received in this study, you would have to take 2.83 g of NMN daily. To get a synergistic effect from the other two compounds, the goal would be 283.5 mg of resveratrol or 283.5 mg of ginsenosides per day.

Are These Human Equivalent Doses Safe?

The documented highest safe NMN dose for daily consumption is about 1250 mg per day (1.25 g), according to clinical studies. [7] This doesn’t mean that going all the way up to 2.83 g per day (more than 2x higher!) would be dangerous. It doesn’t look that way, but we just don’t have enough confirmed data yet. 

As for resveratrol, clinical studies have reported that doses up to 5 g daily are safe and well-tolerated. [8]  Most studies report plenty of resveratrol benefits resulting from doses up to 1 g daily, so there’s no point in going higher than that.

Last but not least, ginsenosides. There’s no data available on the specific safe daily dose of ginsenosides Rh2&Rg3, but there have been reports on Korean red ginseng (KRG) as an herbal supplement. According to the Korean pharmacopeia, up to 30 g of KRG can be taken daily for medicinal purposes. [9] The exact content of ginsenoside fractions is hard to estimate.

Conclusion & Key Points

The bottom line goes more or less like this: it’s better to stick to the proven doses until we have more data. Here’s our recommendation, based on clinical studies:

  • 200 to 1000 mg of NMN daily
  • 1000 mg of resveratrol daily
  • Some Korean red ginseng every once in a while, when you manage to find a high-quality product from a trusted brand

In theory, the above will be enough to give you outstanding results, no matter how you look at it. NMN combinations seem to work extremely well both with resveratrol and ginsenosides, but it’s hard to estimate the exact magnitude of the benefits in humans—we need clinical studies to do that!

Until we have them, the wisest approach would be sticking to what works in the doses that were confirmed to be safe.

Scientific References:

1. Bai LB, Yau LF, Tong TT, Chan WH, Zhang W, Jiang ZH. Improvement of tissue-specific distribution and biotransformation potential of nicotinamide mononucleotide in combination with ginsenosides or resveratrol. Pharmacol Res Perspect. 2022;10(4):e00986. doi:10.1002/prp2.986

2. Lee SM, Bae BS, Park HW, et al. Characterization of Korean Red Ginseng (Panax ginseng Meyer): History, preparation method, and chemical composition. J Ginseng Res. 2015;39(4):384-391. doi:10.1016/j.jgr.2015.04.009

3. Pan LZ, Ahn DG, Sharif T, Clements D, Gujar SA, Lee PW. The NAD+ synthesizing enzyme nicotinamide mononucleotide adenylyltransferase 2 (NMNAT-2) is a p53 downstream target. Cell Cycle. 2014;13(6):1041-1048. doi:10.4161/cc.28128

4. Huang C, Ma WY, Goranson A, Dong Z. Resveratrol suppresses cell transformation and induces apoptosis through a p53-dependent pathway. Carcinogenesis. 1999;20(2):237-242. doi:10.1093/carcin/20.2.237

5. Wang Z, Wu W, Guan X, et al. 20(S)-Protopanaxatriol promotes the binding of P53 and DNA to regulate the antitumor network via multiomic analysis. Acta Pharm Sin B. 2020;10(6):1020-1035. doi:10.1016/j.apsb.2020.01.017

6. Nair AB, Jacob S. A simple practice guide for dose conversion between animals and human. J Basic Clin Pharm. 2016;7(2):27-31. doi:10.4103/0976-0105.177703

7. Fukamizu Y, Uchida Y, Shigekawa A, Sato T, Kosaka H, Sakurai T. Safety evaluation of β-nicotinamide mononucleotide oral administration in healthy adult men and women. Sci Rep. 2022;12(1):14442. Published 2022 Aug 24. doi:10.1038/s41598-022-18272-y

8. Patel KR, Scott E, Brown VA, Gescher AJ, Steward WP, Brown K. Clinical trials of resveratrol. Ann N Y Acad Sci. 2011;1215:161-169. doi:10.1111/j.1749-6632.2010.05853.x

9. Song SW, Kim HN, Shim JY, et al. Safety and tolerability of Korean Red Ginseng in healthy adults: a multicenter, double-blind, randomized, placebo-controlled trial. J Ginseng Res. 2018;42(4):571-576. doi:10.1016/j.jgr.2018.07.002

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