Not All NAD+ Is Created Equally: Here’s Why!

It is now widely accepted that a decreasing NAD+ level is one of the key indicators of aging and plays a vital role in numerous diseases. Therefore, one of the key questions regarding anti-aging that researchers all across the globe want to answer is: “How do we maintain or perhaps even increase our NAD+ levels as we age?”

NMN is a naturally occurring molecule and a basic structural unit of RNA. It is also a precursor of NAD+. Thus, it is no surprise that studies have identified a correlation between NMN supplementation and NAD+ levels.

However, NAD+ levels can vary greatly across different tissues and organs, and researchers also wonder whether a combined supplementation (NMN + other promising nutrients) may elevate NAD levels in specific tissues. A new study from July 2022 delivered some exciting results that partially answer this question!

What did this study look like?

The mice in this study were divided into four groups that received the following:

1. Control Group: Phosphate buffered saline solution (PBS) – A solution that is commonly used for control
2. NMN Group: NMN suspended in PBS
3. NMN + Resveratrol Group: NMN + resveratrol suspended in PBS
4. NMN + Ginsesoniseds Group: NMN + ginsenosides (Rg3 & Rh2) suspended in PBS.

Dosages

• NMN: (500 mg/kg)
• Resveratrol: (50 mg/kg)
• Ginsenosides_ Rg3&Rh2 (50 mg/kg)

These doses were selected based on their therapeutic dose referenced in previous scientific literature. The dose for NMN is relatively high.

What was sampled?

Three animals per group were sampled at different intervals. Namely, at 1, 2, 4, and 6 hours after administration. Tissue samples from the brain, heart, kidney, liver, lung, and muscle were collected.

Why Resveratrol and ginsenosides?

Resveratrol is a polyphenol. Its supplementation was found to have many health benefits. It can decrease oxidative stress, inhibit inflammation, and, most importantly, upregulate the NAD+-dependent deacetylase sirtuins (SIRTs).

Ginsenosides are a group of natural plant compounds primarily found in the ginseng plant and are the primary reason ginseng is often described as a superfood. Ginseonsides’ benefits include immune regulation, antitumor effects, and effects related to antiaging, such as being able to modulate NAMPT, an enzyme in the NAD+ salvage pathway.

In short, these compounds have been found to interact with mechanisms related to our NAD+ levels. Additionally, they are also natural products that are easily absorbed and are virtually non-toxic to humans.

Results of the study

The extracted tissue samples were tested for three parameters:

• NMN (The administered NAD+ precursor)
• NR (Another NAD+precursor, that is synthesized from NMN)
• NAD+ itself

Let’s take a look at the results for each of these parameters separately:

1. NMN

Please see section 3.3 for a graph with the original results.

Overall, the results showed relatively high NMN levels, indicating that NMN is getting into the tissue and not all is broken down into NR.

NMN+ ginsenosides seems to be the ideal combination for increasing NMN-levels in these tissues. Most notably in the kidneys, where NMN levels were increased by a factor of 4.47. NMN + resveratrol was able to increase NMN levels in the heart by a factor of 1.39.

2. NR

Please see section 3.4. for a graph with the original results.

NR is the “middleman” in the conversion from NMN into NAD+. Therefore, it is also a parameter worth investigating.

Just like with NMN levels, a large increase (1.93-fold) in the heart tissues was observed in the resveratrol combination group. The ginsenosides-group remains on top for the brain, kidney, and lung tissue. The NR levels in the lung and muscle tissue were extremely low across all four groups.

3. NAD+

Please see section 3.5 for a graph with the original results

Last but definitely not least, let’s look at the NAD+ levels to help us answer the core question of the researchers.

When combined with resveratrol, the impact on the NAD+ levels in the heart and skeletal muscle was increased by 1.59- and 1.72-times, respectively. Ginsenosides increased NAD+ levels in the lung 1.97-fold.

Takeaways from these results:

We saw that combining NMN and resveratrol could increase NAD+ levels in the heart and muscle with statistical significance compared to NMN by itself. When combined with ginsenosides NAD+ levels in the lung tissue were increased. Meanwhile, oral NMN by itself was most effective at increasing NAD+ levels in the kidney and liver.

These results show that NAD+ levels in different tissues can vary wildly. Therefore, combination therapies could be tailored based on a person's individual medical circumstances. For example, a patient prone to lung disease could be advised to supplement NMN with ginsenosides.

Limitations of the study

While the results and methodology of this study are compelling. There was no conflict of interest declared (i.e., the study was not funded by a supplement brand selling NAD+, resveratrol, ginsenoside supplements). Nevertheless, the study design did not equate to the gold standard. It had a few limitations:

• A small sample size that may skew statistical evaluation.
• It was a mice study. It is likely, but not certain, that similar results could be reproduced in humans.
• Only adult mice were used

References

https://bpspubs.onlinelibrary.wiley.com/doi/10.1002/prp2.986