NMN Nicotinamide Mononucleotide

As we age, NAD+ levels fall. In simple terms, this is the core concept that is behind the science, a clear link between falling NAD levels and aging. This rate of decline is greater than the body’s own natural ability to maintain an adequate supply of NAD+. NMN Nicotinamide Mononucleotide is a direct NAD+ precursor supplement that helps to replenish the NAD+ supply. It has been established in principle, by treating old mice with NMN, that at least some biometric markers used to measure the aging process can be reversed.

Why is NAD+ so critical?

There are three fundamental functions that require NAD+ which are critical for the normal operation of all living cells. First, NAD+ is responsible for the production of ATP, the chemical energy necessary to sustain life. For example, turning food into energy requires the NAD+/NADH redox cycle which drives mitochondrial oxidative phosphorylation. Secondly, SIRTUINS, the so-called "longevity-genes" that regulate or silence other genes, do not work without an adequate supply of NAD+. Thirdly, NAD+ is a facilitator and a substrate that is used for the repair of broken DNA strands. Together SIRTUINS and NAD help to maintain the integrity of the genetic code by protecting against various epigenetic mutations.

What causes NAD+ levels to fall?

NAD levels decline over time because NAD+ is used and CONSUMED as a substrate by SIRTUINS, DNA-Repair enzymes and aggressively by another enzyme called CD38 for calcium balancing and immune function response. Inflammatory cytokines released by the immune system causes the production of CD38. The problem is further exacerbated, at least in theory by senescent cells, cells that can no longer divide but increasingly causes the release of even more inflammatory cytokines and more CD38 expression. Eventually, more NAD gets consumed than the ability to replenish the supply, leading to the over-all decline that is experienced with aging.

It is now evident that supporting the NAD pool is vital for promoting good health & wellness, especially as we age. Will NMN work in people? So far early trial data showed that 100mg, 250mg and 500mg doses are safe for humans. Anecdotally, the customer feedback is very positive but the human clinical trials are still ongoing. As of April 2022, at 7 human trials have shown that NMN is very effective at rasing blood NAD levels in people.

HUMAN DATA

April 2022

Oral Administration of Nicotinamide Mononucleotide Is Safe and Efficiently Increases Blood Nicotinamide Adenine Dinucleotide Levels in Healthy Subjects (125mg twice daily)

1000mg - 1500mg Trial - Video Clip link

June 2021 Results (250mg NMN) - Nicotinamide mononucleotide increases muscle insulin sensitivity in prediabetic women

University of Tokyo – June 9th,2021

Chronic nicotinamide mononucleotide supplementation elevates blood nicotinamide adenine
dinucleotide levels and alters muscle motility in healthy old men

Sixty-five elderly men aged 65 years and above were screened
for the study, which was conducted between July 2019 and November 2019 and
registered on UMIN-CTR under the identifier UMIN000036321.

“We report that supplementation of 250 mg/d NMN for 12 weeks
in healthy old men was safe, well tolerated, and significantly increased NAD+
and NAD+ metabolites in whole blood. Additionally, NMN induced improvements in
muscle strength and performance.”

Whole blood was collected at baseline and at the 12-week
visit from participants for subsequent analysis of NAD+ and related metabolites
using liquid chromatography-mass spectrometry (LC-MS/MS). As shown in Figure 2,
oral NMN supplementation effectively elevated the levels of NMN and NAD+ as
compared to the placebo.

NMN vs NR

Newly discovered NMN transporter gene SLC12A8 shows NMN enters cells directly putting an end to the assertion that NMN must turn into NR before entering cells. In fact, NMN has a rapid transport system that is specific to NMN, one that does NOT transport NR. It is now fair to say NMN is the most powerful NAD supplement and is superior to NR. The study found that when cells are low in NAD+, they respond by expressing more of the SLC12A8 transporters, allowing for the efficient absorption of NMN from the bloodstream. The SLC12A8 transporter gene is found expressed in many tissues and is abundant in the gut, where NMN is rapidly absorbed from the small intestine within 2-3 minutes, turning into NAD+ in 10-30 min (mice study). NMN vs NR video clip - Jan 2022

Sublingual NMN vs Capsules, The Facts

Quote "Human clinical trials show that swallowing NAD precursors raises blood NAD levels just fine." -  June 15th 2019  David Sinclair tweet.

The discovery of slc12a8 also puts an end to the notion that sublingual NMN is necessary, because we now know that the stomach can uptake NMN directly, the small intestine and even the colon have expression of the NMN transporter gene. Contrary to the misinformation that capsules get digested, almost no NMN is expected to go to waste, as the gut has an extremely high concentration of NMN transporters. In fact, what the study suggested, is that the small intestine is the primary place for the absorption of NMN, to supply the whole body. Quote "These results suggest that Slc12a8 in the small intestine is important for transporting NMN from the gut into the circulation, affecting NAD+ levels in the small intestine and the systemic NMN supply in vivo."

Capsules are utilized rapidly - The absorption and utilization of NMN happens very quickly, any testing methodology that freezes blood or waited for 24hrs, such as the older study used to tout sublingual, would have been inaccurate. The newest study points out that testing the effectiveness of NMN must be done in real-time because ingested NMN such as capsules enters blood circulation within 2-3 min and is transported into tissues within 10-30 min. This was confirmed and traced by using doubly labelled isotopic NMN.

Quote "We have previously shown that NMN is absorbed from the gut into blood circulation within 2–3 min and transported into tissues within 10–30 min. NMN is then immediately utilized for NAD+ biosynthesis, significantly increasing NAD+ content in tissues over 60 min. This fast pharmacokinetics has recently been confirmed by using doubly labelled isotopic NMN (C13-D-NMN), showing its rapid absorption and conversion to NAD+ in peripheral tissues."Slc12a8 is a nicotinamide mononucleotide transporter Jan 7, 2019 nature metabolism.

2021 human trials at the University of Tokyo showed ingested NMN increased both NMN and NAD+ levels. NMN not onlyraised NMN and NAD+ levels,but it also raised all the other majorprecursors to NAD+ such as NAMN, NAR and NR.