In 2017, after taking nicotinamide ribose (NR) supplements, Li Ka-shing praised it for "feeling 20 years old after taking it" and invested $25 million in one fell swoop. At the beginning of 2019, Pan Shiyi, who said that he "never believed in health care products", once posted on Weibo to vigorously promote a health care product, the main ingredient of which is also NR.
Once, the "elixir of immortality" that only appeared in myths and stories became a reality, and it was also sought after by many bigwig investors, and was called "the future of mankind"?
Source: Internet
What exactly is the "longevity drug" NR?
NR is a precursor to the important cofactor nicotinamide adenine dinucleotide (NAD+). In fact, the reason why people pay attention to NR is because of its inseparable relationship with NAD+.
NAD+ is a very important coenzyme in the redox reaction of living organisms, providing electrons from glycolysis and the tricarboxylic acid cycle to the mitochondrial electron transport chain in the reduced form of NADH – figuratively speaking, NAD+ is the "fuel" that enables oxidative phosphorylation in mitochondria, i.e., helping adenosine diphosphate (ADP) to be converted to adenosine triphosphate (ATP).
In addition, NAD+ has another important role as a cosubstrate for a variety of enzymatic reactions. In particular, the longevity factor Sirtuins and ADP-ribosyltransferase, two major protein families, need to consume NAD+ during the use of ADP-ribose (ADPR) and the release of nicotinamide (NAM). In addition, SARM1, CD38, and CD157/BST1 all consume NAD+, but release NAM and ADPR/cyclic ADPR.
Pathways for NAD+ biosynthesis and metabolism in mammals
Given the importance of NAD+ in various biological processes such as metabolism, aging, cell death, DNA repair, and gene expression, the potential health benefits of NAD+ or NAD+ precursors (such as NR, β-nicotinamide mononucleotide NMN) as supplements have been explored.
At the cellular level, NR uptake is mediated by a family of balanced nucleoside transporters. Upon entry into cells, NR can be phosphorylated into NMN by NR kinases (NRK1 and NRK2) or deribose to become NAM by purine nucleoside phosphorylase. Regardless of which of the above two conditions, in principle, these transformations enter the salvage synthesis pathway, which further produces NAD+.
Several preclinical studies have confirmed the metabolic benefits of NR: mouse models have shown that supplementation with NMN or NR can significantly reverse aging and prolong lifespan. Then, in 2016, researchers conducted the first clinical trial of NR in the human population to test its safety and efficacy as a human supplement.
In recent years, more and more trials have emerged to determine the benefits of niacinamide for metabolic health and serious disease in humans. So, how does NR perform as an oral supplement in population-based clinical trials?
The results of the latest review are surprising!
However, the results of the latest review on Science Advances have given everyone a "slap in the face"!
A team of researchers from the Faculty of Health and Medical Sciences at the University of Copenhagen evaluated 25 currently published cutting-edge literature, all relevant to clinical trials of human NR supplementation. In summary, there is little clinically relevant effect of oral NR supplementation, and the results of these studies are suspected to be "exaggerated".
Of course, NR cannot be dismissed entirely, as it has certain potential in reducing inflammatory states and treating serious diseases. But if you want to see NR as "Tang monk meat", you may be disappointed.
DOI: 10.1126/sciadv.adi4862
In this review, 25 human clinical trials were reviewed, including trials without placebo, parallel-design trials with placebo control, cross-over trials with placebo control, and clinical trials of NR in combination with pterostilbene (PT).
The first article discussed in this article dates back to 2016, when Trammel et al. conducted the first human clinical trial of NR supplementation. This was a trial without a placebo, and more precisely, the sample size of this trial was 1 – a 52-year-old healthy man weighing 65kg was given 1000mg of NR every morning for a week.
The results showed a steady increase in NAD+ and NAAD levels in this participant's peripheral blood mononuclear cells (PBMCs) after taking NR. In addition, NAM, MeNAM, Me2PY and Me4PY were all increased in urine, indicating that the excretion of NAD-related compounds also increased after NR supplementation.
To make this more convincing, the researchers conducted a small human trial with 12 participants, using 100-1000 mgNR. During the first 24 and 8 hours of oral NR, an increase in NAD+ and NAAD levels was observed, respectively, but there was no change in NAM and NMN. In other words, oral NR can increase the content of NAD metabolites in PBMCs, but it does not explain its "life prolonging" effect.
All articles are summarized
However, in a trial of patients with Parkinson's disease, the investigators observed that receiving 1000 mg of NR per day increased NAD in the brain and Me2PY levels in cerebrospinal fluid, while in muscle, NR treatment also increased NAAD, NAMOX, Me2PY, and Me4PY levels. Therefore, the authors of the study believe that NR treatment can increase NAD and its metabolites in the brain, or may improve Parkinson's disease.
However, in the heart failure trial, no changes in respiratory or inflammatory markers were observed when NR was continuously escalated from 500 mg/day to 2000 mg/day for 12 weeks.
At the same time, a crossover design trial in 12 older adults showed that supplementation with 1000 mg of NR per day barely altered muscle bioavailability, such as muscle mitochondrial function, substrate utilization or blood flow, grip during GTT, and even liver, kidney, and thyroid function markers.
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Taken together, the conclusion is striking: the clinical effect of NR supplementation can be said to be minimal.
Looking back at history, in the more than seven years since the first human NR trial was conducted in 2016, many trials have emerged. However, summarizing most of the trials to date, it can be found that the only reproducible health benefit of NR is the reduction of inflammatory markers in whole blood or immune cells.
Some trials have shown that oral NR supplementation can increase NAD+ and related metabolites in whole blood, and occasionally in PBMCs. With the exception of blood, the vast majority of research has been confined to the brain and muscles – in the brain, the NAD-promoting effects of NR are very encouraging, but there is no evidence that oral NR increases NAD+ levels in muscles.
The authors of this review highlight that, in fact, some of the results in the literature are somewhat "exaggerated", i.e. over-interpreting the meaning of oral NR supplementation.
For example, in some studies, increased levels of NAAD, MeNAM, Me2PY, and Me4PY have been considered indicators of "increased NAD+ metabolism", but the reality is that these NAD-related metabolites do not necessarily have to pass through NAD+ flux. After oral supplementation with NR, the main circulating NAD+ precursors were NA and NAM. Theoretically, NAM would be recovered and entered into the NAD+ pool, but could also be directly methylated and excreted.
This phenomenon becomes especially noticeable in muscles. Although NAM is effectively absorbed by muscles, it is not well converted to NAD+. In other words, the increased levels of MeNAM, Me2PY and Me4PY in the muscles are not through NAD+ flux, but mean that large amounts of NAM are hoarded and urgently need to be excreted. Therefore, oral NR is not equivalent to "replenishing NAD+ levels in muscle" and naturally does not improve muscle strength, mitochondrial function, and exercise performance.
Reading this, I believe you have a deeper understanding of oral NR supplements. Is it a "panacea" or a "leek cut"? Everyone should already have their own answer in their hearts.
However, NR does not have to be "killed with a stick", and it still has certain prospects in reducing inflammatory markers in the blood, treating some serious diseases and hypertension, etc., which is worthy of follow-up in-depth research.
参考资料：[1]Damgaard MV, Treebak JT. What is really known about the effects of nicotinamide riboside supplementation in humans. Sci Adv. 2023 Jul 21; 9(29):eadi4862. doi: 10.1126/sciadv.adi4862. Epub 2023 Jul 21. PMID: 37478182; PMCID: PMC10361580.
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