July 23, 2024

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‘Elixir of Immortality’ Nicotinamide Riboside (NR) Virtually No Effect

‘Elixir of Immortality’ Nicotinamide Riboside (NR) Virtually No Effect



‘Elixir of Immortality’ Nicotinamide Riboside (NR) Virtually No Effect

“Immortality Elixir” Nicotinamide Riboside Faces Setback! Science Subjournal: Comprehensive Analysis of 25 Clinical Trials Reveals Almost No Effect.

In 2017, Hong Kong tycoon Li Ka-shing praised the rejuvenating effects of Nicotinamide Riboside (NR) supplements, claiming to feel “as if he returned to his twenties” after taking them.

He invested a whopping $25 million in this promising venture. What was once considered a mythical “elixir of immortality” became a reality, capturing the attention and investment of numerous high-profile individuals. Is it truly a “medical miracle” or a clever financial move?

What is the “Longevity Pill” NR?

NR is a crucial precursor to Nicotinamide Adenine Dinucleotide (NAD+), an essential coenzyme in cellular redox reactions. The significance of NR lies in its close relationship with NAD+.

NAD+ plays a vital role in cellular energy production and various biological processes, serving as a “fuel” for mitochondrial processes and aiding in the conversion of adenosine diphosphate (ADP) to adenosine triphosphate (ATP).

Apart from its role in energy production, NAD+ acts as a cofactor for several enzyme-catalyzed reactions, particularly involving longevity factors like Sirtuins and ADP-ribosyltransferases. These proteins consume NAD+ during the release of Nicotinamide (NAM) and adenosine diphosphate ribose (ADPR).

'Elixir of Immortality' Nicotinamide Riboside (NR) Virtually No Effect

Mammalian NAD+ Biosynthesis and Metabolism Pathways

Recognizing the vital role of NAD+ in metabolism, aging, cell death, DNA repair, and gene expression, researchers began exploring the potential health benefits of supplementing NAD+ or its precursors like NR and β-nicotinamide mononucleotide (NMN).

At the cellular level, NR absorption is mediated by the equilibrative nucleoside transporter family. Once inside the cell, NR can be phosphorylated into NMN by NR kinases (NRK1 and NRK2) or undergo de-ribosylation to become NAM through the action of purine nucleoside phosphorylase. In both cases, these conversions theoretically enter the salvage synthesis pathway, leading to the production of NAD+.

Numerous preclinical studies have confirmed the metabolic benefits of NR. Mouse models have shown that supplementing NMN or NR can significantly reverse aging and extend lifespan. In 2016, the first clinical trials related to NR in humans were conducted to assess its safety and effectiveness as a supplement.

In recent years, an increasing number of experiments have emerged to clarify the potential benefits of nicotinamide in metabolic health and severe diseases. So, how does NR perform in population-based clinical trials as an oral supplement? Is it indeed the “elixir of immortality”?

Surprising Results in the Latest Review!

However, the latest comprehensive review in Science Advances delivers an unexpected blow! A research team from the University of Copenhagen’s Faculty of Health and Medical Sciences evaluated 25 published studies related to clinical trials of human NR supplements. In summary, oral NR supplements had almost no clinically relevant effects, and the results of these studies raised suspicions of exaggeration.

Certainly, NR cannot be entirely dismissed. It shows some potential in alleviating inflammatory states and treating severe diseases. However, considering it as a panacea may lead to disappointment.

'Elixir of Immortality' Nicotinamide Riboside (NR) Virtually No Effect

DOI: 10.1126/sciadv.adi4862

In this review, the researchers discussed 25 human clinical trials, including trials without a placebo group, parallel-design trials with a placebo control, cross-over design trials with a placebo control, and clinical trials combining NR with purple sandalwood extract (PT).

The first article discussed in this review dates back to 2016 when Trammel and colleagues conducted the first human clinical trial of NR supplements. This trial had no placebo group, with a sample size of 1 – a 52-year-old healthy male weighing 65kg, taking 1000mg of NR every morning for a week.

The results showed a stable increase in NAD+ and NAAD levels in the participant’s peripheral blood mononuclear cells (PBMCs) after taking NR. Additionally, levels of NAM, MeNAM, Me2PY, and Me4PY increased in urine, indicating an increase in the excretion of NAD-related compounds after NR supplementation.

To enhance credibility, the researchers conducted a small human trial with 12 participants, using 100-1000mg NR. Within the first 24 and 8 hours of oral NR, an increase in NAD+ and NAAD levels was observed, but no change in NAM and NMN. In other words, oral NR could increase the content of NAD metabolites in PBMCs but did not prove its “life-extending” effect.

Summary of All Articles:

In a trial involving Parkinson’s disease patients, daily intake of 1000mg NR was observed to increase NAD in the brain and elevate Me2PY levels in cerebrospinal fluid. NR treatment also increased levels of NAAD, NAMOX, Me2PY, and Me4PY in muscles. The authors suggested that NR treatment might increase NAD and its metabolites in the brain, potentially improving Parkinson’s disease.

However, in a heart failure trial, continuous intake of NR ranging from 500mg/day to 2000mg/day for 12 weeks did not show changes in respiratory and inflammation markers.

Simultaneously, a crossover design trial with 12 elderly participants revealed that daily supplementation of 1000mg NR had little impact on muscle bioavailability, including muscle mitochondrial function, substrate utilization, blood flow, grip strength during glucose tolerance test (GTT), and no changes in liver, kidney, and thyroid function markers.


Overall, the conclusions are surprising: the clinical effects of NR supplementation are minimal. Looking back over the seven-plus years since the first human NR trial in 2016, numerous experiments have surfaced. However, summarizing most of these trials to date reveals that the only replicable health benefit of NR is reducing inflammation markers in whole blood or immune cells.

Some trials indicate that oral NR supplements can increase NAD+ and related metabolites in whole blood and occasionally in PBMCs. However, beyond blood, most studies focus on the brain and muscles. In the brain, NR’s promotion of NAD is encouraging, but there is no evidence that oral NR can increase NAD+ levels in muscles.

The authors of this review emphasize that some literature results have been “exaggerated,” interpreting the significance of oral NR supplements beyond reality.

For example, in some studies, an increase in NAAD, MeNAM, Me2PY, and Me4PY levels is considered an indicator of “increased NAD+ metabolism.” However, these NAD-related metabolites do not necessarily have to pass through NAD+ flux. After oral NR supplementation, the main circulating NAD+ precursor is nicotinic acid (NA) and NAM. Theoretically, NAM can be recycled and enter the NAD+ pool, but it can also be methylated and excreted.

This phenomenon becomes particularly evident in muscles. Although muscles can effectively absorb NAM, it does not convert well into NAD+. In other words, an increase in MeNAM, Me2PY, and Me4PY levels in muscles does not signify an increase in NAD+

levels through flux but indicates an accumulation of NAM that needs to be excreted. Therefore, oral NR cannot be equated with “supplementing muscle NAD+ levels” and, naturally, cannot effectively improve muscle strength, mitochondrial function, and exercise performance.

Having reached this point, it is likely that readers now have a deeper understanding of oral NR supplements. Is it a “miracle drug” or a “clever financial move”? The answer likely lies within each individual’s perspective.

However, there’s no need to completely dismiss NR. It holds promise in lowering inflammation markers in the blood, treating certain severe diseases, and addressing issues like hypertension, deserving further in-depth research.

‘Elixir of Immortality’ Nicotinamide Riboside (NR) Virtually No Effect

References:

[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.

(source:internet, reference only)


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