NAD+, an important coenzyme involved in many critical biological processes, including energy production, DNA repair, and gene expression.
NAD+ is produced in the body through two primary pathways: The De Novo Pathway and The Salvage Pathway. (1)
- The De Novo Pathway involves synthesizing NAD+ from scratch using amino acids such as tryptophan and aspartic acid. (1)
- The Salvage Pathway involves recycling nicotinamide (NAM), nicotinamide mononucleotide (NMN) or nicotinamide riboside (NR) to produce endogenous NAD+. (1)
The Complex Issue of NAD+ Decline
As we age our levels of available NAD+ progressively wane. The reasons behind this NAD+ decline is both complex and intricate.
With ever increasing DNA damage, cellular deterioration, inflammation, and a decrease in effective Sirtuins proteins, our ageing cells need more energy to not only function properly but also carry out vital repair mechanisms.
The result, our cells require more NAD+ than they can produce or recycled, leading to common signs of aging like brain fog, energy loss, fatigue, increased recovery time and poor sleep.
But studies have shown that restoring levels of NAD+ through supplementation can help to increase energy levels, improve cognitive function, and reduce the risk of age-related diseases. (2)
The Issue with NMN and NR
The longevity industry has long relied on NAD+ precursor supplements like NMN and NR to boost NAD+ levels. NMN and NR precursors work by providing the cells with more of the raw material used to produce NAD+. (3)
However, the decline in NAD+ throughout the body is not due to a lack of precursor material, but rather because the cells are using more NAD+ than can be produced or recycled.
As such, recent research suggests that these precursors-only NAD supplements (like NMN and NR) may not be the best approach to restoring NAD+ levels, have a number of serious drawbacks and might potentially lead to additional cellular dysfunction and other health issues. (3) (4)
Why NMN & NR Fall Short
Despite their popularity and widespread use, NMN and NR do not address the underlying root cause and fundamental reason for NAD+ decline. Nor do they restore the important recycling properties of The Salvage Pathway.
Taking NMN or NR may result in an initial increase in NAD+. But once the cell uses up the NAD, a waste product called NAM remains in the cell and is not excreted leading to an excessive buildup of NAM.
The only way the cell can remove this excessive build-up of NAM is by using Methyl Donors in a process called “Methylation”. But using methyl donors in this manner is not normal, and can often lead to methyl donor depletion. (5)
The methylation process is normally reserved for critical processes in the body that regulate many biological functions such as DNA repair, cell metabolism, immunity, and neurology. (6)
An accumulation of NAM and the resulting reduction in the availability of methyl donors can result in a number of possible health concerns. These include;
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Precursors only NAD supplements also fail to address the increasing levels of CD38. This inflammatory molecule is known to increase with age, has an extremely high affinity to NAD+, and is a significant consumer of any available NAD+.
If CD38 production is not inhibited, these inflammatory markers will rapidly consume any extra NAD+, leading to more inflammation and cellular damage. (5)
With this alarming list of issues and concerns .. are these NMN and NR precursor-only supplements really the best approach to restore NAD+ levels?
Time+ NAD: A Comprehensive Solution
In order to prevent the potential health issues associated with traditional precursor only methodology, it’s important to consider a comprehensive approach to NAD+ supplementation that supports both the salvage pathway and the body’s own natural processes …. like Time+ NAD.
The developers of Time+ take a uniquely different approach to boosting NAD. They understand that declining NAD as we age is a complex issue that cannot be fixed by precursor substances alone.
TIME+ NAD is different to traditional precursors-only NAD supplements because it offers a whole-system approach to the NAD issue by addressing the root cause of NAD+ decline –
- Restoring the Salvage Pathway
- Restoring the process of Recycling NAM (used NAD+) back into natural NAD+
- Addressing the issues associated with CD38
The patented formulation and components of TIME+ do more than just supply cells with raw material precursors; they also increase NAMPT enzyme levels, improve the activity of the salvage pathway, inhibits enzymes such as CD38, restore the crucial proteins Sirtuins and enable NAM to be recycled back into fresh NAD+. (3)
Backed by Clinically Studies and Proven Results.
This revolutionary next generation NAD+ supplement was developed by Nuchido’s team of highly skilled specialists, including Scientists, Molecular Biologists, and Systems Pharmacologists.
Time+ NAD is unique not just for its next-generation comprehensive and sustainable strategy for restoring NAD+ levels, but it is also one of the only NAD+ supplements to have undergone thorough testing and clinical trials.
This is not common practice in the field of supplementation. We rarely hear of NAD+ supplements being subjected to the rigors of testing, until now.
A randomised, double-blinded, placebo-controlled crossover clinical trial was performed on Time+ NAD. This isn’t just any “run of the mill” clinical trial haphazardly compiled for the sake of a trial. It is well known and recognised as the “Gold Standard” of clinical trials.
The trial measured the following criteria;
1/. NAD+ levels 2/. NAMPT expression 3/. SIRT1 Expression 4/. Biological Age 5/. Safety 6/. Inflammatory Cytokines 7/. Glycated serum proteins
Trial Participants were consisted of both males and females, aged between 20 – 80 years old.
Trial Results are as follows;
- TIME+ NAD significantly increases cellular NAD+ after only 7 days.
- Unlike NR or NMN it works by switching back on youthful cellular NAD+ production by reactivating NAMPT, a key enzyme in the Salvage Pathway.
- A reversal of biological age by 1.26 years after 28 days of supplementation.
- An increase in the longevity protein SIRT1, a downstream target of NAD+.
- A reduction of inflammatory cytokines indicating that NAD+ is being directed towards beneficial processes rather than inflammatory CD38.
- A reduction in biomarkers of glycation – these glycation biomarkers are highly correlated with aging and multiple age-related issues.
The results speak for themselves.
In comparison, it’s extremely difficult to find comparable randomised, double-blinded, placebo-controlled crossover clinical trials involving NMN and NR.
The Future of NAD+ Supplementation
In conclusion, while first-generation NAD+ precursors like NMN and NR have been popular in the longevity industry, they do not address the root causes of NAD+ decline and can inadvertently cause further cellular dysfunction, methyl donor depletion, inflammation and other health issues.
Instead, a comprehensive, whole-system approach, like Time+ NAD, is a more effective and sustainable way to restore NAD+ levels, is backed by conclusive clinical evidence, promotes overall cellular health and addresses the signs and symptoms of aging.
References:
[1] : Bieganowski P., Brenner C. (2004). Discoveries of Nicotinamide Riboside as a Nutrient and Conserved NRK Genes Establish a Preiss-Handler Independent Route to NAD+ in Fungi and Humans.
[2] : Belenky P et al., 2007. Nicotinamide riboside promotes Sir2 silencing and extends lifespan via pathways to NAD+.
[3] : Dr Frank Yap, MD. NMN vs NR: Nuchido version. April 2023.
[4] : Ryan Longstaffe: CD38 ecto-enzyme in immune cells is induced during aging and regulates NAD+ and NMN levels
[5] : Eun Seong Hwang., Seon Beom Song., (2020) Possible Adverse Effects of High-Dose Nicotinamide: Mechanisms and Safety Assessment.
[6] : Dr David Jockers., Understanding the Role of Methylation in Human Health. (2019)
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[11] : Simar D, Versteyhe S, Donkin I, Liu J, Hesson L, Nylander V, Fossum A, Barrès R.Metabolism. DNA methylation is altered in B and NK lymphocytes in obese and type 2 diabetic human. 2014 Sep;63(9):1188-97.
[12] : Pezzi JC, Ens CM, Borba EM, Schumacher-Schuh AF, de Andrade FM, Chaves ML, Fiegenbaum M, Camozzato AL. DNA methyltransferase haplotype is associated with Alzheimer’s disease. Neurosci Lett. 2014 Sep 5;579:70-4.
[13] : Tang L, Wang L, Ye H, Xu X, Hong Q, Wang H, Xu L, Bu S, Zhang L, Cheng J, Liu P, Ye M, Mai Y, Duan S. BCL11A gene DNA methylation contributes to the risk of type 2 diabetes in males. Exp Ther Med. 2014 Aug;8(2):459-463.
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[15] : Paquette AG, Marsit CJ. The developmental basis of epigenetic regulation of HTR2A and psychiatric outcomes. J Cell Biochem. 2014 Dec;115(12):2065-72.
[16] : Dell’Osso B, D’Addario C, Carlotta Palazzo M, Benatti B, Camuri G, Galimberti D, Fenoglio C, Scarpini E, Di Francesco A, Maccarrone M, Altamura AC. Epigenetic modulation of BDNF gene: differences in DNA methylation between unipolar and bipolar patients. J Affect Disord. 2014 Sep;166:330-3.
[17] : Alelú-Paz R, González-Corpas A, Ashour N, Escanilla A, Monje A, Guerrero Márquez C, Algora Weber M, Ropero S. DNA methylation pattern of gene promoters of major neurotransmitter systems in older patients with schizophrenia with severe and mild cognitive impairment. Int J Geriatr Psychiatry. 2015 Jun;30(6):558-65.