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Synergy for Longevity, Performance and Metabolic Efficiency: NMN, 5-Amino-1MQ, JBSNF-00008

Over the last several decades, a number of peptides have been developed in the search for anti-aging compounds. Several have been successfully demonstrated to reduce the effects of aging and often these benefits align with additional benefits in metabolism and performance. In other words, peptides that benefit longevity tend to also have an impact on metabolism and athletic performance. This should come as no surprise given the link between exercise and improved morbidity and mortality.

Until recently, however, these peptides have generally been tested solo in animal models. Few studies have been conducted on the potential for enhanced effects due to the combination of two or more of these peptides. NMN, 5-Amino-1MQ, and JBSNF-000088 (6-Methoxynicotinamide) are excellent candidates for just such a trial looking at the synergistic effects of combining peptides. Here is why.

NNMT and the Futile Cycle

Nicotinamide N-methyltransferase is an enzyme critical to the metabolism of NAD and thus a key player in metabolic regulation. Found primarily in human fat and liver cells, NNMT processes vitamin B3 and catalyzes the conversion of nicotinamide and s-adenosyl-L-methionine to 1-methylnicotinamide and S-adenosyl-L-homocysteine. A-adenosyl-L-homocysteine is a precursor to adenosine (an important component of the energy molecule ATP).

Down-regulation of NNMT results in a futile cycle, which means there is no net biochemical gain and heat is the only product generated. Such cycles essentially waste energy and thus help to fight obesity as well as keep animal’s warms. Silencing NNMT actually increases the sugar transporter GLUT4 and helps to fight insulin resistance. In mouse models, an over-expression of NNMT leads to insulin resistance, diabetes, obesity, and heart issues[1]–[3].

So, why is this important? All of the peptides discussed in this article affect NNMT and the futile cycle. NMN is a precursor to NAD and appears to increase levels of naturally occurring sirtuins. Sirtuins are thought to influence cellular processes like apoptosis, stress response, and aging. Unfortunately, they also turn NAD into nicotinamide and can thus increase flux through NNMT. Too much NNMT is a bad thing as it decreases GLUT4 signaling and promotes obesity.

Fortunately, the effects of too much NAD can be counteracted by 5-amino-1MQ a potent inhibitor of the NNMT enzyme. A combination of the two peptides would yield all of the benefits that sirutins provide while counteracting the negative effects of their production.

JBSNF-000088 has similar effects to 5-amino-1MQ and has been found to inhibit NNMT activity. The peptide has been linked to decreased blood sugar levels and improved glucose tolerance in mice.

So, by combining these three peptides, it might be possible to drastically alter energy metabolism for the better while simultaneously boosting anti-aging, anti-inflammatory, and anti-apoptosis activity in cells. The diagram below shows that inhibition of NNMT means that additional NMN converted to NAD will result in increased energy metabolism and decreased fat mass. Research into each of these individual compounds has been compelling, but research into the combination may result in serious benefits.

It is important to note that not all forms of a peptide are equivalent. In the case of BPC 157, there are two forms of the peptide: an Arginate salt and an Acetate salt. Research with oral administration of standard BPC 157 (acetate salt) has shown that it tends to break down in gastric acid more than the ariginate salt form. The body’s response to this is to simply produce a lot of BPC 157 and only in the areas where it is needed. Of course, this solution is not tenable when delivering the peptide orally and so scientists set out to produce a more stable form of BPC 157 by adding additional chemical structures to the peptide that resist gastric acid but do not alter overall function. The more orally bioavailable “stable” form of BPC 157 is the arginate salt. Studies show that just 5% of BPC 157 arginate is degraded after 5 hours in gastric acid as compared to 98% of the acetate salt. By reducing the degradation of BPC 157, the arginate salt makes the peptide more effective as an orally administered compound. The enhanced oral bioavailability of the arginate salt makes it the preferred choice in BPC 157 oral research[1].

Weight Loss and Energy Metabolism

Each of these peptides has a positive impact of energy metabolism. NMN, for instance, boosts NAD levels. Low NAD has long been associated with obesity while high NAD is generally associated with healthy diets rich in vegetables. High levels of NAD are associated with ideal body mass composition and increased longevity[4].

Now, high NAD levels, as shown in the diagram in the last section, will definitely increase energy metabolism and lower obesity, but there can also be negative effects. The major negative effect is an increase in NNMT activity. This can actually counter the beneficial effects of NMN and may explain why the peptide has not made it out of rodent studies. Fortunately, 5-amino-1MQ and JBSNF-000088 both inhibit NNMT. This not only decreases the side effects of high NAD levels; it actually boosts the positive effects by forcing more NAD down the beneficial pathway of weight loss and fat burning.

Research shows that daily administration of 5-amino-1MQ produces progressive weight loss in mice. After just 11 days, mice given 5-amino-1MQ lose the equivalent of 5.1% of their body weight. In a human weighing 200 pounds, that is the equivalent of losing 10 pounds in a week! What is more, the weight loss occurs even though the mice continue eating just as much food as they did before. Even more remarkable still, however, is that the treated mice show a 35% decrease in white adipose tissue. These mice not only showed a reduction in the numbers of white adipose cells, but those that remained were 30% smaller than the same cells in the control group[5].

Research in mice also shows that JBSNF-000088 reduces body weight.  Once again, this weight loss is seen in spite of continued average rates of food intake. Interestingly, while 5-amino-1MQ appears to improve body weight regardless of genetics, JBSNF-000088 only alters body weight in specific genetic settings. This doesn’t mean that JBSNF-000088 won’t work in those with obesity, but rather may not work in individuals with certain genetic forms of obesity. This suggests that interference with NNMT may not be the only mechanism by which  JBSNF-000088 produces weight loss. It would be interesting to see how a combination trial of the compounds in this article might alter JBSNF-000088 function.

What is interesting about the JBSNF-000088 trial is that it showed reductions in 1-methyl-nicotinamide in white adipose tissue, but not liver. Remember that 1-methyl-nicotinamide is a product of NNMT, so the study showed reduced NNMT levels in white adipose tissue of genetically obese mice, but not in liver. There is currently no explanation for this difference, but it may explain why the peptide was less effective in genetically obese mice and may offer some insight into energy metabolism as it relates the liver versus adipose tissue[6].

Diabetes and Blood Sugar

All three of these compounds can help to reduce the risk of diabetes in mouse models, even among mice that are genetically predisposed to develop diabetes and among mice fed a high fat or high sugar diet. JBSNF-000088 is the most potent anti-diabetic in this group and has been shown in mouse models to drastically improve glucose handling, even in genetically obese mice. This likely arises as a result of its ability to interfere with NNMT function as research in the past has shown that interventions to improve insulin sensitivity, such as exercise and even bariatric surgery, decrease NNMT expression in adipose tissue. This is important because, as noted above, JBSNF-000088 appears to primarily affect NNMT expression in fat cells and not in live cells[6].

Like JBSNF-000088, 5 amino-1MQ helps to regulate blood sugar levels by decreasing activity of NNMT. In this case, the research indicates that 5-amino-1MQ increases the transport of glucose by boosting GLUT-4 expression[6].

The mechanism by which NMN fights diabetes is completely different. Research shows that NMN, which it is capable of reducing adiposity and improving mitochondrial function, may also protect beta cells in the pancreas from damage. This benefit has been shown in both Type I and Type II diabetes, a remarkable feature of NMN and one that has led the healthcare industry to investigate its use as rescue treatment for people suffering from “traditional” diabetes[4].

So, JBSNF-000088 and 5-amino-1MQ work to move sugar from the blood and into cells where it can be used. This improves insulin sensitivity because the GLUT-4 transporter works independently of insulin. Thus, glucose levels drop even as insulin levels remain the same. This takes pressure off of the pancreas and helps to prevent “insulin burnout.” Further protecting the pancreas, through an entirely different mechanism, is NMN, which keeps the beta cells healthy so that they can produce insulin and regulate energy metabolism.

The Anti-Aging Effects of NAD

NAD is a primary marker of aging, declining over time and in certain disease conditions. Remember than NMN enhances NAD biosynthesis as shown in the diagram above. In mouse models, NMN administration has been shown to mitigate age-related physiological decline without any side effects. Things like loss of lean body mass, decreases in bone density, alterations of energy metabolism are virtually halted with NMN supplementation. According to Dr. David Sinclair, professor of genetics at Harvard Medical School, NMN is likely one of the keys to extending human life span to 150 years and may be the closest we have gotten to the fountain of youth yet[7], [8].

New research suggests that 5-amino-1MQ and JBSNF-000088 can, through inhibition of NNMT, actually alter the structure of our DNA and affect cellular senescence. It is important to note that DNA activity is controlled through a process of methylation and demethylation that makes the DNA accessible to enzymes that process it. The science that studies this aspect of DNA is called epigenetics and the changes (methylation/demethylation) are referred to as epigenetic changes. Research has led us to understand that at least some aspects of aging are due to accumulated epigenetic changes to our DNA that renders it less functional than it is in our youth. This can lead to cell and tissue dysfunction and is thought to be an important component of cellular aging (senescence). There is speculation, but not a great deal of research at this point to suggest that 5-amino-1MQ and similar NNMT inhibitors may actually fight against these epigenetic changes and thus reduce the effects of aging. In fact, there is some preliminary research to suggest that preventing these epigenetic changes actually keeps stem cells viable for longer, thus maintaining a pool of cells capable of replacing those that are injured or senescent[9].

Interestingly, the benefits of 5-amino-1MQ in aging are boosted by co-administration of things like NMN. This suggest that all of these peptides may be working together in some way to boost NAD levels and that NAD may, in fact, be the underlying common denominator. A great deal of research needs to be done in this area to unlock all of the secrets of the synergy that exists between 5-amino-1MQ, JBSNF-000088, and NMN in fighting the effects of aging.

Putting Together the Benefits of NMN, 5-Amino-1MQ, and JBSNF-000088

These compounds affect everything from energy metabolism to cellular performance to aging, primarily by affecting levels of NAD, the expression of GLUT-4 receptors, the activity of the NNMT enzyme, and the production of molecules known as sirutins. By increasing levels of NAD and decreasing the activity of NNMT, these molecules work together to improve cellular metabolism, enhance weight loss, and improve glucose control. The latter is further enhanced by the fact that NNMT inhibition boosts the expression of GLUT-4 receptors, insulin-independent glucose transporters that are linked to decreased risk of diabetes and improved insulin sensitivity.

Further benefits of the synergy between these peptides are seen in cellular aging, where increased levels of NAD help stem cells to survive and thrive. This, of course, provides a pool of healthy cells that can readily take the place of those that are worn or damaged, leading to improved tissue function and decreased effects of aging. These anti-aging effects also lead to performance gains as the combination of these molecules helps to ensure that tissue and organ systems are composed of the healthiest, most active cells available.

Storage Instructions:

All of our products are manufactured using the Lyophilization (Freeze Drying) process, which ensures that our products remain 100% stable for shipping 3-4 months reconstituted (mixed with bacteriostatic water) to maintain stability. After reconstitution, the peptides will remain stable for up to 30 days.

Lyophilization is a unique dehydration process, also known as cryodesiccation, where the peptides are frozen and then subjected to low pressure. This causes the water in the peptide vial to sublimate directly from solid to gas, leaving behind a stable, crystalline white structure known as lyophilized peptide. The puffy white powder can be stored at room temperature until you're ready to reconstitute it with bacteriostatic water.

Once peptides have been received, it is imperative that they are kept cold and away from light. If the peptides will be used immediately, or in the next several days, weeks or months, short-term refrigeration under 4C (39F) is generally acceptable. Lyophilized peptides are usually stable at room temperatures for several weeks or more, so if they will be utilized within weeks or months such storage is typically adequate.

However, for longer term storage (several months to years) it is more preferable to store peptides in a freezer at -80C (-112F). When storing peptides for months or even years, freezing is optimal in order to preserve the peptide’s stability.