NMN 500mg (60 Capsules)

NMN Overview

NMN, short for nicotinamide mononucleotide, is a nucleotide derivative of niacin and is used by several enzymes in the body to generate or replenish stores of nicotinamide adenine dinucleotide (NAD+/NADPH). NMN is absorbed in the small intestine and is highly orally bioavailable, making it easy to utilize. Research in mice indicates that NMN is full absorbed in the small intestine via a specific transmitter. This takes place within 10 minutes of consumption [1]. Nicotinamide is known to cross the blood-brain barrier into the central nervous system where it is converted to NAD+, thus increasing cellular NAD+ levels in the brain[2].

Because NAD+ is a cofactor for processes that take place inside of mitochondria, it has long been studied as a neuroprotective and anti-aging agent. In fact, research indicates that aging at the cellular level can be reversed by inhibiting mitochondrial decay and that this decay is, at least in part, a consequence of diminishing levels of NAD+ that occur as a result of aging. The benefits of NMN itself have primarily been demonstrated through in vitro or animal studies[3]. These studies indicate that NMN like benefits a variety of cellular processes by fighting the effects of aging, boosting antioxidant activity, protecting neurological function, and regulating certain metabolic processes.

MNM Research

What is NMN?

NMN is a crucial intermediate in the biosynthesis of NAD+, a key metabolic coenzyme in eukaryotic organisms. NAD+ is essential for numerous enzymatic reactions and plays a significant role in various biological processes such as cell death, aging, gene expression, inflammation, and DNA repair [4]. NAD+ is a critical component in human health and longevity. Recent research has shown that NMN supplementation can help address NAD+ deficiencies and influence various biochemical activities across a variety of disease conditions.

Increased NAD+ levels are the goal of NMN supplementation. NAD+ is produced by the body naturally, but these natural processes decrease with age. NMN can be produced synthetically but is actually a natural intermediate of the NAD+ pathway. Oral NMN can be used to supplement waning NMN levels and restore NAD+ pathways. Within the body, there are three biosynthetic pathways that produce NAD+:

• Synthesis from tryptophan
• Salvage
• Preiss-Handler pathways

NMN is an intermediate by-product and is involved in NAD+ biosynthesis in the salvage and Preiss-Handler pathways. It is via these two pathways that supplemental NMN is able to enter synthetic pathways and boost NAD+ production[5].

Research indicates that NMN directly affects several molecules including sirtuins and parps. Sirtuins have been closely linked to anti-aging processes and have led to lifespan elongation as well as improved health in animal models. Sirtuins were originally discovered in yeast but have since been found in nearly every cell. They are important to cell responses to stress, inflammation, and disease. Many antioxidants (e.g. resveratrol) interact with sirtuins[6].

Parps are a family of proteins important in DNA repair, cell proliferation and differentiation, and programmed cell death. They are also important in inflammatory disorders, particularly diseases of the lungs like asthma. NAD+ is a required substrate for generation the building blocks of parps, so it should come as no surprise that NNM enhances parp production[7].

Ultimately, NNM has a host of beneficial effects in animal models.

NMN Production

Historically, several methods have been employed to prepare and purify NMN. These include the incubation of diphosphopyridine nucleotide in a non-phosphate buffer with fluoride and potato pyrophosphatase, the synthesis of NMN from nicotinamide using human hemolysates and erythrocytes, and the specific hydrolysis of the pyrophosphate bond of NAD+ with NAD+ pyrophosphatase and metal catalysts. However, these approaches are often inefficient and yield low amounts of NMN, resulting in high production costs. Currently, microbial biotechnologies are being explored to produce NMN more effectively. Nonetheless, further innovation and optimization are necessary to reduce costs and improve purity. Research is ongoing to develop simpler and more efficient biotechnological methods using bacteria and yeast to make NMN production more cost-effective.

NMN: Oral Bioavailability

As noted earlier, NMN is rapidly absorbed in the Gl tract. Additionally, the molecule is relatively stable in the environment with research indicating that it remains up to 99% intact when dissolved in water for up to a week. In mice, studies have shown that NMN is found in the plasma just 2.5 minutes after oral consumption and that plasma levels continue to rise for at least 10 minutes after intake before returning to normal. This quite return to normal indicates that NMN is rapidly absorbed by tissues from the bloodstream. Indeed, 30 minutes after consumption NMN can be found in tissues, like skeletal muscle, and NAD+ levels show significant increases[8]. Thus, NMN has been confirmed in animal studies to not only be highly bioavailable when consumed orally, but to penetrate tissue rapidly leading directly to an increase in NAD+ levels.

NMN: Anti-Aging

The decline if NAD+ in various tissues has been linked to many signs of aging. Research in vitro and in animal models shows that NAD+ influences numerous cellular processes, including metabolic pathways, DNA repair, and immune function. These processes are crucial for maintaining homeostasis and the kind of overall tissue function associated with youth. Unfortunately, as individuals age, NAD+ levels decline, so researchers have set out to determine if restoring NAD+ levels has the potential to delay or even reverse some of these conditions. Recent studies in both mice and humans have explored targeting NAD+ metabolism with its intermediates. Among these, nicotinamide mononucleotide (NMN) has shown significant therapeutic promise for age-related chronic conditions such as diabetes, cardiovascular issues, and cognitive decline.

As noted, NAD+ levels decline with aging and this decline is partly due to NAD+ consumption by several enzymes, including poly (ADP-ribose) polymerase (PARP), NADase, NAD+-dependent sirtuins, tankyrase, and bone marrow stromal cell antigen 1 (BST1). Of these, CD38 is particularly significant, as it may contribute to the reduction of NAD+ associated with aging. Sirtuins, which use NAD+ for various functions such as deacetylation and other modifications, are closely linked to aging, lifespan, and age-related changes. CD38 breaks down NAD+ into nicotinamide and ADP-ribose, while PARP uses NAD+ to create ADP-ribose polymers involved in DNA repair. These NAD+-consuming enzymes play critical roles in regulating mitochondrial protection, stem cell rejuvenation, and DNA repair, all of which are essential for cellular health. However, these processes lead to significant NAD+ depletion. Supplementing with NMN can help restore NAD+ levels and balance its biosynthesis.

Many interventions for the aging process have been studied, but only a handful have shown any benefit. Interventions with known benefits for longevity include exercise, calorie restriction, and limited sugar consumption. As it turns out, each of these interventions raises levels of NAD+, indicating once again that NAD+ is a key player in the aging process. The anti-aging benefits of increasing NAD+, either through NMN supplementation or via the mechanisms listed above, are too numerous and too nuanced to cover in detail in a single place, but it is worth hitting the highlights. Here is what we know about NNM, NAD+, and the aging process as of right now.

First, the integrity of the genome, which is to say DNA is paramount to both lifespan and health span. Research indicates that the ability of cells to restore damaged DNA declines as we age and is a major driver of processes like senescence as well as the development of various types of cancer. A number of studies support the role of NNM in protection DNA from the effects of aging. For instance, one recent study found that NMN supplementation may help reduce DNA damage and cellular senescence in human proximal tubule cells caused by hypoxia (low oxygen). In the study, a mouse model of an ischemia- reperfusion injury revealed that NMN has the ability to inhibit DNA damage, exert anti-aging effects, and reduce inflammation. In other studies, NMN has been shown to facilitate DNA repair in lung cancer.

NAD+ has been shown to have activity in preventing or controlling a variety of cancer types. For instance, the Deleted Breast Cancer protein1 (DBC1) contains a region that regulates the activity of PARP, a protein involved in DNA repair. NAD+ interacts with this specific region of DBC1, thereby reversing the inhibition of PARP1 and promoting DNA repair. During aging, as NAD+ levels decline, PARP1 activity is diminished leading to impaired DNA repair. Studies involving mice exposed to gamma radiation, for instance, have shown that NMN administration improves hepatic NAD+ levels, enhances PARP1 activity, and facilitates DNA repair. These findings suggest that NMN can boost NAD+ availability and explicitly support DNA repair mechanisms.
Another profound way in which NMN influences longevity is through its action on mitochondria. Mitochondrial quality and abundance are crucial for health and longevity, and their dysfunction is a key marker of aging. Mitochondrial dysfunction is often seen in heart failure, for instance, and is a known component of metabolic syndrome. NAD+ is known to positively influence mitochondrial function in a number of ways.
Research using heart-specific mouse models, for example, has shown that a lack of Krüppel-like factor 4 (KLF4) leads to mitochondrial dysfunction due to decreased NAD+ and Sirt3, which NMN administration can alleviate by preserving mitochondrial structure, reducing ROS levels, and preventing cell death. Combining NMN with the mitochondrial-targeting drug SS-31 has demonstrated a synergistic effect, improving both systolic and diastolic heart functions.

Mitochondrial dysfunction is also a known component of ovarian aging, which affects reproductive health. Long-term NMN administration in mice has shown benefits in the ovaries that include reduced inflammation, improved organ structure, improved endocrine function, and longer retention of estrous cycle status. NMN also enhances mitochondrial biogenesis and protease activity in granulosa cells and reverses age-related physiological decline and gene expression changes in multiple reproductive organs [9]. These findings and more suggest that NMN can boost NAD+ availability and restore mitochondrial health, potentially mitigating one of the key signs of aging-mitochondrial dysfunction.

Mental and physical fatigue, along with poor sleep quality, in older adults have been associated with reduced life expectancy and increased mortality. In a recent animal trial, NMN was administered daily for 12 weeks. The study assessed various outcomes including sleep quality, fatigue, grip strength, and physical performance. Results indicated that NMN supplementation improved lower limb function and reduced sleepiness when compared to placebo. This indicates that NMN may help mitigate declines in physical performance and fatigue in older adults..

NMN: Neurological Function

Research into the role of NMN in Alzheimer’s disease has shown promising results. This should come as no surprise given that mitochondrial dysfunction is a hallmark of many neurodegenerative diseases. In studies of mice that have a genetic predisposition to developing Alzheimer’s disease, it has been shown that NMN supplementation restores mitochondrial respiratory function and affects levels of SIRT1 and CD38. Mitochondria in these mice do not show oxygen deficits when the mice are treated with NMN, suggesting that the molecule enhances energy production in the brain and central nervous system, giving neurons that nutrients they need to survive and transmit signals[11]. Interestingly, NMN may directly inhibit the building of amyloid-beta plaques, a hallmark of Alzheimer’s disease[12].

The administration of NMN has been shown, in animal models, to directly increase NAD+ level in the hippocampus, a structure highly important to memory can cognition, within 15 minutes of consumption. It also increases levels of NAD+ in the hypothalamus, which is responsible for hormone regulation for everything from growth to thyroid and immune function. In one study, older mice supplemented with NMN had better spatial working memory, better neurovascular health, better gait coordination, and improvements in other essential components of brain function[13].

NMN: Diabetes

Diabetes is known to cause of host of health problems including obesity, heart disease, and metabolic syndrome. It has recently been put forth as a major risk factor for neurodegenerative diseases like Alzheimer’s disease. Research in mice shows that NMN has the potential to lower blood sugar levels in the setting of diabetes by increasing insulin sensitivity.
As a side note, a high-fat diet has often been associated with worsening health and enhanced rates of aging. As it turns out, high-fat diets, particularly those high in saturated fats, can decrease levels of the enzyme nicotinamide phosphoribosyltransferase, which is responsible for the endogenous production of NAD+H in the body. Reductions in levels of this enzyme have been shown to decrease levels of NAD+ in the liver and in fat cells. This reduction is more severe as a person ages. Research in mice has shown that type 2 diabetes can be reversed by dietary alterations but also by the administration of NMN.

Simply supplementing with NMN leads to decrease insulin resistance and reversion of type II diabetes[14]. Of particular interest is the ability of NNM to increase the sensitivity of muscle tissue to insulin. Muscle tissue has a number of different glucose receptors that only come to the surface in response to certain stimuli. Some of those receptors are sensitive to exercise, for instance, while others are sensitive to insulin. Research in mice shows that NMN increase the uptake of glucose by muscle cells, a factor that could not only be of use in treating or preventing diabetes, but may also be of interest to athletes and in those with certain muscle-wasting conditions[15].

NMN: Weight Loss

Research in mice indicates that NMN can suppress age-associated body weight gain in a dose-dependent manner. Finding a dose-dependent response is important for confirming causality in biological studies. In this case, the response is quite strong with lower levels of NMN leading to a 4% body weight reduction in aging mice and higher levels of NMN leading to a 9% reduction in body weight when compared to control animals. These effects are seen in short order after beginning NMN administration and persist for as long as the molecule is consumed. At 12 months, research shows a decrease in fat mass and an increase in lean body mass, suggesting that NMN not only promotes fat loss, but encourages bone and muscle growth [8]. Interestingly, the mice given NMN showed increased food intake and still had reductions in fat mass.

NMN: Energy Levels

At least part of the reason that NMN might encourage weight loss is because it improves energy levels. Research in mice has shown increased oxygen consumption and energy expenditures following NMN administration. In fact, energy expenditure in older mice given NMN closely mirrors that energy expenditure seen in younger mice. In other words, energy burn is more youthful, suggesting that NMN resets mitochondrial metabolism to a more youthful state in some ways [16]. Mice given NMN show increases in physical activity, improved muscle function, and higher levels of energy production at the cellular level.

NMN: Summary

NMN, a small molecular compound produced naturally by most living organisms, has demonstrated significant promise in enhancing NAD+ metabolism and addressing age-related conditions. NMN shows potential benefits in DNA repair, mitochondrial health, and autophagy induction. Additionally, NMN supports cognitive function and reproductive health while improving metabolic markers, aiding in weight management, and enhancing blood sugar control. These attributes suggest that NMN could serve as an effective therapeutic intervention against the ravages of aging.

Further exploration of NAD+ metabolism and NMN’s applications is essential, including detailed studies on optimal dosages, pharmacology, toxicology, and safety. Future investigations should focus on optimizing production methods and exploring NMN’s effects in combination with other compounds. Researchers should also continue to examine NMN’s impact on key biological processes, such as DNA repair, mitochondrial health, and autophagy. With thorough research, NMN supplementation could emerge as an important strategy for managing aging