Nicotinamide mononucleotide, commonly known as NMN, is a molecule naturally present in every living cell across all organisms. On a molecular scale, NMN is categorised under nucleotides, which are foundational elements of RNA and DNA. Breaking down its structure, NMN consists of a phosphate group, a ribose sugar and a nicotinamide base. One of NMN’s primary roles is its conversion into nicotinamide adenine dinucleotide (NAD+), leading to an increase in NAD+ levels. This has led to NMN often being labeled as a NAD+ enhancer.
Why Elevating NAD+ Levels with NMN Matters
Second only to water, NAD+ stands out as one of the most prevalent molecules in our body, essential for our survival. Acting as a coenzyme, NAD+ assists enzymes in their functions. These enzymes are vital proteins that accelerate chemical reactions, making them feasible within our lifespan. For instance, certain biological reactions would take billions of years without the presence of enzymes.
It’s noteworthy that as we age or face chronic ailments like heart diseases, neurodegenerative disorders, or sarcopenia (muscle degeneration due to aging), our NAD+ levels diminish. By replenishing NAD+ levels using precursors like NMN, we might counteract some aging effects and possibly prevent or alleviate chronic diseases. The potential benefits of enhancing NAD+ levels are backed by an expanding collection of scientific research.
The Role of NAD+ in Powering Sirtuins
NAD+ is the driving force behind a vital group of enzymes known as sirtuins. Often dubbed the “cellular sentinels,” sirtuins are instrumental in DNA repair and maintaining mitochondrial health. Mitochondria, often termed the cell’s energy factories, generate a form of energy known as ATP. A decline in mitochondrial health results in reduced ATP production, culminating in cellular demise. Given that excessive DNA damage can also lead to cell death, sirtuins are pivotal in ensuring cell longevity by mending DNA and preserving mitochondrial health.
Harvard geneticist and renowned NAD+ researcher, David Sinclair, points out that the depletion of NAD+ as we age, coupled with the subsequent reduction in sirtuin activity, is believed to be a key factor in the onset of age-related diseases. He posits that elevating NAD+ levels, potentially through NMN, might decelerate or even reverse specific aging processes.
Beyond NMN, there are other avenues to elevate NAD+ levels and stimulate sirtuins. Polyphenols, which are plant-derived molecules known for promoting longevity, along with physical activity and caloric restriction (reducing calorie intake without undernourishment), can also enhance NAD+ concentrations. Sirtuins don’t just bolster cell longevity and DNA protection; they offer a plethora of advantages. They guard against conditions like diabetes and fatty liver by enhancing insulin release, facilitating fat metabolism and increasing glucose production in the liver. Additionally, sirtuins play a protective role against muscle degeneration, neurodegeneration and excessive fat tissue accumulation.
NAD+ and Its Integral Role in Mitochondrial Processes
NAD+ is pivotal in metabolic activities, including glycolysis, the TCA Cycle (also known as the Krebs or Citric Acid cycle) and the electron transport chain, all of which transpire within our mitochondria, the cell’s energy factories.
Functioning as a ligand, NAD+ attaches to enzymes, facilitating electron transfer between molecules. Electrons form the foundation of cellular energy. By shuttling them from one molecule to another, NAD+ operates in a manner akin to recharging a battery. Just as a battery drains when its electrons are used up, NAD+ acts as the recharger, modulating enzyme activity, gene expression and cellular communication.
NAD+ and Its Role in DNA Preservation
As living beings age, they accumulate DNA damage, often due to environmental factors like radiation, pollution, or imperfect DNA replication. Prevailing theories on aging suggest that this DNA damage accumulation is a primary aging driver. Most cells possess the tools to mend this damage, but this repair process consumes both NAD+ and energy. Excessive DNA damage can deplete these vital cellular resources.
A key DNA repair protein, PARP, relies on NAD+ for its functionality. As individuals age, NAD+ levels decline. The natural aging process, coupled with DNA damage, leads to increased PARP activity, further depleting NAD+ levels. Any additional DNA damage in the mitochondria amplifies this depletion.
The Significance of NAD+
Ever since NAD+ was first identified in 1906, scientists have been intrigued by its prevalence in the body and its essential role in the molecular processes that sustain us. Animal studies have indicated that increasing NAD+ concentrations can yield positive outcomes in areas like metabolism and age-related diseases, even hinting at potential anti-aging properties. Age-associated conditions, including diabetes, heart diseases, neurodegenerative disorders and weakened immune systems, further underscore the importance of NAD+.
The Role of NAD+ in Aging
NAD+ serves as the catalyst that enables sirtuins to maintain genome stability and support DNA repair. Much like a vehicle requires fuel to run, sirtuins need NAD+ for activation. Animal studies have indicated that by increasing NAD+ levels, sirtuins are activated, leading to extended lifespans in organisms such as yeast, worms and mice. While these results are encouraging, the application of these findings to human longevity is still being researched.
NAD+ and Metabolic Health
NAD+ is crucial for maintaining healthy mitochondrial functions and consistent energy output. Factors like aging and consuming a high-fat diet can reduce NAD+ levels in the body. Research has shown that using NAD+ enhancers can counter the effects of diet and age-related weight gain in mice and even improve their exercise capacity. Some studies have even demonstrated potential in reversing the effects of diabetes in mice, suggesting new strategies to combat metabolic disorders like obesity.
Heart Health and NAD+
Elevating NAD+ levels can offer protection to the heart and enhance cardiac functions. High blood pressure can lead to conditions like an enlarged heart and blocked arteries, which can result in strokes. In mice studies, NAD+ enhancers have been shown to replenish heart NAD+ levels and prevent heart damage caused by reduced blood flow. Other research has indicated that NAD+ enhancers can shield mice from abnormal heart enlargement.
NAD+ and Brain Health
In mice with Alzheimer’s disease, increasing NAD+ levels can reduce the accumulation of proteins that disrupt cell communication, thereby enhancing cognitive function. Elevating NAD+ levels also offers protection to brain cells from damage due to insufficient blood flow. Numerous studies in animal models suggest promising avenues for promoting healthy brain aging, combating neurodegeneration and improving memory.
NAD+ and Immune Health
As individuals age, the immune system’s efficiency decreases, making them more susceptible to illnesses. Recent research has highlighted the significant role of NAD+ levels in regulating inflammation and cell survival during immune responses and the aging process. This research emphasises the potential therapeutic benefits of NAD+ for immune-related issues.
Understanding NAD+ Production in the Body
Our bodies naturally produce NAD+ using smaller components, known as precursors. These precursors are the foundational elements for NAD+. The body has five primary precursors: tryptophan, nicotinamide (Nam), nicotinic acid (NA or niacin), nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN), with NMN being one of the final steps in NAD+ synthesis.
These precursors can be sourced from our diet. Nam, NA and NR are all variants of vitamin B3, a vital nutrient. Once ingested, our cells can produce NAD+ through various pathways. One such pathway is the de novo pathway, which starts with the earliest NAD+ precursor, tryptophan. Another is the salvage pathway, which recycles the by-products of NAD+ degradation to produce more NAD+.
Understanding NMN Synthesis in the Body
NMN is derived from B vitamins within our bodies. The enzyme nicotinamide phosphoribosyltransferase (NAMPT) is responsible for NMN production. NAMPT combines nicotinamide, a form of vitamin B3, with a sugar phosphate known as PRPP (5’-phosphoribosyl-1-pyrophosphate). Additionally, NMN can be synthesised from ‘nicotinamide riboside’ (NR) by adding a phosphate group.
‘NAMPT’ is pivotal in NAD+ production. When NAMPT levels are low, it results in reduced NMN and NAD+ production. Introducing precursor molecules like NMN can accelerate NAD+ synthesis.
Ways to Elevate NAD+ Levels
Calorie restriction, or simply reducing calorie intake, has been found to elevate NAD+ levels and enhance sirtuin activity. In mice, this elevation has been linked to a deceleration in the aging process. While some foods contain NAD+, the amounts are insufficient to influence intracellular levels. However, supplements like NMN have demonstrated an increase in NAD+ levels.
The Role of NMN as a NAD Supplement
Over time, as a result of regular cellular functions, NAD+ levels decrease with age. By supplementing with NAD+ precursors, it’s believed that healthy NAD+ levels can be restored. Research suggests that precursors like NMN and nicotinamide riboside (NR) can enhance NAD+ production. David Sinclair, a renowned NAD+ researcher, mentions that direct NAD+ supplementation isn’t feasible due to its inability to cross cell membranes. Instead, precursors to NAD+ are utilised to elevate its levels, as they are more absorbable and effective.
NMN Absorption and Distribution
NMN seems to be absorbed into cells via a specific transporter present on the cell surface. Due to its smaller size compared to NAD+, NMN might be more efficiently taken up by cells. NAD+ faces challenges entering the body due to the cell membrane’s barrier. Recent findings suggest that NMN can directly enter cells through an NMN-specific transporter.
When NMN is injected, there’s an increase in NAD+ levels in various body parts, including the pancreas, heart, skeletal muscle and more. Oral NMN administration in mice has shown a rise in liver NAD+ levels within a short time.
NMN’s Conversion to NAD+ and Its Safety
NMN is deemed safe in animals and its promising results have led to the initiation of human clinical trials. Even at high doses, NMN appears to be non-toxic in both mice and preliminary human studies. While a study in 2019 observed elevated bilirubin levels in subjects post-NMN administration, the levels remained within the normal range. Future research should delve into the long-term safety and efficacy of NMN.
The Evolution of NMN and NAD+ Research
NAD, or Nicotinamide adenine dinucleotide, is a pivotal molecule in the body, playing a central role in cellular energy processes. Its discovery in 1906 by Arthur Harden and William John Young marked the beginning of extensive research into its functions.
Over the years, numerous scientists, including Nobel laureates, have contributed to our understanding of NAD and its role in various biological processes. From its role in fermentation to its significance in DNA replication and RNA transcription, NAD has remained a focal point of biological research.
The discovery of NMN and its role in activating crucial enzymes opened doors to further studies on proteins like PARPs, which are vital for DNA repair and lifespan regulation.
The continued interest in NAD, NMN and NR stems from their potential to address several age-related health concerns.
Exploring the Potential of Nicotinamide Mononucleotide
The encouraging results from animal studies regarding NMN have spurred researchers to delve deeper into its effects on humans. A recent clinical trial conducted in Japan has confirmed the safety and tolerability of NMN at the administered doses. As research progresses, more human trials are being planned. NMN remains an intriguing molecule and there’s still a vast expanse of knowledge waiting to be uncovered about its capabilities.