The Impact of NMN, NAD+, and NR, on Longevity

NOMIX

June 27, 2024

Nicotinamide adenine dinucleotide, or NAD+, is a crucial molecule found in every cell of our body. It’s like a spark plug that helps power various essential processes, such as fixing DNA damage, controlling gene activity, producing energy, and regulating calcium levels. NAD+ levels tend to increase when our energy levels are low, like during fasting, calorie restriction, or exercise.

Let’s dive deeper into the role of NAD+ in our bodies, its decline with age and health issues, and the challenges of oral supplementation.

Role of NAD+ in the body:
NAD+ is a crucial molecule that acts as a cofactor and substrate for various cellular processes, including:

  1. DNA repair: NAD+ is essential for repairing damaged DNA, which helps maintain the stability of our genetic information.
  2. Epigenetic regulation: NAD+ plays a role in controlling the expression of genes by modifying their structure. This process is crucial for normal development and cellular function.
  3. Energy production: NAD+ is a key player in the process of oxidative phosphorylation, which generates ATP (the energy currency of our cells).
  4. Intracellular calcium signaling: NAD+ helps regulate calcium levels within our cells, which is important for cellular communication and function.
  5. Immune function: NAD+ is involved in the activation of immune cells, which helps our bodies fight off infections.

Decline of NAD+ with age and health issues:
As we age, our NAD+ levels tend to decrease, which can contribute to various age-related issues. Low NAD+ levels have been linked to:

  1. Aging: Reduced NAD+ levels may play a role in the aging process itself.
  2. Cellular senescence: Senescent cells, which are cells that have stopped dividing and are no longer functional, accumulate with age and contribute to tissue dysfunction. Low NAD+ levels may promote cellular senescence.
  3. Inflammation: Decreased NAD+ levels can lead to chronic inflammation, which is a major contributor to various age-related diseases.
  4. Metabolic dysfunction: Low NAD+ levels have been implicated in insulin resistance, type 2 diabetes, and other metabolic disorders.

Challenges of oral NAD+ supplementation:
Despite the potential benefits of boosting NAD+ levels, taking NAD+ orally is not a straightforward solution. This is because:

  1. Poor bioavailability: Oral NAD+ supplementation has poor bioavailability, meaning that only a small fraction of the ingested NAD+ is absorbed into the bloodstream.
  2. Gut metabolism: NAD+ is metabolized by enzymes in the gut, which further reduces its availability to the body.
  3. Inefficient conversion: When NAD+ is absorbed, it may be converted back to its inactive form, NAM, by the enzyme NADase.

Alternative NAD+ precursors:
Researchers are exploring alternative precursors of NAD+ that might be more effective in boosting NAD+ levels. These precursors include:

  1. Nicotinic acid (NA): NA is a direct precursor of NAD+ and has been shown to increase NAD+ levels in certain tissues.
  2. Nicotinamide riboside (NR): NR is a precursor of NAD+ that is more stable than NAD+ itself and has been shown to increase NAD+ levels in mice.
  3. Nicotinamide mononucleotide (NMN): NMN is another precursor of NAD+ that has been shown to increase NAD+ levels in mice and is currently being studied for its potential benefits in humans.
  4. Nicotinamide adenine dinucleotide ribose (NAR): NAR is a form of NAD+ that contains ribose instead of deoxyribose. It has been shown to increase NAD+ levels in certain tissues.

These alternative precursors are being investigated for their potential to improve NAD+ levels and provide therapeutic benefits. However, more research is needed to understand their efficacy and safety in humans fully. Intravenous infusion of NAD+ remains the most effective way to boost NAD+ levels, but alternative precursors may offer a more convenient and effective option.

The discovery of Sirtuins, a group of enzymes that depend on NAD and are linked to longevity, has opened up a new frontier in aging research. Recently, there has been a surge of interest in using the NAD/Sirtuin pathway to combat brain aging, and therapies based on this principle are expected to become available in the future.

A breakthrough in this field is the identification of nicotinamide riboside (NR) as a vitamin precursor of NAD with excellent oral bioavailability in both mice and humans. Studies have shown that a single daily dose of NR (1000 mg) can increase blood NAD+ levels by 270% within seven days. Additionally, NMN, another NAD+ precursor, is metabolized into NR, which is then converted into NAD+ inside cells.

In mice with metabolic impairments, NR supplementation has been linked to increased SIRT1 expression, reduced oxidative stress, and enhanced mitochondrial function. In a fly model of Parkinson’s disease, NR supplementation has been shown to reduce the loss of dopaminergic neurons and improve motor skills. Furthermore, NR supplementation has been found to reduce tau phosphorylation and enhance cognitive function in a mouse model of Alzheimer’s disease with DNA repair defects.

Another study demonstrated that NMN supplementation promoted mitogenesis in nematode neurons and improved cognitive decline caused by Alzheimer’s disease. In a rat model of Alzheimer’s disease, NMN reduced Aβ aggregation, enhanced spatial memory, and increased neuronal survival, partly by reducing reactive oxygen species (ROS). These findings suggest that NAD+ precursors like NR and NMN may hold promise in treating age-related brain diseases and improving cognitive function.

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