NAD+, NMN and NR: PART 1

🔗 In this Nexus:

❓ What is NAD+?

🔬 Core Physiological Functions of NAD+

🔄 Aging and NAD+ depletion

💊 NAD+ Boosters: NMN and NR

The time has come for me to start talking about what you can do in addition to what I call longevity hygiene (sleep, healthy diet, physical activity, etc.). And the first thing that usually comes up in the conversations among longevity beginners or enthusiasts is the NAD+, NMN or NR. Therefore, this and the upcoming Nexus editions are dedicated to better understand what NAD+ is, how it affects aging, can NMN and NR increase NAD+ levels in our bodies, what are the scientific evidence behind the efficacy of those molecules, and is it really the holy grail of antiaging.

Spoiler alert, Part 1 will be highly scientific, so be prepared. I have tried to explain things in human language where I could, but not sure I’ve succeeded in all cases. Thus, I've highlighted the main facts in bold for those, who hated chemistry and biology in school. As a compensation, Part 2 will be much less rocket science and much more practical. Also, I will release it in a week after this one, not to keep you waiting.

What is NAD+?

Nicotinamide adenine dinucleotide (NAD+) is a coenzyme pivotal in numerous metabolic pathways (1). NAD+ was initially identified during yeast fermentation, and its discovery has revealed its pivotal roles in metabolism, aging, longevity, immune system, and DNA repair (2). Beyond its role as a mediator of redox reactions, NAD+ serves as a substrate for enzymes such as Sirtuins and poly(ADP-ribose) polymerases (PARPs), which regulate cellular processes crucial for longevity and genomic stability.

Sirtuins are a family of NAD+-dependent enzymes that regulate cellular health, aging, and metabolism by deacetylating proteins involved in gene expression, DNA repair, and metabolic processes.

PARPs are a family of enzymes that use NAD+ to detect and repair DNA damage by adding ADP-ribose polymers to target proteins, thereby maintaining genomic stability.

Core Physiological Functions of NAD+

NAD+ is found in the mitochondria, nucleus and cytoplasm in the cells, and throughout the human body in the muscles, brain, liver, adipose tissue, immune system, heart, and pancreas. It plays essential roles in energy production, DNA repair, and metabolic regulation, as shown in the figure below (3):

The core functions of NAD+ include:

1. Energy Metabolism. NAD+ is vital for cellular energy metabolism in glycolysis, Tricarboxylic acid (TCA) cycle, and oxidative phosphorylation (3):

• Glycolysis is the process in which glucose is broken down to produce energy.
• TCA cycle or Krebs cycle is a sequence of chemical reactions, to produce energy through the oxidation of acetyl-coenzyme A (CoA) obtained from carbohydrates, fatty acids, and proteins. Or in human language, it's a cellular process that converts food molecules into energy used by cells, in organisms that require oxygen.
• Oxidative phosphorylation is a cellular process that harnesses the reduction of oxygen to generate high-energy phosphate bonds in the form of adenosine triphosphate (ATP). It is a way in which cells use oxygen to make energy-packed molecules ATP.

2. Redox Reactions. Nicotinamide adenine dinucleotide exists in two forms, including an oxidized (NAD+) and a reduced (NADH) form, and plays a key role in intermediary metabolism, as obligatory partner in numerous oxidation/reduction (redox) reactions (4). As an oxidizing agent, it accepts electrons to become NADH, essential for breaking down nutrients for energy. As a reducing agent, NADH donates electrons to the electron transport chain and biosynthetic pathways, aiding ATP and macromolecule production.

3. DNA Repair. NAD+ maintains genomic stability by supporting DNA repair. PARPs uses NAD+ to transfer ADP-ribose units for single-strand DNA break repair. Also sirtuins, NAD+-dependent enzymes, regulate DNA repair and chromatin structure, promoting genomic integrity. In short, NAD+ helps fix damaged DNA, ensuring our genetic information stays intact (3).

4. Cellular Signaling. NAD+ acts as a signaling molecule, influencing various cellular processes. It is involved in sirtuin activation, regulates metabolism, stress responses, and longevity by deacetylating proteins involved in transcription and DNA repair. Enhanced NAD+ levels activate sirtuins and other pathways, improving metabolic efficiency and stress resistance (3).

5. Immunomodulation. NAD+ and its metabolites regulate the immune response. NAD+ influences how our immune cells respond to threats and manage inflammation. It modulates immune cell activity and inflammatory cytokine production and influences the function of macrophages and other immune cells, affecting infection outcomes (3).

6. Circadian Rhythms. NAD+ levels rise and fall in sync with our circadian rhythms, helping to regulate genes and proteins that control our sleep, metabolism, and overall daily cycles. NAD+ modulates SIRT1, which interacts with CLOCK-BMAL1 to regulate metabolic and behavioural cycles, aligning cellular functions with the day-night cycle (3).

What Does Science Say?

Aging and NAD+ Depletion

It has been identified that NAD+ concentration declines with age affecting mammalian longevity and age-related health conditions through its functions of energy metabolization and activation of specific genes and proteins in tissues as shown in the schematic below (5). An imbalance in the NAD+/NADH ratio can disrupt cellular stability, leading to aging, neurodegenerative diseases, inflammation, infections, cardiovascular diseases, and cancer (6).

The most researched context of NAD+ decrease is aging, which significantly reduces sirtuin activity and its anti-aging effects. NAD+ depletion causes mitochondrial dysfunction, reduced energy production, and increased oxidative stress. This oxidative stress and accumulated genetic mutations lead to chronic activation of PARP enzymes, rapidly depleting NAD+ and further decreasing sirtuin levels, thereby accelerating aging (7).

Aging is characterized by a decline in tissue regeneration due to reduced stem cell function, leading to insufficient tissue repair. NAD+ is crucial for maintaining the pool and pluripotency of stem cells, making it essential during aging. Decreased NAD+ synthesis, contributes significantly to NAD+ depletion. Also worth mentioning that the circadian rhythm-regulating complex (CLOCK:BMAL1) directly influences NAD+ synthesis, and disruptions in these rhythms due to aging further reduce NAD+ levels, accelerating aging (7).

NAD+ Boosters: NMN and NR

NAD+ depletion has been associated with hallmarks of aging (discussed in one of my previous Nexus editions) and may underlie a wide-range of age-related diseases. Restoring NAD+ levels through supplementation has emerged as one of the key strategies in slowing the aging process. And it is quite understandable having in mind the above-mentioned importance of this molecule in our metabolism and longevity. The potential strategies of boosting NAD+ levels and its’ expected health benefits are summarized in the figure below (8):  

NAD+ precursors nicotinamide mononucleotide (NMN) and nicotinamide riboside (NR) has received quite some attention in pre-clinical and clinical research in the recent decade, due to the association between the NAD+ decline and aging. Nicotinamide mononucleotide (NMN) is an intermediate of NAD+ biosynthesis or in other words - precursor of NAD+. Nicotinamide Riboside (NR) is a form of vitamin B3 that acts as a precursor to NAD+. NMN is directly converted into NAD+ within cells, while NR is first converted to NMN before becoming NAD+. Both NMN and NR play crucial roles in enhancing metabolic function, supporting DNA repair, and promoting overall cellular health.

Kept you reading till the end? Want to know more about NAD+, NMN and NR? Wait for my next Nexus, where I will discuss the clinical data available on the efficacy of NAD+ booster supplementation, as well as practical tips on how and when to use NMN or NR, which one of the two is better, what is the safety profile of these compounds and how to choose from the variety of currently available supplements.