The human body synthesizes NAD+ from smaller components, or precursors, which can be considered the “raw materials” for NAD+. There are five main precursors naturally occurring in the body:
- Tryptophan
- Nicotinamide (Nam)
- Nicotinic acid (NA, or niacin)
- Nicotinamide riboside (NR)
- Nicotinamide mononucleotide (NMN): NMN is the final step in NAD+ synthesis.
These precursors are derived from food. Nam, NA, and NR are forms of vitamin B3, an essential nutrient. Once in the body, cells can synthesize NAD+ through multiple pathways. Regardless of the pathway, the result is the same product: NAD+.
Pathways for NAD+ Synthesis
- De Novo Pathway
- “De Novo” is Latin for “starting from scratch.” This process begins with tryptophan, the primary precursor, and builds NAD+ through a series of steps.
- Salvage Pathway
- This pathway is analogous to recycling. It regenerates NAD+ from degraded components of previously used NAD+. Proteins in the body undergo constant breakdown to prevent accumulation. During this cycle, enzymes recycle the by-products into new NAD+.
NAD+ and Mitochondria
NAD+ is a coenzyme crucial for metabolism in the mitochondria. It plays an active role in energy production processes like glycolysis, the TCA cycle (Krebs or Citric Acid Cycle), and the electron transport chain, all of which occur in mitochondria. NAD+ acts as a ligand, binding to enzymes and transferring electrons between molecules. This electron transfer is fundamental for cellular energy, similar to recharging a battery. Without NAD+ as the “carrier,” electrons cannot return to their starting point, disrupting cellular processes.
DNA Repair and NAD+
Accumulated DNA damage is a significant cause of aging. Cells have mechanisms to repair DNA, but these processes require energy molecules and NAD+ as fuel.
- PARP (Poly-ADP-ribose polymerase) is a key protein in DNA repair that relies on NAD+ for its activity.
- Aging individuals tend to have lower NAD+ levels. As DNA damage accumulates, PARP activity increases, consuming more NAD+ and further depleting its levels.
- DNA damage in mitochondria exacerbates the demand for NAD+, accelerating its depletion.
Why is NAD+ Important?
Discovered in 1906, NAD+ has garnered attention because of its abundance and critical role in maintaining molecular processes essential for life. It is the second most abundant molecule in the body (after water) and is vital for sustaining life.
Significance of Increasing NAD+ Levels
As we age, or in conditions such as:
- Obesity
- Heart disease
- Neurodegenerative disorders
- Muscle loss due to aging
NAD+ levels decline. Restoring NAD+ through precursors like NMN may mitigate age-related decline and prevent or treat chronic diseases. Scientific evidence increasingly supports the potential of NAD+ in promoting longevity and slowing aging in animals and humans.
NAD+ Activates Sirtuins
NAD+ activates enzymes known as sirtuins, often called the “cell protectors.” These enzymes play critical roles in DNA repair and maintaining mitochondrial health.
- Mitochondria, the cell’s powerhouses, generate ATP for energy. Poor mitochondrial health leads to reduced ATP production and cell death.
- Sirtuins extend cell lifespan by repairing DNA and preserving mitochondrial function.
David Sinclair, a geneticist at Harvard University and an NAD+ researcher, explains that NAD+ levels decline with age. Reduced sirtuin activity may contribute to age-related diseases. Boosting NAD+ levels with precursors like NMN may help delay aging.
NAD+ and Polyphenols
In addition to NMN, polyphenols, plant-derived molecules, promote longevity. By mimicking calorie restriction (reducing caloric intake without malnutrition), polyphenols increase NAD+ levels and activate sirtuins.
Sirtuin benefits include:
- Preventing diabetes
- Reducing liver fat accumulation by increasing insulin secretion from the pancreas
- Enhancing fat metabolism in the liver
- Increasing glucose production in the liver
- Preventing muscle breakdown, neurodegeneration, and fat tissue accumulation
NAD+ Supplements in the Form of NMN
Cellular NAD+ levels decline with age because normal cellular functions consume it. Supplementing with NAD+ precursors, such as NMN or nicotinamide riboside (NR), can restore optimal NAD+ levels.
Research indicates:
- Direct supplementation with NAD+ is not effective because the molecule cannot cross the cell membrane. Instead, precursors like NMN or NR, which are easily absorbed, are used.
- NMN injections significantly increase NAD+ levels in tissues, including the pancreas, adipose tissue, heart, skeletal muscle, kidneys, testes, eyes, and blood vessels. Oral NMN supplementation increases NAD+ in the liver within 15 minutes.
Laboratory Testing
NAD+ levels can be measured through blood tests.
References
- Clement J, Wong M, Poljak A, Sachdev P, Braidy N. The plasma NAD+ metabolome is dysregulated in “normal” aging. Rejuvenation Res. 2019;22:121–130.
- Lamb DA, Moore JH, Mesquita PHC, et al. Resistance training increases muscle NAD+ and NADH concentrations as well as NAMPT protein levels and global sirtuin activity in middle-aged, overweight, untrained individuals. Aging (Albany NY). 2020;12:9447–9460.
- Verdin E. NAD+ in aging, metabolism, and neurodegeneration. Science. 2015;350:1208–1213
- Elhassan YS, Kluckova K, Fletcher RS, et al. Nicotinamide riboside augments the aged human skeletal muscle NAD+ metabolome and induces transcriptomic and anti-inflammatory signatures. Cell Rep. 2019;28:1717–1728.e6.
