What NAD+ does
NAD+ (nicotinamide adenine dinucleotide) is a coenzyme essential for hundreds of cellular reactions:
- Mitochondrial energy production (electron transport)
- DNA repair (PARP enzymes)
- Cellular signaling (sirtuins)
- Metabolism (countless enzymatic steps)
Adequate NAD+ is essential for cellular function; declining NAD+ produces aging-related dysfunction.
The salvage pathway
The body doesn't constantly synthesize NAD+ from scratch (de novo from tryptophan). Most NAD+ is recycled through the salvage pathway:
- NAD+ used in reactions, producing nicotinamide (NAM) as byproduct
- NAMPT enzyme: NAM → NMN
- NMNAT enzyme: NMN → NAD+
- NAD+ available again for reactions
This recycling is the dominant source of NAD+ in adult cells.
Key enzymes
- NAMPT, rate-limiting enzyme; converts NAM to NMN
- NMNAT (1, 2, 3), converts NMN to NAD+; isoforms in different cellular compartments
NAMPT activity declines with age. This is one mechanism of NAD+ decline.
Aging effects
NAD+ levels drop ~50% from age 20 to 60 because:
- NAMPT activity declines
- NAD+ consumption increases (CD38 enzyme rises with age, more inflammation)
- Reduced biosynthesis
- Increased demands from chronic conditions
Precursor supplementation
- NMN (nicotinamide mononucleotide), feeds into the salvage pathway downstream of NAMPT, bypassing the rate-limiting step
- NR (nicotinamide riboside), converts to NMN via separate enzyme, then continues to NAD+
- Both raise NAD+ levels reliably in human studies
Alternative pathways
- De novo synthesis from tryptophan, slow; minimal contribution in adults
- Nicotinic acid (niacin), rapid NAD+ raising but causes flushing
- Direct NAD+ infusion (IV), bypasses pathway entirely; dramatic acute effect
The clinical pearl: The salvage pathway is the practical route for NAD+ optimization. Precursor supplements (NMN, NR) feed the pathway. IV NAD+ bypasses the pathway entirely for acute high levels. Choose based on goals.
Bottom line
The NAD+ salvage pathway recycles NAM back to NAD+ via NAMPT and NMNAT enzymes. Aging reduces NAMPT activity and NAD+ levels. Precursor supplements feed the pathway. Understanding the biology clarifies why and how NAD+ supplementation works.