NAD+ is the central redox + signaling cofactor whose tissue levels decline with aging. Synthesis routes: (1) de novo from tryptophan via kynurenine → quinolinate → NaMN → NAAD → NAD+; (2) Preiss-Handler pathway from nicotinic acid (vitamin B3) → NaMN → NAAD → NAD+; (3) salvage from nicotinamide via NAMPT → NMN → NAD+ (rate-limiting NAMPT is the major target of pharmacologic NAD+ raising); (4) supplemental nicotinamide riboside (NR) → NMN → NAD+. Sirtuins (SIRT1-7) are NAD+-dependent class III HDACs that deacetylate transcription factors + metabolic enzymes; require NAD+ as obligate cofactor (releases nicotinamide + 2'-O-acetyl-ADP-ribose). Sirtuin activators (resveratrol, pterostilbene) allosterically enhance SIRT1; mechanism debated as direct vs indirect via PGC-1α / AMPK. PARP1 is a major NAD+ consumer (DNA damage); CD38 + SARM1 are others. Cross-link: niacin_nad_synthesis (synthesis pathway in detail) + nrf2_keap1_antioxidant_response (sirtuin-mediated antioxidant gene expression).
Organ Systems
endocrine
musculoskeletal
Pathway Steps
nicotinamide → nmn — via NAMPT — rate-limiting step in NAD+ salvage. NAMPT is the rate-limiting enzyme of the NAD⁺ salvage pathway (recycling the nicotinamide released by NAD-consuming enzymes). Because sirtuins, PARPs, and CD38 all consume NAD⁺, salvage flux — and its age-related decline — sets cellular NAD⁺ availability.
nmn → nad-plus — via NMNAT (1/2/3) adenylylation. NMNAT adenylylates NMN to NAD⁺ (the step NMN/NR supplements ultimately feed). Its isoforms compartmentalize NAD⁺ synthesis (nuclear, cytosolic, mitochondrial); NMNAT2 loss drives axon degeneration via the SARM1 axon-death pathway.
nad-plus → nicotinamide — via sirtuin (SIRT1-7) deacetylation reaction releases NAM + O-acetyl-ADP-ribose. Sirtuins (SIRT1-7) consume NAD⁺ to deacetylate targets, releasing nicotinamide (which feedback-inhibits them) — so they act as energy/redox sensors, coupling the NAD⁺/NADH state to deacetylation of histones, PGC-1α, FoxO, and p53.
nad-plus → sirtuin-activation — via NAD+-dependent class III HDAC activity — substrate availability gates sirtuin function. Sirtuin activity tracks NAD⁺ availability — the premise behind NAD⁺-boosting (NR/NMN/niacin) and direct sirtuin activators (resveratrol, the debated STAC class) aimed at the metabolic/longevity benefits of caloric restriction.
nad plus (substrate) — NAD+ pool (direct, poor oral PK). oral NAD+ has minimal bioavailability — IV NAD+ infusions widely marketed despite limited efficacy data
namn (substrate) — NAD+ de novo + Preiss-Handler intermediate. nicotinic acid mononucleotide; rare direct supplement; lab/research reagent
naad (substrate) — NAD+ biosynthesis (NaMN → NAAD → NAD+). NaAD; de novo + Preiss-Handler intermediate just before NAD synthase step
pterostilbene (activator) — SIRT1 + Nrf2 (dimethyl-resveratrol). resveratrol analog with better PK; cross-link: nrf2_keap1_antioxidant_response
rapamycin (inhibitor) — mTORC1 (downstream of NAD+/sirtuin axis). rapamycin/sirolimus; the canonical "geroprotector"; cross-link: mtor_signaling for direct mTOR mechanism
l tryptophan (substrate) — de novo NAD+ synthesis precursor (kynurenine pathway). tryptophan → kynurenine → quinolinate → NaMN; minor NAD+ route in humans