Category: biosynthesis
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).