NAD+

Nicotinamide adenine dinucleotide (NAD+) is a coenzyme found in every living cell and is essential to hundreds of metabolic reactions. While technically a coenzyme rather than a peptide in the traditional sense, NAD+ is widely categorized alongside peptide therapies in regenerative and longevity medicine due to its injectable administration protocols and overlapping clinical applications. NAD+ exists in two interconvertible forms: the oxidized form (NAD+) and the reduced form (NADH). Its primary biological role is as an electron carrier in cellular respiration, shuttling electrons from metabolic substrates to the mitochondrial electron transport chain to generate ATP.

Beyond energy metabolism, NAD+ functions as a critical signaling molecule and substrate for several enzyme classes. Sirtuins (SIRT1-7), a family of NAD+-dependent deacetylases, use NAD+ to regulate gene expression, DNA repair, mitochondrial biogenesis, and metabolic homeostasis. Poly(ADP-ribose) polymerases (PARPs), which repair DNA strand breaks, are also major consumers of cellular NAD+. CD38, an enzyme involved in immune cell signaling and calcium homeostasis, is another significant NAD+ consumer that becomes increasingly active with age and chronic inflammation, further depleting available NAD+.

A central finding driving clinical interest in NAD+ supplementation is the well-documented decline of cellular NAD+ levels with age. Research has demonstrated that NAD+ levels in human muscle tissue decline by approximately 50 percent between the ages of 40 and 60. This decline correlates with reduced mitochondrial function, impaired DNA repair capacity, increased oxidative stress, and the accumulation of senescent cells. Animal studies in which NAD+ was restored pharmacologically showed reversal of multiple aging biomarkers, extension of lifespan in some models, and improvements in physical function, cognition, and metabolic health. Sirtuins, which require NAD+ to function, control energy homeostasis, enhance metabolic efficiency, upregulate mitochondrial oxidative metabolism, and play a crucial role in regulating gene expression and the circadian clock.

Clinical research in humans is more limited but encouraging. A randomized controlled trial demonstrated that oral NAD+ precursor supplementation (nicotinamide riboside, or NR) produced dose-dependent increases in blood NAD+ levels at doses from 250 to 1,000 mg daily, plateauing at roughly a twofold increase at day 9. Injectable NAD+ produces more immediate and pronounced increases in tissue NAD+ levels compared to oral precursors, which must be converted through multiple enzymatic steps. Patients in clinical settings frequently report rapid improvements in energy, mental clarity, and sleep quality within 24-48 hours of intravenous or subcutaneous NAD+ administration, consistent with acute mitochondrial activation and nervous system recalibration.