Inside the body with NAD+

In a human pilot of intravenous NAD+ (Grant et al., 2019), plasma NAD+ was rapidly and completely removed for at least the first 2 hours (attributed by the authors to tissue uptake and/or metabolism); by the end of the 6-hour infusion plasma NAD+, nicotinamide, ADP-ribose and methylnicotinamide had risen about 4-fold, with NMN raised 2 hours later; the pattern fit NAD+ glycohydrolase and pyrophosphatase activity. The pilot had 8 infused participants and 3 saline controls. Mechanistic cell work shows extracellular NMN must be converted to nicotinamide riboside before cellular uptake via NRK1 (Ratajczak et al., 2016). Some intact NAD uptake has been reported in two cultured cell types at low concentrations (Billington et al., 2008), so uptake of intact NAD+ in vivo is unresolved. Human data: pilot only; cell data: in vitro.[src][src][src]

NAD+ is synthesised de novo from tryptophan, from nicotinic acid via the Preiss-Handler pathway, and by salvage from nicotinamide, NR and NMN. Isotope-tracer work in mice showed NAD is made from tryptophan selectively in the liver, which then excretes nicotinamide; tissues differ widely in NAD flux (high in small intestine and spleen, low in skeletal muscle); intravenous NR or NMN delivered intact molecules to tissues, whereas the same agents given orally were metabolised to nicotinamide in the liver (Liu et al., 2018). These are animal and cell tracer data; they describe precursor handling, not NAD+ infusions in humans.[src][src]

NAD+/NADH is the principal electron-carrier pair in glycolysis, the TCA cycle and fatty-acid oxidation, feeding complex I of the respiratory chain. The NAD+/NADH ratio links energy status to adaptive signalling, including mitochondrial stress responses (Cantó et al., 2015; Verdin, 2015). This is established biochemistry in humans and other species; it does not by itself show that adding NAD+ from outside raises this activity.[src][src]

NAD+ is a co-substrate for sirtuin deacylases (SIRT1-7), PARPs (DNA-damage response and chromatin remodelling) and the NADases CD38 and CD157, which regulate metabolism, DNA repair, cellular senescence and immune function (Covarrubias et al., 2021; Verdin, 2015). Consumption by PARPs and sirtuins accounted for most NAD turnover in cell lines (Liu et al., 2018). Evidence is mostly from cells and rodents; human causal links between NAD+ levels and disease are not established.[src][src][src]

In mice, CD38 expression and NADase activity rise with age and are required for the age-related NAD decline and mitochondrial dysfunction; CD38 is also the main enzyme degrading NMN in vivo (Camacho-Pereira et al., 2016). Reviews describe tissue NAD+ decline with ageing in rodents and humans (Covarrubias et al., 2021), but a 2026 analysis of seven independent human cohorts found whole-blood NAD+ stable with age and across lifestyle interventions, while changing, as expected, with NR supplementation (Trętowicz et al., 2026). Tissue-level human ageing data remain limited.[src][src][src]

In a single-centre, randomised, placebo-controlled trial of 180 adults with ischaemic cardiomyopathy (LVEF <=45%, NYHA II-III), 7 days of intravenous NAD+ added to guideline-directed therapy gave a higher LVEF at 1 month than placebo (45.44 +/- 8.55% vs 42.44 +/- 9.09%, p=0.024). NT-proBNP at day 7 (p=0.102), 6-month MACCE (14.6% vs 24.7%, p=0.089) and NYHA improvement (p=0.088 at 1 month) did not reach significance, and structural echo parameters did not differ. The authors cite sirtuin-mediated mitochondrial effects as the rationale and note limited power for clinical events (ChiCTR2200059169). The study drug and a research grant came from the manufacturer; the paper states the funders had no role in the study or analysis. This is human evidence, but small, from one centre, and awaiting replication.[src][src]

NADPARK, a randomised phase I trial (30 newly diagnosed, treatment-naive people with Parkinson's disease, 30 days of oral NR vs placebo), reported a significant but variable rise in cerebral NAD measured by 31P-MRS, and altered cerebral metabolism with mild clinical improvement in those with increased brain NAD (Brakedal et al., 2022). Oral NR also raises blood NAD+ metabolites in humans (Trammell et al., 2016; Martens et al., 2018). These findings concern an oral precursor and are not evidence that intravenous NAD+ reaches the brain.[src][src][src]