NAD metabolism mediates a sex-specific protection against early life infections

Sex influences early-life immunity and infection outcomes, yet how metabolic mechanisms regulate these effects remain unclear. As nicotinamide adenine dinucleotide (NAD) can support mitochondrial metabolism and immune function, here we explore how NAD metabolism contributes to sex-specific protection against infections in early life. First, in two independent cohorts of 700 and 386 children, we found that females at birth had higher blood NAD levels than males, and strikingly higher birth NAD levels were associated with reduced infection burdens during the first 3 years of life in females, but with tendency of increased burdens in males. At 18 months, plasma nicotinamide associated with sex-specific cytokine responses to antigen challenges and showed a stronger positive association with tricarboxylic acid cycle (TCA) activity in females. Next, we verified the causal effects of NAD metabolism on infection protection by testing the supplementation of NAD precursor nicotinamide riboside (NR) in infected newborn piglets, used as a translational model of infection-sensitive infants. NR treatment improved survival, bacterial clearance, and disease tolerance only in females, but not in males. Mechanistically, NR increased levels of hepatic TCA cycle metabolites fumarate and malate, and enhanced hepatic inflammatory, hormonal, and mitochondrial-associated transcriptional programs, again only in females. Finally, the sex-specific immune functions mediated by NR were also validated in blood and immune cells in vitro. Collectively, we identified NAD metabolism as a sex-dependent immunometabolic mediator in early-life infection. Our findings suggest the potential of sex-stratified nutritional interventions in infection-sensitive infants.