Adult-onset nicotinamide supplementation prevents the emergence of early-life stress driven inflammatory signatures, blood-brain barrier compromise, hippocampal mitochondrial dysfunction and cognitive aging

Abstract Growing evidence suggests that early-life stress history can shape biological aging, yet the pathways through which this lifelong vulnerability manifests remain unclear. Using a maternal separation (MS) rodent model of early-life stress, we show that MS history evokes persistent cognitive, inflammatory, neurovasculature and bioenergetic changes that can accelerate aging trajectories. MS animals exhibit premature decline in object recognition memory in middle-aged life, accompanied by elevated peripheral inflammation, blood-brain barrier (BBB) compromise, heightened neuroinflammasome and microglial reactivity, and deteriorated mitochondrial health in the hippocampus. Notably, we demonstrate that adult-onset systemic supplementation with Nicotinamide (NAM), a NAD + precursor, prevents the emergence of peripheral and central inflammatory signatures, protects BBB integrity, maintains hippocampal mitochondrial health and mitigates cognitive decline in middle-aged MS animals. Collectively, these findings provide mechanistic insights into how early-life stress shapes brain aging, while highlighting NAM supplementation as a gerotherapeutic strategy to prevent premature aging driven by early adversity.