Abstract
Cognitive impairment affects 1 in 6 individuals over 60, with over 75 million projected by 2030. Age-related changes in microglial function and declining nicotinamide adenine dinucleotide (NAD + ) levels may contribute to cognitive decline. Although nicotinamide riboside (NR) supplementation can restore NAD + levels in aged mice, its effects on microglial phenotype and cognition during normal aging remain unclear. We assessed cognitive function, neuroinflammation, and microglial gene expression in 6-month (Young) and 22-month (Aged) mice, along with aged mice supplemented with NR (Aged + NR; 400 mg/kg body weight) for 8 weeks. Aged mice exhibited impaired cognition and increased gene expression related to neuroinflammation. NR supplementation improved or prevented the decline in nest-building ability, Y-maze spontaneous alternation, and novel object recognition, which are reflective of instrumental activities of daily living, spatial working memory, and recognition memory. NR supplementation diminished microglial (IBA1) and astrocytic (GFAP) activation, resembling the young phenotype. Gene expression profiling revealed reduced microglial activation, inflammatory pathways, and chemokine production in Aged + NR mice, along with upregulation of genes associated with learning, memory, and gliogenesis. NR lowered transcriptional signatures from age-dependent (ADEM) and disease-associated (DAM) microglia and enhanced homeostatic state profiles. Metabolic pathway analysis of microglial transcripts indicated that NR suppressed age-induced increases in fatty acid metabolism. This was supported by immunostaining, which showed reduced lipoprotein lipase (LPL), a DAM marker, in the cortex and hippocampus. Overall, NR appeared to mitigate age-related cognitive decline by shifting microglial gene expression and metabolism toward a younger phenotype, suggesting potential therapeutic relevance for healthy brain aging.