Dual roles of basal NLRP3 expression in cognitive and neurogenic aging

Aging is accompanied by increasing inter-individual variability in cognitive and functional outcomes, reflecting differences in biological resilience and vulnerability. Chronic low-grade inflammation (inflammaging) is a central driver of this process, yet the contribution of individual inflammatory pathways to adaptive versus maladaptive brain aging remains incompletely understood. The NLRP3 inflammasome has been widely implicated in age-related neurodegeneration, but its physiological roles during adulthood and early aging are poorly defined. To delineate age-dependent functions of NLRP3 signaling, we combined behavioral, electrophysiological, and cellular analyses in adult (4-5 months) and middle-aged (12-14 months) wild-type and Nlrp3 knockout mice. Physical and cognitive decline were assessed using open field and fear conditioning paradigms. Hippocampal synaptic plasticity was evaluated by ex vivo recordings of long-term potentiation (LTP). Neural stem cells (NSCs) isolated from the hippocampus were used to quantify proliferation, neurogenic lineage markers, and glucose-related metabolic signaling. Acute pharmacological modulation of NLRP3 was examined using glibenclamide. Nlrp3 deletion markedly attenuated age-associated behavioral decline, resulting in preserved locomotor activity, learning, and memory and a substantially reduced prevalence of cognitive pre-frailty in middle-aged mice. In contrast, adult Nlrp3 knockout mice exhibited reduced hippocampal LTP, indicating that basal NLRP3 activity contributes to optimal synaptic function under physiological conditions. Aging was associated with a pronounced decline in LTP in wild-type mice, which was absent in Nlrp3-deficient mice and partially alleviated by glibenclamide. At the cellular level, Nlrp3 deficiency led to a persistent reduction in Nestin⁺ neural precursors and an exacerbation of age-related depletion of DCX⁺ neuroblasts, whereas proliferative capacity declined with aging independently of genotype. Metabolically, Nlrp3 knockout NSCs displayed constitutively reduced GLUT4 expression and complete prevention of the age-associated increase in GSK3β, a key regulator linking insulin signaling to neurodegenerative processes. Acute pharmacological inhibition selectively mitigated aging-related metabolic changes without restoring neurogenic deficits. These findings identify the NLRP3 inflammasome as a bidirectional regulator of brain aging. Basal NLRP3 activity supports the establishment of neurogenic, metabolic, and synaptic reserve in adulthood, whereas chronic activation during aging promotes metabolic dysregulation, synaptic vulnerability, and cognitive pre-frailty. The divergence between genetic ablation and acute pharmacological inhibition underscores the temporal specificity of NLRP3 signaling. Targeting inflammaging through selective, stage-specific modulation of NLRP3 may therefore represent a promising strategy to enhance cognitive resilience during aging.