The role of NLRP3 neuroinflammation in cognitive frailty diversity during aging and after LPS administration in mice.

Aging leads to declines in physical and cognitive functions, with NLRP3-associated neuroinflammation playing a key role. While physical frailty quantifies age-related physiological decline, the concept of cognitive frailty, integrating physical frailty and cognitive impairment, remains underexplored. The relationship between NLRP3-driven neuroinflammation and functional deterioration is not fully understood. Lipopolysaccharide (LPS)-induced systemic inflammation mimics features of cognitive and physical impairment, highlighting its potential as an experimental model for cognitive frailty. This study aims to characterize physical and cognitive frailty phenotypes in aging and inflammation and explore the association between frailty and NLRP3 inflammasome signaling in the mouse brain. Adult, aged, and LPS-treated adult male mice were subjected to a battery of behavioral tests over five consecutive days. Physical frailty was evaluated using the Clinical Frailty Index (CFI), the Eight-item Frailty Index (FI), and the Frailty Phenotype (FP). Mild cognitive impairment was assessed separately, and a novel Cognitive Frailty Index (CogFI), integrating both physical and cognitive parameters, was proposed. Senescent cells were quantified by counting β-galactosidase+ cells. Levels of NLRP3-associated markers were measured in the hippocampus and amygdala. Behavioral assessments revealed that aging leads to heterogeneous declines in physical and cognitive performance, whereas LPS induced a more uniform and severe phenotype 5 days postinjection (dpi). The proposed CogFI effectively captured the variability in age-related behavioral decline. LPS administration did not increase the number of β-galactosidase+ cells, unlike natural aging. Furthermore, only aging induced sustained NLRP3 expression in the hippocampus. Correlational analyses demonstrated strong associations between hippocampal Caspase-1 levels and all frailty indices, including CogFI (r > 0.83), and between NLRP3 levels and both CFI and CogFI (r > 0.56). Notably, the cognitive component alone did not correlate significantly with any NLRP3 pathway markers in either the hippocampus or the amygdala. This study introduces a novel, quantitative measure of cognitive frailty in mice and establishes NLRP3 inflammasome activation as a relevant molecular correlate of frailty. While LPS-induced inflammation models certain severe aspects of cognitive frailty at 5 dpi, it does not recapitulate the full molecular complexity of natural aging. These findings underscore the importance of distinguishing between induced and intrinsic aging processes in the study of frailty. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1038/s41598-026-41104-2.