NLRP3 haploinsufficiency unmasks a compensatory NLRP1-NLRP3 interaction that drives accelerated aging in mice

The NLRP3 inflammasome has been implicated in a wide range of human diseases, including cardiovascular, metabolic, neurodegenerative (such as Alzheimer's disease), and other age-related conditions. This has positioned NLRP3 as a promising pharmacological target. Numerous studies have shown that complete NLRP3 ablation can prevent or mitigate these diseases. However, total elimination of NLRP3 is not a feasible therapeutic strategy for the millions of patients affected by these degenerative disorders. Consequently, drug development efforts have focused on partial inhibition of NLRP3 using compounds that reduce its expression or activity. Paradoxically, although many studies have used Nlrp3 knockout mouse models, Nlrp3 haploinsufficient mice-more representative of the effects of pharmacological inhibition-are rarely included and remain poorly characterized. Here, we report the long-term effects of Nlrp3 haploinsufficiency during aging. Although no overt differences were observed in early life, by 16 months of age, Nlrp3 heterozygous mice exhibited signs of accelerated inflammatory aging, driven by compensatory overexpression of NLRP1. Mechanistic studies provide evidence of a previously unidentified interaction between NLRP1 and NLRP3, forming a hybrid inflammasome that drives NLRP1-mediated inflammatory overactivation when NLRP3 expression is reduced. Accordingly, anti-inflammatory treatment provided notable but moderate improvement of the inflammatory phenotype, whereas genetic inhibition of Nlrp1 more consistently reduced inflammation and extended health span. Our findings reveal a previously unidentified compensatory interaction between NLRP1 and NLRP3 and suggest that multiinflammasome inhibition may offer a more effective strategy for treating aging and age-related diseases.