Emerging data that innate immune sensor NLRP3 inflammasome links aging to functional decline support Metchnikoff’s original prediction that phagocytes or macrophages drive aging-associated degenerative diseases in an organism. Here we detail a mechanism by which the macrophage-expressed NLRP3 inflammasome controls age-related inflammation in periphery as well as brain. Ablation of NLRP3 inflammasome protected mice from age-related increases in the innate immune activation, alterations in CNS transcriptome, and astrogliosis.
Furthermore, downregulation of NLRP3 in aged mice protected against age-related loss of memory and cognition. The ketone metabolite β hydroxybutyrate (BHB) that is elevated by caloric restriction, high-intensity exercise, or the low-carbohydrate ketogenic diet serves as an endogenous negative regulator of NLRP3-driven inflammation. These studies suggest that NLRP3 inflammasome is a major driver of age-related inflammation and therefore dietary or pharmacological approaches to lower NLRP3 holds promise in reducing multiple chronic diseases of age.