IMMUNOMETABOLIC REGULATORS OF AGING

Evidence that innate immune sensor NLRP3 inflammasome links aging to functional decline supports Metchnikoff’s original prediction that phagocytes or macrophages drive aging-associated degenerative diseases in an organism. Assembly of the NLRP3 inflammasome in macrophages in response to metabolic ‘danger signals’ controls the secretion of bioactive IL-1β and IL-18. 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-inflammation in multiple organs and improved their healthspan. The ketone metabolite β-hydroxybutyrate (BHB) that is are elevated by caloric restriction, high-intensity exercise, or the low-carbohydrate ketogenic diet serves as an endogenous negative regulator of NLRP3-driven inflammation in aging. 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.