Inhibition of asparagine endopeptidase extends the lifespan and improves health span during aging

Asparagine endopeptidase (AEP), also known as legumain, is a lysosomal cysteine protease whose activity increases with age and contributes to age-related tissue dysfunction. We tested whether chronic AEP inhibition could slow aging phenotypes in naturally aged mice. Here, we show that chronic treatment with the AEP inhibitor #11a extended lifespan and improved health span in aged C57BL/6 mice, together with reduced frailty and improved physical and cognitive performance. #11a treatment also attenuated several senescence- and inflammation-associated readouts in multiple organs. Mechanistically, #11a treatment suppressed AEP-dependent cleavage of nicotinamide phosphoribosyltransferase (NAMPT), accompanied by an increased NAD + /NADH ratio and higher SIRT1 levels. These findings support further investigation of pharmacological AEP inhibition as a strategy to promote healthy aging.