Recovering matrikine-induced immune dysfunction extends health- and lifespan (PRJCA025375)

This study investigates the effects of age-related pathological remodeling of the extracellular matrix and its matrix-derived fragments, known as matrikines. We specifically found that elastin-derived fragments (ELN fragments) are strongly correlated with aging and a reduction in lifespan. Mechanistically, the VGVAPG oligopeptide within ELN fragments activates macrophages and monocytes via the transmembrane protein NEU1, leading to prolonged lymphocyte dysfunction and chronic inflammation. Therapeutically, a NEU1 inhibitor was shown to extend the health and lifespan of naturally-aged wild-type mice. Additionally, we confirmed in a human cohort of 1068 samples that serum ELN fragments correlate with aging indicators, and demonstrated in pig and immune-humanized mouse models that the NEU1 inhibitor can reverse the aging indicators induced by ELN fragments. This research provides new insights into matrikine-induced aging, unveils the underlying immunological mechanisms, and proposes a novel direction for aging intervention by targeting matrikine signaling.