Senescence-associated Migrasomes (SAM) Promote Brain Ageing through Apoptosis Inhibitor of Macrophage (AIM)

Ageing constitutes the main risk factor for multiple neurological disorders including Alzheimer's disease (AD). During ageing, pioneer cells of cellular senescence produce pro-ageing products, thus disseminate the ageing signals and reinforce the senescent process. Here we identify border associated macrophage (BAM) as an forerunner of brain ageing due to continuous exposure to stimulants such as amyloid protein beta. In senile BAMs, migrasomes productivity is increased, which convey the pro-ageing signals to bystander cells. Mechanistically, apoptosis inhibitor of macrophage (AIM), is packed in migrasomes. By activating CD16 in recipients, AIM triggers proliferation and shields recipient cells from apoptosis, thus induces replicative senescence. Treatment of Tspan4-siRNA-encapsulated liposomes to aged mice, which suppress migrasome production by senescent BAM, retards brain ageing and ameliorates cognitive deficit. Our data suggest that migrasome represents a potent carrier of pro-ageing signal, which is a prospective target for senomorphic therapy.