Characterizing the SASP ‐Dependent Paracrine Spreading of Senescence Between Human Brain Cell Types

ABSTRACT

One of the defining phenotypes of a senescent cell is the senescence‐associated secretory phenotype (SASP), which can propagate senescence in neighboring cells both in vitro and in vivo. Importantly, this paracrine spreading of senescence can act in a cell non‐autonomous manner, influencing neighboring cell populations and contributing to immune cell recruitment. As cellular senescence has recently been linked to both age‐related neurodegenerative phenotypes and local inflammation and is more clearly defined across brain cell types in a cell‐type‐dependent manner, an urgent question remains regarding how a cell‐type‐specific paracrine spreading of senescence occurs in the brain. Here, we set out to profile the cell‐type‐specific features of the SASP and characterize the directionality of paracrine senescence‐spreading between major brain cell types. Through this analysis, we identified key SASP ligand‐receptor pairs involved in this paracrine dissemination. Targeting selected factors with specific inhibitors, we ameliorated some aspects of the paracrine spreading of senescence in a brain cell‐type‐dependent manner. Taken together, we identified specific SASP targets for therapeutic intervention in the context of human brain cells and thereby informed the SASP‐dependent reaction of immune cells and age‐related tissue dysfunction across both normal aging and models of neurodegenerative disease.