Blocking PD-L2 prevents senescent cell accumulation and age-related dysfunction.

Senescent cells, which are normally cleared by the immune system but accumulate with age, contribute to multiple disorders including metabolic dysfunction and impaired fitness. While immune checkpoint inhibitors have been well studied in cancer, the role of programmed cell death ligand 2 (PD-L2) in non-cancerous, age-associated cellular senescence remains unclear. We found that PD-L2 is upregulated in isolated senescent human cells and during aging, and senolytics can remove age-associated, highly PD-L2-expressing senescent cells. Old PD-L2 knockout mice accumulate fewer senescent cells than old wild-type mice, and their insulin sensitivity and grip strength are greater. Anti-PD-L2 therapy restored insulin sensitivity in aged wild-type mice. PD-L2 acts as an immune checkpoint on senescent cells, allowing them to evade immune clearance and promoting their persistence during aging. Targeting PD-L2 in senescent cells may be a strategy for alleviating the age-related dysfunction associated with cellular senescence.