Single-cell profiling of skeletal muscle reveals a novel senolytic target; CRYAB

Skeletal muscle mass and function decline with aging, a process known as sarcopenia, and is linked to functional alterations of critical cell types within mature muscle, including fibro-adipogenic progenitors (FAPs) and satellite cells (SCs). Senescence is a form of cellular arrest linked with degenerative diseases of aging, and is thought to be a key driver of aging pathophysiology. We utilized single-cell RNA sequencing to identify novel targets in isolated FAPs and SCs which potentiate senescent cell killing - a process termed senolysis. Using molecular and cellular approaches, we identified the small alpha crystalline heat shock protein CRYAB as a novel senolytic target. We targeted CRYAB using chemical inhibitor screening to identify 25-hydroxycholesterol (25HC), an endogenous metabolite of cholesterol biosynthesis as a potent senolytic capable of killing senescent cells. We validated the potential of 25HC as a senolytic in both mouse and human cells, and in vivo in several tissues including muscle and fat. 25HC treatment therefore represents a potential new class of senolytics, which may be useful in combating diseases or physiologies in which cellular senescence is a key driver. We utilized single-cell RNA sequencing to identify novel targets in isolated FAPs and SCs which potentiate senescent cell killing - a process termed senolysis