Intermittent clearance of p21-highly-expressing cells extends lifespan and confers sustained benefits to health and physical function.

A key challenge in aging research is extending lifespan in tandem with slowing down functional decline so that life with good health (healthspan) can be extended. Here, we show that monthly clearance, starting from 20 months, of a small number of cells that highly express p21(Cip1) (p21(high)) improves cardiac and metabolic function and extends both median and maximum lifespans in mice. Importantly, by assessing the health and physical function of these mice monthly until death, we show that clearance of p21(high) cells improves physical function at all remaining stages of life, suggesting healthspan extension. Mechanistically, p21(high) cells encompass several cell types with a relatively conserved proinflammatory signature. Clearance of p21(high) cells reduces inflammation and alleviates age-related transcriptomic signatures of various tissues. These findings demonstrate the feasibility of healthspan extension in mice and indicate p21(high) cells as a therapeutic target for healthy aging.