Senescent cells exhibit a pro-inflammatory phenotype, and are thought to accelerate ageing and the onset of age-related diseases. Baar et al. report a key role for forkhead box protein O4 (FOXO4) in maintaining senescent cell viability. In vitro, a FOXO4-derived peptide designed to inhibit the interaction of this transcription factor with the tumour suppressor p53 reduced senescent cell viability through p53-mediated cell-intrinsic apoptosis. In mice, the FOXO4-derived peptide counteracted doxorubicin-induced chemotoxicity and restored fitness, fur density and renal function in models of ageing.