The accumulation of irreparable cellular damage restricts healthspan after acute stress
or natural aging. Senescent cells are thought to impair tissue function, and their
genetic clearance can delay features of aging. Identifying how senescent cells avoid
apoptosis allows for the prospective design of anti-senescence compounds to address
whether homeostasis can also be restored. Here, we identify FOXO4 as a pivot in senescent
cell viability. We designed a FOXO4 peptide that perturbs the FOXO4 interaction with
p53. In senescent cells, this selectively causes p53 nuclear exclusion and cell-intrinsic
apoptosis. Under conditions where it was well tolerated in vivo, this FOXO4 peptide
neutralized doxorubicin-induced chemotoxicity. Moreover, it restored fitness, fur
density, and renal function in both fast aging XpdTTD/TTD and naturally aged mice.
Thus, therapeutic targeting of senescent cells is feasible under conditions where
loss of health has already occurred, and in doing so tissue homeostasis can effectively
be restored.