The FOXO4 inhibitory peptide FOXO4-DRI promotes targeted apoptosis of senescent cells.

  • Major finding: The FOXO4 inhibitory peptide FOXO4-DRI promotes targeted apoptosis of senescent cells.

  • Mechanism: FOXO4-DRI disrupts the FOXO4–p53 interaction to promote nuclear exclusion of p53 in senescent cells.

  • Impact: Therapeutic targeting of senescent cells may reverse the effects of chemotoxicity and aging.

Senescent cells develop a senescence-associated secretory phenotype (SASP), a persistent proinflammatory phenotype that may contribute to accelerated aging and chemotoxicity. However, it is not known how cells avoid apoptosis to undergo senescence or whether targeting senescent cells could counteract the effects of accelerated aging and chemotoxicity. Baar and colleagues found that despite their resistance to apoptosis, senescent fibroblasts exhibited an upregulation of the proapoptotic proteins PUMA and BIM, and a downregulation of the antiapoptotic protein BCL2. FOXO4 was upregulated in senescent cells and FOXO4 depletion prior to the induction of senescence induced apoptosis, whereas FOXO4 depletion in senescent cells reduced cell viability, indicating that FOXO4 may repress apoptosis to maintain the viability of senescent cells. FOXO4 localized to senescence-associated promyelocytic leukemia bodies that fused to 53BP1-containing DNA segments with chromatin alterations reinforcing senescence (DNA-SCARS) to regulate SASP. p53 associates with the DNA-SCARS in senescent cells and interacts with FOXO4, and, as p53 regulates apoptosis and senescence, these findings suggested the potential for therapeutic targeting of the FOXO4–p53 interaction. A FOXO4 inhibitory peptide, FOXO4-DRI, was designed that disrupted the FOXO4–p53 interaction, which resulted in nuclear exclusion of active p53 and the induction of p53-dependent apoptosis in senescent cells. In vivo, FOXO4-DRI reversed doxorubicin-induced chemotoxicity, including increasing body weight and reducing levels of the liver damage indicator aspartate aminotransferase. Further, FOXO4-DRI counteracted the negative effects of senescence in mouse models of natural and accelerated aging. In addition to generating an inhibitory FOXO4 peptide that disrupts the interaction with p53 to induce apoptosis of senescent cells, these findings indicate that senescent cells may be therapeutically targeted to reverse the effects of chemotoxicity and aging.

Baar MP, Brandt RM, Putavet DA, Klein JD, Derks KW, Bourgeois BR, et al. Targeted apoptosis of senescent cells restores tissue homeostasis in response to chemotoxicity and aging. Cell 2017;169:132–47.e16.