Journal
CELL
Volume 169, Issue 1, Pages 132-+Publisher
CELL PRESS
DOI: 10.1016/j.cell.2017.02.031
Keywords
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Categories
Funding
- NIH [R37-AG009909]
- NIA [PPG AG-17242-02]
- Austrian Science Fund [FWF P28854, DK-MCD W1226]
- Royal Netherlands Academy of Arts and Sciences
- Erasmus University Medical Center: EMC fellowship
- Dutch Kidney Foundation [15OP11]
- Dutch Cancer Society [Buit-4649, EMCR 20147141]
- Austrian Science Fund (FWF) [P28854] Funding Source: Austrian Science Fund (FWF)
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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 Xpd(TTD/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.
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