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Cell. 2017 Mar 23;169(1):132-147.e16. doi: 10.1016/j.cell.2017.02.031.

Targeted Apoptosis of Senescent Cells Restores Tissue Homeostasis in Response to Chemotoxicity and Aging.

Author information

1
Department of Molecular Genetics, Erasmus University Medical Center Rotterdam, Wytemaweg 80, 3015CN, Rotterdam, the Netherlands.
2
Institute of Molecular Biology & Biochemistry, Center of Molecular Medicine, Medical University of Graz, 8010 Graz, Austria.
3
Department of Molecular Genetics, Erasmus University Medical Center Rotterdam, Wytemaweg 80, 3015CN, Rotterdam, the Netherlands; Department of Vascular Surgery, Erasmus University Medical Center Rotterdam, Wytemaweg 80, 3015CN, Rotterdam, the Netherlands.
4
Department of Molecular Genetics, Erasmus University Medical Center Rotterdam, Wytemaweg 80, 3015CN, Rotterdam, the Netherlands; Department of Vascular Surgery, Erasmus University Medical Center Rotterdam, Wytemaweg 80, 3015CN, Rotterdam, the Netherlands; Department of Radiation Oncology, Erasmus University Medical Center Rotterdam, Wytemaweg 80, 3015CN, Rotterdam, the Netherlands.
5
Erasmus Optical Imaging Center and Department of Pathology, Erasmus University Medical Center Rotterdam, Wytemaweg 80, 3015CN, Rotterdam, the Netherlands.
6
Department of Cell Biology, Erasmus University Medical Center Rotterdam, Wytemaweg 80, 3015CN, Rotterdam, the Netherlands.
7
Department of Surgery, Erasmus University Medical Center Rotterdam, Wytemaweg 80, 3015CN, Rotterdam, the Netherlands.
8
The Buck Institute for Research on Aging, 8001 Redwood Blvd., Novato, CA 94945, USA; Lawrence Berkeley National Laboratories, Berkeley, CA 94720, USA.
9
Department of Molecular Genetics, Erasmus University Medical Center Rotterdam, Wytemaweg 80, 3015CN, Rotterdam, the Netherlands; The Buck Institute for Research on Aging, 8001 Redwood Blvd., Novato, CA 94945, USA. Electronic address: p.dekeizer@erasmusmc.nl.

Abstract

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.

KEYWORDS:

FOXO4; IL6; LMNB1; Senescence; TP53; aging; apoptosis; cell-penetrating peptide; chemotherapy; tissue homeostasis

PMID:
28340339
PMCID:
PMC5556182
DOI:
10.1016/j.cell.2017.02.031
[Indexed for MEDLINE]
Free PMC Article

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