Targeted Apoptosis of Senescent Cells Restores Tissue Homeostasis in Response to Chemotoxicity and Aging.
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/TTDand 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.
Department of Molecular Genetics, Erasmus University Medical Center Rotterdam, Wytemaweg 80, 3015CN, Rotterdam, the Netherlands.
Marjolein P
MP
Baar
Department of Molecular Genetics, Erasmus University Medical Center Rotterdam, Wytemaweg 80, 3015CN, Rotterdam, the Netherlands.
Renata M C
RMC
Brandt
Department of Molecular Genetics, Erasmus University Medical Center Rotterdam, Wytemaweg 80, 3015CN, Rotterdam, the Netherlands.
Diana A
DA
Putavet
Department of Molecular Genetics, Erasmus University Medical Center Rotterdam, Wytemaweg 80, 3015CN, Rotterdam, the Netherlands.
Julian D D
JDD
Klein
Department of Molecular Genetics, Erasmus University Medical Center Rotterdam, Wytemaweg 80, 3015CN, Rotterdam, the Netherlands.
Kasper W J
KWJ
Derks
Institute of Molecular Biology & Biochemistry, Center of Molecular Medicine, Medical University of Graz, 8010 Graz, Austria.
Benjamin R M
BRM
Bourgeois
Institute of Molecular Biology & Biochemistry, Center of Molecular Medicine, Medical University of Graz, 8010 Graz, Austria.
Sarah
S
Stryeck
Department of Molecular Genetics, Erasmus University Medical Center Rotterdam, Wytemaweg 80, 3015CN, Rotterdam, the Netherlands.
Yvonne
Y
Rijksen
Department of Molecular Genetics, Erasmus University Medical Center Rotterdam, Wytemaweg 80, 3015CN, Rotterdam, the Netherlands.
Hester
H
van Willigenburg
Department of Molecular Genetics, Erasmus University Medical Center Rotterdam, Wytemaweg 80, 3015CN, Rotterdam, the Netherlands.
Danny A
DA
Feijtel
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.
Ingrid
I
van der Pluijm
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.
Jeroen
J
Essers
Erasmus Optical Imaging Center and Department of Pathology, Erasmus University Medical Center Rotterdam, Wytemaweg 80, 3015CN, Rotterdam, the Netherlands.
Wiggert A
WA
van Cappellen
Department of Cell Biology, Erasmus University Medical Center Rotterdam, Wytemaweg 80, 3015CN, Rotterdam, the Netherlands.
Wilfred F
WF
van IJcken
Erasmus Optical Imaging Center and Department of Pathology, Erasmus University Medical Center Rotterdam, Wytemaweg 80, 3015CN, Rotterdam, the Netherlands.
Adriaan B
AB
Houtsmuller
Department of Molecular Genetics, Erasmus University Medical Center Rotterdam, Wytemaweg 80, 3015CN, Rotterdam, the Netherlands.
Joris
J
Pothof
Department of Surgery, Erasmus University Medical Center Rotterdam, Wytemaweg 80, 3015CN, Rotterdam, the Netherlands.
Ron W F
RWF
de Bruin
Institute of Molecular Biology & Biochemistry, Center of Molecular Medicine, Medical University of Graz, 8010 Graz, Austria.
Tobias
T
Madl
Department of Molecular Genetics, Erasmus University Medical Center Rotterdam, Wytemaweg 80, 3015CN, Rotterdam, the Netherlands.
Jan H J
JHJ
Hoeijmakers
The Buck Institute for Research on Aging, 8001 Redwood Blvd., Novato, CA 94945, USA; Lawrence Berkeley National Laboratories, Berkeley, CA 94720, USA.
Judith
J
Campisi
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.
Peter L J
PLJ
de Keizer
D000375:Aging / Q000187:drug effects / Q000473:pathology*; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000009:adverse effects* / Q000494:pharmacology; D017209:Apoptosis; D018797:Cell Cycle Proteins; D002460:Cell Line; D002470:Cell Survival; D057846:Cell-Penetrating Peptides / Q000494:pharmacology*; D016922:Cellular Senescence / Q000187:drug effects; D004317:Doxorubicin / Q000008:administration & dosage / Q000009:adverse effects* / Q000494:pharmacology; D005260:Female; D005347:Fibroblasts / Q000166:cytology; D051858:Forkhead Transcription Factors / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D002479:Inclusion Bodies / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D007668:Kidney / Q000187:drug effects / Q000502:physiology; D008099:Liver / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D054463:Trichothiodystrophy Syndromes / Q000188:drug therapy; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D000903:Antibiotics, Antineoplastic; D018797:Cell Cycle Proteins; D057846:Cell-Penetrating Peptides; D051858:Forkhead Transcription Factors; C525394:FoxO4 protein, mouse; D016159:Tumor Suppressor Protein p53; D004317:Doxorubicin
FOXO4; IL6; LMNB1; Senescence; TP53; aging; apoptosis; cell-penetrating peptide; chemotherapy; tissue homeostasis