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 which 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.
Auteurs: Marjolein P. Baar1, Renata M.C. Brandt1, Diana A. Putavet1, Julian D.D. Klein1, Kasper W.J. Derks1, Benjamin R. M. Bourgeois7, Sarah Stryeck7, Yvonne Rijksen1, Hester van Willigenburg1, Danny A. Feijtel1, Ingrid van der Pluijm1,4, Jeroen Essers1,4,5, Wiggert A. van Cappellen2, Wilfred F.J. van IJcken3, Adriaan B. Houtsmuller2, Joris Pothof1, Ron W.F. de Bruin6, Tobias Madl7, Jan H.J. Hoeijmakers1, Judith Campisi8,9, Peter L.J. de Keizer1,8,10,11
Affiliates: 1 Department of Molecular Genetics, 2 Erasmus Optical Imaging Center and Department of Pathology, 3 Department of Cell Biology, 4 Department of Vascular Surgery, 5 Department of Radiation Oncology, 6 Department of Surgery Erasmus University Medical Center Rotterdam, Wytemaweg 80, 3015CN, Rotterdam, the Netherlands , 7 Institute of Molecular Biology & Biochemistry, Center of Molecular Medicine, Medical University of Graz,
8010 Graz, Austria, 8 The Buck Institute for Research on Aging, 8001 Redwood Blvd., Novato, CA 94945, USA, 9 Lawrence Berkeley National Laboratories, Berkeley, CA, USA, 10 Lead contact , 11 To whom correspondence should be addressed: firstname.lastname@example.org
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