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

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

Cell (2017-03-25)
Marjolein P Baar, Renata M C Brandt, Diana A Putavet, Julian D D Klein, Kasper W J Derks, Benjamin R M Bourgeois, Sarah Stryeck, Yvonne Rijksen, Hester van Willigenburg, Danny A Feijtel, Ingrid van der Pluijm, Jeroen Essers, Wiggert A van Cappellen, Wilfred F van IJcken, Adriaan B Houtsmuller, Joris Pothof, Ron W F de Bruin, Tobias Madl, Jan H J Hoeijmakers, Judith Campisi, Peter L J de Keizer
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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Monoclonal Anti-α-Tubulin antibody produced in mouse, ascites fluid, clone B-5-1-2
Sigma-Aldrich
Anti-FOXO4 antibody produced in rabbit, Prestige Antibodies® Powered by Atlas Antibodies, affinity isolated antibody, buffered aqueous glycerol solution
Sigma-Aldrich
Anti-FOXO3a/FKHRL1 Antibody, Upstate®, from rabbit