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

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

doi:10.1016/j.cell.2017.02.031

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

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 CampisiPeter L.J. de Keizer

Research output: Contribution to journal › Article › peer-review

977 Citations (Scopus)

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 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.

Original language	English
Pages (from-to)	132-147.e16
Journal	Cell
Volume	169
Issue number	1
DOIs	https://doi.org/10.1016/j.cell.2017.02.031
Publication status	Published - 23 Mar 2017
Externally published	Yes

Keywords

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

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Baar, M. P., Brandt, R. M. C., Putavet, D. A., Klein, J. D. D., Derks, K. W. J., Bourgeois, B. R. M., Stryeck, S., Rijksen, Y., van Willigenburg, H., Feijtel, D. A., van der Pluijm, I., Essers, J., van Cappellen, W. A., van IJcken, W. F., Houtsmuller, A. B., Pothof, J., de Bruin, R. W. F., Madl, T., Hoeijmakers, J. H. J., ... de Keizer, P. L. J. (2017). Targeted Apoptosis of Senescent Cells Restores Tissue Homeostasis in Response to Chemotoxicity and Aging. Cell, 169(1), 132-147.e16. https://doi.org/10.1016/j.cell.2017.02.031

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title = "Targeted Apoptosis of Senescent Cells Restores Tissue Homeostasis in Response to Chemotoxicity and Aging",

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 = "aging, apoptosis, cell-penetrating peptide, chemotherapy, FOXO4, IL6, LMNB1, Senescence, tissue homeostasis, TP53",

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

note = "Publisher Copyright: {\textcopyright} 2017 Elsevier Inc.",

year = "2017",

month = mar,

day = "23",

doi = "10.1016/j.cell.2017.02.031",

language = "English",

volume = "169",

pages = "132--147.e16",

journal = "Cell",

issn = "0092-8674",

publisher = "Cell Press",

number = "1",

}

Baar, MP, Brandt, RMC, Putavet, DA, Klein, JDD, Derks, KWJ, Bourgeois, BRM, Stryeck, S, Rijksen, Y, van Willigenburg, H, Feijtel, DA, van der Pluijm, I, Essers, J, van Cappellen, WA, van IJcken, WF, Houtsmuller, AB, Pothof, J, de Bruin, RWF, Madl, T, Hoeijmakers, JHJ, Campisi, J & de Keizer, PLJ 2017, 'Targeted Apoptosis of Senescent Cells Restores Tissue Homeostasis in Response to Chemotoxicity and Aging', Cell, vol. 169, no. 1, pp. 132-147.e16. https://doi.org/10.1016/j.cell.2017.02.031

TY - JOUR

T1 - Targeted Apoptosis of Senescent Cells Restores Tissue Homeostasis in Response to Chemotoxicity and Aging

AU - Baar, Marjolein P.

AU - Brandt, Renata M.C.

AU - Putavet, Diana A.

AU - Klein, Julian D.D.

AU - Derks, Kasper W.J.

AU - Bourgeois, Benjamin R.M.

AU - Stryeck, Sarah

AU - Rijksen, Yvonne

AU - van Willigenburg, Hester

AU - Feijtel, Danny A.

AU - van der Pluijm, Ingrid

AU - Essers, Jeroen

AU - van Cappellen, Wiggert A.

AU - van IJcken, Wilfred F.

AU - Houtsmuller, Adriaan B.

AU - Pothof, Joris

AU - de Bruin, Ron W.F.

AU - Madl, Tobias

AU - Hoeijmakers, Jan H.J.

AU - Campisi, Judith

AU - de Keizer, Peter L.J.

PY - 2017/3/23

Y1 - 2017/3/23

N2 - 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.

AB - 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.

KW - aging

KW - apoptosis

KW - cell-penetrating peptide

KW - chemotherapy

KW - FOXO4

KW - IL6

KW - LMNB1

KW - Senescence

KW - tissue homeostasis

KW - TP53

UR - http://www.scopus.com/inward/record.url?scp=85016052515&partnerID=8YFLogxK

U2 - 10.1016/j.cell.2017.02.031

DO - 10.1016/j.cell.2017.02.031

M3 - Article

C2 - 28340339

AN - SCOPUS:85016052515

SN - 0092-8674

VL - 169

SP - 132-147.e16

JO - Cell

JF - Cell

IS - 1

ER -

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

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