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

被引：1220

作者：

Baar, Marjolein P. ^{[1
]}

Brandt, Renata M. C. ^{[1
]}

Putavet, Diana A. ^{[1
]}

Klein, Julian D. D. ^{[1
]}

Derks, Kasper W. J. ^{[1
]}

Bourgeois, Benjamin R. M. ^{[8
]}

Stryeck, Sarah ^{[8
]}

Rijksen, Yvonne ^{[1
]}

van Willigenburg, Hester ^{[1
]}

Feijtel, Danny A. ^{[1
]}

van der Pluijm, Ingrid ^{[1
,5
]}

Essers, Jeroen ^{[1
,5
,6
]}

van Cappellen, Wiggert A. ^{[2
,3
]}

van IJcken, Wilfred F. ^{[4
]}

Houtsmuller, Adriaan B. ^{[2
,3
]}

Pothof, Joris ^{[1
]}

de Bruin, Ron W. F. ^{[7
]}

Madl, Tobias ^{[8
]}

Hoeijmakers, Jan H. J. ^{[1
]}

Campisi, Judith ^{[9
,10
]}

de Keizer, Peter L. J. ^{[1
,9
]}

机构：

[1] Erasmus Univ, Med Ctr Rotterdam, Dept Mol Genet, Wytemaweg 80, NL-3015 CN Rotterdam, Netherlands

[2] Erasmus Univ, Med Ctr Rotterdam, Erasmus Opt Imaging Ctr, Wytemaweg 80, NL-3015 CN Rotterdam, Netherlands

[3] Erasmus Univ, Med Ctr Rotterdam, Dept Pathol, Wytemaweg 80, NL-3015 CN Rotterdam, Netherlands

[4] Erasmus Univ, Med Ctr Rotterdam, Dept Cell Biol, Wytemaweg 80, NL-3015 CN Rotterdam, Netherlands

[5] Erasmus Univ, Med Ctr Rotterdam, Dept Vasc Surg, Wytemaweg 80, NL-3015 CN Rotterdam, Netherlands

[6] Erasmus Univ, Med Ctr Rotterdam, Dept Radiat Oncol, Wytemaweg 80, NL-3015 CN Rotterdam, Netherlands

[7] Erasmus Univ, Med Ctr Rotterdam, Dept Surg, Wytemaweg 80, NL-3015 CN Rotterdam, Netherlands

[8] Med Univ Graz, Inst Mol Biol & Biochem, Ctr Mol Med, A-8010 Graz, Austria

[9] Buck Inst Res Aging, 8001 Redwood Blvd, Novato, CA 94945 USA

[10] Lawrence Berkeley Natl Labs, Berkeley, CA 94720 USA

来源：

CELL | 2017年 / 169卷 / 01期

基金：

奥地利科学基金会;

关键词：

REPAIR SYNDROME TRICHOTHIODYSTROPHY; INFLAMMATORY CYTOKINE SECRETION; FORKHEAD BOX O; DNA-DAMAGE; CELLULAR SENESCENCE; PEPTIDE INHIBITOR; HUMAN FIBROBLASTS; MOUSE MODEL; CANCER; TRANSCRIPTION;

D O I：

10.1016/j.cell.2017.02.031

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

070307 [化学生物学]; 071010 [生物化学与分子生物学];

摘要：

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.

引用

页码：132 / +

页数：32

共 58 条

[1]

Naturally occurring p16Ink4a-positive cells shorten healthy lifespan [J].

Baker, Darren J. ;

Childs, Bennett G. ;

Durik, Matej ;

Wijers, Melinde E. ;

Sieben, Cynthia J. ;

Zhong, Jian ;

Saltness, Rachel A. ;

Jeganathan, Karthik B. ;

Verzosa, Grace Casaclang ;

Pezeshki, Abdulmohammad ;

Khazaie, Khashayarsha ;

Miller, Jordan D. ;

van Deursen, Jan M. .

NATURE, 2016, 530 (7589) :184-+

[2]

Subconjunctival Injection of XG-102, a JNK Inhibitor Peptide, in Patients with Intraocular Inflammation: A Safety and Tolerability Study [J].

Beydoun, Talal ;

Deloche, Catherine ;

Perino, Julien ;

Kirwan, Bridget-Anne ;

Combette, Jean-Marc ;

Behar-Cohen, Francine .

JOURNAL OF OCULAR PHARMACOLOGY AND THERAPEUTICS, 2015, 31 (02) :93-99

[3]

A peptide inhibitor of c-Jun N-terminal kinase protects against excitotoxicity and cerebral ischemia [J].

Borsello, T ;

Clarke, PGH ;

Hirt, L ;

Vercelli, A ;

Repici, M ;

Schorderet, DF ;

Bogousslavsky, J ;

Bonny, C .

NATURE MEDICINE, 2003, 9 (09) :1180-1186

[4]

Analysis of osteoarthritis in a mouse model of the progeroid human DNA repair syndrome trichothiodystrophy [J].

Botter, Sander M. ;

Zar, Michel ;

van Osch, Gerjo J. V. M. ;

van Steeg, Harry ;

Dolle, Martijn E. T. ;

Hoeijmakers, Jan H. J. ;

Weinans, Harrie ;

van Leeuwen, Johannes P. T. M. .

AGE, 2011, 33 (03) :247-260

[5]

Bypass of senescence after disruption of p21(CIP1/WAF1) gene in normal diploid human fibroblasts [J].

Brown, JP ;

Wei, WY ;

Sedivy, JM .

SCIENCE, 1997, 277 (5327) :831-834

[6]

Senescence-associated secretory phenotype favors the emergence of cancer stem-like cells [J].

Cahu, J. ;

Bustany, S. ;

Sola, B. .

CELL DEATH & DISEASE, 2012, 3 :e446-e446

[7]

Aging, Cellular Senescence, and Cancer [J].

Campisi, Judith .

ANNUAL REVIEW OF PHYSIOLOGY, VOL 75, 2013, 75 :685-705

[8]

Clearance of senescent cells by ABT263 rejuvenates aged hematopoietic stem cells in mice [J].

Chang, Jianhui ;

Wang, Yingying ;

Shao, Lijian ;

Laberge, Remi-Martin ;

Demaria, Marco ;

Campisi, Judith ;

Janakiraman, Krishnamurthy ;

Sharpless, Norman E. ;

Ding, Sheng ;

Feng, Wei ;

Luo, Yi ;

Wang, Xiaoyan ;

Aykin-Burns, Nukhet ;

Krager, Kimberly ;

Ponnappan, Usha ;

Hauer-Jensen, Martin ;

Meng, Aimin ;

Zhou, Daohong .

NATURE MEDICINE, 2016, 22 (01) :78-+

[9]

Senescence-Associated Secretory Phenotypes Reveal Cell-Nonautonomous Functions of Oncogenic RAS and the p53 Tumor Suppressor [J].

Coppe, Jean-Philippe ;

Patil, Christopher K. ;

Rodier, Francis ;

Sun, Yu ;

Munoz, Denise P. ;

Goldstein, Joshua ;

Nelson, Peter S. ;

Desprez, Pierre-Yves ;

Campisi, Judith .

PLOS BIOLOGY, 2008, 6 (12) :2853-2868

[10]

An Evaluation of Hepatotoxicity in Breast Cancer Patients Receiving Injection Doxorubicin [J].

Damodar, G. ;

Smitha, T. ;

Gopinath, S. ;

Vijayakumar, S. ;

Rao, Y. A. .

ANNALS OF MEDICAL AND HEALTH SCIENCES RESEARCH, 2014, 4 (01) :74-79

← 1 2 3 4 5 6 →