Cellular senescence in ageing: from mechanisms to therapeutic opportunities

被引：1337

作者：

Di Micco, Raffaella ^{[1
]}

Krizhanovsky, Valery ^{[2
]}

Baker, Darren ^{[3
,4
]}

di Fagagna, Fabrizio d'Adda ^{[5
,6
]}

机构：

[1] IRCCS San Raffaele Sci Inst, San Raffaele Telethon Inst Gene Therapy SR TIGET, Milan, Italy

[2] Weizmann Inst Sci, Dept Mol Cell Biol, Rehovot, Israel

[3] Mayo Clin, Dept Pediat, Rochester, MN USA

[4] Mayo Clin, Dept Biochem & Mol Biol, Rochester, MN USA

[5] IFOM FIRC Inst Mol Oncol, Milan, Italy

[6] CNR, Ist Genet Mol, Pavia, Italy

来源：

NATURE REVIEWS MOLECULAR CELL BIOLOGY | 2021年 / 22卷 / 02期

基金：

欧洲研究理事会; 美国国家卫生研究院; 以色列科学基金会;

关键词：

DNA-DAMAGE-RESPONSE; ONCOGENE-INDUCED SENESCENCE; LEUKOCYTE TELOMERE LENGTH; HEMATOPOIETIC STEM-CELLS; SECRETORY PHENOTYPE; DOUBLE-BLIND; LIFE-SPAN; RHEUMATOID-ARTHRITIS; TUMOR SUPPRESSION; MITOCHONDRIAL DYSFUNCTION;

D O I：

10.1038/s41580-020-00314-w

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Cellular senescence, first described in vitro in 1961, has become a focus for biotech companies that target it to ameliorate a variety of human conditions. Eminently characterized by a permanent proliferation arrest, cellular senescence occurs in response to endogenous and exogenous stresses, including telomere dysfunction, oncogene activation and persistent DNA damage. Cellular senescence can also be a controlled programme occurring in diverse biological processes, including embryonic development. Senescent cell extrinsic activities, broadly related to the activation of a senescence-associated secretory phenotype, amplify the impact of cell-intrinsic proliferative arrest and contribute to impaired tissue regeneration, chronic age-associated diseases and organismal ageing. This Review discusses the mechanisms and modulators of cellular senescence establishment and induction of a senescence-associated secretory phenotype, and provides an overview of cellular senescence as an emerging opportunity to intervene through senolytic and senomorphic therapies in ageing and ageing-associated diseases.

引用

页码：75 / 95

页数：21

共 288 条

[81] Mature natural killer cells with phenotypic and functional alterations accumulate upon sustained stimulation with IL-15/IL-15Rα complexes [J].

Elpek, Kutlu G. ;

Rubinstein, Mark P. ;

Bellemare-Pelletier, Angelique ;

Goldrath, Ananda W. ;

Turley, Shannon J. .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2010, 107 (50) :21647-21652

[82] IL-6 receptor inhibition with tocilizumab improves treatment outcomes in patients with rheumatoid arthritis refractory to anti-tumour necrosis factor biologicals: results from a 24-week multicentre randomised placebo-controlled trial [J].

Emery, P. ;

Keystone, E. ;

Tony, H. P. ;

Cantagrel, A. ;

van Vollenhoven, R. ;

Sanchez, A. ;

Alecock, E. ;

Lee, J. ;

Kremer, J. .

ANNALS OF THE RHEUMATIC DISEASES, 2008, 67 (11) :1516-1523

[83] PAI-1-regulated extracellular proteolysis governs senescence and survival in Klotho mice [J].

Eren, Mesut ;

Boe, Amanda E. ;

Murphy, Sheila B. ;

Place, Aaron T. ;

Nagpal, Varun ;

Morales-Nebreda, Luisa ;

Urich, Daniela ;

Quaggin, Susan E. ;

Budinger, G. R. Scott ;

Mutlu, Goekhan M. ;

Miyata, Toshio ;

Vaughan, Douglas E. .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2014, 111 (19) :7090-7095

[84] Robust, universal biomarker assay to detect senescent cells in biological specimens [J].

Evangelou, Konstantinos ;

Lougiakis, Nikolaos ;

Rizou, Sophia V. ;

Kotsinas, Athanassios ;

Kletsas, Dimitris ;

Munoz-Espin, Daniel ;

Kastrinakis, Nikolaos G. ;

Pouli, Nicole ;

Marakos, Panagiotis ;

Townsend, Paul ;

Serrano, Manuel ;

Bartek, Jiri ;

Gorgoulis, Vassilis G. .

AGING CELL, 2017, 16 (01) :192-197

[85] Aging and the Burden of Multimorbidity: Associations With Inflammatory and Anabolic Hormonal Biomarkers [J].

Fabbri, Elisa ;

An, Yang ;

Zoli, Marco ;

Simonsick, Eleanor M. ;

Guralnik, Jack M. ;

Bandinelli, Stefania ;

Boyd, Cynthia M. ;

Ferrucci, Luigi .

JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES, 2015, 70 (01) :63-70

[86] Unmasking senescence: context-dependent effects of SASP in cancer [J].

Faget, Douglas V. ;

Ren, Qihao ;

Stewart, Sheila A. .

NATURE REVIEWS CANCER, 2019, 19 (08) :439-453

[87] Targeting cellular senescence prevents age-related bone loss in mice [J].

Farr, Joshua N. ;

Xu, Ming ;

Weivoda, Megan M. ;

Monroe, David G. ;

Fraser, Daniel G. ;

Onken, Jennifer L. ;

Negley, Brittany A. ;

Sfeir, Jad G. ;

Ogrodnik, Mikolaj B. ;

Hachfeld, Christine M. ;

LeBrasseur, Nathan K. ;

Drake, Matthew T. ;

Pignolo, Robert J. ;

Pirtskhalava, Tamar ;

Tchkonia, Tamara ;

Oursler, Merry Jo ;

Kirkland, James L. ;

Khosla, Sundeep .

NATURE MEDICINE, 2017, 23 (09) :1072-+

[88] Senescence determines the fate of activated rat pancreatic stellate cells [J].

Fitzner, Brit ;

Mueller, Sarah ;

Walther, Michael ;

Fischer, Madlen ;

Engelmann, Robby ;

Mueller-Hilke, Brigitte ;

Puetzer, Brigitte M. ;

Kreutzer, Michael ;

Nizze, Horst ;

Jaster, Robert .

JOURNAL OF CELLULAR AND MOLECULAR MEDICINE, 2012, 16 (11) :2620-2630

[89] Replication stress is a potent driver of functional decline in ageing haematopoietic stem cells [J].

Flach, Johanna ;

Bakker, Sietske T. ;

Mohrin, Mary ;

Conroy, Pauline C. ;

Pietras, Eric M. ;

Reynaud, Damien ;

Alvarez, Silvia ;

Diolaiti, Morgan E. ;

Ugarte, Fernando ;

Forsberg, E. Camilla ;

Le Beau, Michelle M. ;

Stohr, Bradley A. ;

Mendez, Juan ;

Morrison, Ciaran G. ;

Passegue, Emmanuelle .

NATURE, 2014, 512 (7513) :198-+

[90] The effects of graded caloric restriction: XII. Comparison of mouse to human impact on cellular senescence in the colon [J].

Fontana, Luigi ;

Mitchell, Sharon E. ;

Wang, Boshi ;

Tosti, Valeria ;

van Vliet, Thijmen ;

Veronese, Nicola ;

Bertozzi, Beatrice ;

Early, Dayna S. ;

Maissan, Parcival ;

Speakman, John R. ;

Demaria, Marco .

AGING CELL, 2018, 17 (03)

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