Length-independent telomere damage drives post-mitotic cardiomyocyte senescence

被引：417

作者：

Anderson, Rhys ^{[1
,2
]}

Lagnado, Anthony ^{[1
,2
]}

Maggiorani, Damien ^{[3
]}

Walaszczyk, Anna ^{[4
]}

Dookun, Emily ^{[2
,4
]}

Chapman, James ^{[1
,2
]}

Birch, Jodie ^{[1
,2
]}

Salmonowicz, Hanna ^{[1
,2
]}

Ogrodnik, Mikolaj ^{[1
,2
]}

Jurk, Diana ^{[1
,2
,5
]}

Proctor, Carole ^{[1
,2
]}

Correia-Melo, Clara ^{[1
,2
]}

Victorelli, Stella ^{[1
,2
]}

Fielder, Edward ^{[1
,2
]}

Berlinguer-Palmini, Rolando ^{[6
]}

Owens, Andrew ^{[4
]}

Greaves, Laura C. ^{[7
]}

Kolsky, Kathy L. ^{[8
]}

Parini, Angelo ^{[3
]}

Douin-Echinard, Victorine ^{[3
]}

Lebrasseur, Nathan K. ^{[8
]}

Arthur, Helen M. ^{[4
]}

Tual-Chalot, Simon ^{[4
]}

Schafer, Marissa J. ^{[8
]}

Roos, Carolyn M. ^{[8
]}

Miller, Jordan D. ^{[8
]}

Robertson, Neil ^{[9
]}

Mann, Jelena ^{[10
]}

Adams, Peter D. ^{[9
,11
]}

Tchkonia, Tamara ^{[8
]}

Kirkland, James L. ^{[8
]}

Mialet-Perez, Jeanne ^{[3
]}

Richardson, Gavin D. ^{[4
]}

Passos, Joao F. ^{[1
,2
,5
]}

机构：

[1] Newcastle Univ, Inst Ageing, Ageing Res Labs, Newcastle Upon Tyne, Tyne & Wear, England

[2] Newcastle Univ, Inst Cell & Mol Biosci, Newcastle Upon Tyne, Tyne & Wear, England

[3] Univ Toulouse, INSERM, Inst Metab & Cardiovasc Dis, Toulouse, France

[4] Newcastle Univ, Cardiovasc Res Ctr, Inst Genet Med, Newcastle Upon Tyne, Tyne & Wear, England

[5] Mayo Clin, Dept Physiol & Biomed Engn, Rochester, MN 55905 USA

[6] Newcastle Univ, Bioimaging Unit, Newcastle Upon Tyne, Tyne & Wear, England

[7] Newcastle Univ, Wellcome Trust Ctr Mitochondrial Res, Ctr Ageing & Vital, Newcastle Upon Tyne, Tyne & Wear, England

[8] Mayo Clin, Robert & Arlene Kogod Ctr Aging, Rochester, MN USA

[9] Univ Glasgow, Inst Canc Sci, CR UK Beatson Inst, Glasgow, Lanark, Scotland

[10] Newcastle Univ, Inst Cellular Med, Newcastle Upon Tyne, Tyne & Wear, England

[11] Sanford Burnham Prebys Med Discovery Inst, La Jolla, CA USA

来源：

EMBO JOURNAL | 2019年 / 38卷 / 05期

基金：

英国生物技术与生命科学研究理事会;

关键词：

ageing; cardiomyocytes; senescence; senolytics; telomeres; CELLULAR SENESCENCE; HEART-FAILURE; MAMMALIAN HEART; DNA-DAMAGE; CELLS; DYSFUNCTION; COMPLEX; MOUSE; PATHOPHYSIOLOGY; IDENTIFICATION;

D O I：

10.15252/embj.2018100492

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：

Ageing is the biggest risk factor for cardiovascular disease. Cellular senescence, a process driven in part by telomere shortening, has been implicated in age-related tissue dysfunction. Here, we address the question of how senescence is induced in rarely dividing/post-mitotic cardiomyocytes and investigate whether clearance of senescent cells attenuates age-related cardiac dysfunction. During ageing, human and murine cardiomyocytes acquire a senescent-like phenotype characterised by persistent DNA damage at telomere regions that can be driven by mitochondrial dysfunction and crucially can occur independently of cell division and telomere length. Length-independent telomere damage in cardiomyocytes activates the classical senescence-inducingpathways, p21(CIP) and p16(INK4a), and results in a non-canonicalsenescence-associated secretory phenotype, which is pro-fibrotic and pro-hypertrophic. Pharmacological or genetic clearance of senescent cells in mice alleviates detrimental features of cardiac ageing, including myocardial hypertrophy and fibrosis. Our data describe a mechanism by which senescence can occur and contribute to age-related myocardial dysfunction and in the wider setting to ageing in post-mitotic tissues.

引用

页数：21

共 58 条

[1]

A complex secretory program orchestrated by the inflammasome controls paracrine senescence [J].