Cardiometabolic Aging

Background

One of the greatest challenges for the future of healthcare is dealing with diseases of ageing. The concept of extending healthspan is viewed as the single most effective approach for extending life expectancy. Targeting the biological ageing processes, common to many diseases, may afford far greater increases in life expectancy than targeting individual diseases, like cancers, cardiac or kidney disease. Additionally, there are potential large economic benefits to enhance healthspan reflecting decreased healthcare costs and increased productivity. Singapore has an increasingly high rate of population ageing projected to reach 1 in 4 by 2030 (MOH, Singapore). Over the last few decades, large advances in our understanding of the shared biological processes that occur across organs during ageing has been referred to as the “Hallmarks of Ageing” comprising of primary causes of cellular damage, deleterious adaptive processes and culprit drivers of ageing phenotypes, namely altered intercellular communication and stem cell exhaustion. Inflammation is a key component of altered intercellular communication in ageing, associated with maladaptive immunosenescence and deleterious immunometabolism, which lead to the term ‘Inflammaging’. The group uses bioinformatics, disease and reporter mouse models, cell and molecular biology, physiology and collaborates to find disease mechanisms and targets in ageing.

                                                          Prof Stuart Alexander Cook                    Dr Lim Wei Wen

Research Area

1. Determinants of cardiovascular and metabolic ageing
2. Ageing disease mechanisms

Achievements​

Grants

1. NMRC STaR Award (Prof Stuart Cook) "Integrated multi-phenotype and systems-level analysis of human heart failure"
2. A*STAR AME YIRG Award (Dr Lim Wei Wen) "Dissecting the role of interleukin-11 in Marfan Syndrome"
3. NMRC OF-YIRG Award (Dr Benjamin Ng) "The role of IL11 in alveolar epithelial cell dysfunction: implications for lung regeneration in severe respiratory diseases"

Publications

1. Schafer S, Viswanathan S, Widjaja AA, Lim WW, Moreno-Moral A, DeLaughter DM, Ng B, Patone G, Chow K, Khin E, Tan J, Chothani SP, Ye L, Rackham OJL, Ko NSJ, Sahib NE, Pua CJ, Zhen NTG, Xie C, Wang M, Maatz H, Lim S, Saar K, Blachut S, Petretto E, Schmidt S, Putoczki T, Guimarães-Camboa N, Wakimoto H, van Heesch S, Sigmundsson K, Lim SL, Soon JL, Chao VTT, Chua YL, Tan TE, Evans SM, Loh YJ, Jamal MH, Ong KK, Chua KC, Ong BH, Chakaramakkil MJ, Seidman JG, Seidman CE, Hubner N, Sin KYK, Cook SA. IL-11 is a crucial determinant of cardiovascular fibrosis. Nature. 2017 Dec 7;552(7683):110-115.
2. Widjaja AA, Singh BK, Adami E, Viswanathan S, Dong J, D'Agostino GA, Ng B, Lim WW, Tan J, Paleja BS, Tripathi M, Lim SY, Shekeran SG, Chothani SP, Rabes A, Sombetzki M, Bruinstroop E, Min LP, Sinha RA, Albani S, Yen PM, Schafer S, Cook SA. Inhibiting Interleukin 11 Signaling Reduces Hepatocyte Death and Liver Fibrosis, Inflammation, and Steatosis in Mouse Models of Nonalcoholic Steatohepatitis. Gastroenterology. 2019 Sep;157(3):777-792.e14.
3. Chothani S, Schäfer S, Adami E, Viswanathan S, Widjaja AA, Langley SR, Tan J, Wang M, Quaife NM, Jian Pua C, D'Agostino G, Guna Shekeran S, George BL, Lim S, Yiqun Cao E, van Heesch S, Witte F, Felkin LE, Christodoulou EG, Dong J, Blachut S, Patone G, Barton PJR, Hubner N, Cook SA, Rackham OJL. Widespread Translational Control of Fibrosis in the Human Heart by RNA-Binding Proteins. Circulation. 2019 Sep 10;140(11):937-951.
4. Ng B, Dong J, D'Agostino G, Viswanathan S, Widjaja AA, Lim WW, Ko NSJ, Tan J, Chothani SP, Huang B, Xie C, Pua CJ, Chacko AM, Guimarães-Camboa N, Evans SM, Byrne AJ, Maher TM, Liang J, Jiang D, Noble PW, Schafer S, Cook SA. Interleukin-11 is a therapeutic target in idiopathic pulmonary fibrosis. Sci Transl Med. 2019 Sep 25;11(511):eaaw1237.
5. Lim WW, Ng B, Widjaja A, Xie C, Su L, Ko N, Lim SY, Kwek XY, Lim S, Cook SA, Schafer S. Transgenic interleukin 11 expression causes cross-tissue fibro-inflammation and an inflammatory bowel phenotype in mice. PLoS One. 2020 Jan 9;15(1):e0227505.
6. Cook SA, Schafer S. Hiding in Plain Sight: Interleukin-11 Emerges as a Master Regulator of Fibrosis, Tissue Integrity, and Stromal Inflammation. Annu Rev Med. 2020 Jan 27;71:263-276.
7. Corden B, Adami E, Sweeney M, Schafer S, Cook SA. IL-11 in cardiac and renal fibrosis: Late to the party but a central player. Br J Pharmacol. 2020 Apr;177(8):1695-1708.
8. Ng B, Dong J, Viswanathan S, Widjaja AA, Paleja BS, Adami E, Ko NSJ, Wang M, Lim S, Tan J, Chothani SP, Albani S, Schafer S, Cook SA. Fibroblast-specific IL11 signaling drives chronic inflammation in murine fibrotic lung disease. FASEB J. 2020 Sep;34(9):11802-11815.
9. Widjaja AA, Chothani SP, Cook SA. Different roles of interleukin 6 and interleukin 11 in the liver: implications for therapy. Hum Vaccin Immunother. 2020 Oct 2;16(10):2357-2362.
10. Sweeney M, Corden B, Cook SA. Targeting cardiac fibrosis in heart failure with preserved ejection fraction: mirage or miracle? EMBO Mol Med. 2020 Oct 7;12(10):e10865.
11. Lim WW, Corden B, Ng B, Vanezis K, D'Agostino G, Widjaja AA, Song WH, Xie C, Su L, Kwek XY, Tee NGZ, Dong J, Ko NSJ, Wang M, Pua CJ, Jamal MH, Soh B, Viswanathan S, Schafer S, Cook SA. Interleukin-11 is important for vascular smooth muscle phenotypic switching and aortic inflammation, fibrosis and remodeling in mouse models. Sci Rep. 2020 Oct 20;10(1):17853.
12. Ng B, Cook SA, Schafer S. Interleukin-11 signaling underlies fibrosis, parenchymal dysfunction, and chronic inflammation of the airway. Exp Mol Med. 2020 Dec;52(12):1871-1878.
13. Widjaja AA, Viswanathan S, Jinrui D, Singh BK, Tan J, Wei Ting JG, Lamb D, Shekeran SG, George BL, Schafer S, Carling D, Adami E, Cook SA. Molecular Dissection of Pro-Fibrotic IL11 Signaling in Cardiac and Pulmonary Fibroblasts. Front Mol Biosci. 2021 Sep 28;8:740650.
14. Dong J, Viswanathan S, Adami E, Singh BK, Chothani SP, Ng B, Lim WW, Zhou J, Tripathi M, Ko NSJ, Shekeran SG, Tan J, Lim SY, Wang M, Lio PM, Yen PM, Schafer S, Cook SA, Widjaja AA. Hepatocyte-specific IL11 cis-signaling drives lipotoxicity and underlies the transition from NAFLD to NASH. Nat Commun. 2021 Jan 4;12(1):66.
15. Adami E, Viswanathan S, Widjaja AA, Ng B, Chothani S, Zhihao N, Tan J, Lio PM, George BL, Altunoglu U, Ghosh K, Paleja BS, Schafer S, Reversade B, Albani S, Ling ALH, O'Reilly S, Cook SA. IL11 is elevated in systemic sclerosis and IL11-dependent ERK signalling underlies TGFβ-mediated activation of dermal fibroblasts. Rheumatology (Oxford). 2021 Dec 1;60(12):5820-5826.
16. Lim WW, Corden B, Ye L, Viswanathan S, Widjaja AA, Xie C, Su L, Tee NGZ, Schafer S, Cook SA. Antibody-mediated neutralization of IL11 signalling reduces ERK activation and cardiac fibrosis in a mouse model of severe pressure overload. Clin Exp Pharmacol Physiol. 2021 Apr;48(4):605-613.
17. Corden B, Lim WW, Song W, Chen X, Ko NSJ, Su L, Tee NGZ, Adami E, Schafer S, Cook SA. Therapeutic Targeting of Interleukin-11 Signalling Reduces Pressure Overload-Induced Cardiac Fibrosis in Mice. J Cardiovasc Transl Res. 2021 Apr;14(2):222-228.
18. Widjaja AA, Dong J, Adami E, Viswanathan S, Ng B, Pakkiri LS, Chothani SP, Singh BK, Lim WW, Zhou J, Shekeran SG, Tan J, Lim SY, Goh J, Wang M, Holgate R, Hearn A, Felkin LE, Yen PM, Dear JW, Drum CL, Schafer S, Cook SA. Redefining IL11 as a regeneration-limiting hepatotoxin and therapeutic target in acetaminophen-induced liver injury. Sci Transl Med. 2021 Jun 9;13(597):eaba8146.
19. Ng B, Widjaja AA, Viswanathan S, Dong J, Chothani SP, Lim S, Shekeran SG, Tan J, McGregor NE, Walker EC, Sims NA, Schafer S, Cook SA. Similarities and differences between IL11 and IL11RA1 knockout mice for lung fibro-inflammation, fertility and craniosynostosis. Sci Rep. 2021 Jul 8;11(1):14088.
20. Dong J, Viswanathan S, Adami E, Schafer S, Kuthubudeen FF, Widjaja AA, Cook SA. The pro-regenerative effects of hyperIL6 in drug-induced liver injury are unexpectedly due to competitive inhibition of IL11 signaling. Elife. 2021 Aug 26;10:e68843