The Role of Pathological Aging in Cardiac and Pulmonary Fibrosis
Lucy A. Murtha1,3, Matthew Morten1,3, Michael J. Schuliga2,3, Nishani S. Mabotuwana1,3, Sean A. Hardy1,3, David W. Waters2,3, Janette K. Burgess4,5,6, Doan TM. Ngo2,3, Aaron L. Sverdlov1,3, Darryl A. Knight2,3,7,8,9, Andrew J. Boyle1,3,*
1School of Medicine and Public Health, The University of Newcastle, Callaghan, NSW, Australia. 2School of Biomedical Sciences and Pharmacy, The University of Newcastle, Callaghan, NSW, Australia. 3Hunter Medical Research Institute, New Lambton Heights, NSW, Australia. 4University of Groningen, University Medical Center Groningen, Department of Pathology & Medical Biology, GRIAC (Groningen Research Institute for Asthma and COPD), Groningen and W. J. Kolff Research Institute, The Netherlands. 5Respiratory Cellular and Molecular Biology Group, Woolcock Institute of Medical Research, Glebe, NSW 2037, Australia. 6Discipline of Pharmacology, The University of Sydney, NSW 2006, Australia. 7Department of Anesthesiology, Pharmacology and Therapeutics, University of British Columbia, Canada. 8Adjunct Professor, Department of Medicine, University of Western Australia, Australia. 9Research and Innovation Conjoint, Hunter New England Health District, Australia
Aging promotes a range of degenerative pathologies characterized by progressive losses of tissue and/or cellular function. Fibrosis is the hardening, overgrowth and scarring of various tissues characterized by the accumulation of extracellular matrix components. Aging is an important predisposing factor common for fibrotic heart and respiratory disease. Age-related processes such as senescence, inflammaging, autophagy and mitochondrial dysfunction are interconnected biological processes that diminish the regenerative capacity of the aged heart and lung and have been shown to play a crucial role in cardiac fibrosis and idiopathic pulmonary fibrosis. This review focuses on these four processes of aging in relation to their role in fibrosis. It has long been established that the heart and lung are linked both functionally and anatomically when it comes to health and disease, with an ever-expanding aging population, the incidence of fibrotic disease and therefore the number of fibrosis-related deaths will continue to rise. There are currently no feasible therapies to treat the effects of chronic fibrosis therefore highlighting the importance of exploring the processes of aging and its role in inducing and exacerbating fibrosis of each organ. The focus of this review may help to highlight potential avenues of therapeutic exploration
Figure 1. Regulation of senescence growth arrest and the senescence-associated secretory phenotype (SASP) in the aging heart and lung
Stresses inducing senescence vary depending on the context, resulting in a variety of effector pathways. However, there is considerable overlap in processing of the stress-response signal and activating effectors of senescence, with a common final outcome, arrest of cell growth.
Figure 2. Impact of aging on the formation of autolysosome & degradation of contents
Aging increases the cardiomyocyte’s need for autophagy to maintain intracellular homeostasis, but simultaneously reduces the activity of lysosomes and thereby inhibits autophagic flux. The effects of aging on autophagy are opposing in the heat and the lung leading to variable pathological outcomes.
Figure 3. Alterations in dysfunctional mitochondria in the aging or diseased heart and lung
Reduction in the ability of dysfunctional mitochondria in the heart and lung to create energy causes an energy deficit that disrupts physiological cellular functioning. Mitochondrial dysfunction in the aging heart and may result in the development of mitochondrial cardiomyopathy or IPF respectively. Mitochondrial dysfunction induced by an acute event in the heart significantly disrupts the contraction and relaxation of contractile cells in the heart and perpetuates a cycle of detrimental effect.
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