Advanced age has been described as an important factor associated with various medical conditions such as diabetes, kidney diseases, osteoporosis, arthritis, neurodegenerative disorders (Alzheimer´s and Parkinson´s diseases) and different cardiovascular alterations (atherosclerosis and hypertension) (1-3) . In addition, available literature has indicated the existence of the “physiological ageing of the respiratory system” and development of the lung parenchyma structural changes which may be characterized as emphysema-like (4) . With regard to the pulmonary circulation, it has been revealed that pulmonary artery systolic pressure increased in healthy elders compared to the younger individuals, suggesting the presence of the “physiological ageing of the pulmonary vascular system” (5-7). However, what does it mean for the development of pulmonary arterial hypertension (PAH)? Importantly, the recent intriguing findings postulated a clear shift from our previous point of view of PAH as a disease of younger females to a disease of older patients with no sharp difference in gender distribution(8-11). In order to identify and precisely delineate the potential role of ageing in the pathology of pulmonary hypertension (PH), with the main focus on group 1(12), we would like to start this interactive discussion among those interested in this topic. Our brief discussion will serve just to scratch the surface of this complex clinical and scientific issue.
Accumulated evidences from the scientific and clinical literature sources clearly indicated that the ultimate (and still unavoidable) effects of ageing are “visible” at all levels of organism´s biology, starting from the whole body, organs and tissues up to the cellular and molecular dimensions (13,14). For example, “molecular ageing” may be reflected by fact that there is an accumulation of the reactive oxygen species (ROS) over time, which may lead to the subsequent ROS-induced damage of the essential macromolecules, such as DNA, proteins and lipids (14). At the cell level, it has been suggested that the cellular senescence represents an important event crucially associated with age (1,13) . Even more, this process is sometimes called as “cellular ageing” (13) . In general, the cellular senescence is defined as an event when the proliferating cells achieve the state of permanent cell-cycle arrest, and this phenomenon is characterized by a significant alteration in “normal” cell morphology, physiology and behaviour (1,13). Several different triggers apart from the historically known telomere shortening, including DNA damage, oncogene signals and oxidative stress, have been identified(1,13). Despite these advances in the knowledge, it still remains unresolved how exactly the cellular senescence contributes to the development of age-related diseases.
With regard to the cardiovascular disorders, it is known for a long time that these diseases, including atherosclerosis and hypertension, are associated with ageing and such age-induced pathological events consider endothelial dysfunction, vascular remodeling and disorganized angiogenesis(1). The detailed description about the characteristics of endothelial (ECs) and vascular smooth muscle cell senescence and its potential connection with altered miRNA signaling in orchestrating the cardiovascular pathologies is nicely reviewed in the paper from Schraml and Grillari(1). Furthermore, an intriguing summary from Lakatta´s review article indicated enhancement of various signals and events which occur in humans over 65, such as pro-inflammatory and oxidative stress-related mediators (transforming growth factor-β, monocyte chemoattractant protein-1, nicotinamide adenine dinucleotide phosphate oxidase, tumor necrosis factor-α…), matrix metalloproteinases and dysregulated cellular processes including endothelial dysfunction, intimal thickening, proliferation and migration(3). All people working in the field of pulmonary vascular research have already recognized that these signaling molecules and cellular events are also important players in development of pulmonary vascular remodeling and PAH (15-21).
Finally, focusing to the field of pulmonary vasculature and cellular senescence, some interesting findings have been demonstrated in the context of PH associated with chronic obstructive pulmonary disease (COPD), a lung disease known to be eo ipso age-dependent and characterized by telomere shortening (22,23). The authors revealed that pulmonary artery smooth muscle cells (PASMCs) senescence is indeed a significant player in pulmonary vascular remodeling process, a hallmark of PH (22) . Based on this knowledge, one can expect that senescent PASMCs may have similar properties and functions in development of PAH as compared to the lung disease associated PH, since many pathological events and features that underlie remodeling process are shared between different PH forms (24) . Therefore, future research is crucially needed. Another interesting aspect is the potential involvement of dysregulated caveolae (invagination of the membrane, rich in cholesterol and sphingolipids) and its structural protein caveolin-1 in age-related cardiovascular pathologies, including PH/PAH (25-29). The contribution of caveolin-1 to the pathology of PAH is very complex story, and this protein actually may exert compartment-specific opposite role in disease development and progression, dependent on the pulmonary vascular cell type involved (ECs versus PASMCs) (26-29) . In the end, since the right heart failure is the ultimate pathological event of this severe pulmonary vascular disease, it is worth noting that ageing healthy subjects and PAH patients show some similarities with regard to the right atrial function, compared to the younger healthy subjects and non-PAH controls, respectively (30).
The question for interactive discussion
Based on the above described scientific and clinical facts, ideas and suggestions, we would like to postulate the following question: Is there a connection between pulmonary arterial hypertension and ageing? Our question is directed to all scientists, clinicians and others interested in this topic across the world to try to answer and expose their own views, perspectives and visions in the next volume/issue of the PVRI Chronicle.
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