Fibrosis as a Consequence of Processes of Aging
Fibrosis is a malfunction of tissue maintenance and regeneration in which scar-like collagen deposits form, disrupting tissue structure and function. It almost always occurs in later life, even in fibrotic conditions clearly caused by environmental factors, such as smoking in the case of chronic obstructive pulmonary disease. Why is this? The authors of the open access paper noted here consider the mechanistic reasons as to why fibrosis is age-related, enumerating the processes associated with aging that are thought to have the greatest influence over fibrosis.
There is presently little that can be done to turn back fibrosis in established medical practice. That said, clearance of senescent cells has produced promising results in animal studies and an initial human study. That removal of senescent cells appears to reliably produce benefits ties in with the connection of fibrosis to chronic inflammation and its effects on regenerative processes. Senescent cells generate inflammation, and this appears to drive, to a sizable degree, many of the diseases and dysfunctions of aging.
Aging is a predisposing factor for cardiac and pulmonary fibrosis, with the prevalence of heart failure and fibrotic respiratory diseases such as idiopathic pulmonary fibrosis (IPF) increasing dramatically with advancing age. The aging of cardiac and lung tissue ultimately results in structural remodeling of the extracellular matrix (ECM) caused by alterations in the concentration and organization of ECM components such as collagen and elastin. Biological aging is accelerated by the cumulative damage and stress that occurs during a lifetime. This premature aging is particularly pertinent to the pulmonary system, which is subjected to lifelong challenges by airborne pollutants, particulates, and pathogens. Similarly, due to the high metabolic demand of the heart, large mitochondrial population and infrequent cardiomyocyte turnover, the heart is also highly susceptible to cumulative oxidative damage and stress with age. Cellular and immunological changes occur concomitantly with age-related tissue remodeling.
There are a great many hallmarks that represent common denominators of aging, such as stem cell exhaustion, genomic instability, telomere attrition, epigenetic alteration, and loss of proteostasis; in this review we focus on four processes of aging which play an integral role in fibrosis. Senescence, inflammaging, compromised autophagy and mitochondrial dysfunction are interrelated processes, which reduce the regenerative capacity of the aged heart and lung, and have been shown to be involved in cardiac fibrosis and IPF. As a consequence, challenges to an aging heart or lung are more likely to lead to pathological tissue remodeling rather than wound resolution and tissue restitution. This is exemplified in experimental models that show cardiac fibrosis in mice post-myocardial infarction increases with age. Similarly, pulmonary fibrosis in experimental lung injury is exacerbated by aging.
Age-related processes such as senescence and inflammaging diminish the regenerative capacity of damaged cardiac and pulmonary tissue, increasing the likelihood of pathological fibrosis following injury or challenge. What is interesting about these two processes is that at low levels, they mediate beneficial effects, but as you age and the level increases, they become deleterious. This is most evident with senescence, which protects the organism from cancer but which, in excess, can promote aging and the hallmark features of fibrosis. Furthermore, inflammaging and its sustained increase of inflammatory markers, which at normal levels regulate the immune response, contributes to the acquired resistance of myofibroblasts to apoptosis, and the low grade chronic inflammation which sustains the persistent fibrosis of cardiovascular disease and IPF. Given the similarities between cardiac and pulmonary fibrosis, investigating targets and testing future treatments in both organs with a focus on these key age-related processes seems justifiable and may lead to better treatment opportunities.
An additional age-related driver of fibrosis is glycation, which alters gene expression and drives fibrosis through at least two mechanisms: direct alteration of tensional homeostasis (in a manner that prevents myofibroblast apoptosis) in ECM and RAGE receptor stimulation.