Fibrosis is a feature of aging, in which the normal processes of tissue maintenance run awry and scar-like structures form to disrupt tissue structure and function. The proximate cause is altered behavior on the part of fibroblast cells that largely responsible for maintenance of the extracellular matrix. After than, one can point to the continual inflammatory signaling that takes place in aged tissue, and disrupts many forms of cell activity, not just this one. As is usually the case in matters relating to aging, a more comprehensive picture of causes and consequences leading to inflammation and altered fibroblast behavior, one that encompasses all of the mechanisms involved and their various layers and interactions, has yet to emerge. Biochemistry is exceedingly complex.
Cardiovascular aging is a multifactorial and systemic process that contributes significantly to the global burden of cardiovascular disease, particularly in older populations. This review explores the molecular and cellular mechanisms underlying cardiovascular remodeling in age-related conditions such as hypertension, atrial fibrillation, atherosclerosis, and heart failure. Central to this process are chronic low-grade inflammation (inflammaging), oxidative stress, cellular senescence, and maladaptive extracellular matrix (ECM) remodeling.
The ECM is a complex and dynamic network composed of proteins, proteoglycans, polysaccharides, and biologically active factors. It plays a crucial role in maintaining tissue integrity and function by undergoing remodeling in response to inflammation or injury, adapting its structure and composition to maintain tissue integrity and function. However, a persistent expansion of the ECM may evolve into maladaptive fibrosis and organ dysfunction. This pathological remodeling can be triggered by various factors such as hypoxia, inflammation, biomechanical stress, and excessive neurohormonal activation.
Inflammation contributes to ECM remodeling by releasing cytokines that activate fibroblasts, increasing the production of ECM components. It also upregulates matrix metalloproteinases (MMPs) that degrade ECM proteins. This dual action can lead to pathological ECM remodeling, contributing to fibrosis and tissue dysfunction. Senescence, on the other hand, leads to the accumulation of senescent cells that secrete pro-inflammatory factors known as the SASP. SASP factors, including cytokines, chemokines, growth factors, and proteases, further alter the ECM by promoting degradation, impairing its turnover, and reshaping its composition.
Emerging molecular therapies offer promising strategies to reverse or halt maladaptive remodeling. These include senescence-targeting agents (senolytics), Nrf2 activators, RNA-based drugs, and ECM-modulating compounds such as MMP inhibitors. Additionally, statins and anti-inflammatory biologics (e.g., IL-1β inhibitors) exhibit pleiotropic effects that extend beyond traditional risk factor control. Understanding the molecular basis of remodeling is essential for guiding future research and improving outcomes in older adults at risk of cardiovascular disease.
Link: https://doi.org/10.3390/biom15101452
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