A Unified Model of Age-Related Cardiovascular Disease

SIMPLE SUMMARY: Age-related cardiovascular disease is the foremost cause of death globally. Despite medical advances, we have been unable to stop or reverse the underlying pathology. We offer a model that is consistent with all clinical and laboratory data, can explain the clinical heterogeneity of age-related disease both within (e.g., human patients) and between species, and is predictively valid for interventional clinical trials. Cell aging is not only the central mechanism of such disease, but studies of human cells, of human tissues, and in animals demonstrate that we can effectively reverse cell aging at the cellular, genetic, and epigenetic levels. Given current biotechnology techniques, the reversal of cell aging is now technically feasible in human trials. The implications for our ability to cure and prevent cardiovascular disease are without historical precedent. This approach may not only allow us to intervene effectively in age-related cardiovascular disease but will likely lower (rather than raise) the costs of global medicine. ABSTRACT: Despite progress in biomedical technologies, cardiovascular disease remains the main cause of mortality. This is at least in part because current clinical interventions do not adequately take into account aging as a driver and are hence aimed at suboptimal targets. To achieve progress, consideration needs to be given to the role of cell aging in disease pathogenesis. We propose a model unifying the fundamental processes underlying most age-associated cardiovascular pathologies. According to this model, cell aging, leading to cell senescence, is responsible for tissue changes leading to age-related cardiovascular disease. This process, occurring due to telomerase inactivation and telomere attrition, affects all components of the cardiovascular system, including cardiomyocytes, vascular endothelial cells, smooth muscle cells, cardiac fibroblasts, and immune cells. The unified model offers insights into the relationship between upstream risk factors and downstream clinical outcomes and explains why interventions aimed at either of these components have limited success. Potential therapeutic approaches are considered based on this model. Because telomerase activity can prevent and reverse cell senescence, telomerase gene therapy is discussed as a promising intervention. Telomerase gene therapy and similar systems interventions based on the unified model are expected to be transformational in cardiovascular medicine.