A Unified Model of Age-Related Cardiovascular Disease

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.

Endothelial‐specific telomerase inactivation causes telomere‐independent cell senescence and multi‐organ dysfunction characteristic of aging

“…Progress in ameliorating aging‐associated cardiovascular and degenerative disease remains limited, at least in part, because current clinical approaches do not adequately take into account aging as a driver (Fossel et al., 2022). The causes of EC senescence have remained incompletely understood; however, inactivation of TERT in postnatal human development appears to play a pivotal role (Chakravarti, LaBella, & DePinho, 2021).…”

“…However, it remains unclear which cells in organs become senescent first. There is evidence that EC senescence affects other components of the vascular system, the perivascular/smooth muscle cells, and the parenchyma (Fossel et al., 2022; Han & Kim, 2023). The resulting concerted cell dysfunction leads to inefficient vasodilation and obstructed blood flow (Donato et al., 2018), which sets the stage for cardiovascular and degenerative disease (Xu et al., 2022).…”

“…In distinct organs, EC are exposed to different microenvironmental pressures and, hence, have different rates of proliferation and self‐renewal leading to telomere shortening and replicative senescence (Fossel et al., 2022). The lack of progress in our understanding of EC senescence mechanisms and repercussions in distinct organs is in part due to laboratory mice being suboptimal as a model of replicative senescence.…”

GLP1 Receptor Agonists—Effects beyond Obesity and Diabetes

“…Accumulation of senescent cells is responsible for tissue changes leading to aging-related diseases [ 97 , 98 ]. Because cell senescence contributes to biological aging [ 99 ], approaches to suppress or reverse senescence would be integral in preventing and treating aging-associated diseases [ 100 ].…”

“…Evidence from preclinical studies has suggested that GLP1R activation can suppress some cellular changes that accompany aging. It has been shown that the shortening of telomeres and a decline in DNA repair mechanisms induce cell senescence and aging [ 100 ]. In fact, mutations in DNA repair genes are responsible for Werner Syndrome and Hutchinson–Gilford progeria syndrome, the diseases of accelerated aging [ 99 ].…”