Dysfunction in the cells making up the inner lining of blood vessels, the vascular endothelium, is thought to be an important first step in the aging of the vasculature more generally, setting the stage for the development of atherosclerotic lesions, a declining capacity of smooth muscle to contract and dilate vessels in order to control blood pressure, and leakage of the blood-brain barrier, among other issues. Researchers here review the contribution of two important aspects of cellular aging to the aging of the vascular endothelium; firstly the growing number of senescent cells, and secondly the decline in mitochondrial function. These are connected, as mitochondrial dysfunction is considered to contribute to an increased pace at which cells become senescent.
The vascular endothelium performs numerous regulatory functions that impact inflammatory responses, thrombosis, vascular tone, and angiogenesis. Endothelial dysfunction is a key contributor to the pathogenesis of various human diseases, either as a primary trigger or as a consequence of organ damage. This review examines how ageing reshapes endothelial cell metabolism and mitochondrial function, progressively undermining endothelial homeostasis and resilience.
Age-related endothelial alterations, including reduced nitric oxide bioavailability, heightened oxidative stress, impaired vasodilatory capacity and pro-inflammatory activation, arise from coordinated shifts in energy production, substrate utilization and redox signaling. In this context, cellular senescence, a stable arrest of the cell cycle accompanied by distinct metabolic, secretory, and inflammatory changes, appears to be an important response to cumulative metabolic and mitochondrial stress. Senescent endothelial cells not only reflect this stress burden but also actively propagate dysfunction through sustained pro-inflammatory and pro-oxidant signalling, thereby accelerating vascular ageing. We highlight the central role of mitochondria in these events. Age-associated mitochondrial dysfunction disrupts bioenergetics, enhances reactive oxygen species generation, and fuels chronic low-grade inflammation, amplifying endothelial decline.
By bringing together current evidence-based knowledge on endothelial cell bioenergetics, mitochondrial impairment, and metabolic reprogramming, this review identifies mitochondria-driven metabolic deterioration as a key mechanism underlying endothelial ageing and underscores mitochondrial metabolism as a promising, yet underexploited, therapeutic target in age-related vascular dysfunction.
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