Humanity is poorly supported by its vasculature. Vascular aging is the primary cause of human mortality, giving rise to atherosclerosis, the formation of fatty plaques that narrow vessels and eventually rupture to produce a fatal blockage and thus a heart attack or stroke. The quality of the vasculature suffers in other ways along the road to old age: vessels become leaky where they should not be, allowing the passage of disruptive cells and molecules into tissues; the network of capillaries becomes less dense, reducing delivery of necessary nutrients into tissues; the smooth muscle surrounding vessels becomes less capable of constriction and relaxation, leading to a range of issues relating to blood pressure and pulsatile flow; and so forth. One can find dozens of scientific papers in which Thomas Sydenham's most famous maxim is quoted, that "a man is as old as his arteries." There is of course more to aging that the decline of one important system, but the vasculture is an important system, and its dysfunction does include the single largest cause of mortality, atherosclerosis.
The authors of today's open access paper cast a summary view over the aging of the vasculature, taking the Hallmarks of Aging as their theme, and discussing each hallmark as it aligns with what is known of age-related dysfunction in vascular tissues. Of the hallmarks, study of the age-related accumulation of senescent cells is perhaps the most well advanced when it comes to the construction of therapies and preclinical evidence for rejuvenation following treatment. The parts of this review covering the role of senescent cells and the potential application of senotherapeutics to the treatment of vascular aging are thus the least speculative. Nonetheless, there remains a way to go yet if the goal is the widespread availability of senotherapies in old people; much of the system of medical regulation has yet to be convinced, and large, slow, and expensive clinical trials remain the only practical way to carry out that process of persuasion. This is unfortunately, given that many of the first, readily available senotherapeutics cost very little, but must sit on the sidelines until the regulators and physicians are more engaged on this topic.
Decoding Vascular Senescence: Cellular Insights and Therapeutic Strategies
The vascular system, an intricate network spanning the entire human body, serves as the primary conduit for nutrient delivery, gas exchange, and metabolic waste removal. With advancing age, the vascular wall undergoes a series of degenerative transitions that compromise these vital functions, laying the pathological groundwork for systemic organ decay. The arterial wall is composed of three anatomical layers: the tunica intima, a single layer of endothelial cells (ECs); the tunica media, composed of multiple layers of vascular smooth muscle cells (VSMCs) interspersed with elastic fibers; and the tunica adventitia, containing adipocytes, fibrous connective tissue, and extracellular matrix (ECM). Although each layer has distinct physiological properties, their collective integrity relies on a delicate balance between cellular homeostasis and microenvironmental stability. During aging, this homeostasis is disrupted as the specialized cells within these layers-including ECs, VSMCs, and pericytes-undergo profound phenotypic and functional shifts. Furthermore, exhaustion of the endothelial progenitor cells (EPCs) reservoir and the progressive remodeling of the ECM redefine the vascular niche, shifting it from a regenerative environment toward one characterized by chronic inflammation and structural decay.
In the process of aging in humans, senescent cells tend to accumulate at divergent rates in numerous tissues. Cellular senescence is defined as a terminal state of cell cycle arrest characterized by the irreversible loss of proliferative capacity. This program is primarily executed through the p53/p21WAF1/Cip1 and p16INK4A/pRB axes, which inhibit cyclin-dependent kinases to prevent E2F-mediated DNA replication. While initially a tumor-suppressive mechanism, the excessive accumulation of senescent cells drives vascular aging. In elderly individuals, p53, p21, and p16 levels are significantly elevated in the endothelium, an effect that is attenuated by regular physical activity. Mechanistically, p53 hyperactivation drives capillary rarefaction, whereas its downstream effector p21 (encoded by Cdkn1a) functions as a complicated regulator of vascular homeostasis. Moderate p21 expression is essential for maintaining the quiescence of EPCs and supporting angiogenesis. Furthermore, p16-INK4A (encoded by Cdkn2a) serves as a definitive marker of the senescent state. Although the clearance of p16-positive cells has been shown to delay age-associated disorders, subsequent studies have revealed that age-induced p16 accumulation is a gradual process and that the majority of p16-high cells are vascular ECs. Ultimately, the progressive accumulation of these senescent populations results in a systemic decay in vascular compliance and the functional collapse of capillary networks.
Senolytics represent a specialized class of pharmacological agents that selectively eliminate senescent cells. Intermittent oral administration of the representative senolytic cocktails, dasatinib and quercetin, significantly decreases the burden of senescent cells within the aortic inner layer of aged mice, thereby remarkably improving vasodilatory function. Mechanistically, these agents achieve selectivity by disabling distinct nodes of senescent cell anti-apoptotic pathways (SCAPs). Dasatinib predominantly inhibits ephrin receptors and tyrosine kinases, whereas quercetin targets the PI3K/AKT, p21, and BCL-2 protein families. This targeted elimination holds pivotal therapeutic potential to diminish macrovascular and microvascular morbidity.
View the full article at FightAging
