Endothelial Cellular Senescence Contributes to Loss of Capillary Density

The consensus of the research community on senescent cells in old tissues is that (a) their presence causes harm, and (b) treatments based on the selective removal of such cells will be beneficial, reversing many aspects of aging and age-related disease. These cells secrete a pro-inflammatory mix of signal molecules that is disruptive to tissue structure and function when maintained over time. Cells become senescent constantly throughout life, only to be destroyed by programmed cell death or by the immune system. With advancing age, newly created senescent cells are cleared ever more slowly, however, and thus the burden of lingering senescent cells grows throughout the body.

As the authors of today's open access paper note, the presence of senescent endothelial cells in blood vessel walls is considered to be an important contributing cause of many of the age-related dysfunctions of the vasculature. One of the more consequential of these dysfunctions is the loss of capacity to grow new capillaries, leading to a decline in capillary density in tissues throughout the body. A more sparse capillary network reduces blood flow and delivery of oxygen and nutrients to cells, harming tissue function, particularly in energy-hungry tissues such as the brain and muscles. To the extent that senolytic therapies to clear senescent cells can reverse this particular aspect of aging, we should all be in favor of senolytic therapies.

Endothelial Senescence: From Macro- to Micro-Vasculature and Its Implications on Cardiovascular Health

Cellular senescence is originally defined as the irreversible loss of proliferative potential in somatic cells, which enter a viable and metabolically active state of permanent growth arrest that is distinct from quiescence and terminal differentiation. Accumulation of senescent cells contributes to age-related tissue degeneration by developing a complex senescence-associated secretory phenotype (SASP). By secreting a plethora of factors, including pro-inflammatory cytokines, chemokines, growth modulators, matrix metalloproteinases, and compromised extracellular vesicles which represent senescence-associated phenotype, senescent cells reprogram the surrounding microenvironment and cause tissue damage, thus promoting ageing and the development of age-associated diseases.

Intervention experiments have proven that senescent cell accumulation is an important driver of age-associated functional decline, multi-morbidity, and mortality, while systemic clearance of senescent cells delays ageing and extend lifespan. Therapeutically targeting cellular senescence, known as senotherapy, to eliminate senescent cells or induce senolysis, represents a rapidly growing and promising strategy for the prevention and/or treatment of ageing-related diseases. Targeting senescent cells can improve both health-span and life-span in mice.

Endothelial cells line at the most inner layer of blood vessels. They act to control hemostasis, arterial tone/reactivity, wound healing, tissue oxygen, and nutrient supply. With age, endothelial cells become senescent, characterized by reduced regeneration capacity, inflammation, and abnormal secretory profile. Endothelial senescence represents one of the earliest features of arterial ageing and contributes to many age-related diseases.

Compared to those in arteries and veins, endothelial cells of the microcirculation exhibit a greater extent of heterogeneity. Microcirculatory endothelial senescence leads to a declined capillary density, reduced angiogenic potentials, decreased blood flow, impaired barrier properties, and hypoperfusion in a tissue or organ-dependent manner. The heterogeneous phenotypes of microvascular endothelial cells in a particular vascular bed and across different tissues remain largely unknown. Accordingly, the mechanisms underlying macro- and micro-vascular endothelial senescence vary in different pathophysiological conditions, thus offering specific targets for therapeutic development of senolytic drugs.


Epigen reprogramming gets a lot of money & attention. How about senescence? Are there some well funded startups working on novel senolytics?

Posted by: Matt at April 19th, 2024 3:28 AM

I'm pretty sure it is possible to kill/edit cells based on RNA in the cytoplasm. Using a good lipid nanoparticle (eg. Oisin's one with the viral entry proteins) surely these endothelial senescent cells could be cleared out?

I wish there was some funding to develop the animal models to test this. Anyone from lifespan.io reading this? Steve?

Posted by: jimofoz at April 19th, 2024 5:46 AM

@Matt - it is mental that epigentic reset drugs are getting billions invested, yet aside from Unity there is not much interest in Senolytics. I'd guess they have about equal potential for restoring health and lifespan.

Posted by: jimofoz at April 19th, 2024 10:15 AM
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