The growing presence of senescent cells contributes to near all of the declines and tissue dysfunctions of aging, judging by the results produced in extensive research carried out in animal models of age-related disease. Senescent cells secrete a mix of inflammatory and other signals that, when present for the long term, cause considerable harm to tissue structure, function, and maintenance. The research here is focused on just one form of dysfunction, but is illustrative of many other studies in the field of senescence carried out in recent years.
Endothelial cells (ECs) line the inner surface of blood vessels, and plays an essential role in vascular biology, such as vasodilation, hormone trafficking, and neovessel formation. Moreover, EC produces many secreted angiocrine factors that are crucially involved in maintaining tissue homeostasis. Aging causes cellular senescence in various types of cells including EC, and cellular senescence plays an important role in age-related organ dysfunction.
Senescent cells produce senescence-messaging secretomes that have deleterious effects on the tissue microenvironment, referred as the senescence-associated secretory phenotype (SASP); therefore, cellular senescence is considered to be a primary cause for age-related diseases, such as diabetes, stroke, and heart attack. Because of the crucial roles of EC in tissue homeostasis, EC senescence is presumed to play significant roles in age-related organ dysfunction; however, whether and the mechanism by which EC senescence causes age-related diseases remained unknown.
Here we show that EC senescence induces metabolic disorders through the SASP. Senescence-messaging secretomes from senescent ECs induced a senescence-like state and reduced insulin receptor substrate-1 in adipocytes, which thereby impaired insulin signaling. We generated EC-specific progeroid mice. This EC-specific progeria impaired systemic metabolic health in mice in association with adipose tissue dysfunction. Notably, shared circulation with EC-specific progeroid mice by parabiosis sufficiently transmitted the metabolic disorders into wild-type recipient mice. Our data provides direct evidence that EC senescence impairs systemic metabolic health, and thus establishes EC senescence as a bona fide risk for age-related metabolic disease.