The worldwide population is aging exponentially, creating burdens to patients, their families and society. Increasing age is associated with higher risk of a wide range of chronic diseases, and aging of the vascular system is closely linked to the development of many age-related diseases. Endothelial glycocalyx is a layer of proteoglycan polymers on the surface of the inner lumen of blood vessels. It plays an important role in maintaining vascular homeostasis and protecting various organ functions. Endothelial glycocalyx loss happens through the aging process and repairing the endothelial glycocalyx may alleviate the symptoms of age-related diseases. Given the important role of the glycocalyx and its regenerative properties, it is posited that the endothelial glycocalyx may be a potential therapeutic target for aging and age-related diseases and repairing endothelial glycocalyx could play a role in the promotion of healthy aging and longevity. Here, we review the composition, function, shedding, and manifestation of the endothelial glycocalyx in aging and age-related diseases, as well as regeneration of endothelial glycocalyx.