Premature vascular aging and senescence in chronic kidney disease

Abstract Patients with advanced chronic kidney disease (CKD) have an impaired health status, reduced quality of life, and show an excess premature cardiovascular mortality that cannot be explained by traditional risk factors, such as dyslipidemia, hypertension, etc. The concept of vascular senescence and early vascular aging (EVA) is an important risk factor for the development of premature cardiovascular complications. Pathomechanisms of vascular senescence and EVA in CKD include uremic toxins, cellular senescence, inflammation and oxidative stress, klotho deficiency, and repressed expression of nuclear factor-erythroid 2-related factor (NRF2). Translationally, prevention and treatment of EVA are crucial to reduce the burden of disease in CKD, and we highlight potential, holistic approaches for inhibiting EVA, including klotho and NRF2 activation, as well as senotherapeutics. Klotho and the NRF2/KEAP1 signaling pathway are currently the most promising candidates for the holistic prevention and treatment of EVA in CKD.