Pathological Roles of Senometabolites in Cardiovascular Disorders

Mechanisms contributing for the synchronization of aging are yet to be defined. Here, we define “senometabolite” as circulating metabolites having causal roles for the synchronization and progression of aging. Analyzing metabolomic studies in coronary plaque corrected with directional coronary atherectomy (DCA), we found that hydroxyl-metabolite significantly increased in patients with unstable angina compared with stable angina. We generated murine diet induced obese model and found this metabolite increased in aorta and plasma. Administration of this metabolite into human umbilical vein endothelial cells (HUVECs) induced cellular senescence, and immunofluorescence study showed that putative transhydrogenase increased in patients with atherosclerotic disorders. We did metabolomics studies in aged individuals or patients with heart failure and identified another metabolite, oxidized choline, increased under these conditions compared to respective controls. We generated murine left ventricular (LV) pressure overload model and found that oxidized choline increased both in plasma and failing heart. Administration of oxidized choline deteriorated cardiac function, in contrast, genetic model showed suppression of this metabolite ameliorated systolic dysfunction in LV pressure overload model. Proteomic study showed that oxidized choline reduced the expression of cytochrome c oxidase subunit1, and metabolomics study showed that both ATP and phosphocreatine level significantly reduced in cardiac tissues of wild type mice administrated with this metabolite. Administration of oxidized choline also reduced muscle strength, induced fibrosis in skeletal muscle, and electron microscopy showed an increase in dysfunctional mitochondria both in the heart and skeletal muscle. In aged wild type mice, metabolomic study showed oxidized choline increased in plasma. Aging process is still mysterious and continues to be an interesting topic to be explored. Our findings indicate that circulating senometabolites contribute for the progression of pathologies in age related disorders.