Fig. 3.

Age-related induction of thrombospondin-1 (TSP1) limits key survival and renewal pathways to propel the aging wheel. Age increases TSP1 expression widely, directly limiting 1) biogas nitric oxide (NO) and downstream intermediates cGMP and cAMP, 2) growth factors VEGF/PDGF, and 3) self-renewal transcription factors octamer-binding transcription factor 3/4 (Oct3/4), sex-determining region Y-box 2 (Sox2), Kruppel like factor 4 (Klf4), and V-myc myelocytomatosis viral oncogene homolog (cMyc; OSKM). Age-related overactive TSP1 directly stimulates increased NADPH-oxidase production of reactive oxygen species (ROS), which then act to impede these same survival/renewal moieties. Further, TSP1, in part via negative effects on mitochondria, dysregulates glucose homeostasis and metabolism.