Fig. 2.

CD47 signaling pathways mediating effects of elevated thrombospondin-1 (TSP1) in aging. Physiological levels of TSP1 control nitric oxide (NO) biosynthesis and downstream cGMP signaling in vascular cells to regulate vascular homeostasis and mitochondrial biogenesis. Chronically, elevated TSP1 levels in aging impair these functions and contribute to age-related impairment of recovery from ischemic injuries and cardiovascular diseases of aging. Suppression of the stem cell 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), by increased TSP1/cluster of differentiation 47 (CD47) signaling, results in loss of stem cells, which are required for wound repair and tissue regeneration. Inhibition of protective autophagy responses and metabolic adaptation to stress impair recovery from the genotoxic stress caused by radiotherapy and chemotherapy.