Thrombospondin-1 in maladaptive aging responses: a concept whose time has come

Abstract

Numerous age-dependent alterations at the molecular, cellular, tissue and organ systems levels underlie the pathophysiology of aging. Herein, the focus is upon the secreted protein thrombospondin-1 (TSP1) as a promoter of aging and age-related diseases. TSP1 has several physiological functions in youth, including promoting neural synapse formation, mediating responses to ischemic and genotoxic stress, minimizing hemorrhage, limiting angiogenesis, and supporting wound healing. These acute functions of TSP1 generally require only transient expression of the protein. However, accumulating basic and clinical data reinforce the view that chronic diseases of aging are associated with accumulation of TSP1 in the extracellular matrix, which is a significant maladaptive contributor to the aging process. Identification of the relevant cell types that chronically produce and respond to TSP1 and the molecular mechanisms that mediate the resulting maladaptive responses could direct the development of therapeutic agents to delay or revert age-associated maladies.

Keywords: CD47; aging; cardiovascular and metabolic disease; self-renewal; senescence; thrombospondin-1.

Fig. 1.

Aging increases thrombospondin-1 (TSP1) expression and dysregulates its physiological functions. TSP1 is transiently secreted into the extracellular matrix during embryonic development and in response to wounding in adults, but it is efficiently cleared by cell uptake via calreticulin (CRT) and the LDL receptor-related protein receptor (LRP1). Various physiological functions of TSP1 are mediated by its interactions with specific cell surface receptors and by modulating the function of other extracellular matrix proteins and growth factors. Several chronic and acute conditions associated with aging result in increased TSP1 biosynthesis and accumulation in the extracellular matrix, which perturb TSP1 signaling functions mediated by cell surface receptors and increase the activation of latent TGFβ1.

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.

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.