Aging, atherosclerosis, and IGF-1

Abstract

Insulin-like growth factor 1 (IGF-1) is an endocrine and autocrine/paracrine growth factor that circulates at high levels in the plasma and is expressed in most cell types. IGF-1 has major effects on development, cell growth and differentiation, and tissue repair. Recent evidence indicates that IGF-1 reduces atherosclerosis burden and improves features of atherosclerotic plaque stability in animal models. Potential mechanisms for this atheroprotective effect include IGF-1-induced reduction in oxidative stress, cell apoptosis, proinflammatory signaling, and endothelial dysfunction. Aging is associated with increased vascular oxidative stress and vascular disease, suggesting that IGF-1 may exert salutary effects on vascular aging processes. In this review, we will provide a comprehensive update on IGF-1's ability to modulate vascular oxidative stress and to limit atherogenesis and the vascular complications of aging.

Figure 1.

Insulin-like growth factor (IGF)-1 signal transduction. IGF-1 binds to IGF-1R and IGF-1/Insulin hybrid receptor, whereas insulin binds only to the insulin receptor (Insulin-R), and triggers several signaling pathways. IGF binding proteins modulate IGF-1 signaling by altering IGF-1 binding to the receptors. The IGF-1R is a tyrosine kinase that undergoes autophosphorylation and catalyzes the phosphorylation of multiple cellular proteins, including members of the insulin receptor substrate (IRS) family. On phosphorylation, IRSs interact with signaling molecules, including Akt, Ras/Raf, and Rac. Activation of the phosphoinositide 3-kinase and Akt pathway supports cell survival and enhances endothelial nitric oxide synthase activity, thereby inducing vasodilation. The Ras/Raf pathway is critical for proliferative responses, whereas activation of Rac is important for cell migration.

Figure 2.

Paradoxical effects of insulin-like growth factor (IGF)-1 on atherogenesis and the aging process. IGF-1 blunts multiple processes (in box, left) that are relevant to atherosclerosis development and to vascular aging. However, whereas evidence suggests that reduced IGF-1 promotes atherosclerosis and an increase in IGF-1 is antiatherogenic, paradoxically, IGF-1 deficiency has been linked to increased longevity (dotted line), although a final proof is still awaited.

Figure 3.

Low circulating insulin-like growth factor (IGF)-1 increases atherosclerosis in Apoe^-/- mice. We generated atherosclerosis-prone apolipoprotein E-deficient (Apoe^-/-) mice with 6T alleles (6T/Apoe^-/-) with a 20% decline in circulating IGF-I. After 12 weeks of high-fat diet feeding, 6T/Apoe^-/- mice developed significantly more atherosclerosis. Left: Representative images of en face Oil Red O staining of aorta. Right: Atheroma covered area on en face aorta was expressed as % total luminal surface area. This figure is modified from; Shai S et al. Am J Physiol Heart Circ Physiol 2011; 300:H1898–H1906.

Figure 4.

Effects of insulin-like growth factor (IGF)-1 on cell types involved in atherogenesis. IGF-1 exerts cell type specific effects and also alters cell–cell interactions, leading to a reduction in atherosclerosis and a more stable atherosclerotic plaque phenotype.