IGF-I: Panacea or Poison?

Abstract

In the area of aging research, the “holy grail” has been to discover the genetic or circulating factors that could predict longevity, with the aim of understanding causation and thus developing strategies that can enable individuals to enjoy a long and healthy life. One of the systems that has received much attention recently has been the GH/IGF-I/insulin system of ligands and receptors. In more primitive organisms such as Caenorhabditis elegans and Drosophila melanogaster, there is solid evidence that decreasing signaling through the insulin/IGF-I receptors leads to longevity (1). In mice, caloric restriction resulting in a similar reduction in insulin/IGF-I receptor signaling has also been associated with longevity. The exact causality remains to be determined, although reductions in reactive oxygen species and other noxious factors have been proposed as possible mediators (2). More specifically, in mammalian species, the role of the IGF system has been studied in the cardiovascular system (CVS) and cancer to determine causality, as in the study by Van Bunderen et al. (3) in this issue of JCEM. The association of the IGF-I system, namely IGF-I and the IGF binding proteins (IGFBPs), and cardiovascular disorders has been studied in older populations. In a large group of Danish men and women, low IGF-I and IGFBP-3 levels were associated with an increased risk of ischemic strokes (4). In a German cohort, higher IGF-I levels in men but lower IGF-I levels in women showed increased odds ratios for coronary artery disease (5). In a separate nested case-control study from Denmark, individuals without ischemic heart disease (IHD) were followed for 15 yr; those with low IGF-I levels and higher IGFBP-3 levels had an increased risk for developing IHD (6). On the other hand, other studies have shown that whereas there is an increased risk of fatal IHD with low IGF-I levels, all-cause mortality was not increased. As described in this issue of JCEM, Van Bunderen et al. (3) studied over 1200 Dutch subjects from Amsterdam that were participating in a Longitudinal Aging Study. All subjects had serum IGF-I measurements, and the endpoints were all-cause mortality, cardiovascular disease (CVD), and nonfatal CVD and cancer. Their results demonstrated a “U-shaped” relationship between IGF-I levels and CVD mortality, i.e. low and high levels were related to the increased CVD mortality. In contrast, there was no relationship between serum IGF-I levels and the other outcomes including cancer. The study therefore supports some previous studies, but not others. Questions remain, however. First, how can we explain the “U-shaped” relationship between IGF-I levels and CVD mortality; and second, because epidemiological studies are purely associations, is there a causal relationship between IGF-I levels and the outcomes? Mouse models have provided insights into the effects of IGF-I and the CVS. Reductions in circulating IGF-I levels were associated with impaired cardiac tissue development, and mice with specific IGF-IR-KO in cardiac muscle fail to demonstrate exercise-induced cardiac hypertrophy (7). Transgenic overexpression of IGF-I in cardiomyocytes leads to cardiomegaly mediated by an increased number of cells in the heart (8) and prevents activation of cell death in the viable myocardium after infarction, limiting ventricular dilation, myocardial loading, and cardiac hypertrophy (9). IGF-I can enhance proliferation of vascular smooth muscle cells (10), and transgenic IGF-I expression in vascular smooth muscle cells affected regeneration after aortic balloon denuvation of the endothelium. Thus, it was concluded that lack of IGF-I is detrimental to cardiovascular homeostasis. However, in mice with reduced circulating IGF-I levels (created by liver-specific IGF-I gene deletion), aging-induced cardiomyocyte mechanical dysfunction was prevented (11). Interestingly, persistent local IGF-I expression is sufficient to initially induce physiological cardiac hypertrophy in which peak aortic outflow velocity is increased relative to controls in the absence of any ISSN Print 0021-972X ISSN Online 1945-7197 Printed in U.S.A. Copyright © 2010 by The Endocrine Society doi: 10.1210/jc.2010-1737 Received July 28, 2010. Accepted August 9, 2010.