The prevalence of cardiovascular disease (CVD) increases with aging. Aging affects the integrity of the cardiovascular system in the absence of any disease [1]. Cardiac aging is a slow, heterogeneous process characterized by the inability of the heart to maintain appropriate function in response to greater stress or workload, such as ischemia or exercise. Cellular senescence was originally described as a process that limits cell division of normal human cells in culture [6], and its definition has been expanded to include growth arrest caused by diverse cellular stresses, including oxidative stress and DNA damage [2].
One of the most conserved signaling pathways involved in longevity is the insulin-like growth factor-1 (IGF-1)/insulin signaling pathway. Indeed, mutations in insulin-like receptor (daf-2), IGF-1 receptor (IGF-1R), insulin receptor (IR), and their downstream targets have been shown to prolong lifespan in invertebrates and vertebrates [3]. The hormone IGF-1 is a 70-amino acid peptide of 7.6 kDa, which has pleiotropic effects, including autocrine, paracrine, and endocrine effects. About 75% of IGF-1 is synthesized in the liver in response to growth hormone (GH) stimulation and it shares approximately 50% structural homology with pro-insulin and more than 60% homology with IGF-2. IGF-1 exerts negative feedback on the somatotropic axis, consisting of GH-releasing hormone (GHRH), GH, and IGF-1, in the peripheral circulation. However, some IGF-1 can also be produced in target tissues, including the heart, kidney, and cartilage. To control IGF-1, approximately 98% of circulating IGF-1 is bound to IGF binding protein (IGFBP) consisting of 6 subtypes with varying homology. For this particular review, we will focus on IGFBP3, the most abundant IGFBP, that binds with approximately 80% of circulating IGF-1. The IGF-1–IGFBP3 complex binds to a third protein termed acid-labile subunit (ALS). This ternary complex has a half-life of 16 h. Conversely, the half-life of free IGF-1 is less than 15 min [4]. As the concentration of free IGF-1 in normal subjects is less than 1% of the total IGF-1 concentration, the formation of this tripartite complex results in most of the IGF-1 and IGF-2 in blood being present in a stable reservoir [5]. The second most abundant IGFBP is IGFBP2. IGFBP2 does not bind to ALS and the IGF-1–IGFBP2 or IGF-2–IGFBP2 complexes have much shorter half-lives of about 90 min [6], [15]. A third IGFBP, IGFBP1, accounts for only a small percentage of the IGF carrying capacity. Like IGFBP2, IGFBP1 is generally unsaturated and, therefore, represents a potential regulator of free IGF-1 and IGF-2. IGFBP1 is suppressed by insulin [7]. IGFBP4, IGFBP5, and IGFBP6 are present in lower concentrations and appear to be less important for regulating free IGF concentrations in serum [18]
Extensive studies in cancer, diabetes, and CVD have explored the area of IGF-1 signaling. Particularly in the heart, IGF-1 regulates a number of cellular processes, including senescence, apoptosis, growth, metabolism, and autophagy [8] The cardiac effects of IGF-1 are coordinated by activation of plasma membrane IGF-1R, which belongs to the receptor tyrosine kinase family. IGF-1R comprises an α2β2 heterotetrameric complex of approximately 400 kDa (Fig. 1). Structurally, IGF-1R has two extracellular α-subunits, including the ligand-binding sites, and each α-subunit matches one of two transmembrane β-subunits, which cover an intracellular domain with intrinsic tyrosine kinase activity. The binding of IGF-1 to its cognate receptor starts a complex signaling cascade in cardiomyocytes [9]. Activation is initiated by triggering the kinase domain in the β subunits, leading to receptor tyrosine phosphorylation and autophosphorylation of multiple substrates. After these initial incidents, the activated signaling is transduced to a complex network of second messengers, intracellular lipids, and serine/threonine kinases that ultimately connect IGF-1 to the regulation of cardiomyocyte hypertrophy, proliferation, metabolism, differentiation, and protection from cell death [10].
Significant progress has been made using mouse models to extend lifespan using mutations that interfere with GH/IGF-1 and IGF-1 signaling cascades. Although the underlying molecular mechanisms are not fully understood, IGF-1 signaling is known to have an important role in the control of senescence and longevity.
References
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[2] E.G. Lakatta, D. Levy Arterial and cardiac aging: major shareholders in cardiovascular disease enterprises: part II: the aging heart in health: links to heart disease Circulation, 107 (2003), pp. 346-354
[3] S. Boudina Cardiac aging and insulin resistance: could insulin/insulin-like growth factor (IGF) signaling to be used as a therapeutic target? Curr. Pharm. Des., 19 (2013), pp. 5684-5694
[4] J.L. Fleg, S. Schulman, F. O'Connor, L.C. Becker, G. Gerstenblith, J.F. Clulow, D.G. Renlund, E.G. Lakatta
Effects of acute beta-adrenergic receptor blockade on age-associated changes in cardiovascular performance during dynamic exercise Circulation, 90 (1994), pp. 2333-2341
[5] J.B. Strait, E.G. Lakatta Aging-associated cardiovascular changes and their relationship to heart failure
Heart Fail. Clin., 8 (2012), pp. 143-164
[6] L. Hayflick The limited in vitro lifetime of human diploid cell strains Exp. Cell Res., 37 (1965), pp. 614-636
[7] Y. Takahashi The regulation of aging and cellular senescence by IGF-I Anti-Aging Medicine, 9 (2012), pp. 174-179
[8] M. Serrano, M.A. Blasco Putting the stress on senescence Curr. Opin. Cell Biol., 13 (2001), pp. 748-753
[9] C. Kenyon The plasticity of aging: insights from long-lived mutants Cell, 120 (2005), pp. 449-460
[10] R. Troncoso, C. Ibarra, J.M. Vicencio, E. Jaimovich, S. Lavandero New insights into IGF-1 signaling in the heart Trends Endocrinol. Metab., 25 (2014), pp. 128-137
Jamila Aug 11, 2020
