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How is IGF-1 Involved in Longevity?

Image credit: Vitale et al. 2019 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6367275/)

Jamila Aug 11, 2020
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How is IGF-1 Involved in Longevity? How does it mediate its anti-aging effects? What does it do to the other aging hallmarks?

Insulin-like Growth Factor 1 (IGF-1) is a hormone that is vital for growth, it is produced in the liver upon stimulation with growth hormone (GH). Several studies have shown that low IGF-1 levels are associated with increased lifespan. The disruption of GH reduces IGF-1 levels which subsequently improves insulin sensitivity. The improved insulin sensitivity has been linked to the anti-aging effects of IGF-1. Centenarians are the model of longevity. Therefore, determining the physiology of centenarians can uncover important factors and pathways involved in longevity. Long-lived individuals have reduced levels of IGF-1. Furthermore, centenarians have a higher IGF-1 to IGFBP-3 (IGF Binding Protein 3) ratio compared to elderly non-centenarians; this may contribute towards the improved insulin sensitivity observed in centenarians. Also, it has been reported that centenarians are more likely to have a genetic variant in the IGF-1 receptor gene containing an A allele (G/A, codon 1013). Individuals with Laron syndrome have a mutation in the GH receptor, this causes them to have low levels of IGF-1. Although these individuals are less prone to age-related diseases there is no substantial evidence that individuals with Laron syndrome have an enhanced lifespan.

[1]Nishad, Rajkishor, et al. "Growth hormone and metabolic homeostasis." EMJ Diabet, 6, 2018, pp. 78-87.

[2]Harper, James M., et al. "Genetic modulation of hormone levels and life span in hybrids between laboratory and wild-derived mice." The Journals of Gerontology Series A: Biological Sciences and Medical Sciences, 61.10, 2006, pp. 1019-1029.

[3]Van Heemst, Diana. "Insulin, IGF-1 and longevity." Aging and disease, 1.2, 2010, pp. 147.

[4]Paolisso, Giuseppe, et al. "Serum levels of insulin-like growth factor-I (IGF-I) and IGF-binding protein-3 in healthy centenarians: relationship with plasma leptin and lipid concentrations, insulin action, and cognitive function." The Journal of Clinical Endocrinology & Metabolism, 82.7, 1997, pp. 2204-2209.

[5]Bonafè, Massimiliano, et al. "Polymorphic variants of insulin-like growth factor I (IGF-I) receptor and phosphoinositide 3-kinase genes affect IGF-I plasma levels and human longevity: cues for an evolutionarily conserved mechanism of life span control." The Journal of Clinical Endocrinology & Metabolism, 88.7, 2003, pp. 3299-3304.

[6]Guevara-Aguirre, Jaime, et al. "Growth hormone receptor deficiency is associated with a major reduction in pro-aging signaling, cancer, and diabetes in humans." Science translational medicine, 3.70, 2011, pp. 70ra13-70ra13.

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Relationship between IGF-1 and lifespan

Shubhankar Kulkarni
Shubhankar Kulkarni Aug 12, 2020
Several in vivo studies from worms to mice showed that downregulated activity of the GH/IGF-1/insulin pathway could be beneficial for the extension of human life span, whereas results are contradictory in humans. If we weigh the positive and negative effects of IGF-1, we find that on the positive side, IGF-1 contributes to tissue homeostasis, cardiovascular and neural protection, insulin-like effects, skeletal development, skeletal development, and skeletal muscle plasticity. On the negative side, IGF-1 increases the risk of cancer due to its potent proliferative activity. The contradiction around the role of IGF-1 in longevity may arise since the positive side of IGF-1 positively regulates longevity and the negative side negatively. Therefore, the answer to “is more IGF-1 in the elderly beneficial?”, is complicated. Studies in invertebrate models unequivocally demonstrate that disrupting IGF-1 signaling improves old-age health and lifespan. In contrast, increasing IGF-1 signaling has detrimental effects. Although, there might be quantitative differences across tissues and species. In vertebrates too, most studies have concluded that decreased IGF-1 signaling increases lifespan. However, most IGF-1-null mice die at birth suggesting that IGF-1 is essential early in life. IGF-1 may, therefore, be another example of antagonistic pleiotropy. However, data on IGF-1 are contradicting in humans. We cannot rule out the ethnic differences across human populations. Another issue with studies on centenarians is the lack of an age-matched control group. I can think of a couple of ways to describe the relationship between IGF-1 and lifespan: 1. The graph of IGF-1 vs lifespan might follow a J-shaped or a U-shaped curve. High IGF-1 levels might be required early in life and lower levels later in life. However, in case of centenarians, that is in case of extreme ages, high levels of IGF-1 might be required. 2. Insulin and IGF-1 pathways are highly interconnected. This connectivity might be partially disconnected in centenarians, where, they present high IGF-1 levels along with high insulin sensitivity (which is not the case in healthy non-centenarians). Reference: Vitale, Giovanni, et al. “ROLE of IGF-1 System in the Modulation of Longevity: Controversies and New Insights From a Centenarians’ Perspective.” Frontiers in Endocrinology, vol. 10, Feb. 2019, doi:10.3389/fendo.2019.00027.
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IGF-1 Prolong Lifespan

Mohammad Shazaib
Mohammad Shazaib Sep 12, 2020
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 [1] D. Czuriga, Z. Papp, I. Czuriga, Á. Balogh Cardiac aging — a review Eur. Surg., 43 (2011), pp. 69-77 [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
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