Role of the GH/IGF-1 axis in lifespan and healthspan: Lessons from animal models

Berryman, Darlene E.; Christiansen, Jens Sandahl; Johannsson, Gudmundur; Thorner, Michael O.; Kopchick, John J.

doi:10.1016/j.ghir.2008.05.005

Cited by 255 publications

(192 citation statements)

References 187 publications

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“…GH is generally thought to be associated with positive attributes such as growth, health, youth, muscle mass and well-being, yet the bulk of the scientific evidence suggests that signalling through GH, IGF-1 and insulin receptors is related to a shortened lifespan in adults [25]. Our clinical data do not provide information as to whether high sKlotho levels do indeed attenuate insulin and IGF-1 receptor signalling in patients with acromegaly, but it is clear that excess Klotho does not predict longevity in these patients.…”

Section: Discussionmentioning

confidence: 99%

Excessively high soluble Klotho in patients with acromegaly

Sze

Bernays

Zwimpfer³

et al. 2012

Journal of Internal Medicine

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Objectives. Klotho-deficient mice develop a syndrome resembling accelerated ageing, and genetic variants of Klotho have been associated with human ageing. In humans, serum levels of soluble Klotho decrease with age and with chronic renal failure. The aim of our study was to examine the relationship between excess growth hormone (GH) and serum levels of Klotho in patients with acromegaly, a disease usually caused by a pituitary adenoma, which is associated with high phosphate levels and reduced life expectancy.Patients and design. We determined the levels of soluble Klotho, GH and insulin-like growth factor 1 (IGF-1) in serum samples from 24 consecutive patients with acromegaly (nine women ⁄ 15 men, age 28-76 years) before and after transsphenoidal surgery.Results. Soluble Klotho levels were excessively high at baseline (mean ± SEM, 4.2 ± 0.7 ng mL )1 ) and correlated with GH (r = 0.64), IGF-1 (r = 0.57) and tumour size (r = 0.5). In multiple regression analysis, soluble Klotho was associated with GH after correction for age, gender and levels of creatinine and phosphate (P = 0.029). After surgery, GH and IGF-1 levels decreased in all patients (from 26.3 ± 5.2 to 2.6 ± 0.6 lg L )1 , P < 0.0001, and from 588 ± 35 to 193 ± 12 lg L )1 , P < 0.001, 0.0001, respectively). Creatinine increased from 71 ± 3 to 80 ± 3 lmol L )1 (P < 0.001), and phosphate decreased from 1.37 ± 0.04 to 1.06 ± 0.02 mmol L )1 (P < 0.001). The markedly increased preoperative levels of soluble Klotho returned towards normal after surgery (0.7 ± 0.1 ng mL )1 , P < 0.0001).Conclusions. This is the first study to show dramatically increased soluble Klotho levels in an acquired disease in humans. Reversal following tumour removal suggests a causal relation between the GH-producing adenoma and high serum Klotho concentration in acromegaly.

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Section: Discussionmentioning

confidence: 99%

Excessively high soluble Klotho in patients with acromegaly

Sze

Bernays

Zwimpfer³

et al. 2012

Journal of Internal Medicine

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“…A progressive decrease in GH secretion has been hypothesized; however, recent experimental evidences have suggested that, besides the age-dependent decline of GH and IGF1 serum levels, dysregulation of GH and IGF1 action may be due to an impairment of the post-receptor signaling of GHR (42). In rodents, complete inhibition of GH action by disrupting or knocking out of the GHR gene (which resulted in GH resistance, elevated GH levels, and markedly reduced IGF1 levels) led to reduced muscle mass and BMD (43). In line with these observations, some authors reported that subjects receiving GH replacement therapy showed no significant changes in BMD (44,45), probably because of other mechanisms being involved in elderly subjects affected by pituitary disease (i.e.…”

Section: European Journal Of Endocrinologymentioning

confidence: 99%

GH receptor isoforms and skeletal fragility in acromegaly

Mormando¹,

Nasto²,

Bianchi³

et al. 2014

European Journal of Endocrinology

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Objective: Acromegaly is associated with an increased prevalence of vertebral fractures (VFs) in close relationship with GH hypersecretion. Two isoforms of the GH receptor (GHR) have been identified; the two isoforms differ or not by the expression of the protein fragment encoded by exon 3 of the GHR gene. Deletion of the exon 3 may influence the functional properties of the GHR and affect fracture risk in acromegalic patients. Design: A cross-sectional study was designed to investigate the association between the d3-GHR isoform and the prevalence of VFs in patients with acromegaly. Methods: In this study, 109 acromegalic patients were included (M/F, 48/61): 73 with controlled/cured acromegaly and 36 with active disease. GHR genotype was assessed in each patient. All patients were evaluated for VFs and bone mineral density at lumbar spine and hip. Serum IGF1 levels and bone metabolism markers were measured. A multivariate analysis was performed to establish risk factors for VFs in our population. Results: d3-GHR carriers showed an increased prevalence of VFs when compared with patients expressing full-length GHR (35/55 vs 12/54; P!0.001). The association between GHR deletion and VFs was demonstrated both in patients with active disease and in those with controlled/cured disease. Out of 35 patients who were prospectively evaluated, 13 (37.1%) developed incident VFs. The incidence of VFs was significantly higher in patients for whom the GHR gene has been deleted when compared with those harboring the fl gene (PZ0.04). In multivariate analysis, male sex (odds ratio (OR), 3.250; PZ0.041), IGF1 levels (OR, 1.183; PZ0.031), length of active diseases (OR, 1.038; PZ0.001), and d3-GHR genotype (OR, 3.060; PZ0.015) were all confirmed as risk factors of VFs in our population. Conclusions: This study suggests for the first time that exon 3 deletion of GHR may predispose patients with active and controlled acromegaly to a higher risk of VFs.

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“…Many physiological factors play an important role in aging, one of which is the growth factor Insulinlike (IGF) system. The researches show that local inhibition of signal pathway mediated by insulin like growth factor (Insulin-like growth factors, IGFs) lead to an increase in invertebrate and vertebrate model organisms, which may delay the aging [1]. The study of Caenorhabditis elegans for the first time found that the inhibition of signaling pathway of DAF-2 (encoding insulin-like growth factor-1 receptor,IGF-1R) could increase the lifespan [2][3][4].…”

Section: Introductionmentioning

confidence: 99%

Insulin-like Growth Factor System and Aging

Li¹,

Sun²,

Cai³

et al. 2017

J Aging Sci

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IGF (insulin-like growth factor, IGF) system is composed of three ligands (insulin, IGF-1, IGF-2), three cell surface binding receptors (Ins R, IGF-1R, IGF-2 R), and Insulin-like growth factor binding proteins (IGF binding proteins, IGFBPs) and IGFBP protease. Delaying aging and exploring the molecular mechanism of aging have always been important research topics. IGF system plays an important role in the life processes by binding with the receptor or activating multiple intracellular signaling cascades. The researches have showed IGF system plays an important role in regulating signal pathways about senescence and aging related diseases such as cardiovascular disease, osteoporosis and vertebral aging.

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Role of the GH/IGF-1 axis in lifespan and healthspan: Lessons from animal models

Cited by 255 publications

References 187 publications

Excessively high soluble Klotho in patients with acromegaly

Excessively high soluble Klotho in patients with acromegaly

GH receptor isoforms and skeletal fragility in acromegaly

Insulin-like Growth Factor System and Aging

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