Abstract
BackgroundIn mammals, the IGF-1 pathway affects the phenotype of aging. Since the function of the immune system is modulated by IGF-1, it is plausible that immunosenescence might in part result from altered control by this pathway. We therefore examined whether the expression of IGF-1R, FOXO1, and FOXO3a in peripheral blood mononuclear cells (PBMC) changes with age and if this might be due to changes in the expression of select miRNAs.MethodsThe expression of IGF-1R, FOXO1, FOXO3a, as well as of miR-9, miR-96, miR-99a, miR-132, miR-145, and miR-182 was examined in PBMC of young (27.8 ± 3.7 years), elderly (65.6 ± 3.4 years), and long-lived (94.0 ± 3.7 years) Polish Caucasians using real-time PCR. mRNA/miRNA interactions were studied in HEK 293 cells using luciferase-expressing pmirGLO reporter vector.ResultsThe median expression of IGF-1R decreased with age (p < 0.000001), as did the expression of FOXO1 (p < 0.000001), while the expression of FOXO3a remained stable. We also found an age-associated increase of the median expression of miR-96 (p = 0.002), miR-145 (p = 0.024) and miR-9 (p = 0.026), decrease of the expression of miR-99a (p = 0.037), and no changes regarding miR-132 and miR-182. Functional studies revealed that miR-96 and miR-182 interacted with human IGF-1R mRNA, and that miR-145 and miR-132 interacted with human FOXO1 mRNA.ConclusionsThe age-associated higher expression of miR-96 and miR-145 might contribute to the lower expression of IGF-1R while the higher expression of miR-96, miR-145 and miR-9 might contribute to the lower expression of FOXO1 in peripheral blood mononuclear cells of aging humans. Sustained expression/function of FOXO3a but not of the other two genes might be important for the maintenance of the immune system function in these individuals.
Highlights
In mammals, the IGF-1 pathway affects the phenotype of aging
Expression of the Insulin-like growth factor-1 receptor (IGF-1R), Forkhead box O1 transcription factor (FOXO1), and Forkhead box O3a transcription factor (FOXO3a) mRNA in peripheral blood mononuclear cells (PBMC) of young, elderly, and long-lived individuals We first established whether age affected the mean Cp values for the Gene encoding β-actin (ACTB) control gene
In this work we showed that the expression of key components of the IGF-1 pathway, the IGF1-R and FOXO1 genes, decreases with age, while the median expression of FOXO3a remains stable in PBMC of aging humans
Summary
The IGF-1 pathway affects the phenotype of aging. Since the function of the immune system is modulated by IGF-1, it is plausible that immunosenescence might in part result from altered control by this pathway. Stimulation of IGF-1R leads to Akt-dependent phosphorylation of FOXO, its sequestration in the cytoplasm, and to inhibition of its longevity-promoting activity [9, 10],while overexpression of FOXO increases the duration of life [11, 12]. Involvement of this pathway in longevity control was further confirmed in Drosophila melanogaster [13, 14]. It is well established that modifications of this pathway significantly affect the phenotype of aging, as age-related decrease in circulating IGF-1 levels contributes to the development of cardiovascular disease, stroke, type 2 diabetes mellitus, osteoporosis, sarcopenia, and frailty but, at the same time, lowers the risk of cancer [23,24,25,26,27,28]
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