IGFBP1
Insulin-like growth factor-binding protein 1 precursor (IBP-1) (IGF-binding protein 1) (IGFBP-1) (Placental protein 12) (PP12) [IBP1]
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The association between aging and idiopathic pulmonary fibrosis is established. The associations between aging-related biomarkers and interstitial lung abnormalities (ILA) have not been comprehensively evaluated. Evaluate associations between aging biomarkers, ILA, and all-cause mortality. In the Framingham Heart Study (FHS), we evaluated associations between plasma biomarkers (interleukin-6 [IL-6], C-reactive protein [[[CRP]]], tumor necrosis factor alpha receptor II [TNFR], growth differentiation factor 15 [[[GDF15]]], cystatin-C, hemoglobin A1C [HGBA1C], insulin, insulin like growth factor [IGF] 1, and IGF binding proteins 1 and 3 [[[IGFBP1]] and 3]), ILA, and mortality. Causal inference analysis was used to determine if biomarkers mediated age. GDF15 results were replicated in COPDGene. In FHS, there was higher odds of ILA per increase in natural log-transformed (ln) GDF15 (OR [95% CI] = 3.4 [1.8-6.4], p=0.0002), TNFR (3.1 [1.6-5.8], p=0.004), IL-6 (1.8 [1.4-2.4], p<0.0001), and CRP (1.7 [1.3-2.0], p<0.0001). In FHS, after adjustment for multiple comparisons, no biomarker was associated with increased mortality, but GDF15 (HR = 2.0 [1.1-3.5], P=0.02), TNFR (1.8 [1.0-3.3], p=0.05), and IGFBP1 (1.3 [1.1-1.7], P=0.01) approached significance. In COPDGene, higher ln(GDF15) was associated with ILA (OR = 8.1 [3.1-21.4], p<0.0001) and mortality (HR = 1.6 [1.1-2.2], p=0.01). Causal inference analysis showed the association of age with ILA was mediated by IL-6 (p<0.0001), TNFR (p=0.002), and likely GDF15 (p=0.008) in FHS, and by GDF15 (p=0.001) in COPDGene. Some aging-related biomarkers are associated with ILA. GDF15, in particular, may explain some of the association between age, ILA, and mortality.
Keywords
- aging
- growth differentiation factor 15
- idiopathic pulmonary fibrosis
- interstitial lung abnormalities
- mortality
The senescence of vascular endothelial cells (ECs) plays a critical role in aging‑related cardiovascular diseases. We previously reported the causal relation of Jagged1 in ECs and the thickening of the arterial wall in aging mice. The aim of the present study was to further investigate the correlation between insulin‑like growth factor‑binding protein 1 (IGFBP1), one of the secretory proteins regulated by Jagged1, and the severity of coronary atherosclerosis and patient age, as well as its effect on EC senescence. First, microarray analysis was performed to screen the differentially expressed genes regulated by Jagged1 in human coronary arterial ECs (HCAECs). Inhibition of the Jagged1 expression using a small interfering RNA knockdown method in HCAECs led to the upregulation of 17 and the downregulation of 78 genes by >3‑fold, and IGFBP1 was confirmed to be a secretory protein expressed by HCAECs and regulated by Jagged1. Subsequently, in 112 consecutively enrolled patients with acute chest pain who underwent coronary angiography, the circulating level of IGFBP1 was found to be positively correlated with age (r=0.512, P<0.001) and Synergy between PCI with TAXUS and Cardiac Surgery (SYNTAX) score (r=0.409, P<0.001). Among age‑comparable patients, the circulating IGFBP1 level was found to be increased in patients with higher SYNTAX scores. In cultured HCAECs, IGFBP1 was shown to protect ECs against passage‑ or H2O2‑induced senescence, and these protective effects of IGFBP1 may be partially reversed by LY294002, a known Akt signaling inhibitor. Therefore, the results of the present study suggested that, as a downstream protein of Jagged1, IGFBP1 was correlated with the severity of coronary atherosclerosis in aging patients, and the increase of circulating IGFBP1 levels with aging may be an adaptive response to counter HCAEC senescence through Akt signaling.
MeSH Terms
- Adult
- Aged
- Aged, 80 and over
- Aging
- Atherosclerosis
- Cells, Cultured
- Cellular Senescence
- Coronary Artery Disease
- Coronary Vessels
- Down-Regulation
- Endothelial Cells
- Female
- Humans
- Insulin-Like Growth Factor Binding Protein 1
- Jagged-1 Protein
- Male
- Middle Aged
- Signal Transduction
- Up-Regulation
To investigate the impact of the androgen precursor dehydroepiandrosterone (DHEA) on the decidualization of human endometrial stromal cells isolated from women of advanced reproductive age. In vitro study. University research institute. Proliferative phase primary human endometrial stromal fibroblasts (hESFs) were isolated from women of advanced reproductive age (n = 16; mean age, 44.7 ± 2.3). None of the women were receiving hormone therapy or had endometriosis. Isolated hESFs were decidualized in vitro by incubation with P (1 μM) and cAMP (0.1 mg/mL) in the presence, or absence, of DHEA (10 nM, 100 nM). Secretion of androgens was assessed by ELISA. Expression of decidualization markers and endometrial receptivity markers was assessed by quantitative polymerase chain reaction and ELISA. Decidualization responses were retained in hESF isolated from women of advanced reproductive age. Supplementation with DHEA increased androgen biosynthesis and concentrations of T and dihydrotestosterone were ∼3× greater after coincubation with DHEA compared with hESF stimulated with decidualization alone. Addition of DHEA to decidualized hESF increased expression of the decidualization markers IGFBP1 and PRL and the endometrial receptivity marker SPP1. DHEA enhanced secretion of IGFBP1, PRL, and SPP1 proteins maximally by day 8 of the decidualization time course concomitant with peak androgen concentrations. These novel results demonstrate DHEA can enhance in vitro decidualization responses of hESF from women of advanced reproductive age. Supplementation with DHEA during the receptive phase may augment endometrial function and improve pregnancy rates in natural or assisted reproductive cycles.
MeSH Terms
- Adult
- Biomarkers
- Cell Proliferation
- Cells, Cultured
- Decidua
- Dehydroepiandrosterone
- Dihydrotestosterone
- Female
- Fibroblasts
- Humans
- Insulin-Like Growth Factor Binding Protein 1
- Maternal Age
- Middle Aged
- Osteopontin
- Prolactin
- Reproductive Health
- Stromal Cells
- Time Factors
Keywords
- DHEA
- aging
- androgens
- decidualization
- fertility
Senescent changes in body composition and muscle strength are accompanied by reduced production of GH and IGF1, but the causal relationship remains elusive. We speculate that serum bioactive IGF1, measured by the IGF1 kinase receptor activation assay, is closer related to human physiological ageing than total IGF1 measured by immunoassay. We conducted a cross-sectional study in 150 adult males and females, between 20 and 70 years. After an overnight fasting, serum levels of bioactive IGF1, total IGF1 and IGF-binding protein 1 (IGFBP1) and IGFBP3 were assessed. Furthermore, body composition and muscle strength was measured. Total IGF1 levels were higher in females (P=0.048). Bioactive IGF1 were identical in males and females (P=0.31), decreasing with age. Total IGF1 tended to decrease more with age compared with bioactive IGF1 (-1.48 vs -0.89 percent/year, P=0.052). Total body fat (TBF) was lower and BMI was higher in males (P<0.001 and P=0.005), and both increased with age. Knee extension and elbow flexion force were higher in males (P=0.001 and P=0.001), but decreased with age in both genders. Total but not bioactive IGF1 was positively correlated to TBF, knee extension and muscle function in males. In multiple linear regression, only age predicted total IGF1, whereas age and IGFBP1 predicted bioactive IGF1. Bioactive IGF1 tends to decrease to a lesser extent than total IGF1 with age and was not correlated with measures of body composition or muscle strength. Therefore, levels of circulating bioactive IGF1 does not appear to be a better biomarker of physiological ageing than total IGF1.
MeSH Terms
- Adult
- Aged
- Aging
- Body Composition
- Body Mass Index
- Cross-Sectional Studies
- Female
- Humans
- Insulin-Like Growth Factor Binding Protein 1
- Insulin-Like Growth Factor Binding Protein 3
- Insulin-Like Growth Factor I
- Male
- Middle Aged
- Muscle Strength
- Sex Factors