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Association of the insulin-like growth factor binding protein 3 (IGFBP-3) polymorphism with longevity in Chinese nonagenarians and centenarians.

ABSTRACT: Human lifespan is determined greatly by genetic factors and some investigations have identified putative genes implicated in human longevity. Although some genetic loci have been associated with longevity, most of them are difficult to replicate due to ethnic differences. In this study, we analyzed the association of 18 reported gene single nucleotide polymorphisms (SNPs) with longevity in 1075 samples consisting of 567 nonagenarians/centenarians and 508 younger controls using the GenomeLab SNPstream Genotyping System. Our results confirm the association of the forkhead box O3 (FOXO3) variant (rs13217795) and the ATM serine/threonine kinase (ATM) variant (rs189037) genotypes with longevity (p=0.0075 and p=0.026, using the codominant model and recessive model, respectively). Of note is that we first revealed the association of insulin-like growth factor binding protein 3 (IGFBP-3) gene polymorphism rs11977526 with longevity in Chinese nonagenarians/centenarians (p=0.033 using the dominant model and p=0.035 using the overdominant model). The FOXO3 and IGFBP-3 form important parts of the insulin/insulin-like growth factor-1 signaling pathway (IGF-1) implicated in human longevity, and the ATM gene is involved in sensing DNA damage and reducing oxidative stress, therefore our results highlight the important roles of insulin pathway and oxidative stress in the longevity in the Chinese population.

SUBMITTER: He YH

PROVIDER: S-EPMC4276788 | biostudies-literature | 2014 Nov

REPOSITORIES: biostudies-literature

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Association of the insulin-like growth factor binding protein 3 (IGFBP-3) polymorphism with longevity in Chinese nonagenarians and centenarians.

He Yong-Han YH Lu Xiang X Yang Li-Qin LQ Xu Liang-You LY Kong Qing-Peng QP

Aging 20141101 11

Human lifespan is determined greatly by genetic factors and some investigations have identified putative genes implicated in human longevity. Although some genetic loci have been associated with longevity, most of them are difficult to replicate due to ethnic differences. In this study, we analyzed the association of 18 reported gene single nucleotide polymorphisms (SNPs) with longevity in 1075 samples consisting of 567 nonagenarians/centenarians and 508 younger controls using the GenomeLab SNPs ...[more]

PMID: 25553725

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Project description:BackgroundLarge fluctuations in blood glucose levels greatly impact the health and life span of elderly individuals. This study describes the characteristics of variability in glycemic indices in centenarians with the aim of emphasizing the importance of glycemic variability in elderly people.MethodsWe recruited individuals from Rugao City, Jiangsu Province, China from April 2020 to May 2021. The study cohort included 60 centenarians and 60 first-generation offspring, as well as 20 randomly selected non-cohabitant control individuals aged 60-80 years. A FreeStyle Libre H (hospital version) continuous glucose monitoring (CGM) device (Abbott Ireland UK) was used to measure glycemic variability. The indices measured included the time in target glucose range (TIR), time below target glucose range (TBR), time above target glucose range (TAR), mean amplitude of glycemic excursions (MAGE), mean of daily differences (MODD), coefficient of variation (CV), standard deviation of blood glucose (SDBG), continuous overlapping net glycemic action (CONGA), glucose management indicator (GMI) and estimated glycated hemoglobin (eHbA1c). Logistic regression was used to analyze the association between glycemic variability and longevity.ResultsMean blood glucose (MBG), eHbA1c, GMI, mean fasting plasma glucose (M-FPG) and CONGA were lower in the centenarian group (p all < 0.05). PPGE-2 was higher in the control group than that measured in the centenarian and first-generation offspring groups (p < 0.05). There were no differences between the groups in MAGE, MODD, MAG, or TIR (p > 0.05). The risk of not achieving longevity increased with each one unit increase in MBG by 126% [2.26 (1.05-4.91)], eHbA1c by 67% [1.67 (1.03-2.72)], GMI by 568% [6.68 (1.11-40.30)], M-FPG by 365% [4.65 (1.57-13.75)], M-PPG1h by 98% [1.98 (1.18-3.31)], CONGA1 by 102% [2.02 (1.01-4.06)], Li by 200% [3.00 (1.04-8.61)], and PPGE-2 by 150% [2.50 (1.39-4.50)]. However, the risk of achieving longevity decreased with each unit increase of LBGI by 53% [0.47 (0.28-0.80)], ADRR by 60% [0.40 (0.18-0.86)], and TBR by 11% [0.89 (0.80-0.98)].ConclusionFluctuation in blood glucose levels in centenarians is relatively small. Maintaining an average blood glucose level and keeping blood glucose fluctuations in the normal range is conducive to longevity.

Project description:IGFBP-1 is elevated in fetuses with long-term, chronic hypoxia and intrauterine growth restriction. We investigated the hypothesis that hypoxia regulates IGFBP-1 in the human fetus in vivo and IGFBP-1 gene expression and protein in vitro. Umbilical artery IGFBP-1 levels (mean +/- SEM) from term babies with respiratory acidosis (acute hypoxia), normal babies, and those with mixed respiratory/metabolic acidosis (more profound and prolonged hypoxia) were measured using an immunoradiometric assay. IGFBP-1 levels were similar in normal (n = 12) and acutely hypoxic (n = 6) babies (189.1 +/- 71.8 vs. 175.8 +/- 45.9 ng /ml, respectively, P = 0.789). However, with more profound and prolonged hypoxia (n = 19), IGFBP-1 levels were markedly elevated (470.6 +/- 80.0 ng /ml, P = 0.044). To investigate IGFBP-1 regulation by hypoxia in vitro, HepG2 cells were incubated under hypoxia (pO2 = 2%) and normoxia (pO2 = 20%). IGFBP-1 protein and mRNA increased 8- and 12-fold, respectively, under hypoxic conditions. Hypoxia did not affect protein or mRNA levels of IGFBP-2 or -4. IGFBP-5 and -6 mRNAs, undetectable in control cells, were not induced by hypoxia, whereas minimally expressed IGFBP-3 mRNA increased twofold. Investigation into IGFBP-1 gene structure revealed three potential consensus sequences for the hypoxia response element (HRE) in the first intron. To investigate functionality, a 372-bp fragment of IGFBP-1 intron 1, containing putative HREs, was placed 5' to a heterologous hsp70 promoter in a plasmid using luciferase as a reporter gene. Under hypoxia, reporter gene activity increased up to 30-fold. Mutations in the middle HRE abolished reporter activity in response to hypoxia, suggesting that this HRE is functional in the IGFBP-1 hypoxia response. Cotransfection of HRE reporter genes with a constitutively expressing hypoxia-inducible factor 1 plasmid in HepG2 cells resulted in a fourfold induction of reporter activity, suggesting a role for hypoxia-inducible factor 1 in hypoxia induction of IGFBP-1 gene expression. These data support the hypothesis that hypoxia regulation of IGFBP-1 may be a mechanism operating in the human fetus to restrict insulin-like growth factor-mediated growth in utero under conditions of chronic hypoxia and limited substrate availability.

Project description:INTRODUCTION:Genetic factors contribute to the variation of human life span which is believed to be more profound after 85 years of age. The aim of the present study was to evaluate the frequency of 5 gene polymorphisms between nonagenarians, centenarians and average individuals. MATERIAL AND METHODS:Single nucleotide polymorphisms (SNPs) of telomerase reverse transcriptase (TERT; rs2736098), insulin-like growth factor-1 binding protein-3 (IGFBP3; A-202C, rs2857744), fork-head box O3A (FOXO3A; rs13217795 and rs2764264) factor and adiponectin (ADIPOQ; rs2241766) were evaluated in 405 individuals: n = 256 nonagenarians and centenarians (study group) and n = 149 average lifespan individuals (control group aged 18 - < 80 years). RESULTS:The frequency of women was significantly higher in the study group than the control group (64.5 vs. 49.7%, p = 0.004). Genotypic and allele frequencies did not differ between groups according to gender. However, in men, the frequency of TT genotype of FOXO3A; rs2764264 was higher in the study group than the control group (45.6 vs. 28.0%, p = 0.05). Overall, the frequency of the C allele of FOXO3A; rs2764264 was significantly lower in the study group than the control group (3.9 vs. 9.5%, respectively, p = 0.023). Furthermore, in the study group, the T allele was significantly more frequent in the nonagenarians (n = 239) than the centenarians (n = 17) in both FOXO3A; rs13217795 and rs2764264 (64.4 vs. 44.1%, p = 0.018 and 69.7 vs. 50.0%, p = 0.017, respectively). CONCLUSIONS:According to survival status, there is differentiation in the prevalence of both studied FOXO3A gene polymorphisms. The study group had half of the C alleles compared with the control group and centenarians less frequently had the T allele of both FOXO3A gene polymorphisms compared with nonagenarians. No difference was found between groups according to TERT, IGFBP3 and ADIPOQ gene polymorphisms. It seems that some polymorphisms may be significant in prolonging our lifespan. Nevertheless, confirmation in additional study populations is needed.

Dataset Information

Association of the insulin-like growth factor binding protein 3 (IGFBP-3) polymorphism with longevity in Chinese nonagenarians and centenarians.

Publications

Association of the insulin-like growth factor binding protein 3 (IGFBP-3) polymorphism with longevity in Chinese nonagenarians and centenarians.

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