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PLoS Genet:衰老关键基因或成抗衰老疗法的潜在靶标

来源:生物谷 2012-04-20 16:41

近日,伦敦大学国王学院的研究人员与威康信托基金会桑格研究所合作,发现一组“衰老”基因,这组基因能调控称为表观遗传因素自然机制的开启和闭合,该表观遗传因素自然机制影响老年人的健康和长寿率。

这项研究还揭示了由外部因素如饮食、生活方式和环境造成的表观遗传过程。研究人员说,他们已经确定的表观遗传变化可以作为潜在的生物衰老的标记物,并在未来可能用于抗衰老治疗的靶标。

相关研究论文发表在PLoS Genetics杂志上,研究人员基于伦敦大学国王学院和圣托马斯医院的数据分析研究了172对32至80岁的双胞胎。

研究者对双胞胎的DNA表观遗传变化进行了研究,并进行了表观基因组扫描分析。他发现490个与年龄有关的表观遗传变化。他们还分析了与年龄相关的DNA修改,发现四个基因的表观遗传变化与胆固醇、肺功能和产妇长寿等有关。

研究人员说这些结果表明,随着年龄的增长,许多与年龄有关的表观遗传变化发生一个人的整个生命中,这些变化可能在生命的早期阶段就开始了。

Jordana Bell博士来自伦敦大学国王学院,领导了这项研究。

我们发现许多与年龄有关的表观遗传变化,我们可以运用这些研究的结果成为老龄化的潜在标志物。这些结果可以帮助我们了解老龄人的基本健康情况以及与年龄有关的疾病的生物学机制。

伦敦大学国王学院Tim Spector教授表示:这项研究首次进行大规模的双胞胎研究,并找到的与衰老有关的关键基因。我们的生活方式可以修改这些基因,根据这些基因开发未来抗老化疗法将是非常激动人心的研究。(生物谷:Bioon.com)

Epigenome-Wide Scans Identify Differentially Methylated Regions for Age and Age-Related Phenotypes in a Healthy Ageing Population

Jordana T. Bell, Pei-Chien Tsai, Tsun-Po Yang, Ruth Pidsley, James Nisbet, Daniel Glass, Massimo Mangino,et al.

Age-related changes in DNA methylation have been implicated in cellular senescence and longevity, yet the causes and functional consequences of these variants remain unclear. To elucidate the role of age-related epigenetic changes in healthy ageing and potential longevity, we tested for association between whole-blood DNA methylation patterns in 172 female twins aged 32 to 80 with age and age-related phenotypes. Twin-based DNA methylation levels at 26,690 CpG-sites showed evidence for mean genome-wide heritability of 18%, which was supported by the identification of 1,537 CpG-sites with methylation QTLs in cis at FDR 5%. We performed genome-wide analyses to discover differentially methylated regions (DMRs) for sixteen age-related phenotypes (ap-DMRs) and chronological age (a-DMRs). Epigenome-wide association scans (EWAS) identified age-related phenotype DMRs (ap-DMRs) associated with LDL (STAT5A), lung function (WT1), and maternal longevity (ARL4A, TBX20). In contrast, EWAS for chronological age identified hundreds of predominantly hyper-methylated age DMRs (490 a-DMRs at FDR 5%), of which only one (TBX20) was also associated with an age-related phenotype. Therefore, the majority of age-related changes in DNA methylation are not associated with phenotypic measures of healthy ageing in later life. We replicated a large proportion of a-DMRs in a sample of 44 younger adult MZ twins aged 20 to 61, suggesting that a-DMRs may initiate at an earlier age. We next explored potential genetic and environmental mechanisms underlying a-DMRs and ap-DMRs. Genome-wide overlap across cis-meQTLs, genotype-phenotype associations, and EWAS ap-DMRs identified CpG-sites that had cis-meQTLs with evidence for genotype–phenotype association, where the CpG-site was also an ap-DMR for the same phenotype. Monozygotic twin methylation difference analyses identified one potential environmentally-mediated ap-DMR associated with total cholesterol and LDL (CSMD1). Our results suggest that in a small set of genes DNA methylation may be a candidate mechanism of mediating not only environmental, but also genetic effects on age-related phenotypes.

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