Cell-to-cell variation in gene expression increases among homologous cells within multiple tissues during aging. We call this phenomenon variegated gene expression (VGE). Long, healthy life requires robust and coordinated gene expression. We posit that nature may have evolved VGE as a bet-hedging mechanism to protect reproductively active populations. The price we may pay is accelerated aging. That hypothesis will require the demonstration that genetic loci are capable of modulating degrees of VGE. While loci controlling VGE in yeast and genes controlling inter-individual variation in gene expression in C. elegans have been identified, there has been no compelling evidence for the role of specific genetic loci in modulations of VGE of specific targets in humans. With the assistance of a core facility, we used a customized library of siRNA constructs to screen 1,195 human genes to identify loci contributing to the control of VGE of a gene with relevance to the biology of aging. We identified approximately 50 loci controlling VGE of the prolongevity gene, SIRT1. Because of its partial homology to FOXO3A, a variant of which is enriched in centenarians, our lab independently confirmed that the knockdown of FOXF2 greatly diminished VGE of SIRT1 but had little impact upon the VGE of WRN. While the role of these VGE-altering genes on aging in vivo remains to be determined, we hypothesize that some of these genes can be targeted to increase functionality during aging.

中文翻译：

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培养的人类细胞的基因表达中的细胞间差异反过来由不同的基因控制：衰老的病理生物学意义。

在衰老期间，多个组织内的同源细胞之间基因表达的细胞间变化增加。我们称这种现象为杂色基因表达（VGE）。长期健康的生活需要稳定而协调的基因表达。我们认为自然界可能已经将VGE演变为保护生殖活跃人口的对冲机制。我们可能要付出的代价是加速老化。该假设需要证明遗传基因座能够调节VGE的程度。虽然已经确定了控制酵母中VGE的基因座和控制秀丽隐杆线虫基因表达的个体间差异的基因，但尚无令人信服的证据表明特定基因座在人类特定靶标VGE调节中的作用。在核心设施的协助下，我们使用定制的siRNA构建文库筛选了1,195个人类基因，以鉴定与衰老生物学相关的基因VGE调控位点。我们确定了大约50个控制延长基因SIRT1的VGE的基因座。由于它与FOXO3A的部分同源性，它的变体富含百岁老人，我们的实验室独立地证实，敲低FOXF2可以大大减少SIRT1的VGE，但对WRN的VGE影响很小。尽管这些改变VGE的基因在体内衰老中的作用尚待确定，但我们假设这些基因中的某些可被靶向增加衰老过程中的功能。我们确定了大约50个控制延长基因SIRT1的VGE的基因座。由于它与FOXO3A的部分同源性，它的变体富含百岁老人，我们的实验室独立地证实，敲低FOXF2可以大大减少SIRT1的VGE，但对WRN的VGE影响很小。尽管这些改变VGE的基因在体内衰老中的作用尚待确定，但我们假设这些基因中的某些可被靶向增加衰老过程中的功能。我们确定了大约50个控制延长基因SIRT1的VGE的基因座。由于它与FOXO3A的部分同源性，它的变体富含百岁老人，我们的实验室独立地证实，敲低FOXF2可以大大减少SIRT1的VGE，但对WRN的VGE影响很小。尽管这些改变VGE的基因在体内衰老中的作用尚待确定，但我们假设这些基因中的某些可被靶向增加衰老过程中的功能。