Age-dependent skewing of X chromosome inactivation appears delayed in centenarians' offspring. Is there a role for allelic imbalance in Healthy Aging and Longevity?
Age-dependent skewing of X chromosome inactivation appears delayed in centenarians' offspring. Is there a role for allelic imbalance in Healthy Aging and Longevity?
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DOI：
10.1111/j.1474-9726.2012.00790.x
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发表时间：
2012-04-01
期刊：
影响因子：
7.8
通讯作者：
Vitale, Giovanni
中科院分区：
文献类型：
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作者：
Gentilini, Davide;Castaldi, Davide;Vitale, Giovanni
最近，有人提出年龄相关的X染色体失活(XCI)偏斜在临床上可导致迟发性X连锁疾病。这一观察结果导致了一种假设，即与年龄相关的偏斜的XCI也可能影响女性的寿命。为了研究这一问题，我们采用了一种新的长寿和健康老龄化的实验模型，包括55名百岁女性、40名她们的后代、33名年龄匹配的非长寿父母的后代和41名年轻女性。对169名女性外周血DNA进行了Humara基因座杂合性筛查。我们证实了XCI的偏斜是一种年龄相关的现象。然而，与年龄匹配的非长寿父母的子女(DS=0.24+/-0.02)相比，百岁老人子女的XCI偏斜的严重程度和频率显著降低[偏斜度(DS)=0.16+/-0.02](P<；0.05)。第二个目标是评估XCI模式的变化是否可能是X染色体甲基化缺失的结果。使用甲基化阵列评估了X染色体上的1085个CpG位点和Humara基因座上的11个CpG位点，所有被分析的组之间的甲基化水平和分布没有差异，因此表明与年龄相关的表观遗传学变化不会影响Humara的结果。总之，这里提出的结果首次强调了XCI偏斜与健康衰老和长寿之间的有趣联系。我们推测，XCI偏斜产生的等位基因不平衡可能损害了组成雌性马赛克的两个细胞群体之间发生的合作和补偿组织。
Recently, it has been proposed that age-related X chromosome inactivation (XCI) skewing can clinically result in late-onset X-linked disorders. This observation leads to hypothesize that age-related skewed XCI might also influence lifespan in women. To investigate this issue, we employed a new experimental model of longevity and healthy aging including 55 female centenarians, 40 of their offspring, 33 age-matched offspring of both non-long-lived parents and 41 young women. Peripheral blood DNA from 169 females was screened for heterozygosity at the HUMARA locus. We confirmed that skewing of XCI is an age-dependent phenomenon. However, skewed XCI was significantly less severe and frequent in centenarians offspring [degree of skewing (DS) = 0.16 +/- 0.02] compared to age-matched offspring of both non-long-lived parents (DS = 0.24 +/- 0.02) (P < 0.05). A second goal was to assess whether changes in XCI pattern could be a consequence of loss of methylation on X chromosome. Using a methylation array evaluating 1085 CpG sites across X chromosome and eleven CpG sites located at HUMARA locus, no differences in methylation levels and profiles emerged between all groups analysed, thus suggesting that age-associated epigenetic changes could not influence HUMARA results. In conclusion, the results presented herein highlight for the first time an interesting link between skewing of XCI and healthy aging and longevity. We speculate that the allelic imbalance produced by XCI skewing may compromise the cooperative and compensatory organization occurring between the two cell populations that make up the female mosaic.