Insights into ageing rates comparison across tissues from recalibrating cerebellum DNA methylation clock.
Insights into ageing rates comparison across tissues from recalibrating cerebellum DNA methylation clock.
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通过重新校准小脑DNA甲基化时钟对不同组织的老化率比较的见解。
DOI：
10.1007/s11357-023-00871-w
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发表时间：
2024-02
期刊：
影响因子：
5.6
通讯作者：
Schalkwyk, Leonardo C.
中科院分区：
文献类型：
--
作者：
Wang, Yucheng;Grant, Olivia A.;Zhai, Xiaojun;Mcdonald-Maier, Klaus D.;Schalkwyk, Leonardo C.
基于DNA甲基化（DNAm）的年龄钟作为人类衰老的生物标志物和年龄相关疾病的危险因素已被广泛研究。尽管不同的组织具有截然不同的增殖速率，但它们是否以不同的速率老化仍然是未知的。以前有报道称小脑的衰老速度很慢;然而，这一说法是使用相对较小的样本量从单个时钟中得出的，因此需要进一步调查。我们收集了迄今为止最大的小脑DNA数据集（N = 752）。我们发现，六个代表性的DNA年龄时钟都严重低估了各自的表观遗传年龄，其中低估效应在训练数据集不包括大脑相关组织的四个时钟中更为明显。我们在小脑中鉴定了613个年龄相关的CpG，仅占同一人群中颞中回（N = 404）中发现的数量的14.5%。从613个小脑年龄相关的CpG中，我们建立了一个高度准确的小脑年龄预测模型，称为小脑时钟特异性模型（Pearson相关系数= 0.941，MAD = 3.18岁）。基于在201个重叠的年龄相关CpG上构建的两个组织特异性时钟的衰老速率比较支持小脑具有更年轻的DNA年龄。然而，我们构建了BrainCortexClock来证明单个DNAm时钟能够无偏地估计小脑和大脑皮层的DNAm年龄，当它们在训练数据集中得到充分和平等的表示时。使用DNA甲基化多组织时钟比较组织间的衰老率是有缺陷的。以往的年龄钟对小脑年龄预测的低估主要反映了这些年龄钟的使用不当。小脑甲基化存在强烈和一致的衰老效应，我们认为小脑中与年龄相关的CpG位点数量较少主要归因于其极低的平均细胞复制率。在线版本包含补充材料，可通过10.1007/s11357 - 023 - 00871-w获得。
DNA methylation (DNAm)-based age clocks have been studied extensively as a biomarker of human ageing and a risk factor for age-related diseases. Despite different tissues having vastly different rates of proliferation, it is still largely unknown whether they age at different rates. It was previously reported that the cerebellum ages slowly; however, this claim was drawn from a single clock using a relatively small sample size and so warrants further investigation. We collected the largest cerebellum DNAm dataset (N = 752) to date. We found the respective epigenetic ages are all severely underestimated by six representative DNAm age clocks, with the underestimation effects more pronounced in the four clocks whose training datasets do not include brain-related tissues. We identified 613 age-associated CpGs in the cerebellum, which accounts for only 14.5% of the number found in the middle temporal gyrus from the same population (N = 404). From the 613 cerebellum age-associated CpGs, we built a highly accurate age prediction model for the cerebellum named CerebellumClockspecific (Pearson correlation=0.941, MAD=3.18 years). Ageing rate comparisons based on the two tissue-specific clocks constructed on the 201 overlapping age-associated CpGs support the cerebellum has younger DNAm age. Nevertheless, we built BrainCortexClock to prove a single DNAm clock is able to unbiasedly estimate DNAm ages of both cerebellum and cerebral cortex, when they are adequately and equally represented in the training dataset. Comparing ageing rates across tissues using DNA methylation multi-tissue clocks is flawed. The large underestimation of age prediction for cerebellums by previous clocks mainly reflects the improper usage of these age clocks. There exist strong and consistent ageing effects on the cerebellar methylome, and we suggest the smaller number of age-associated CpG sites in cerebellum is largely attributed to its extremely low average cell replication rates. The online version contains supplementary material available at 10.1007/s11357-023-00871-w.
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影响因子：
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作者：
Hannum, Gregory;Guinney, Justin;Zhao, Ling;Zhang, Li;Hughes, Guy;Sadda, SriniVas;Klotzle, Brandy;Bibikova, Marina;Fan, Jian-Bing;Gao, Yuan;Deconde, Rob;Chen, Menzies;Rajapakse, Indika;Friend, Stephen;Ideker, Trey;Zhang, Kang
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DOI：
10.1126/science.aaz6876
发表时间：
2020-09-11
期刊：
Science (New York, N.Y.)
影响因子：
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作者：
Demanelis K;Jasmine F;Chen LS;Chernoff M;Tong L;Delgado D;Zhang C;Shinkle J;Sabarinathan M;Lin H;Ramirez E;Oliva M;Kim-Hellmuth S;Stranger BE;Lai TP;Aviv A;Ardlie KG;Aguet F;Ahsan H;GTEx Consortium;Doherty JA;Kibriya MG;Pierce BL
通讯作者：
Pierce BL
DOI：
10.1093/gerona/glw185
发表时间：
2017-08-01
影响因子：
5.1
作者：
Bacalini, Maria Giulia;Deelen, Joris;Garagnani, Paolo
通讯作者：
Garagnani, Paolo