Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
The Danish Twin registry and the Danish Aging Research Center at Epidemiology, Biostatistics and Biodemography, Department of Public Health, University of Southern Denmark, Odense, Denmark.
EBioMedicine. 2019 Feb;40:710-716. doi: 10.1016/j.ebiom.2019.01.040. Epub 2019 Jan 28.
BACKGROUND: Measures based on DNA methylation, epigenetic clocks, have recently gained attraction as predictors of mortality and age-related pathologies. However, the origins of variation in these measures are not well understood. METHODS: In a pooled sample of 104 Swedish and Danish twin pairs, we estimated, at the mean age of 70 (baseline) and 79 years (follow-up), the genetic and environmental influences on the Horvath and Levine clocks. FINDINGS: A model incorporating additive genetic (A) and person-specific environmental (E) influences best explained the variation in both clocks. Heritability was estimated at 55% at baseline and at 51% at follow-up for the Horvath clock and 34% at baseline and 41% at follow-up for the Levine clock. For the Horvath clock, new sources of A influences emerged at follow-up, whereas for the Levine clock, the same A influences accounted for the genetic variance at both measurement occasions. The cross-time phenotypic correlations, 0·52 for the Horvath clock and 0·36 for the Levine clock, were mediated primarily by genetic factors, whereas the person-specific environmental factors were completely different at the two measurement occasions. INTERPRETATION: For both clocks, new sources of person-specific environmental influences emerge with age. The epigenetic clocks might thus be responsive to new environmental stimuli even at old age. FUND: NIH (R01;AG04563;AG10175;AG028555) the MacArthur Foundation Research Network on Successful Aging, FAS/FORTE (97:0147:1B;2009-0795), Swedish Research Council (825-2007-7460;825-2009-6141;521-2013-8689;2015-03255;2015-06796;2018-02077), FORTE (2013-2292), the Strategic Research Program in Epidemiology at KI, VELUX FOUNDATION, NIA (P01-AG08761), the EU (FP7/2007-2011;259679) and The Danish National Program for Research Infrastructure 2007 (9-063256).
背景:基于 DNA 甲基化的表观遗传时钟最近作为预测死亡率和与年龄相关的病理的指标受到关注。然而,这些指标的变化来源尚不清楚。
方法:在 104 对瑞典和丹麦双胞胎的合并样本中,我们在平均年龄为 70 岁(基线)和 79 岁(随访)时,估计了 Horvath 和 Levine 时钟的遗传和环境影响。
发现:一个包含加性遗传(A)和个体特异环境(E)影响的模型最好地解释了两个时钟的变化。在基线时,Horvath 时钟的遗传率估计为 55%,在随访时为 51%;Levine 时钟的遗传率估计为 34%,在基线时为 41%,在随访时为 41%。对于 Horvath 时钟,新的 A 影响源在随访时出现,而对于 Levine 时钟,相同的 A 影响在两个测量时间点上都解释了遗传方差。Horvath 时钟的跨时间表型相关系数为 0.52,Levine 时钟的表型相关系数为 0.36,主要由遗传因素介导,而个体特异环境因素在两个测量时间点上完全不同。
解释:对于两个时钟,新的个体特异环境影响源随着年龄的增长而出现。因此,表观遗传时钟可能会对老年时的新环境刺激做出反应。
资助:美国国立卫生研究院(R01;AG04563;AG10175;AG028555)成功老龄化麦克阿瑟基金会研究网络、FAS/FORTE(97:0147:1B;2009-0795)、瑞典研究理事会(825-2007-7460;825-2009-6141;521-2013-8689;2015-03255;2015-06796;2018-02077)、FORTE(2013-2292)、KI 流行病学战略研究计划、VELUX 基金会、NIA(P01-AG08761)、欧盟(FP7/2007-2011;259679)和丹麦国家研究基础设施计划 2007(9-063256)。
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