Foley Erin E B, Thomas Christian L, Kyriacou Charalambos P, Mallon Eamonn B
Department of Genetics, Genomics and Cancer Sciences, University of Leicester, Leicester LE1 7RH, United Kingdom.
Proc Natl Acad Sci U S A. 2025 Aug 5;122(31):e2513020122. doi: 10.1073/pnas.2513020122. Epub 2025 Jul 28.
Epigenetic clocks based on DNA methylation provide robust biomarkers of biological age, yet the mechanistic basis and functional significance of slowing these clocks remain unclear. Progress has been limited by the lack of short-lived, genetically tractable model organisms with functional DNA methylation systems. The jewel wasp, , offers a unique solution. It combines a functional DNA methylation system with a short lifespan and established tools for experimental manipulation. We previously developed an epigenetic clock in , but whether this clock reflects plastic, environmentally driven aging processes was unknown. Here, we test this directly by experimentally inducing larval diapause, a naturally occurring developmental arrest triggered by environmental cues. Diapause extended median adult lifespan by 36% and significantly slowed the rate of epigenetic aging. Using whole-genome bisulfite sequencing across multiple adult timepoints, we show that while adults that have passed through diapause as larvae initially emerge epigenetically older, their subsequent epigenetic aging proceeds 29% more slowly than adults that have not passed through diapause as larvae. Clock CpGs were enriched for gene ontology terms related to conserved nutrient-sensing and developmental pathways, including insulin/IGF signaling and mTOR, supporting the established mechanistic link between development and epigenetic aging. These findings demonstrate that epigenetic aging is plastic in and can be experimentally modulated by early-life environment, establishing this animal model as a tractable system for dissecting the causal mechanisms of epigenetic aging.
基于DNA甲基化的表观遗传时钟提供了强大的生物学年龄生物标志物，但减缓这些时钟的机制基础和功能意义仍不清楚。由于缺乏具有功能性DNA甲基化系统的短命、遗传上易于处理的模式生物，进展有限。宝石黄蜂提供了一个独特的解决方案。它将功能性DNA甲基化系统与短寿命和成熟的实验操作工具结合在一起。我们之前在宝石黄蜂中开发了一种表观遗传时钟，但尚不清楚这个时钟是否反映了可塑性的、环境驱动的衰老过程。在这里，我们通过实验诱导幼虫滞育来直接测试这一点，幼虫滞育是一种由环境线索触发的自然发生的发育停滞。滞育使成虫的平均寿命延长了36%，并显著减缓了表观遗传衰老的速度。通过对多个成虫时间点进行全基因组亚硫酸氢盐测序，我们发现，虽然幼虫经历过滞育的成虫最初表观遗传年龄更大，但它们随后的表观遗传衰老速度比幼虫未经历过滞育的成虫慢29%。时钟相关的CpG在与保守的营养感应和发育途径相关的基因本体术语中富集，包括胰岛素/胰岛素样生长因子信号传导和mTOR，这支持了发育与表观遗传衰老之间已确立的机制联系。这些发现表明，在宝石黄蜂中表观遗传衰老具有可塑性，并且可以通过早期生活环境进行实验调节，从而将这种动物模型确立为剖析表观遗传衰老因果机制的易于处理的系统。
