Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang, China.
School of Life Sciences, Westlake University, Hangzhou, Zhejiang, China.
Cell Res. 2023 Nov;33(11):821-834. doi: 10.1038/s41422-023-00854-8. Epub 2023 Jul 27.
Maternal age at childbearing has continued to increase in recent decades. However, whether and how it influences offspring adult traits are largely unknown. Here, using adult body size as the primary readout, we reveal that maternal rather than paternal age has an evolutionarily conserved effect on offspring adult traits in humans, Drosophila, and Caenorhabditis elegans. Elucidating the mechanisms of such effects in humans and other long-lived animals remains challenging due to their long life course and difficulties in conducting in vivo studies. We thus employ the short-lived and genetically tractable nematode C. elegans to explore the mechanisms underlying the regulation of offspring adult trait by maternal aging. By microscopic analysis, we find that old worms transmit aged mitochondria with a donut-like shape to offspring. These mitochondria are rejuvenated in the offspring's early life, with their morphology fully restored before adulthood in an AMPK-dependent manner. Mechanistically, we demonstrate that early-life mitochondrial dysfunction activates AMPK, which in turn not only alleviates mitochondrial abnormalities but also activates TGFβ signaling to increase offspring adult size. Together, our findings provide mechanistic insight into the ancient role of maternal aging in shaping the traits of adult offspring.
近年来，生育年龄持续增加。然而，它是否以及如何影响后代的成年特征在很大程度上是未知的。在这里，我们使用成年体型作为主要指标，揭示了母本年龄而不是父本年龄对人类、果蝇和秀丽隐杆线虫的后代成年特征具有进化保守的影响。由于人类和其他长寿动物的生命周期长，并且进行体内研究困难，阐明这种影响的机制仍然具有挑战性。因此，我们利用寿命短且遗传上易于处理的线虫秀丽隐杆线虫来探索母本衰老调节后代成年特征的机制。通过显微镜分析，我们发现年老的线虫将具有甜甜圈形状的衰老线粒体传递给后代。这些线粒体在后代的早期生命中得到了恢复，其形态在成年前完全以 AMPK 依赖的方式得到了恢复。在机制上，我们证明了早期生命中线粒体功能障碍激活了 AMPK，这反过来不仅缓解了线粒体异常，而且激活了 TGFβ 信号通路，增加了后代的成年体型。总之，我们的研究结果为母本衰老在塑造成年后代特征方面的古老作用提供了机制上的见解。
