Gou Mo, Li Jie, Yi Lizhi, Li Huiyu, Ye Xiaoying, Wang Huasong, Liu Linlin, Sun Baofa, Zhang Song, Zhu Zhengmao, Liu Jiang, Liu Lin
Department of Genetics and Cell Biology, College of Life Science, Nankai University, Tianjin 300071, China.
State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin, 300350, China.
PNAS Nexus. 2022 Dec 24;2(2):pgac310. doi: 10.1093/pnasnexus/pgac310. eCollection 2023 Feb.
Resveratrol is an antiaging, antioxidant, and anti-inflammatory natural polyphenolic compound. Growing evidence indicates that resveratrol has potential therapeutic effects for improving aging ovarian function. However, the mechanisms underlying prolonged reproductive longevity remain elusive. We found that resveratrol ameliorates ovarian aging transcriptome, some of which are associated with specific changes in methylome. In addition to known aging transcriptome of oocytes and granulosa cells such as decline in oxidoreductase activity, metabolism and mitochondria function, and elevated DNA damage and apoptosis, actin cytoskeleton are notably downregulated with age, and these defects are mostly rescued by resveratrol. Moreover, the aging-associated hypermethylation of actin cytoskeleton is decreased by resveratrol. In contrast, deletion of , involved in DNA demethylation, abrogates resveratrol-reprogrammed ovarian aging transcriptome. Consistently, deficiency results in additional altered pathways as shown by increased mTOR and Wnt signaling, as well as reduced DNA repair and actin cytoskeleton with mouse age. Moreover, genes associated with oxidoreductase activity and oxidation-reduction process were hypermethylated in -deficient oocytes from middle-age mice treated with resveratrol, indicating that loss of abolishes the antioxidant effect of resveratrol. Taking together, our finding provides a comprehensive landscape of transcriptome and epigenetic changes associated with ovarian aging that can be reprogrammed by resveratrol administration, and suggests that aberrantly increased DNA methylation by deficiency promotes additional aging epigenome that cannot be effectively restored to younger state by resveratrol.
白藜芦醇是一种具有抗衰老、抗氧化和抗炎作用的天然多酚化合物。越来越多的证据表明，白藜芦醇对改善衰老的卵巢功能具有潜在的治疗作用。然而，延长生殖寿命的潜在机制仍不清楚。我们发现白藜芦醇可改善卵巢衰老转录组，其中一些与甲基化组的特定变化有关。除了卵母细胞和颗粒细胞已知的衰老转录组变化，如氧化还原酶活性、代谢和线粒体功能下降，以及DNA损伤和细胞凋亡增加外，肌动蛋白细胞骨架随年龄增长显著下调，而这些缺陷大多可被白藜芦醇挽救。此外，白藜芦醇可降低肌动蛋白细胞骨架与衰老相关的高甲基化。相反，参与DNA去甲基化的基因缺失会消除白藜芦醇重编程的卵巢衰老转录组。一致地，基因缺陷导致随着小鼠年龄增长出现额外的通路改变，如mTOR和Wnt信号增加，以及DNA修复和肌动蛋白细胞骨架减少。此外，在用白藜芦醇处理的中年小鼠的基因缺陷卵母细胞中，与氧化还原酶活性和氧化还原过程相关的基因发生了高甲基化，这表明基因缺失消除了白藜芦醇的抗氧化作用。综上所述，我们的研究结果提供了与卵巢衰老相关的转录组和表观遗传变化的全面图景，这些变化可通过白藜芦醇给药进行重编程，并表明基因缺陷导致的异常DNA甲基化增加促进了额外的衰老表观基因组，而白藜芦醇无法有效地将其恢复到年轻状态。
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