2. Academic Validation
  3. Reprogramming of ovarian aging epigenome by resveratrol

Reprogramming of ovarian aging epigenome by resveratrol

  • PNAS Nexus. 2022 Dec 24;2(2):pgac310. doi: 10.1093/pnasnexus/pgac310.
Mo Gou 1 2,  Jie Li 1 2,  Lizhi Yi 3,  Huiyu Li 1 2,  Xiaoying Ye 1 2,  Huasong Wang 1 2,  Linlin Liu 1 2,  Baofa Sun 4,  Song Zhang 5,  Zhengmao Zhu 1 2,  Jiang Liu 3,  Lin Liu 1 2 6
Affiliations

Affiliations

  • 1 Department of Genetics and Cell Biology, College of Life Science, Nankai University, Tianjin 300071, China.
  • 2 State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin, 300350, China.
  • 3 CAS Key Laboratory of Genome Sciences and Information, Beijing Institute of Genomics, Chinese Academy of Sciences, 100101 Beijing, China.
  • 4 Department of Zoology, College of Life Science, Nankai University, Tianjin 300071, China.
  • 5 Department of Biochemistry and Molecular Biology, College of Life Science, Nankai University, Tianjin 300071, China.
  • 6 Institute of Translational Medicine, Nankai Union Medical Center, Nankai University, Tianjin 300000, China.
PMID: 36743471 DOI: 10.1093/pnasnexus/pgac310
Abstract

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 Tet2, involved in DNA demethylation, abrogates resveratrol-reprogrammed ovarian aging transcriptome. Consistently, Tet2 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 Tet2-deficient oocytes from middle-age mice treated with resveratrol, indicating that loss of Tet2 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 Tet2 deficiency promotes additional aging epigenome that cannot be effectively restored to younger state by resveratrol.

Keywords

cumulus cells; methylome; oocytes; ovarian aging; transcriptome.

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