title: Increased DNA damage and repair deficiency in granulosa cells are associated with ovarian aging in rhesus monkey.
abstract: OBJECTIVE
  Ovarian aging is closely tied to the decline in ovarian follicular reserve and oocyte quality. During the prolonged reproductive lifespan of the female, granulosa cells connected with oocytes play critical roles in maintaining follicle reservoir, oocyte growth and follicular development. We tested whether double-strand breaks (DSBs) and repair in granulosa cells within the follicular reservoir are associated with ovarian aging.
  
  
  METHODS
  Ovaries were sectioned and processed for epi-fluorescence microscopy, confocal microscopy, and immunohistochemistry. DNA damage was revealed by immunstaining of γH2AX foci and telomere damage by γH2AX foci co-localized with telomere associated protein TRF2. DNA repair was indicated by BRCA1 immunofluorescence.
  
  
  RESULTS
  DSBs in granulosa cells increase and DSB repair ability, characterized by BRCA1 foci, decreases with advancing age. γH2AX foci increase in primordial, primary and secondary follicles with advancing age. Likewise, telomere damage increases with advancing age. In contrast, BRCA1 foci in granulosa cells of primordial, primary and secondary follicles decrease with monkey age. BRCA1 positive foci in the oocyte nuclei also decline with maternal age.
  
  
  CONCLUSIONS
  Increased DSBs and reduced DNA repair in granulosa cells may contribute to ovarian aging. Discovery of therapeutics that targets these pathways might help maintain follicle reserve and postpone ovarian dysfunction with age.
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology; Collaborative Innovation Center for Biotherapy, College of Life Sciences, Nankai University, Tianjin, 300071, China.
authors.forename: Dongdong
authors.initials: D
authors.lastname: Zhang
authors.forename: Xiaoqian
authors.initials: X
authors.lastname: Zhang
authors.forename: Ming
authors.initials: M
authors.lastname: Zeng
authors.forename: Jihong
authors.initials: J
authors.lastname: Yuan
authors.forename: Mengyuan
authors.initials: M
authors.lastname: Liu
authors.forename: Yu
authors.initials: Y
authors.lastname: Yin
authors.forename: Xueqing
authors.initials: X
authors.lastname: Wu
authors.forename: David L
authors.initials: DL
authors.lastname: Keefe
authors.forename: Lin
authors.initials: L
authors.lastname: Liu
mesh_terms: D000375:Aging / Q000502:physiology*; D000818:Animals; D019313:BRCA1 Protein / Q000378:metabolism; D053904:DNA Breaks, Single-Stranded; D004249:DNA Damage / Q000502:physiology*; D004260:DNA Repair / Q000502:physiology*; D005260:Female; D006107:Granulosa Cells / Q000502:physiology*; D008253:Macaca mulatta; D009865:Oocytes / Q000502:physiology; D065851:Ovarian Reserve / Q000235:genetics; D010053:Ovary / Q000166:cytology / Q000502:physiology*; D016615:Telomere
chemical_list: D019313:BRCA1 Protein