Insulin Signaling Regulates Oocyte Quality Maintenance with Age via Cathepsin B Activity

Nicole M. Templeman, Shijing Luo, Rachel Kaletsky, Cheng Shi, Jasmine Ashraf, William Keyes, Coleen T. Murphy

Research output: Contribution to journalArticle

10 Scopus citations

Abstract

A decline in female reproduction is one of the earliest hallmarks of aging in many animals, including invertebrates and mammals [1–4]. The insulin/insulin-like growth factor-1 signaling (IIS) pathway has a conserved role in regulating longevity [5] and also controls reproductive aging [2, 6]. Although IIS transcriptional targets that regulate somatic aging have been characterized [7, 8], it was not known whether the same mechanisms influence reproductive aging. We previously showed that Caenorhabditis elegans daf-2 IIS receptor mutants extend reproductive span by maintaining oocyte quality with age [6], but IIS targets in oocytes had not been identified. Here, we compared the transcriptomes of aged daf-2(−) and wild-type oocytes, and distinguished IIS targets in oocytes from soma-specific targets. Remarkably, IIS appears to regulate reproductive and somatic aging through largely distinct mechanisms, although the binding motif for longevity factor PQM-1 [8] was also overrepresented in oocyte targets. Reduction of oocyte-specific IIS targets decreased reproductive span extension and oocyte viability of daf-2(−) worms, and pqm-1 is required for daf-2(−)’s long reproductive span. Cathepsin-B-like gene expression and activity levels were reduced in aged daf-2(−) oocytes, and RNAi against cathepsin-B-like W07B8.4 improved oocyte quality maintenance and extended reproductive span. Importantly, adult-only pharmacological inhibition of cathepsin B proteases reduced age-dependent deterioration in oocyte quality, even when treatment was initiated in mid-reproduction. This suggests that it is possible to pharmacologically slow age-related reproductive decline through mid-life intervention. Oocyte-specific IIS target genes thereby revealed potential therapeutic targets for maintaining reproductive health with age. Templeman, Luo, et al. provide evidence that insulin/IGF-1 signaling regulates reproductive and somatic aging through largely distinct mechanisms. Moreover, their transcriptomic approach indicates that cathepsin-B-like proteases negatively regulate oocyte quality with age, identifying a target to potentially slow age-related reproductive decline.

Original languageEnglish (US)
Pages (from-to)753-760.e4
JournalCurrent Biology
Volume28
Issue number5
DOIs
StatePublished - Mar 5 2018

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Keywords

  • aging
  • cysteine protease
  • daf-2
  • insulin signaling
  • oocyte quality
  • oocyte-specific transcriptome
  • pqm-1
  • reproductive aging

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