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

Author(s): Templeman, Nicole M; Luo, Shijing; Kaletsky, Rachel; Shi, Cheng; Ashraf, Jasmine; et al

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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.
Publication Date: 5-Mar-2018
Citation: Templeman, Nicole M, Luo, Shijing, Kaletsky, Rachel, Shi, Cheng, Ashraf, Jasmine, Keyes, William, Murphy, Coleen T. (2018). Insulin Signaling Regulates Oocyte Quality Maintenance with Age via Cathepsin B Activity. Current Biology : CB, 28 (5), 753 - 760.e4. doi:10.1016/j.cub.2018.01.052
DOI: doi:10.1016/j.cub.2018.01.052
ISSN: 0960-9822
EISSN: 1879-0445
Pages: 753 - 760.e4
Language: eng
Type of Material: Journal Article
Journal/Proceeding Title: Current Biology
Version: Author's manuscript

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