Insulin Signaling Regulates Oocyte Quality Maintenance with Age via Cathepsin B Activity
| Autor: | Cheng Shi, Rachel Kaletsky, Shijing Luo, Jasmine Ashraf, Nicole M. Templeman, William Keyes, Coleen T. Murphy |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Aging media_common.quotation_subject Biology Article General Biochemistry Genetics and Molecular Biology Cathepsin B Transcriptome 03 medical and health sciences 0302 clinical medicine RNA interference medicine Animals Insulin Caenorhabditis elegans Caenorhabditis elegans Proteins media_common Longevity Oocyte biology.organism_classification Cell biology Insulin receptor 030104 developmental biology medicine.anatomical_structure Oocytes biology.protein Daf-2 General Agricultural and Biological Sciences 030217 neurology & neurosurgery Signal Transduction |
| Zdroj: | Current Biology. 28:753-760.e4 |
| ISSN: | 0960-9822 |
| Popis: | Summary 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. |
| Databáze: | OpenAIRE |
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