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

TitleInsulin Signaling Regulates Oocyte Quality Maintenance with Age via Cathepsin B Activity.
Publication TypeJournal Article
Year of Publication2018
AuthorsTempleman, NM, Luo, S, Kaletsky, R, Shi, C, Ashraf, J, Keyes, W, Murphy, CT
JournalCurr Biol
Date Published2018 Mar 05
KeywordsAging, Animals, Caenorhabditis elegans, Caenorhabditis elegans Proteins, Cathepsin B, Insulin, Oocytes, Signal Transduction, Transcriptome

<p>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.</p>

Alternate JournalCurr Biol
PubMed ID29478855
PubMed Central IDPMC5893159
Grant ListDP2 OD004402 / OD / NIH HHS / United States