Title | Insulin Signaling Regulates Oocyte Quality Maintenance with Age via Cathepsin B Activity. |
Publication Type | Journal Article |
Year of Publication | 2018 |
Authors | Templeman, NM, Luo, S, Kaletsky, R, Shi, C, Ashraf, J, Keyes, W, Murphy, CT |
Journal | Curr Biol |
Volume | 28 |
Issue | 5 |
Pagination | 753-760.e4 |
Date Published | 2018 03 05 |
ISSN | 1879-0445 |
Keywords | Aging, Animals, Caenorhabditis elegans, Caenorhabditis elegans Proteins, Cathepsin B, Insulin, Oocytes, Signal Transduction, Transcriptome |
Abstract | <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> |
DOI | 10.1016/j.cub.2018.01.052 |
Alternate Journal | Curr Biol |
PubMed ID | 29478855 |
PubMed Central ID | PMC5893159 |
Grant List | DP2 OD004402 / OD / NIH HHS / United States |