TY - JOUR
T1 - Insulin Signaling Regulates Oocyte Quality Maintenance with Age via Cathepsin B Activity
AU - Templeman, Nicole M.
AU - Luo, Shijing
AU - Kaletsky, Rachel
AU - Shi, Cheng
AU - Ashraf, Jasmine
AU - Keyes, William
AU - Murphy, Coleen T.
N1 - Funding Information:
We thank the Caenorhabditis Genetics Center (CGC) for strains, members of the Murphy Lab for comments on the manuscript, and Jessica Landis for discussion on microarray data analyses. N.M.T. was supported by a Banting Postdoctoral Fellowship . The study was supported by the Glenn Foundation for Medical Research and NIH New Innovator ( 1DP2OD004402-01 ) and March of Dimes awards to C.T.M.
Publisher Copyright:
© 2018 Elsevier Ltd
PY - 2018/3/5
Y1 - 2018/3/5
N2 - 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.
AB - 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.
KW - aging
KW - cysteine protease
KW - daf-2
KW - insulin signaling
KW - oocyte quality
KW - oocyte-specific transcriptome
KW - pqm-1
KW - reproductive aging
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UR - http://www.scopus.com/inward/citedby.url?scp=85042297107&partnerID=8YFLogxK
U2 - 10.1016/j.cub.2018.01.052
DO - 10.1016/j.cub.2018.01.052
M3 - Article
C2 - 29478855
AN - SCOPUS:85042297107
SN - 0960-9822
VL - 28
SP - 753-760.e4
JO - Current Biology
JF - Current Biology
IS - 5
ER -