Research Paper Volume 15, Issue 11 pp 4600—4624

Impaired telomere pathway and fertility in Senescence-Accelerated Mice Prone 8 females with reproductive senescence

Alba M. Polonio1, , Marta Medrano1, , Lucía Chico-Sordo1, , Isabel Córdova-Oriz1, , Mauro Cozzolino2, , José Montans3, , Sonia Herraiz1, , Emre Seli4,5, , Antonio Pellicer2,6, , Juan A. García-Velasco1,7,8, , Elisa Varela1,8, ,

  • 1 IVI Foundation, The Health Research Institute La Fe (IIS La Fe), Valencia, Spain
  • 2 IVIRMA Rome, Rome, Italy
  • 3 Centro Anatomopatológico, Madrid, Spain
  • 4 IVIRMA New Jersey, Basking Ridge, NJ 07920, USA
  • 5 Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, New Heaven, CT 06510, USA
  • 6 Department of Pediatrics, Obstetrics and Gynecology, University of Valencia, Valencia, Spain
  • 7 IVIRMA Madrid, Madrid, Spain
  • 8 Department of Obstetrics and Gynecology, Rey Juan Carlos University, Madrid, Spain

Received: December 16, 2022       Accepted: May 4, 2023       Published: May 23, 2023
How to Cite

Copyright: © 2023 Polonio et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


Ovarian aging is the main cause of infertility and telomere attrition is common to both aging and fertility disorders. Senescence-Accelerated Mouse Prone 8 (SAMP8) model has shortened lifespan and premature infertility, reflecting signs of reproductive senescence described in middle-aged women. Thus, our objective was to study SAMP8 female fertility and the telomere pathway at the point of reproductive senescence. The lifespan of SAMP8 and control mice was monitored. Telomere length (TL) was measured by in situ hybridization in blood and ovary. Telomerase activity (TA) was analyzed by telomere-repeat amplification protocol, and telomerase expression, by real-time quantitative PCR in ovaries from 7-month-old SAMP8 and controls. Ovarian follicles at different stages of maturation were evaluated by immunohistochemistry. Reproductive outcomes were analyzed after ovarian stimulation. Unpaired t-test or Mann-Whitney test were used to calculate p-values, depending on the variable distribution. Long-rank test was used to compare survival curves and Fisher’s exact test was used in contingency tables. Median lifespan of SAMP8 females was reduced compared to SAMP8 males (p = 0.0138) and control females (p < 0.0001). In blood, 7-month-old SAMP8 females presented lower mean TL compared to age-matched controls (p = 0.041). Accordingly, the accumulation of short telomeres was higher in 7-month-old SAMP8 females (p = 0.0202). Ovarian TA was lower in 7-month-old SAMP8 females compared to controls. Similarly, telomerase expression was lower in the ovaries of 7-month-old SAMP8 females (p = 0.04). Globally, mean TL in ovaries and granulosa cells (GCs) were similar. However, the percentage of long telomeres in ovaries (p = 0.004) and GCs (p = 0.004) from 7-month-old SAMP8 females was lower compared to controls. In early-antral and antral follicles, mean TL of SAMP8 GCs was lower than in age-matched controls (p = 0.0156 for early-antral and p = 0.0037 for antral follicles). Middle-aged SAMP8 showed similar numbers of follicles than controls, although recovered oocytes after ovarian stimulation were lower (p = 0.0068). Fertilization rate in oocytes from SAMP8 was not impaired, but SAMP8 mice produced significantly more morphologically abnormal embryos than controls (27.03% in SAMP8 vs. 1.22% in controls; p < 0.001). Our findings suggest telomere dysfunction in SAMP8 females, at the time of reproductive senescence.


A.U.: Arbitrary Units; DAPI: 4′,6-Diamidino-2-phenylindole; DNA: Deoxyribonucleic Acid; FISH: Fluorescence In Situ Hybridization; GAPDH: Glyceraldehyde-3-phosphate dehydrogenase; GCs: Granulosa Cells; HT q-FISH: High Throughput Quantitative Fluorescence In Situ Hybridization; H&E: Hematoxylin–Eosin; OS: Ovarian Stimulation; PBMCs: Peripheral Blood Mononuclear Cells; RNA: Ribonucleic Acid; RT: Room Temperature; RTqPCR: Real-Time Quantitative Polymerase Chain Reaction; SAMP8: Senescence Accelerated Mouse Prone 8; SAMR1: Senescence Accelerated Mouse Resistant 1; SMAI: Microscopy and Image Analysis Service; TA: Telomerase Activity; TERC: Telomerase RNA Component; TERT: Telomerase Reverse Transcriptase Component; TL: Telomere Length; TRAP: Telomerase-repeat amplification protocol.