Highlights

  • Rapamycin-treated oocytes from aged women mature into high-quality embryos at a higher rate than non-treated ones following insemination.
  • Oocytes from aged mice exhibit better chromosome structure and less DNA damage than those that aren’t treated.
  • With rapamycin, reduced levels of harmful, oxygen-containing molecules (reactive oxygen species) that cause cellular stress are found in mouse oocytes.

The average child-bearing age of women continues to increase globally. As women age, the number of healthy oocytes that give rise to high-quality, multicellular embryos following insemination dissipates. This reduces the chance of achieving pregnancy at later ages. For this reason, researchers who study fertility have continued their search for ways of improving oocyte health for aged women, especially those 35 years and older.

Published in Aging, Jin and colleagues from Tongji Medical College in China showed that treating human oocytes with rapamycin in laboratory dishes while they mature improves the quality of their embryos following sperm injection. To find how this happens, they examined aged mouse oocytes subjected to rapamycin treatment, which exhibited better chromosome structure and less DNA damage. In aged mouse oocytes, the researchers also found that rapamycin treatment diminished the levels of reactive oxygen species that cause cell stress and damage. The study’s findings suggest that rapamycin can be used to improve oocyte health and increase the probability of achieving high-quality embryos for healthy childbirths.

Rapamycin Increases Embryo Developmental Potential and Reduces Oocyte DNA Damage

After inseminating human oocytes via injection, Jin and colleagues compared embryo development in the presence or absence of rapamycin. The research team found that the rapamycin-treated oocytes transformed into higher-quality embryos compared to non-treated oocytes. Jin and colleagues measured embryo quality with standards including whether the embryos contained at least six cells and whether the cells displayed symmetry. These findings indicate that rapamycin-treated oocytes that mature in laboratory dishes give rise to better multi-celled embryos than those that aren’t treated.

(Yang et al., 2022 | Aging) Treating oocytes with rapamycin significantly increases the percentage of resulting high-quality embryos. The percentage of high-quality embryos resulting from intracytoplasmic sperm injection (ICSI) of oocytes was 35.3% for the rapamycin-treated group, a significantly greater percentage than the non-treated (Control) group’s 12.8%.

To find what mechanism may be behind the rapamycin-induced embryo quality improvements, Jin and colleagues used aged (40 to 48 weeks old or the equivalent of about 40 years old for humans) mouse oocytes. They let the oocytes mature in a solution that contained rapamycin. The treated oocytes displayed about half the abnormal chromosomes – those with structural aberrations – compared to untreated oocytes. Moreover, treated oocytes exhibited reduced DNA damage as indicated with a marker that stains for DNA damage when viewed under a microscope (𝜸H2AX). These findings suggest that higher quality embryos from oocytes treated with rapamycin may result from improvements in chromosomal structural integrity and reduced DNA damage.

(Yang et al., 2022 | Aging) Maturing mouse oocytes in rapamycin significantly reduced their abnormal chromosome percentage and DNA damage. Rapamycin reduced the percentage of abnormal chromosomes in oocytes from ~40% in the non-treated (Con) group to ~20%. The amount of DNA damage as measured with a stain for DNA damage – 𝜸H2AX – was more than cut in half in rapamycin-treated oocytes.

To find out why improved chromosomal structure and less DNA damage occur in rapamycin-treated oocytes, Jin and colleagues examined how rapamycin treatment influences reactive oxygen species buildup. The China-based researchers found lower levels of reactive oxygen species in oocytes matured within a solution that contained rapamycin. These results show that rapamycin reduces reactive oxygen species accumulation, which likely helps reduce DNA damage and improve chromosome structural integrity. 

(Yang et al., 2022 | Aging) Rapamycin reduces levels of harmful reactive oxygen species that cause cell damage. Mouse oocytes matured in a solution with rapamycin contained about ⅔ less reactive oxygen species than non-treated (Con) mouse oocytes.

“In conclusion, our study preliminarily proved the effects of 10 nM rapamycin for improving [in vitro maturation] outcomes in oocytes from aged mice and older women,” said Jin and colleagues. “The specific mechanism might be reducing [reactive oxygen species] levels, mitigating DNA damage, and promoting developmental potential.”

Rapamycin May Enhance Aged Women’s Fertility

Jin and colleagues’ study provides evidence that aged women may potentially turn to in vitro fertilization in the presence of rapamycin. Doing so could improve the chances of conceiving healthy offspring and having a normal childbirth that results from starting with healthy embryos.

Rapamycin is a pro-longevity compound that may provide benefits that mitigate against age-related disorders, including reduced fertility. Previous research has shown that rapamycin reduces reactive oxygen species buildup, improves DNA damage repair, and enhances the developmental potential of younger mouse oocytes. Other research has gone on to show that rapamycin significantly improves young women’s oocyte maturation when matured in a laboratory dish (unpublished data from Jin and colleagues). Yet this study was the first to demonstrate rapamycin’s benefits for aged oocytes in humans. Rapamycin may provide a new way to improve fertility for aging women.