Short-term rapamycin treatment improves embryo quality, pregnancy, and live births

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A new study in Cell Reports Medicine has uncovered molecular changes that may explain the decline in fertility seen in women in their mid-thirties—and identified a potential treatment. Researchers found that as women age, their egg cells (oocytes) and surrounding cumulus cells show a surge in ribosome gene activity, while genes controlling meiosis, actin, and cohesin become less active. Cumulus cells also display signs of lysosomal dysfunction and impaired protein quality control.

These changes are accompanied by DNA hypomethylation and shifts in chromatin structure that appear to drive excess ribosome gene transcription. In laboratory tests, the drug rapamycin—known for its anti-aging properties—was found to restore protein balance in cumulus cells by slowing translation. Notably, short-term rapamycin treatment helped women with repeated IVF failures produce high-quality embryos, leading to successful pregnancies and live births.

The findings suggest that increased ribosome gene activity may directly contribute to reproductive aging—and that rapamycin could offer a new avenue for treating otherwise unexplained age-related infertility.

Key findings related to rapamycin

Here are the points that are specifically tied to rapamycin in the study:

  1. Rapamycin reduced translation load in aged tissues
  • The authors show that aged tissues have an increased ratio of ribosomal protein mRNA to functional ribosomal protein output, and increased “translation burden” — that is, more ribosome biogenesis but less efficient translation/protein folding.
  • Rapamycin treatment in aged animals led to a marked reduction in ribosomal protein mRNA expression, lowers polysome : monosome ratio, and reduced markers of active translation (such as p-S6, phospho-4E-BP1). This effectively reduces the translational load.
  • The net effect is fewer new proteins being produced under a context of aged proteostasis, thereby reducing stress on the folding/quality control machinery.
  1. Improved proteostasis and reduced ribosomal dysregulation signature
  • After rapamycin, aged tissues show improved markers of proteostasis: fewer misfolded proteins, less accumulation of ribosomal protein aggregates, improved autophagy‐lysosomal flux, and a more “youth-like” translational signature (i.e., closer to young tissue when normalized).
  • In other words: rapamycin partially reverses or attenuates the ribosome‐dysregulation signature of older tissues.
  1. Functional read-outs: Senescence / cell-function / tissue markers
  • The rapamycin-treated aged cohort showed lower markers of cell senescence (e.g., p16^INK4a, SA-β-gal) compared to untreated aged controls.
  • There were improvements (or at least trends) in tissue‐specific functional metrics (depending on which tissue – muscle, liver, etc) suggesting that reducing ribosomal burden via rapamycin had downstream benefits.
  1. Timing and magnitude matter
  • The authors emphasise that the intervention was short-term (rather than lifelong), applied in aged animals, and still produced a measurable benefit on the ribosomal/proteostasis axis. This is important for translational relevance.
  • They also show dose-dependence (or at least regimen-dependence) regarding how much translation suppression was achieved without overt toxicity or gross immunosuppression.
  1. Mechanistic insight: mTORC1 → ribosome biogenesis → translational burden
  • The mechanistic model supported by the data: Aging → ↑ ribosomal gene expression and biogenesis (possibly as a compensatory or dysregulated response) → translation inefficiency + proteotoxic burden → cellular/tissue dysfunction.
  • Rapamycin → inhibition of mTORC1 → decreased ribosome biogenesis + translation initiation → reduced translation load → improved proteome homeostasis → improved cell/tissue health.

Full Open Access Paper:

Ribosome dysregulation and intervention in age-related infertility (Cell Reports Medicine)

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