Rapamycin Restores Fertility Potential in Endometriosis by Reversing Ovarian Aging in Mice

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A new study from Tongji University’s Shanghai Institute of Maternal Fetal Medicine reveals that the anti-aging drug rapamycin may counteract infertility caused by endometriosis — by rejuvenating aging ovarian cells and restoring healthy follicle development.

Endometriosis, which affects up to 15% of women of reproductive age and half of those seeking fertility treatment, is characterized by endometrial tissue growing outside the uterus. The disorder fosters an inflammatory, oxidative environment in the pelvis, which damages the ovaries and impairs egg maturation. Previous work has linked this oxidative stress to cellular senescence — a process in which cells permanently stop dividing but continue releasing pro-inflammatory molecules that disrupt tissue function.

In the new study, researchers induced endometriosis in mice and treated one group weekly with rapamycin, an mTOR inhibitor known to suppress senescence and extend lifespan. Compared with untreated animals, rapamycin-treated mice showed lower levels of oxidative stress markers in their peritoneal fluid and fewer senescence markers (p16, p21, γH2AX) in ovarian tissue. Levels of antioxidants such as superoxide dismutase and glutathione peroxidase were restored to near-normal values.

The drug’s effects were also evident in ovarian structure. Untreated endometriosis mice had an overabundance of dormant primordial follicles but few mature or luteal follicles — a pattern consistent with impaired follicle maturation. Rapamycin reversed this, restoring the number of mature follicles and increasing expression of gonadotropin receptors necessary for ovulation.

At the molecular level, the team identified a key regulatory pathway: rapamycin activated the PPARα–IGFBP2 axis, a signaling route previously linked to metabolism and anti-aging mechanisms. Both PPARα (peroxisome proliferator-activated receptor-α) and IGFBP2 (insulin-like growth factor-binding protein 2) were sharply reduced in endometriotic ovaries but normalized with rapamycin treatment. Follow-up experiments in cultured granulosa cells confirmed that activating PPARα boosted IGFBP2 expression and protected against oxidative stress–induced senescence, while silencing PPARα worsened it.

The findings suggest that oxidative stress drives ovarian aging in endometriosis through suppression of the PPARα/IGFBP2 pathway — and that rapamycin can interrupt this cascade to preserve fertility.

Although fertility outcomes such as pregnancy rates were not directly measured, the research offers a mechanistic bridge between cellular aging biology and reproductive medicine, pointing to rapamycin and related senescence-modulating drugs as promising therapeutic candidates for endometriosis-related infertility .

Open Access Paper:

Rapamycin improves endometriosis‑related infertility involving ovarian senescence via the PPARα/IGFBP2 pathway

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In-depth Summary and analysis of paper

Here is a structured critique of the paper “Rapamycin improves endometriosis‑related infertility involving ovarian senescence via the PPARα/IGFBP2 pathway” by Wu et al., alongside a summary of novelty and an assessment of journal quality.

Summary

Wu et al. examine whether the mTOR inhibitor Rapamycin (sirolimus) can ameliorate infertility related to Endometriosis-driven ovarian senescence in a mouse model. They induce endometriosis in mice, treat with rapamycin, then assess markers of oxidative stress, senescence (p16, p21, γH2AX), follicle dynamics (primordial → growing → luteal), gonadotropin receptor expression, and the signalling axis involving PPARα (peroxisome proliferator-activated receptor α) and IGFBP2 (insulin-like growth factor binding protein 2). They find that rapamycin reduces oxidative stress in peritoneal fluid, lowers senescence markers in ovarian tissue, restores antioxidant enzyme activities towards normal, shifts the follicle pool away from a large excess of dormant primordial follicles toward more mature follicles, increases gonadotropin receptor expression, and up-regulates PPARα/IGFBP2 signalling compared to untreated endometriosis mice. They further confirm in cultured granulosa (ovarian follicle) cells that PPARα knockdown worsens oxidative stress and senescence while PPARα activation boosts IGFBP2 and mitigates senescence. The authors conclude that endometriosis accelerates ovarian aging via suppression of PPARα/IGFBP2, and that rapamycin interrupts this cascade to preserve follicle maturation, thus suggesting a mechanistic link between cellular aging biology and infertility in endometriosis.

Novelty

Key novel contributions include:

  • Mechanistic link: The identification of the PPARα → IGFBP2 axis as a mediator of ovarian senescence in the context of endometriosis appears to be a new finding. This takes the field beyond general mTOR/oxidative stress to a more specific pathway.
  • Endometriosis + senescence frame: While mTOR inhibitors have been studied in ovarian aging (e.g., primordial follicle preservation) and endometriosis independently, the combination—examining how endometriosis promotes ovarian aging and then targeting it with rapamycin—is relatively novel.
  • Therapeutic hypothesis: By linking an anti-aging intervention (rapamycin) to a fertility-disease context (endometriosis), the study blends longevity/aging biology with reproductive pathology—an emerging interdisciplinary space.
  • Granulosa-cell in vitro validation: The follow-up cellular experiments add mechanistic depth (PPARα knockdown vs activation) rather than simply reporting in vivo associations.

For a researcher oriented to longevity and biomarker mechanistics (as you are), this bridging of senescence biology and ovarian pathology is a strength.

Critique

There are several relevant strengths and weaknesses:

Strengths:

  • The study uses multiple levels of evidence: in vivo model, peritoneal fluid oxidative stress markers, ovarian histology/follicle counts, gene/protein marker assays, and in vitro granulosa experiments.
  • The mechanistic focus (PPARα / IGFBP2) adds depth beyond descriptive phenotype.
  • The context of endometriosis as an ovarian aging accelerator is clinically relevant.

Weaknesses / Limitations:

  • Model limitations: Mice experimentally induced with endometriosis may not fully mimic human disease heterogeneity (lesion locations, hormonal milieu, chronicity).
  • Outcome scope: They report changes in follicle counts and markers of maturation, but do not show actual fertility endpoints (e.g., live births, pregnancy rates) in this model. Thus translational relevance is incomplete.
  • Dosage/timing clarity: The exact rapamycin dosing/timing relative to disease induction may influence both beneficial and adverse effects (rapamycin has known reproductive/ovarian side-effects). It’s unclear how the timing aligns with translational windows.
  • Human relevance: The PPARα/IGFBP2 axis is shown in mouse and cell models; human granulosa/ovarian validation is lacking. For a translational-longevity minded researcher, human biomarker corollaries would be desirable.
  • Side-effects / safety considerations: Rapamycin has known metabolic and immunologic effects; impact on fertility itself (ovulation, embryo quality) needs careful balancing in humans.
  • Journal and peer review context: As discussed below, the journal’s impact may not be top-tier, so caution is warranted.

Interpretation risk: Because mTOR/rapamycin work in ovarian reserve is complex (some studies suggest rapamycin may suppress follicle activation acutely, which could reduce immediate fertility), there is a risk of over-interpreting the benefit in this context without careful timing. Moreover, “restoration” of maturation markers does not guarantee improved live-birth outcome.

Journal Quality, Ranking & Rating

The article was published in the journal Molecular Medicine Reports (MMR).

Here is a rough assessment of its standing:

  • Molecular Medicine Reports is published by Spandidos Publications. It is a peer-reviewed, open access journal focused on experimental and preclinical medicine.
  • Impact factor: According to available metrics (Spandidos website), the journal has an impact factor in the modest (~2-3) range. (I did not locate a high current IF in this search.)
  • Ranking: It would likely be considered a mid- or lower-mid tier journal within molecular medicine / reproductive biology fields—not among the top 10 journals in reproductive/ovarian biology or longevity research.
  • Editorial/peer-review rigor: While peer-review exists, some observers regard Spandidos journals as less selective than leading titles (e.g., Human Reproduction, Journal of Clinical Endocrinology & Metabolism, Aging Cell). That doesn’t invalidate the work, but it suggests more caution in interpreting translational significance.

In summary: The paper is worth attention for its mechanistic hypotheses and cross-disciplinary link (endometriosis + ovarian aging + rapamycin), but the fact it’s in a moderate-tier journal means one should treat the findings as pilot/lead evidence, not definitive. For your biomarker-driven longevity/health optimisation track, this is an interesting “early-stage” result: promising, but not yet ready for human translation or clinical application.

The study used a total of 50 female BALB/c mice — each 8 weeks old and weighing 18–22 grams .

Here’s the detailed breakdown from the Materials and Methods section:

  • 20 donor mice – used to provide endometrial tissue for transplantation
  • 20 recipient mice – received intraperitoneal injections of endometrial debris to induce endometriosis
  • 10 control mice – injected with saline

After induction, the 30 recipient + control animals were divided into three experimental groups (10 mice each):

  1. CTL (Control) – received saline only
  2. EM (Endometriosis) – induced with endometrial debris
  3. EM-R (Endometriosis + Rapamycin) – induced with endometrial debris and treated weekly with 250 µg rapamycin

So:

Total = 50 mice (20 donor + 20 recipient + 10 control), with 30 mice in the main experimental comparisons.

The dosing level of rapamycin used in the study was:

250 µg per mouse, administered intraperitoneally once per week , starting one week after endometriosis induction .

Additional details:

  • The rapamycin used was from Sigma-Aldrich (Merck KGaA; cat. no. 553210) .
  • The authors cite Ren et al., 2016 as the reference for this dosing regimen, which had been previously used in a murine endometriosis model .
  • The treatment continued for four weeks (the entire experimental duration before euthanasia).

Given that adult female BALB/c mice weigh about 20 g, this corresponds roughly to a dose of ~12.5 mg/kg/week—a moderate systemic dose in murine rapamycin studies, high enough to achieve mTOR inhibition but below toxic thresholds used in lifespan trials.