Mechanisms of Ovarian Aging: A Target for Geroprotection in Women, Yousin Suh, Columbia U

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This is a talk by Yousin Suh, the Columbia University researcher who is running the rapamycin study focused on delaying menopause in women. If you’re interested in understanding ovarian aging and its impact on female health overall, this is a good talk to listen to.

The ovary is the first organ to undergo early-onset aging in the human body, with profound consequences for both fertility and overall health in women. However, the biological mechanisms driving ovarian aging remain poorly understood. To understand the molecular, cellular, and genetic basis of ovarian aging in humans, we performed integrative single-nucleus multi-omics analyses of young and reproductively aged human ovaries, uncovering coordinated changes in gene regulation across all ovarian cell types. We found that ovarian aging is marked by transcriptomic and chromatin accessibility signatures of the canonical Hallmarks of Aging. By integrating our multi-omics data with genome-wide association study (GWAS) variants linked to age at natural menopause, we demonstrate how functional genetic variants shape gene regulatory networks across ovarian cell types. Our work provides a comprehensive multimodal landscape of human ovarian aging and mechanistic insights into inherited variation influencing the timing of menopause. Our results raise the hope that geroprotectors targeting the “Hallmarks of Aging” may be used to delay ovarian aging, thereby promoting reproductive health and extending healthspan and longevity in women.

Building on this research, we have initiated a clinical trial (NCT05836025) to test low-dose rapamycin, a well-known geroprotector, as an intervention strategy against aging in the ovary to explore the potential for rapamycin to delay ovarian aging and improve reproductive health.

The mTOR / Rapamycin portion of her talk begins here, if you want to skip to that section: https://youtu.be/zimcAoODJDU?si=_6ReXWlTrHBAqFGi&t=2405

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I. Executive Summary

Ovarian aging represents a biological anomaly in human senescence: ovaries undergo precipitous functional failure decades ahead of somatic tissues, culminating in menopause around age 51 while human life expectancy routinely surpasses 80 years. This lecture presents a reverse-translational geroscience framework demonstrating that the ovary is not merely a gamete repository, but a primary pacemaker of female somatic aging. Epidemiological, genetic, and surgical data confirm that ovarian senescence accelerates DNA methylation age and increases all-cause mortality, multimorbidity, cardiovascular disease, neurodegeneration, and osteoporosis.

Integrating large-scale human genomics—principally the 290 loci identified in genome-wide association studies (GWAS) for age at natural menopause (ANM)—with paired single-nucleus RNA sequencing (snRNA-seq) and single-nucleus ATAC-seq (snATAC-seq) across young (20s) and reproductively aged (50s) ovaries, Suh’s group discovered that ~94% of menopause-associated variants reside within non-coding cis-regulatory elements. Unlike monogenic syndromes or tissue-restricted pathologies (e.g., PCOS, ovarian epithelial malignancies), these regulatory variants exert broad transcriptomic effects across somatic ovarian cell types (granulosa, theca, stromal, endothelial, and smooth muscle cells). Using CRISPR-engineered human pluripotent stem cell (hPSC) differentiation, allele-specific expression (ASE) assays, and high-throughput pooled CRISPR interference (CRISPRi) screens, the lab functionally resolved cryptic loci: showing that variants in the HELB helicase modulate homologous recombination dynamics; that the classic BRCA1 GWAS peak is driven by regulatory disruption of the primate-specific long non-coding RNA MBR2; and identifying CPNE1 as a pleiotropic regulator of mitochondrial and proteostatic stress.

Crucially, transcriptomic profiling revealed high intra-organ synchronization of classical hallmarks of aging across all ovarian somatic cell types, characterized by heightened mechanistic target of rapamycin (mTOR) signaling relative to other somatic tissues. This mechanistic insight has been translated into the randomized, double-blind, placebo-controlled VIBRANT trial (Validating Benefits of Rapamycin for Reproductive Aging Treatment) in women aged 35–45, utilizing low-dose weekly rapamycin (5 mg/week) to assess ovarian reserve preservation and systemic geroprotective biomarkers.

II. Insight Bullets

  • Ovarian failure initiates in a woman’s mid-30s, preceding the functional senescence of other human vital organ systems by 15 to 20 years.
  • Natural menopause timing has remained constant at approximately 50 to 52 years of age despite human life expectancy doubling over the past two centuries.
  • Surgical oophorectomy before natural menopause dramatically elevates all-cause mortality, coronary artery disease, cognitive decline, and multimorbidity.
  • Murine heterochronic ovarian transplantation demonstrated that grafting young ovaries into aged post-reproductive mice extends median lifespan and preserves metabolic health.
  • Young mouse ovaries chemically depleted of oocytes via 4-vinylcyclohexene diepoxide (VCD) still confer healthspan extension upon transplantation, proving ovarian somatic tissue provides systemic protection independent of gamete release.
  • Epigenetic clock quantification confirms menopause acts as a biological accelerant, advancing somatic biological age across multiple tissues.
  • Strong familial heritability patterns link female reproductive longevity to broader survival, with brothers of late-menopause women showing extended lifespans.
  • Large-scale GWAS encompassing over 200,000 women identified 290 independent genetic loci regulating the age at natural menopause.
  • Over 94% of identified menopause-associated variants map to non-coding regions, operating as distal cis-regulatory enhancers or promoters rather than protein-altering mutations.
  • Unlike polycystic ovary syndrome (PCOS) or ovarian carcinomas, which display cell-type-restricted genetic footprints, menopause loci exert transcriptomic influence across all ovarian cell types.
  • Single-nucleus multiomics (snRNA-seq paired with snATAC-seq) on young versus post-reproductive human ovaries revealed marked global synchronization in transcriptomic shifts across cell types.
  • Cross-tissue comparative analyses show that coordinated transcriptomic decline across distinct cell types is a unique signature of the ovary compared to other human tissues.
  • Menopause GWAS variants heavily enrich in the DNA damage response (DDR) and double-strand break (DSB) repair pathways, uniquely among complex human traits.
  • Non-coding variants linked to delayed menopause at the HELB locus correlate with downregulation of HELBacross dozens of tissues in Genotype-Tissue Expression (GTEx) profiles.
  • Allele-specific expression assays confirm that the protective HELB allele represses HELB helicase expression in primary human granulosa cells derived from IVF patients at the Columbia University Fertility Center.
  • CRISPR-engineered human pluripotent stem cell differentiation models provide a reliable experimental system to resolve causal regulatory variants from linked GWAS passengers.
  • Fine-mapping and CRISPRi screening at the canonical BRCA1 menopause locus established that the primate-specific lncRNA MBR2, not BRCA1, is the functional causal gene.
  • High-throughput pooled single-cell CRISPRi screens targeting over 100 non-coding GWAS variants identified CPNE1 (Copine-1) as a major regulator of downstream organelle aging.
  • Repression of CPNE1 orchestrates transcriptomic shifts encompassing classical hallmarks of aging, notably mitochondrial oxidative phosphorylation and apoptotic cascades.
  • The transcription factor CCAAT/enhancer-binding protein delta (CEBPD) acts as an upstream transcriptional driver governing cell-type-wide aging in the human ovary, as documented in Nature Aging.
  • Comparative pathway amplitude indexing revealed that hyperactive mechanistic target of rapamycin (mTOR) signaling is elevated across all somatic ovarian cell types in advanced chronological age.
  • Interventions targeting mTOR signaling via low-dose rapamycin attenuate the activation of the primordial follicle pool, decelerating ovarian reserve exhaustion in rodent models.
  • The pilot phase of the human VIBRANT clinical trial investigated oral rapamycin at 5 mg once weekly versus placebo over three months in healthy women aged 35–45.
  • The 5 mg weekly rapamycin regimen demonstrated safety and tolerability in this cohort, with no reported stomatitis, severe toxicities, or disruption of menstrual cycle regularities.
  • Human stem-cell-derived ovarian organoids generated in collaboration with investigators at Columbia Universityserve as high-throughput phenotypic screening platforms for downstream small-molecule geroprotectors.

III. Adversarial Claims & Evidence Table

Claim from Video Speaker’s Evidence Scientific Reality (Current Data) Evidence Grade Verdict
Bilateral Oophorectomy accelerates systemic somatic aging and increases all-cause mortality. Epidemiological studies; preclinical young-to-old ovary transplantation models. Robust human observational data confirm that premenopausal bilateral oophorectomy significantly increases risks for coronary artery disease, cognitive decline, osteoporosis, and all-cause mortality (Rocca et al., 2021; Rivera et al., 2022). Estrogen and non-hormonal ovarian secretory signals provide multi-system cytoprotection. Level C Strong Support
Menopause-associated regulatory SNPs act across nearly all somatic human tissues, not just the ovary. GTEx cis-eQTL cross-tissue query demonstrating that the HELB protective allele suppresses transcription across 49 distinct tissues (including skeletal muscle, brain, and myocardium). GTEx multi-tissue eQTL analyses validate that vast numbers of non-coding loci associated with polygenic traits operate across broad somatic niches (GTEx Consortium, 2020). However, phenotypic translation remains complex; whole-body downregulation of DNA repair enzymes carries uncertain pleiotropic risks, including potential oncogenesis or altered genomic stability in non-ovarian tissues. Level C Plausible
The canonical BRCA1menopause locus is causally driven by the lncRNA MBR2, not BRCA1. snATAC-seq footprinting, CRISPRi functional assays, and isogenic hPSC-derived cell differentiation showing MBR2expression changes without BRCA1perturbation. Fine-mapping of the 17q21 locus demonstrates high linkage disequilibrium where non-coding enhancers directly loop to the bidirectional MBR2 promoter (Nature Aging, 2024). While MBR2 regulates homologous recombination and cellular metabolism, germline pathogenic loss-of-function variants in BRCA1 itself also clinically accelerate ovarian reserve depletion and early menopause in humans (Turki et al., 2023). Dismissing BRCA1’s biological role entirely represents premature over-interpretation of cis-eQTL data. Level D(Translational Gap) Plausible
Weekly low-dose rapamycin (5 mg/wk) safely slows ovarian reserve decline and delays menopause in humans. Preliminary, blinded safety data from the pilot phase of the VIBRANT clinical trial (n=50); rodent lifespan and follicle preservation studies. Multiple animal studies show mTORC1 inhibition preserves primordial follicle pools by preventing hyperactivation (Dou et al., 2021). In humans, an investigator-initiated trial reported improved oocyte yield and blastocyst quality in poor-responder IVF patients using short-course low-dose rapamycin (GetHealthspan / Clinical Data 2025). However, completed Phase 2/3 RCT data evaluating the delay of natural menopause and true functional fertility extension in healthy cohorts remain unpublished. Level B(Preliminary Phase 1/2) Speculative
The ovarian stroma secretes non-hormonal geroprotective factors sufficient to extend organismal healthspan. Preclinical murine experiments where VCD-treated (follicle-depleted, hormone-deficient) young ovaries extended lifespan and healthspan when transplanted into aged recipients. Mouse heterochronic ovarian transplantation models robustly illustrate life- and health-span extension (Mason et al., 2021). However, isolation and identification of distinct non-steroidal endocrine factors in human translational cohorts remain unverified. Clinical translation to humans without intact steroidogenesis remains unproven. Level D(Translational Gap) Speculative

IV. Actionable Protocol (Prioritized)

` [OVARIAN GEROPROTECTION CONTINUUM]
│
┌───────────────────────────────────┴───────────────────────────────────┐
▼ ▼
[HIGH CONFIDENCE TIER] [EXPERIMENTAL TIER]

  • Preserve Native Endocrine Tissue - Off-label mTORC1 Inhibition (Rapamycin)
  • Timely Systemic HRT at Perimenopause - Targeted Micronutrient / CoQ10 Therapy
    (Level A/B Evidence) (Level C/D Evidence; High Safety Margin)
    │
    ▼
    [RED FLAG ZONE]
    - Megadosing Rapamycin (>10 mg/wk) Without Monitoring
    - Unmonitored Experimental Peptides
    (Safety Data Absent / High Toxicity Risk)`

High-Confidence Tier (Level A/B Evidence)

  • Ovarian Tissue Preservation During Benign Pelvic Surgeries: Given the systemic geroprotective and metabolic role of the ovarian somatic stroma, bilateral oophorectomy during routine benign gynecologic procedures (e.g., hysterectomy for fibroids) should be avoided in premenopausal patients unless clear oncologic indications exist (ACOG Practice Guidelines).
  • Evidence-Based Menopausal Hormone Therapy (MHT): For women undergoing premature ovarian insufficiency (POI) or surgical menopause prior to age 45, physiological systemic estrogen plus progestogen (for women with an intact uterus) should be initiated promptly and maintained until the average age of natural menopause (51 years) to preserve bone mineral density, attenuate visceral adiposity, and minimize excess cardiovascular mortality (The NAMS 2022 Hormone Therapy Position Statement).

Experimental Tier (Level C/D Evidence, High Safety Margin)

  • Pulsed Low-Dose Rapamycin (mTORC1 Modulation): Emerging data indicate that intermittent low-dose rapamycin (e.g., 5 mg orally once weekly) modulates cellular senescence and ovarian mTOR hyperactivity without triggering significant systemic immunosuppression, metabolic dysregulation, or luteal disruption. Patients considering off-label regimens must undergo continuous clinical supervision, serial reproductive hormone monitoring (AMH, FSH, estradiol), and periodic lipid/glycemic panels until full-scale Phase 2/3 trials conclude.
  • Mitochondrial Support Strategies: Preclinical data indicate that aging somatic follicles experience oxidative phosphorylation failure and excessive reactive oxygen species (ROS). Adjunctive supplementation with mitochondrial antioxidants (such as bioavailable Ubiquinol/CoQ10 at 200–600 mg daily) shows moderate Level C/B evidence for supporting oocyte mitochondrial ATP generation in assisted reproduction.