A landmark study published in Nature Aging has produced the first comprehensive, multi-organ atlas of female reproductive ageing, using artificial intelligence and supercomputing to analyse over a thousand tissue images alongside gene expression data from hundreds of donors. The findings reveal that menopause is far more than the end of fertility – it is a biological turning point that triggers profound, asynchronous molecular transformations across the reproductive system.
For decades, menopause has been understood primarily through the lens of ovarian decline. The ovaries run out of follicles, oestrogen drops, menstruation ceases. Job done, scientifically speaking. But a sweeping new study from the Barcelona Supercomputing Center (BSC-CNS) suggests this picture is dangerously incomplete – and that the true biological story of menopause is playing out simultaneously, and quite differently, across multiple organs at once.
The research, led by Marta Mele and her Transcriptomics and Functional Genomics group at BSC, integrates deep learning analysis of 1,112 histological images with RNA sequencing from 659 samples spanning seven female reproductive organs – the uterus, ovary, vagina, cervix (endocervix and ectocervix), breast, and fallopian tubes – drawn from donors aged 20 to 70 years. The result is the first large-scale, tissue-resolved atlas of female reproductive system ageing, and it challenges the assumption that these organs decline in concert.
Organs on different clocks
The headline finding is striking: reproductive organs do not age uniformly. Using convolutional neural networks (CNNs) trained to distinguish histological images from young (s35 years) and old (>60 years) donors, the team achieved test accuracy exceeding 0.75 per tile and reaching 1.0 per sample in the ovary, uterus, and vagina – meaning the AI could reliably “read” age from tissue architecture alone.
When the trained model was applied across all age groups to generate organ-specific ageing trajectories, a clear divergence emerged. The ovary and vagina showed gradual, linear increases in their probability of being classified as “old” across the lifespan. The uterus told a very different story.
The uterus displays a sharply nonlinear trajectory, with most samples from donors aged 20 to 40 classified as young, followed by an abrupt transition beginning around age 45. The steepest change in uterine ageing probability occurs at age 53 – strikingly close to the average age of natural menopause at 51 years.
As the authors write in the paper: “Our results show that histological and transcriptional aging dynamics are asynchronous across female reproductive organs with the ovary and vagina starting to age gradually earlier in life and the uterus undergoing an abrupt change around the age of menopause.”
Mele commented: “Until now, we tended to consider menopause mainly as the end of the ovary’s reproductive function. However, our results show that it acts as a turning point that profoundly reorganises other organs and tissues of the reproductive system, and allow us to identify the genes and molecular processes that could be behind these changes.”
The myometrium in the spotlight
Drilling deeper into organ-level data using Vision Transformers (ViTs) – a more sophisticated class of neural network capable of capturing complex spatial relationships in tissue architecture – the researchers segmented individual tissue types within each organ to ask: which specific tissues are most affected by ageing?
The answer was unambiguous. The myometrium, the muscular wall of the uterus, emerged as one of the most dramatically age-affected tissues in the entire reproductive tract. Some myometrial image features had over 40% of their variation explained by age alone -an extraordinary figure. Visual inspection of myometrial tissue tiles across the age range revealed a pronounced structural transition between younger and older donors, consistent with molecular changes seen in independent single-cell studies of the menopausal myometrium.
At the molecular level, multi-omics factor analysis (MOFA) – which integrates histological image features with bulk RNA-sequencing data identified that the most age-associated genes in the myometrium are those governing extracellular matrix (ECM) organisation and collagen metabolism. These genes decline sharply around menopause, pointing to a wholesale remodelling of the uterine wall’s structural scaffolding. Simultaneously, genes involved in chromatin remodelling increase, consistent with the epigenetic reprogramming that accompanies hormonal withdrawal.
The clinical implications are significant. The study found that uterine myometrial age-differentially expressed genes (ageDEGs) are enriched for genes associated with pelvic organ prolapse in genome-wide association studies -a condition affecting millions of women post-menopausally and a leading reason for hysterectomy. The authors suggest this represents “a mechanistic link between menopause-associated tissue weakening and this highly prevalent condition.”
Epithelial changes across the reproductive tract
While the uterus undergoes the most abrupt shift, the vaginal epithelium also shows as sharp menopausal transition. the researchers directly measured epithelial thickness from segmented histological images using CellProfiler, observing a significant thinning specifically between the 41-50 and 51-60 age decades – a measurable, structural correlated of the hormonal withdrawal that clinicians see reflected in symptoms of genitourinary syndrome of menopause.
More broadly, coordinated epithelial remodelling was observed across the reproductive tract, including in the cervix and fallopian tubes, with an increased nuclear-to-cytoplasm ratio in older donors’ epithelial cells. The authors note that this epithelial ageing may compromise barrier integrity and innate immunity, potentially contributing to pelvic inflammatory disease later in life.
In the ovary, a distinct pattern emerged: one cluster of genes enriched in fertility markers – including AMH, a biomarker of ovarian reserve – shows earlier downregulation, consistent with ovarian fertility decay beginning well before the menopausal transition. Meanwhile, vasculature-related gene expression declines more abruptly around menopause, in keeping with the known age-related suppression of ovarian angiogenesis.
Ageing signals detectable in blood
One of the most clinically translatable aspects of the study is its demonstration that organ-specific ageing signatures are not confined to the tissues themselves. Using plasma proteomics data from 40-70 years int he UK Biobank, the team trained random forest classifiers on sets of proteins selectively enriched in each reproductive organ.
The result, as first co-author Oleksandra Soldatkina noted, opens the door to non-invasive monitoring: “We not only identified the molecular changes underlying the ageing of these organs, but we also saw that they can be detected in blood, which opens the door to new clinical tools.”
The uterine protein signature showed the same abrupt inflection at around age 50 that was observed in the tissue data – and, crucially, the transition aligned precisely with each donor’s self-reported age at menopause. These results held from after adjusting for menstrual cycle phase, hormone therapy use, and reproductive history.
A new framework for women’s health
The study’s authors are candid about limitations. The GTEx dataset, which provided the tissue samples, lacks detailed reproductive metadata – menopausal status, parity, hormone therapy use – though validation against the UK Biobank largely mitigates this gap. Age predictions from vaginal tissue showed lower overall accuracy and a tendency to overestimate age in younger donors, warranting caution in interpreting vaginal trajectories. There is also a notable absence of single-cell datasets covering the endometrium, myometrium, and vagina across both pre-and postmenopausal states – a resource the authors identify as critical for future work.
Nevertheless, the conceptual advance is substantial. As the authors conclude: “Our findings reposition menopause not merely as the end of the reproductive lifespan but as a biological inflection point that initiates divergent ageing trajectories across reproductive tissues.”
In a context where women over 50 already represent 26% of the global population according to the WHO – a figure that will only grow with increasing life expectancy – understanding the full molecular basis of menopause has never been more urgent. This atlas provides the first serious map.
Reference: Soldatkina, O., Ventura-San Pedro, L., Pujol-Gualdo, N., et al. (20026). Multimodal data analysis reveals asynchronous aging dynamics across female reproductive organs. Nature Ageing. https://doi.org/10.1038/s43587-026-01098-y
