Theca cells: active orchestrators of ovarian aging

Ovarian aging is characterized by the progressive depletion of the follicular reserve and deterioration of reproductive endocrine function, yet its cellular basis has been disproportionately attributed to oocyte and granulosa cell decline. Theca cells - the principal androgen-producing cell type of the ovarian follicle - have remained critically underappreciated in this context. Operating through the classical two-cell, two-gonadotropin model, theca cells supply androgen precursors that granulosa cells aromatize into estradiol, and their dysfunction therefore impairs estrogen biosynthesis irrespective of granulosa cell competence. During ovarian aging, theca cells undergo quantitative decline, transcriptional reprogramming, and progressive steroidogenic impairment. Single-cell transcriptomic analyses reveal age-dependent upregulation of senescence pathways - including CDKN1A, NF-κB, and SASP-associated factors - alongside downregulation of FOXP1, a transcription factor that normally suppresses cellular senescence through direct repression of CDKN1A. Senescent theca-interstitial cells elaborate pro-inflammatory mediators, most notably CCL5, TNF-α, IL-1β, and IL-6, which suppress steroidogenic gene expression, induce granulosa cell apoptosis, and promote ovarian fibrosis, collectively accelerating follicular atresia. At the molecular level, mitochondrial dysfunction driven by aberrant GSK3β activation impairs oxidative phosphorylation and steroidogenic capacity, while dysregulation of the PTEN/PI3K/Akt/FOXO1 axis uncouples theca cells from LH-dependent gonadotropin signaling. Theca cell dysfunction further underlies distinct clinical entities, including premature ovarian insufficiency, diminished ovarian reserve, and polycystic ovary syndrome. Emerging therapeutic strategies - encompassing mesenchymal stem cell-derived exosomes, senolytics, mitochondria-targeted interventions, and Wnt/β-catenin pathway modulation - have demonstrated efficacy in restoring theca cell function in preclinical models. This review repositions theca cells as active, bidirectionally regulated participants in ovarian aging-integral to, rather than upstream of, the oocyte-granulosa-theca unit-and proposes theca-specific biomarkers and targeted interventions as priorities for future translational research.