An old ovary can be rewritten by its host: aged grafts ovulate and produce live pups in young mice

Ovarian molecular age moves in both directions with the host's age environment rather than advancing only with time. Aged ovaries placed in young hosts dropped in transcriptomic age, young ovaries placed in aged hosts rose, and in both directions the shift was partial, so the graft and the contralateral ovary of the same animal occupied distinct molecular age states. Young ovarian grafts were already known to extend reproductive cycling in middle-aged mice and to affect lifespan and cardiac pathology, but whether host age can in turn change the ovary's own molecular age had not been tested. In unilateral orthotopic transplantation, the graft was compared directly with the contralateral endogenous ovary of the same host, ruling out between-animal endocrine variation; in bilateral transplantation, transcriptomic age shifted for aged ovaries in young hosts and young ovaries in aged hosts with P = 2.6 × 10⁻⁵ and P = 0.0017, matching the unilateral direction.

Aged ovaries retain reproductive potential that a young host can release. Ovaries from 13-month-old donors supported full-term pregnancy and live births in young recipients when the grafts reached 17-18 months of age, and 17-18-month-old recipients delivered live pups after receiving young ovaries. The same aged ovaries produced no offspring in aged hosts, indicating that the limitation lies in the host environment rather than in a complete loss of ovarian capacity. After bilateral transplantation and mating, aged ovaries yielded live births in 5 of 7 young recipients versus 0 of 6 old recipients (Fisher's exact P = 0.021), and young ovaries yielded live births in 4 of 6 old recipients versus 0 of 6 with old ovaries (P = 0.061). Both heterochronic groups produced fewer pups per recipient than young-in-young controls but more than old-in-old recipients.

Ovarian age propagates to organs beyond the reproductive tract. Donor ovary age changed transcriptomic age in the recipient brain, liver and uterus; young ovaries lowered transcriptomic age in the aged brain, liver and uterus, whereas old ovaries raised it only in the young uterus. Previously only epidemiological associations of oophorectomy with cardiovascular and cognitive outcomes, and reports that young ovarian grafts extend lifespan, linked ovarian status to other organs; direct intervention evidence that ovarian age changes molecular aging elsewhere was missing. In old recipients, young ovaries lowered transcriptomic age in brain (P = 0.026), liver (P = 0.0027) and uterus (P = 0.018); pituitary age did not change significantly in either recipient age group, indicating tissue-specific responses.

The inflammatory and stromal compartments of the aged ovary are partly remodeled by host age. Aged ovaries in young hosts showed lower interferon, IL6-JAK-STAT3 and TNFα-NF-κB pathway expression and higher oxidative phosphorylation, mitochondrial translation and fatty acid metabolism; multinucleated giant cell-rich stromal regions had higher transcriptomic age than surrounding stroma, and their associated genes responded to host age. Multinucleated giant cells had been described as hallmarks of aged ovarian stroma, but whether the molecular features of these regions change with host age had not been examined. Laser-captured multinucleated giant cell-rich regions, macrophages and stroma separated by transcriptome (PERMANOVA P = 5 × 10⁻⁴), and OvaAge was higher in giant cell-rich regions than in stroma (P = 3.7 × 10⁻⁴); mapping the mouse giant cell signature onto human ovarian single-nucleus data identified a macrophage subset with higher predicted transcriptomic age than other macrophages (P = 0.02) and stromal cells (P = 0.0012) from the same donors.

The work was performed in mice, donors and recipients were of the same inbred strain, and the graft origin of offspring was inferred from removal of both host ovaries rather than confirmed genetically. Molecular measurements cover transcriptomes, DNA methylation, pathway-specific methylation clocks, plasma metabolomics and MALDI spatial metabolic imaging, and reproductive outcomes come from mating, pregnancy and live-birth records after bilateral transplantation. The intended readers are researchers studying reproductive aging, inter-organ communication and aging clocks; determining whether a specific signal mediates these effects would require cell-type-resolved clocks that separate regulation within cells from changes in cell composition.

All molecular measurements were made in bulk tissue, so shifts in estimated age combine regulation within resident cells with changes in cell composition, and host-derived immune, vascular and stromal cells may enter a graft after revascularization. In heterochronic parabiosis, the ovaries of older partners did not show the transcriptomic rejuvenation seen after transplantation into young hosts; the authors note that the experiments differed in animal age, surgery and timing of collection, so this divergence cannot be attributed to the mode of systemic exposure alone. Reproductive output in aged recipients of young ovaries remained below that of young controls, so functional restoration was incomplete.