Rapamycin Mitigates a Sex-biased Convergent Aging Trajectory

Lu, T.-C.; Liang, C.-Y.; Park, Y.-J.; Auld, N.; Jackson, T.; Yin, Z.; Harrison, E.; Sun, B.; Qadiri, M.; Perrimon, N.; Hsu, A.-L.; Qi, Y.; Li, H.

doi:10.64898/2026.07.02.736117

bioRxiv · 10.64898/2026.07.02.736117

Rapamycin Mitigates a Sex-biased Convergent Aging Trajectory

Lu, T.-C.·Liang, C.-Y.·Park, Y.-J.·Auld, N.·Jackson, T.·Yin, Z.·Harrison, E.·Sun, B.·Qadiri, M.·Perrimon, N.·Hsu, A.-L.·Qi, Y.·Li, H.

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Abstract

Rapamycin extends lifespan across species, yet its cell-type-specific benefits and vulnerabilities remain unclear at whole-organism scale. Here, we present the Rapamycin Fly Cell Atlas (Rapa-FCA), a whole-organism single-nucleus transcriptomic atlas of Drosophila spanning both sexes, multiple ages, 18 cell classes, and 181 cell types. Rapamycin elicited a highly heterogeneous response, with prominent effects in reproductive, digestive, and neuromuscular systems and modest responses in most neuronal populations. Across diverse tissues, we identified a rapamycin-sensitive Convergent Aging Trajectory (CAT), marked by Fkbp12 enrichment and mTORC1-linked metabolic programs, including glycolysis and lipid synthesis. CAT-high nuclei accumulated with age and were preferentially reduced by rapamycin, especially in females, consistent with stronger female lifespan extension. By integrating CAT abundance, aging-clock predictions, and nucleus-ratio changes, we mapped sex- and cell-type-specific geroprotection effects of rapamycin. Together, the Rapa-FCA provides an organism-wide framework for resolving how rapamycin reshapes cellular aging across sex, tissue, and cellular state.

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Lu, T.-C., Liang, C.-Y., Park, Y.-J., Auld, N., Jackson, T., Yin, Z., Harrison, E., Sun, B., Qadiri, M., Perrimon, N., Hsu, A.-L., Qi, Y., Li, H.. 2026-07-03. Rapamycin Mitigates a Sex-biased Convergent Aging Trajectory. https://doi.org/10.64898/2026.07.02.736117

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