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.

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USADepartment of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA · biorxiv

Paper

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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Research summary

The study utilizes a comprehensive single-nucleus transcriptomic atlas to demonstrate that rapamycin mitigates a specific, sex-biased cellular aging trajectory driven by mTORC1 activity, thereby providing a mechanistic explanation for differential lifespan extension between sexes. This work is relevant because it moves beyond simple lifespan counts to identify specific cellular states and molecular pathways (Fkbp12/mTORC1) that constitute the root causes of aging vulnerability, offering a framework for targeted geroprotection rather than just symptom management.

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