Research Paper|Volume 18|pp 575—592

Transcriptional programs diverge in aging mouse and human skeletal muscle

Charles D. Hwang¹, Siti Rahmayanti¹, Yori Endo¹, Seamus P. Caragher¹, Luisa Weber^1,², Jessica Mroueh¹, Simone Marini³, Indranil Sinha¹

¹Division of Plastic and Reconstructive Surgery, Department of Surgery, Brigham and Women’s Hospital, Harvard University, Boston, MA 02115, USA
²Ludwig Maximilian University, Munich, BY 80539, Germany
³Department of Epidemiology, University of Florida College of Public Health and Health Professions, Gainesville, FL 32611, USA

* Equal contribution

Received: October 28, 2024Accepted: May 6, 2026Published: May 18, 2026

https://doi.org/10.18632/aging.206382

Copyright: © 2026 Hwang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Animal models provide a crucial scientific substrate for medical innovation, yet findings in these models do not always translate directly to humans. Although murine models are extensively employed to study skeletal muscle aging, the extent to which they diverge from the human aging process remains poorly understood. This study examined transcriptional changes with aging in mouse and human skeletal muscle. RNA bulk-sequencing was performed on gastrocnemius muscles from young and old C57BL/6 mice and compared to transcriptomic data from young and old healthy human vastus lateralis muscles obtained from the GESTALT study (NIA/NIH) via the Gene Expression Omnibus database. Cross-species comparison revealed substantial divergence in age-associated transcriptional profiles, with fewer than 5% of significant GO and KEGG terms shared between species. Hypoxia signaling, VEGFA, and inflammatory pathways showed concordant downregulation with aging in both species; however, angiogenesis, neurogenesis, and myogenesis demonstrated opposing or non-significant trends. These findings caution against direct extrapolation of murine aging transcriptomics to human skeletal muscle biology, though select conserved pathways may represent viable cross-species targets for future investigation.