“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.”

BUFFALO, NY — June 10, 2026 — A new research paper was published in Volume 18 of Aging on May 18, 2026, titled “Transcriptional programs diverge in aging mouse and human skeletal muscle.”

The study was led by co-first authors Charles D. Hwang and Siti Rahmayanti and corresponding author Indranil Sinha from Brigham and Women’s Hospital, Harvard University.  

Aging is widely associated with the gradual loss of muscle mass, strength, and physical function. Much of what scientists know about these changes comes from studies in laboratory mice, which are frequently used to investigate the biological mechanisms of aging and to identify potential therapeutic targets. However, an important question remains: how closely do aging-related changes in mouse muscle reflect what actually occurs in humans?

To address this question, researchers performed a detailed comparison of gene expression patterns in skeletal muscle from young and old mice and humans. The team analyzed RNA sequencing data from mouse gastrocnemius muscle and compared it with transcriptomic data from healthy young and older adults obtained through the National Institute on Aging’s GESTALT study.

The results revealed substantial differences between the two species. Despite both mice and humans experiencing age-related muscle decline, fewer than 5% of significantly altered biological pathways were shared between them. Many of the genetic programs that changed with aging in mice showed little resemblance to those observed in human skeletal muscle.

The investigators found that aging mouse muscle displayed strong changes in genes related to tissue remodeling, inflammation, and structural maintenance. In contrast, aging human muscle showed more pronounced alterations in metabolic pathways, including those involved in energy production, mitochondrial function, and muscle contraction.

The study also examined several biological pathways that have long been associated with muscle aging. Hypoxia signaling, VEGFA signaling, and inflammatory pathways showed similar age-related changes in both species. However, other pathways—including angiogenesis, neurogenesis, and myogenesis—displayed markedly different patterns. In some cases, pathways that declined with aging in mice were unchanged or even increased in humans.

The researchers noted that aging human muscle exhibited considerably greater variability than mouse muscle. While young and old mice formed distinct transcriptional groups, human samples displayed substantial overlap, highlighting the complexity and diversity of human aging.

“Cross-species comparison revealed substantial divergence in age-associated transcriptional profiles, with fewer than 5% of significant GO and KEGG terms shared between species.”

According to the authors, these findings highlight an important challenge in aging research. Although mouse models remain invaluable for studying biological mechanisms and testing new therapies, molecular changes observed in mice may not always translate directly to humans.

The conservation of hypoxia signaling, VEGFA signaling, and inflammatory responses across species may be particularly important. Because these pathways changed similarly in both mice and humans, they may represent promising targets for future interventions aimed at preserving muscle health during aging.

Overall, the study provides new insight into the similarities and differences between aging mouse and human skeletal muscle. The findings underscore the importance of integrating human data into aging research while continuing to use animal models to uncover biological mechanisms that may contribute to age-related muscle decline.

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

Corresponding author: Indranil Sinha – [email protected]

Keywords: hypoxia, angiogenesis, aging, skeletal muscle, regeneration

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