Caloric restriction reprograms skeletal muscle molecular pathways in non-human primates: potential relevance to human aging biology

BACKGROUND: Caloric restriction (CR), achieved by reducing energy intake without malnutrition, has been shown to preserve muscle function and delay age-related declines in strength and mobility by modulating key metabolic and molecular pathways involved in muscle maintenance. While most initial research on CR was done in rodents, non-human primates (NHPs) offer a higher translatable animal model for understanding CR effects due to their close genetic, physiological and cognitive similarities to humans. METHODS: In this cross-sectional study, we investigated skeletal muscle gene expression changes induced by 30% CR in skeletal muscle in rhesus monkeys (n = 18 CR, n = 18 control). We performed high-depth RNA sequencing to profile gene expression and alternative splicing variants and identify pathways linked to aging, regeneration/degeneration, and energy metabolism. RESULTS: Transcriptomic profiling revealed widespread gene expression differences between CR animals compared to controls. Genes that were overexpressed were mainly involved in pathways related to energy metabolism, mitochondrial function, signaling, and oxidative stress response. Conversely, underexpressed genes were connected to immune response, extracellular matrix organization, apoptosis, and ribosomal RNA processing. Further, we identify alternative splicing as a major mechanism by which CR modulates genes involved in muscle function, metabolism, and aging. CONCLUSIONS: Caloric restriction preserves skeletal muscle by enhancing metabolism, limiting degeneration and inflammation, and engaging conserved mechanisms across species.