Sexually Dimorphic Response to Dietary Restriction-Induced Longevity and Muscle Preservation in Nothobranchius furzeri.

Age-related skeletal muscle decline (sarcopenia) contributes to frailty and mortality, yet how sex influences muscle aging and dietary interventions remains unclear. Using the short-lived vertebrate Nothobranchius furzeri, we investigated how sex and intermittent fasting (IF) interact to regulate lifespan and skeletal muscle aging.

We establish an IF regimen that extends lifespan in both males and females, despite trade-offs including reduced growth and reproductive output. Importantly, IF improves swimming performance in aged animals of both sexes.

Under normal feeding, muscle aging exhibits pronounced sexual dimorphism. Males show age-associated myofiber hyperplasia, whereas females preserve fiber number but undergo hypertrophic remodeling.

IF partially attenuates both phenotypes, maintaining a youthful fiber size distribution in males and females. Single-nucleus RNA-sequencing reveals sex-specific remodeling of muscle-fiber composition with age: females shift toward oxidative slow-twitch fibers under normal feeding, a change attenuated by IF, while males maintain relatively stable fiber-type proportions across diets.

Cell-cell communication analyses show a global age-associated decline in intercellular signaling, with IF restoring distinct pathways in a sex-specific manner, including IGF signaling in females and metabolic ANGPTL signaling in males. Bulk transcriptomic profiling indicates largely sexually dimorphic aging trajectories, whereas IF induces both shared and sex-specific responses.

Notably, IF upregulates ribosome biogenesis and genes supporting myofibrillar organization and contraction in both sexes, likely contributing to preserved muscle function. Together, these findings demonstrate that IF promotes longevity and muscle health through conserved anabolic mechanisms alongside sex-specific cellular preservation and adaptation, underscoring the importance of sex as a biological variable in interventions for healthy aging.