Abstract
There is increasing evidence that nutrient composition, even without lowering total calorie intake, can shape lifespan through mechanisms independent of mitochondrial regulation. Brandon and colleagues recently reported that a low-protein, high-carbohydrate (LPHC) diet enriched with non-digestible cellulose, extends lifespan in mice by shifting the liver proteome through altered RNA splicing, a response different from the mitochondrial improvements typically seen with caloric restriction. The authors' findings support the "energy-splicing resilience axis," which proposes that changes in splicing help cells adapt to energetic and nutritional stress. We discuss how diet influences spliceosomal components such as SRSF1, linking nutrient sensing, AMPK signaling, and tissue-specific resilience pathways. We also consider the splicing paradox in aging, where beneficial isoforms increase despite a concomitant increase in splicing errors. Understanding how dietary and pharmacologic interventions modulate splicing may shed light on strategies to maintain homeostatic proteomes and support healthy longevity.