Duration of Caloric Restriction Modulates Brain Redox Adaptation and Frailty During Aging

Caloric restriction (CR) is among the most effective nutritional interventions for promoting healthy aging, yet the influence of intervention duration and age at initiation on its efficacy remains incompletely understood. This study investigated the effects of short-term caloric restriction (STCR) and long-term caloric restriction (LTCR) on frailty and brain redox homeostasis in male Wistar rats. Animals were maintained under ad libitum (AL) feeding, or subjected to LTCR initiated at 6 months of age or STCR initiated at 15 or 21 months, and were sacrificed at 18 or 24 months. Frailty, brain oxidative damage, antioxidant defense, systemic redox status, and the protein expression of key redox-related enzymes were evaluated. Both LTCR and STCR improved frailty and enhanced antioxidant defenses in 18-month-old rats. In contrast, in 24-month-old rats STCR was associated with a pronounced glutathione-related antioxidant response and reduced macromolecular oxidation without improving frailty. Systemic redox indices further supported age-dependent metabolic adaptation rather than a uniform antioxidant effect of CR. Overall, these findings demonstrate that CR is associated with age- and duration-dependent differences in redox-related parameters in the brain tissue. The results indicate differential regulation of antioxidant responses under the experimental conditions applied, while the underlying mechanisms and their functional significance require further investigation.