ISOCALORIC INTERMITTENT FASTING TO FIGHT AGED-ASSOCIATED BEHAVIORAL ANOMALIES BY WESTERN DIET

Western diet, rich in fats and widely adopted worldwide, is associated with health deterioration, especially when it comes to aging. As an alternative to caloric restriction¹, isocaloric intermittent fasting (IF) has been proposed as a promising dietary approach that can improve metabolic and cognitive outcomes with better adherence². However, its effects on brain metabolism and function across aging remain unclear. This investigation involved three cohorts of C57BL/6 mice (n=50 per group) assigned to four experimental conditions resulting from the combination of two feeding regimens — Ad Libitum (AL) or isocaloric Intermittent Fasting (IF) — with two diets: Standard Diet (SD) or High-Fat Diet (HFD). At 6 months of age, mice followed these conditions for either 3, 6, or 12 months, corresponding to mature adulthood, middle age, and senescence. Metabolic blood markers and cognitive performance were assessed before tissue and plasma collection. Preliminary findings indicate distinct metabolic profiles across the four groups. At all ages, AL-HFD mice exhibited glucose intolerance compared with other conditions. AL-SD mice showed higher fasting-induced blood ketone levels, an effect that was reversed in both IF groups. Consistent with these metabolic changes, increased hepatic lipid droplet accumulation was observed in both HFD conditions. Behavioral testing showed that IF preserved locomotor activity and short-term memory and protected against an anxiety-like phenotype throughout aging. These effects are likely linked to brain metabolic adaptations, particularly in ketone body utilization. Overall, the results suggest that IF may help preserve metabolic health and higher-order cognitive behaviors during aging, even under Western-like high-fat dietary conditions.