Dietary duration and composition differentially influence mitochondrial activity and gene expression in a tissue-specific manner in aged rats.

Mitochondrial dysfunction is a hallmark of aging, affecting multiple systems and tissues, contributing to impairments in function. The resultant decreases in energy availability, along with increased oxidative stress, may be attenuated through diet. Fasting paradigms (including time restricted feeding (TRF)) and ketogenic diets (keto) both influence mitochondrial function, potentially mitigating these effects. However, the duration and modality of dietary intervention required for ameliorating age-related mitochondrial impairments remain unknown. Therefore, this study investigated the effects of a chronically (8-24 months; cTRFc) and acutely (22-24 months; aTRFc) administered TRF diet with standard macronutrients, as well as a chronically (8-24 months) administered TRF with ketogenic macronutrients (cTRFk), on mitochondrial activity and gene expression in aged male rats across tissues (brain, liver, muscle). Despite some synergy across the chronic diet groups, keto and TRF duration influenced mitochondrial function in a tissue- and diet-specific manner. Mitochondrial complex II activity was higher in cTRFk rats within the liver. Mitochondrial complex IV activity was lower in muscle and hippocampal tissue in both chronic TRF-fed groups. Relatedly, expression of the complex IV-related gene Cox2 increased within the CA3 subregion of the hippocampus of cTRFk. In this same region, expression of the mitochondrial biogenesis related gene Pgc1a was increased in cTRFc diet rats only. Within the liver, Cox5b expression increased in both groups of chronic TRF rats. Together, these findings highlight complex, tissue-specific responses to long-term dietary interventions, emphasizing the need for further research to develop targeted nutritional strategies for enhancing mitochondrial function and metabolic health in aging populations.