Neuroenergetic Flexibility in the Aging Brain: Cellular Mechanisms and Diet-Induced Metabolic Switching.

The aging brain undergoes progressive alterations in energy metabolism that may reduce its capacity to match energy supply with changing functional demands. Declining glucose metabolism, mitochondrial dysfunction, and altered neuron-glia and neurovascular interactions may contribute to this vulnerability, but these changes do not necessarily indicate complete loss of metabolic capacity. Neuroenergetic flexibility refers to the capacity to coordinate changes in substrate utilization with energetic demand while maintaining cellular and functional homeostasis. This review synthesizes evidence from cellular, animal, imaging, and clinical studies to examine the mechanisms underlying this capacity, how it changes with aging, and whether diet-induced metabolic switching can enhance it. Particular attention is given to the distinction between metabolic switching, defined as a change in the relative contribution of available substrates, and neuroenergetic flexibility, which requires coordinated adaptation across substrate delivery, cellular metabolism, mitochondrial processing, neurovascular support, and functional demand. Evidence indicates that ketogenic diets, intermittent fasting, and caloric restriction can alter substrate availability and utilization and can engage mitochondrial, cellular stress-response, and nutrient-sensing pathways. However, the strength of evidence differs across biological levels: changes in alternative-substrate utilization are more consistently demonstrated than coordinated improvements in mitochondrial, vascular, cellular, and functional outcomes. Thus, increased ketone utilization or other metabolic shifts should not, by themselves, be interpreted as evidence of restored neuroenergetic flexibility. Instead, the available evidence suggests that aging may preserve individual metabolic capacities while reducing the coordination and reserve required to adapt effectively to changing energetic demands. Dietary interventions therefore provide useful models for testing metabolic adaptability, but their ability to restore integrated neuroenergetic flexibility in aging or neurodegenerative disease remains uncertain and appears to depend on age, metabolic state, disease context, intervention characteristics, and adherence.