Harnessing Metabolism to Combat Neurodegeneration: Strategies for Reversing Age-Related Cognitive Decline

Age-related cognitive decline, a hallmark of neurodegenerative disorders such as Alzheimer's disease, has been increasingly associated with metabolic dysregulation. Targeting metabolic pathways to enhance brain function and slow neurodegeneration presents a novel therapeutic approach. This review discusses key metabolic interventions that may reverse or delay cognitive decline. Mitochondrial dysfunction, oxidative stress, and impaired energy metabolism are central to neurodegenerative progression. Therapies aimed at boosting mitochondrial biogenesis, such as nicotinamide adenine dinucleotide (NAD⁺) precursors, adenosine monophosphate-activated protein kinase (AMPK) activators, and peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) modulators, have shown promise in improving neuronal energy balance and reducing oxidative damage. Metabolic interventions like caloric restriction, intermittent fasting, and ketogenic diets have demonstrated neuroprotective effects by enhancing insulin sensitivity, promoting autophagy, and shifting the brain's energy reliance toward ketone bodies, which improves cognitive function. These strategies also mitigate neuroinflammation, a key driver of neuronal damage, by modulating immune responses and reducing the accumulation of toxic protein aggregates. Lipid metabolism also plays a crucial role in maintaining neuronal integrity. Enhancing lipid turnover, optimizing fatty acid profiles, and regulating cholesterol homeostasis may improve synaptic plasticity and reduce neuroinflammation, offering additional therapeutic avenues. By integrating current insights into metabolic regulation, this review underscores the potential of metabolic therapies to reverse or mitigate the cognitive decline associated with aging. Advancing our understanding of the intricate relationship between metabolism and neurodegeneration may pave the way for novel treatments targeting age-related cognitive impairment.