Energy Metabolism and Brain Aging: Strategies to Delay Neuronal Degeneration

Abstract

Aging is characterized by a gradual decline in physiological functions, with brain aging being a major risk factor for numerous neurodegenerative diseases. Given the brain's high energy demands, maintaining an adequate ATP supply is crucial for its proper function. However, with advancing age, mitochondria dysfunction and a deteriorating energy metabolism lead to reduced overall energy production and impaired mitochondrial quality control (MQC). As a result, promoting healthy aging has become a key focus in contemporary research. This review examines the relationship between energy metabolism and brain aging, highlighting the connection between MQC and energy metabolism, and proposes strategies to delay brain aging by targeting energy metabolism.

Keywords: Brain aging; Energy metabolism; Mitochondrial quality control; Neurons.

Fig. 1

Neuronal energy metabolism is a complex process involving multiple interconnected pathways, primarily glycolysis, the tricarboxylic acid (TCA) cycle, and mitochondrial oxidative phosphorylation. Glucose uptake into neurons is mediated by specific glucose transporters, notably GLUT3 and GLUT4, located on the neuronal membrane. Following cellular entry, glucose undergoes glycolysis to yield pyruvate and a limited amount of ATP. Pyruvate is subsequently transported into mitochondria, where it is converted to acetyl-CoA via pyruvate dehydrogenase. This acetyl-CoA enters the TCA cycle, producing NADH and FADH2, which donate electrons to the electron transport chain (ETC) for ATP synthesis, while also generating reactive oxygen species (ROS) as metabolic byproducts. Cells can utilize ROS for physiological signal transduction processes. Beyond glucose metabolism, neurons can utilize alternative energy substrates. Dietary fatty acids are catabolized into acetyl-CoA through mitochondrial β-oxidation, with the resulting acetyl-CoA feeding into the TCA cycle to support oxidative phosphorylation. Furthermore, neurons benefit from metabolic coupling with astrocytes. Astrocyte-derived lactate, produced via glycolysis, is transported to neurons and converted to pyruvate for ATP generation. Similarly, ketone bodies generated from astrocytic fatty acid breakdown are delivered to neurons, where their conversion to acetyl-CoA fuels the TCA cycle, thereby maintaining neuronal energy homeostasis

Fig. 2

Starvation can promote mitophagy and MDV production. Starvation triggers the activation of the energy sensor AMP-activated protein kinase (AMPK), which can activate the mammalian target of rapamycin (mTOR) or directly activate Autophagy Activating Kinase 1/2. This leads to the phosphorylation of Beclin1 and the promotion of mitochondrial autophagosome formation by Microtubule-associated protein 1 A/1B-light chain 3 (LC3). PTEN-induced putative kinase 1, located on the outer mitochondrial membrane, recruits Parkin from the cytoplasm, catalyzing the attachment of ubiquitin chains to outer mitochondrial membrane proteins. Under the action of LC3, autophagosomes are transported to lysosomes for degradation. During starvation, the production of MDVs also increases. The single-membrane MDVs labeled with mitochondria-associated protein ligase (MAPL) are directed to peroxisomes for degradation, while those labeled with translocase of outer mitochondrial membrane 20 (TOM20), as well as double-membrane MDVs labeled with pyruvate dehydrogenase (PDH), are transported to lysosomes for degradation. Notably, MDVs maintain membrane potential, contain ATP synthase subunits, and possess the ability to produce ATP