Age-dependent metabolic dysregulation in cancer and Alzheimer's disease.

Age is the main risk factor for cancer and neurodegeneration; two radically divergent diseases. Yet selective pressure to meet cellular metabolic needs may provide a common mechanism linking these two disorders. The exclusive use of glycolysis, despite the presence of oxygen, is commonly referred to as aerobic glycolysis and is the primary metabolic pathway of cancer cells. Recent evidence suggests that aerobic glycolysis is also a key regulator of synaptic plasticity in the brain that may positively influence cognition. Elevated aerobic glycolysis is a contributing factor to the development of cancer as increased glycolytic flux plays an important role in the biosynthesis of macromolecules and promotes proliferation. In contrast, decreased aerobic glycolysis in the brain occurs with age and could lead to a loss of cell survival mechanisms that counter pathogenic processes underlying neurodegeneration. In this review we discuss the recent findings from epidemiological studies demonstrating an inverse comorbidity of cancer and Alzheimer's disease. We summarize evidence linking the two diseases through changes in metabolism over the course of normal aging. We discuss the key steps and regulatory mechanisms of aerobic glycolysis and mitochondrial oxidative phosphorylation which could be exploited for the development of novel therapies. In addition, we outline the regulation of aerobic glycolysis at the transcriptional level by HIF-1α and Pin1 and their roles in cancer and neurodegeneration. Finally, we provide a possible explanation for metabolic dysregulation that occurs with age, and how it may be a contributing factor to age-related diseases. Determining how metabolism becomes dysregulated over time could lead to the development of effective interventions for ensuring metabolic homeostasis and healthy aging.