Directly Reprogrammed Human Neurons to Understand Age-Related Energy Metabolism Impairment and Mitochondrial Dysfunction in Healthy Aging and Neurodegeneration

Figure 1

Brain and neuronal aging. The aged brain is characterized by accumulation of organelle dysfunction affecting neuronal nuclei, lysosomes, and mitochondria, accumulation of oxidized macromolecules such as proteins, lipids, and nucleic acids, impaired adaptative responses to stress, and deregulated energy metabolism. These changes end up targeting two of the main cellular features that nerve cells require to fulfill brain functions: maintenance of neurogenesis and preservation of neuronal network activity. At a cellular level, aging leads to synapse loss and neuronal death, which exacerbate NDD. Despite their postmitotic nature, neurons exhibit a senescence-like phenotype. Mitochondrial energy metabolism is key to neuronal function and synaptic transmission and is dysregulated during aging. Morphological and functional alterations have been reported in aging and NDD; however, cellular and molecular mechanisms remain poorly understood.