ALS/FTD: Evolution, Aging, and Cellular Metabolic Exhaustion.

Amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD) are neurodegenerations with evolutionary underpinnings, expansive clinical presentations, and multiple genetic risk factors involving a complex network of pathways. This perspective considers the complex cellular pathology of aging motoneuronal and frontal/prefrontal cortical networks in the context of evolutionary, clinical, and biochemical features of the disease. We emphasize the importance of evolution in the development of the higher cortical function, within the influence of increasing lifespan. Particularly, the role of aging on the metabolic competence of delicately optimized neurons, age-related increased proteostatic costs, and specific genetic risk factors that gradually reduce the energy available for neuronal function leading to neuronal failure and disease.