Abstract
'Metabolism' refers to the vast collection of chemical processes that occur within a living organism. Within this broad designation, one can identify metabolism events that relate specifically to energy homeostasis, whether they occur at the subcellular, cellular, organ, or whole organism level. This review operationally refers to this type of metabolism as 'energy metabolism' or 'bioenergetics.' Changes in energy metabolism/bioenergetics have been linked to brain aging and a number of neurodegenerative diseases, and research suggests mitochondria may uniquely contribute to this. Interventions that manipulate energy metabolism/bioenergetic function and mitochondria may have therapeutic potential and efforts intended to accomplish this are playing out at basic, translational, and clinical levels. This review follows evolving views of energy metabolism's role in neurodegenerative diseases but especially Alzheimer's disease, with an emphasis on the bench-to-bedside process whose ultimate goal is to develop therapeutic interventions. It further considers challenges encountered during this process, which include linking basic concepts to a medical question at the initial research stage, adapting conceptual knowledge gained to a disease-associated application in the translational stage, extending what has been learned to the clinical arena, and maintaining support for the research at each of these fundamentally linked but functionally distinct stages. A bench-to-bedside biomedical research process is discussed that moves through conceptual, basic, translational, and clinical levels. For example, herein a case was made that bioenergetics is a valid Alzheimer's disease therapeutic target. Following this, a fundamental strategy for manipulating bioenergetics was defined, potential implications studied, and the approach extended to the clinical arena. This article is part of the 60th Anniversary special issue.