There is a pressing need to develop therapeutics that can promote brain health with aging. Such therapeutics would postpone the deterioration in cognition and mental health that occurs with age. The proposed research will identify, optimize, and then test in laboratory animals such therapeutics as steps towards future clinical use. The research focus is on mitochondria, the organelle in brain neurons that provides energy and many other functions for neurons to function and remain healthy. Mitochondria become impaired with age; mitochondrial impairment is one of the well-known hallmarks of aging. In pilot studies, we have identified a few new drugs that have the potential to enhance mitochondrial function across age. We will search for and identify five times more to enlarge the set of potential “mitotherapeutics.” These drugs will then be tested in laboratory animals to determine whether they can protect mitochondria from the insults associated with age and enhance brain function; postponing or eliminating the cognitive and mental health issues that occur with age. Drugs with the potential to postpone or eliminate these issues would have an enormous impact on brain health for the late adult and elderly in the U.S. population.