Alterations in homeostatic functions such as energy balance and sleep patterns are frequently seen in the elderly and these changes may precede and predict subsequent cognitive decline. A novel hypothesis is that some of these seemingly disparate manifestations of age-related deficits may share common underlying neurobiological mechanisms; that is, brain regions that are involved in homeostasis regulate the activity of brain regions that mediate the appropriate behavioral and cognitive responses to physiological challenges, and these interactions may be impacted in aging. The hypothalamic orexin/hypocretin neuropeptide system regulates energy balance, arousal and cognition via widespread ascending and descending projections. We have shown in animal models that the orexin system plays an important role in modulating cognitive—particularly attentional—function and that aging is associated with dramatic reductions in the number of orexin neurons and deficits in activation of cortical and hippocampal circuitry by homeostatically-relevant stimuli. Recent clinical literature has also shown significant loss of these neurons in age-related neurological disorders, including Alzheimer’s and Parkinson’s disease. Here, I will review and expand on these findings and discuss the potential of the orexin system as a therapeutic target for “healthy brain aging”, with effects on both cognitive and physiological correlates of aging.