The anti-aging protein α-Klotho has several therapeutic effects on different pathophysiological conditions, mainly its anti-inflammatory and antioxidant effects. Experimental evidence and observational studies suggest that there are several strategies to increase α-Klotho in the brain and enhance its beneficial effects, thus contributing to improving its neuroprotective and neuroplasticity mechanisms in brain aging, Alzheimer’s, Parkinson’s, and ischemic stroke diseases. In this article, we summarize the relevant information on α-Klotho, brain aging, Alzheimer’s, Parkinson’s, and ischemic stroke diseases and analyze the role of α-Klotho in each of these alterations, as well as the effect of physical exercise, exogenous application of α-klotho, and various drugs approved for different human diseases on α-Klotho production.