Abstract: Klotho is one of a number of well-known longevity-associated genes. Its depletion in aging or disease may promote several neuropathologies associated with the central nervous system, including hypomyelination and phosphorylation of neurofilaments, synaptic loss and modulation of their plasticity, behavioral impairments, neuroinflammation, and finally neurodegeneration. Therefore, the complexity of neuronal physiology and function raises some fundamental questions about the molecular mechanisms involved in Klotho action. To date, the evidence is summarized that the common link between Klotho and neuropathological changes are perturbations in oxidative homeostasis leading to the irreversible accumulation of molecular damage in DNA, protein, and lipids fractions, and finally to cell death or senescence. However, recent studies shed more detailed light on a possible protective mechanism of Klotho in neuronal cells through modulation of endoplasmic reticulum (ER) stress pathways, autophagic process, and inflammatory reaction in response to misfolded protein accumulation.