Aging is a physiological process that occurs in all living organisms; however, cognitive decline and physical frailty during aging can be linked to high-calorie diets, chronic illnesses, and a sedentary lifestyle. The Klotho protein is inherently linked to the aging process, while also serving a role in various other physiological processes. Klotho has been shown to have a neuroprotective effect in various neurodegenerative diseases, potentially through its ability to modulate antioxidant defenses and energy metabolism. Our previous data showed that pharmacological inhibition of FGFR1, ERK phosphorylation, and monocarboxylic acid transporters prevents Klotho-induced lactate release from astrocytes. In addition, Klotho treatment has anti-inflammatory properties, as shown by its ability to inhibit NF-κB activation in astrocytes after an inflammatory stimulus. Here we demonstrate that AKT inhibition by Klotho treatment induces transcriptional activity of FOXO transcription factors and promotes antioxidant defense in astrocytes by inducing catalase expression. In addition, Klotho treatment induced PFKFB3 ubiquitination and proteasome activity in neurons. Taken together these data suggest that Klotho is an important player in the adaptive defense response in astrocytes and it increases proteasomal activity in neurons, which are both protective actions involving coupling between neurons and astrocytes against neurodegenerative processes.