Klotho Improves Cell Defenses in Brain Cells
Klotho is a longevity-associated protein; more of it produces life extension in mice, while less of it shortens life span. Separately, why does increased expression of circulating klotho protein produce cognitive benefits? Klotho appears to operate functionally in the kidney, given what is known of the protein, and there has been some thought that it is kidney function that is important to the effects of klotho on tissues elsewhere in the body, that protecting the kidney from age-related decline will naturally improve function everywhere else. However, that doesn't explain why klotho can increase cognitive function in young mice; that strongly suggests that there must be effects on cells in the brain.
Klotho is an antiaging protein, and its levels decline with age and chronic stress. The exogenous administration of Klotho can enhance cognitive performance in mice and negatively modulate the Insulin/IGF1/PI3K/AKT pathway in terms of metabolism. In humans, insulin sensitivity is a hallmark of healthy longevity. Therefore, this study aimed to determine if exogenous Klotho, when added to neuronal and astrocytic cell cultures, could reduce the phosphorylation levels of certain insulin signaling effectors and enhance antioxidant strategies in these cells.
Primary cell cultures of cortical astrocytes and neurons from mice were exposed to 1 nM Klotho for 24 hours, with or without glucose. Klotho decreased phosphorylated AKT and mTOR levels. However, in astrocytes, Klotho increased FOXO-3a activity and catalase levels, shielding them from intermediate oxidative stress. In neurons, Klotho did not alter FOXO-3 phosphorylation levels but increased proteasome activity, maintaining lower levels of PFKFB3. This study offers new insights into the roles of Klotho in regulating energy metabolism and the redox state in the brain.