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.
"A decade ago, Dubal, a member of the UCSF Weill Neurosciences Institute, showed that klotho enhances cognition in young and old animals and also makes the brain more resistant to age-related degeneration. But she knew its effects had to be indirect because klotho molecules, injected into the body, never reached the brain. Dubal's team found that one connection was PF4, released by platelets after an injection of klotho.
PF4 had a dramatic effect on the hippocampus, the brain region responsible for making memories, where it enhanced the formation of new neural connections at the molecular level.
It also gave both old and young animals a brain boost in behavioral tests, suggesting that "there's room to go even in young brains to improve cognitive function," according to Dubal."
https://medicalxpress.com/news/2023-08-blood-factor-aging-brain.html
You need a proper functioning vitamin D receptor (VDR) to make Klotho. And I don't mean by taking more Vitamin D.
Chronic viral and microbial burden knocks out proper VDR function, or suppresses it via other gene expression. VDR is the foundation of innate immune function.
Vitamin D Receptor Mediates a Myriad of Biological Actions Dependent on Its 1,25-Dihydroxyvitamin D Ligand: Distinct Regulatory Themes Revealed by Induction of Klotho and Fibroblast Growth Factor-23
https://pubmed.ncbi.nlm.nih.gov/33553988/