Chen CD, Sloane JA, Li H, Aytan N, Giannaris EL, Zeldich E, Hinman JD, Dedeoglu A, Rosene DL, Bansal R, Luebke JI, Kuro-O M, Abraham CR. The Anti-aging Protein Klotho Enhances Oligodendrocyte Maturation and Myelination of the CNS. J Neurosci. 2013;33:1927-1939.
We have previously shown that myelin abnormalities characterize the normal aging process of the brain and that an age-associated reduction in Klotho is conserved across species. Predominantly generated in brain and kidney, Klotho overexpression extends life span, whereas loss of Klotho accelerates the development of aging-like phenotypes. Although the function of Klotho in brain is unknown, loss of Klotho expression leads to cognitive deficits. We found significant effects of Klotho on oligodendrocyte functions, including induced maturation of rat primary oligodendrocytic progenitor cells (OPCs) in vitro and myelination. Phosphoprotein analysis indicated that Klotho’s downstream effects involve Akt and ERK signal pathways. Klotho increased OPC maturation, and inhibition of Akt or ERK function blocked this effect on OPCs. In vivo studies of Klotho knock-out mice and control littermates revealed that knock-out mice have a significant reduction in major myelin protein and gene expression. By immunohistochemistry, the number of total and mature oligodendrocytes was significantly lower in Klotho knock-out mice. Strikingly, at the ultrastructural level, Klotho knock-out mice exhibited significantly impaired myelination of the optic nerve and corpus callosum. These mice also displayed severe abnormalities at the nodes of Ranvier. To decipher the mechanisms by which Klotho affects oligodendrocytes, we used luciferase pathway reporters to identify the transcription factors involved. Together, these studies provide novel evidence for Klotho as a key player in myelin biology, which may thus be a useful therapeutic target in efforts to protect brain myelin against age-dependent changes and promote repair in multiple sclerosis.
This shows a 7-week-old normal mouse (left) and a klotho mouse, an animal model that shows multiple phenotypes resembling human aging. Klotho protein deficiency (top panel in Western blot) leads to the overactivation of -calpain (second and third panels), a decrease of calpastatin (fourth panel), and the cleavage of II-spectrin (fifth panel), which in turn result in growth retardation, inactivity, and premature death at 8-9 weeks.
Klotho is a transmembrane protein that, in addition to other effects, provides some control over the sensitivity of the organism to insulin and appears to be involved in aging. The Klotho protein is a novel β-glucuronidase capable of hydrolyzing steroid β-glucuronides. Genetic variants inKLOTHO have been associated with human aging, and Klotho protein has been shown to be a circulating factor detectable in serum that declines with age. Klotho-deficient mice manifest a syndrome resembling accelerated human aging and display extensive and accelerated arteriosclerosis. Additionally, they exhibit impaired endothelium dependent vasodilation and impaired angiogenesis (production of blood vessels.
Although the vast majority of research has been based on lack of Klotho, it was demonstrated that an over-expression of Klotho in mice might extend their average life span between 19% and 31% compared to normal mice. Klotho-deficient mice show increased production of vitamin D, and altered mineral-ion homeostasis is suggested to be a cause of premature aging–like phenotypes, because the lowering of vitamin D activity by dietary restriction reverses the premature aging–like phenotypes and prolongs survival in these mutants. These results suggest that aging–like phenotypes were due to klotho-associated vitamin D metabolic abnormalities.
This study shows that Klotho is involved in myelination, so if we can stimulate Klotho it may be a new avenue to myelination. Again some way off aa treatment but more bits of the jigsaw.