The Anti-Aging and Tumor Suppressor Protein Klotho Enhances Differentiation of a Human Oligodendrocytic Hybrid Cell Line

Abstract

Klotho functions as an aging suppressor, which, in mice, extends lifespan when overexpressed and accelerates development of aging-like phenotypes when disrupted. Klotho is mainly expressed in brain and kidney and is secreted into the serum and CSF. We have previously shown that Klotho is reduced in brains of old monkeys, rats, and mice. We further reported the ability of Klotho to enhance oligodendrocyte differentiation and myelination. Here, we examined the signaling pathways induced by Klotho in MO3.13, a human oligodendrocytic hybrid cell line. We show that exogenous Klotho affects the ERK and Akt signaling pathways, decreases the proliferative abilities and enhances differentiation of MO3.13 cells. Furthermore, microarray analysis of Klotho-treated MO3.13 cells reveals a massive change in gene expression with 80 % of the differentially expressed genes being downregulated. Using gene set enrichment analysis, we predicted potential transcription factors involved in regulating Klotho-treated MO3.13 cells and found that these cells are highly enriched in the gene sets, that are similarly observed in cancer, cardiovascular disease, stress, aging, and hormone-related chemical and genetic perturbations. Since Klotho is downregulated in all brain tumors tested to date, enhancing Klotho has therapeutic potential for treating brain and other malignancies.

Klotho regulates postnatal neurogenesis and protects against age-related spatial memory loss

“…Decreased KO dendritic complexity (Figure 2D,4F) suggests impaired maturation of immature neurons that resembles the phenotype of immature neurons from aged brain (Rao et al 2005). KL is also important for oligodendrocyte maturation (Chen et al 2015; Zeldich et al 2015), suggesting that trophic activity of KL could be required throughout the brain or that different forms of KL protein could have independent effects on different cell populations. Together data from the KO shows that the absence of immature neurons at 7 weeks (Figure 2A) is the product of progenitors failing to proceed through stages of differentiation and maturation causing suppression of neurogenesis.…”

The Three Sisters of Fate in Multiple Sclerosis: Klotho (Clotho), Fibroblast Growth Factor-23 (Lachesis), and Vitamin D (Atropos)

“…In this study, the authors have shown that Klt is co-localized with neuronal and oligodendrocyte markers but not with microglial and astrocyte markers. Chen et al [29] showed another important function of Klt in CNS. In CNS, Klt leads to the differentiation and maturation of oligodendrocyte progenitor cells to mature oligodendrocytes, but does not increase the proliferation of these cells.…”

Frequent methylation of the KLOTHO gene and overexpression of the FGFR4 receptor in invasive ductal carcinoma of the breast

“…KL is a primarily type I transmembrane protein that is further processed to produce a secreted form with wide spectrum of tissue expression and functions [9]. KL has overlapping functions including the regulation of FGF23 signaling and subsequently affecting the regulation of calcium homeostasis and nitric oxide production [10], suppression of the insulin/insulin-like growth factor 1 (IGF-1) signaling [11], suppression of Wnt signaling and oxidative stress [12,13], oligodendrocyte maturation, and developmental myelination of the CNS and inhibition of cancer development [14]. The relationship of KL and human cancers is suggested by the observation of its downregulation in several cancer types through methylation of its promoter region [15][16][17][18][19][20].…”