Abstract
Aging is a major risk factor for many neurodegenerative diseases. Klotho (KL) is a glycosylated transmembrane protein that is expressed in the choroid plexus and neurons of the brain. KL exerts potent anti-aging effects on multiple cell types in the body but its role in human brain cells remains largely unclear. Here we show that human cortical neurons, derived from human pluripotent stem cells in 2D cultures or in cortical organoids, develop the typical hallmarks of senescent cells when maintained in vitro for prolonged periods of time, and that moderate upregulation or repression of endogenous KL expression in cortical organoids inhibits and accelerates senescence, respectively. We further demonstrate that KL expression alters the expression of senescence-associated genes including, extracellular matrix genes, and proteoglycans, and can act in a paracrine fashion to inhibit neuronal senescence. In summary, our results establish an important role for KL in the regulation of human neuronal senescence and offer new mechanistic insight into its role in human brain aging.
Highlights
Klotho (KL) is a type I transmembrane protein with remarkable anti-aging properties[1], but is progressively downregulated during ageing[2]
We show that cortical neurons in brain organoids cultured for prolonged periods of time show increased senescence that is accompanied by a reduction in KL expression levels
Having established that human embryonic stem cells-derived cortical expression of endogenous KL did not significantly alter the proportion of CTIP2+ neurons in cortical brain organoids (Fig. 3d), brain organoids display a marked increase in senescence between weeks 10 and 13 that coincides with downregulation of KL, we but significantly reduced the upregulation of p21 observed in CTIP2+ neurons in cortical brain organoids cultured in the absence examined whether enforced expression of KL would affect of dox (Fig. 3e)
Summary
Klotho (KL) is a type I transmembrane protein with remarkable anti-aging properties[1], but is progressively downregulated during ageing[2]. KL expression in murine retinal pigment epithelial cells[9] or rat hippocampal neurons[10] enhances cell survival by inhibiting oxidative stress. In agreement with these data, Klotho-deficient mice show impaired cognition, while overexpression of Klotho in mice increases lifespan by 30–40%11, improves cognitive function in young and old mice, and enhances re-myelination in cuprizonetreated mice[12]. To date, KL’s impact and role in human neurons remains unclear To address this and explore the neural cell autonomous and potential paracrine effects of KL, we here utilized human pluripotent stem cell (PSC)-derived neurons and brain organoids. Our data demonstrate that KL has direct beneficial effects on human neurons and holds significant potential for improving human brain function with advanced age and for treating aging-related neurodegenerative diseases such as Alzheimer’s disease
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