Klotho inhibits neuronal senescence in human brain organoids

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 re...

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Autores principales:	Mohammed R. Shaker, Julio Aguado, Harman Kaur Chaggar, Ernst J. Wolvetang
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Geriatrics RC952-954.6
Acceso en línea:	https://doaj.org/article/74fa64d5680d4bdba32351255a2b38ac
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spelling	oai:doaj.org-article:74fa64d5680d4bdba32351255a2b38ac2021-12-02T17:06:23ZKlotho inhibits neuronal senescence in human brain organoids10.1038/s41514-021-00070-x2056-3973https://doaj.org/article/74fa64d5680d4bdba32351255a2b38ac2021-08-01T00:00:00Zhttps://doi.org/10.1038/s41514-021-00070-xhttps://doaj.org/toc/2056-3973Abstract 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.Mohammed R. ShakerJulio AguadoHarman Kaur ChaggarErnst J. WolvetangNature PortfolioarticleGeriatricsRC952-954.6ENnpj Aging and Mechanisms of Disease, Vol 7, Iss 1, Pp 1-12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Geriatrics RC952-954.6
spellingShingle	Geriatrics RC952-954.6 Mohammed R. Shaker Julio Aguado Harman Kaur Chaggar Ernst J. Wolvetang Klotho inhibits neuronal senescence in human brain organoids
description	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.
format	article
author	Mohammed R. Shaker Julio Aguado Harman Kaur Chaggar Ernst J. Wolvetang
author_facet	Mohammed R. Shaker Julio Aguado Harman Kaur Chaggar Ernst J. Wolvetang
author_sort	Mohammed R. Shaker
title	Klotho inhibits neuronal senescence in human brain organoids
title_short	Klotho inhibits neuronal senescence in human brain organoids
title_full	Klotho inhibits neuronal senescence in human brain organoids
title_fullStr	Klotho inhibits neuronal senescence in human brain organoids
title_full_unstemmed	Klotho inhibits neuronal senescence in human brain organoids
title_sort	klotho inhibits neuronal senescence in human brain organoids
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/74fa64d5680d4bdba32351255a2b38ac
work_keys_str_mv	AT mohammedrshaker klothoinhibitsneuronalsenescenceinhumanbrainorganoids AT julioaguado klothoinhibitsneuronalsenescenceinhumanbrainorganoids AT harmankaurchaggar klothoinhibitsneuronalsenescenceinhumanbrainorganoids AT ernstjwolvetang klothoinhibitsneuronalsenescenceinhumanbrainorganoids
_version_	1718381619307347968

Klotho inhibits neuronal senescence in human brain organoids

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