Lifespan-increasing drug nordihydroguaiaretic acid inhibits p300 and activates autophagy

Abstract Aging is characterized by the progressive loss of physiological function in all organisms. Remarkably, the aging process can be modulated by environmental modifications, including diet and small molecules. The natural compound nordihydroguaiaretic acid (NDGA) robustly increases lifespan in...

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Autores principales:	Tugsan Tezil, Manish Chamoli, Che-Ping Ng, Roman P. Simon, Victoria J. Butler, Manfred Jung, Julie Andersen, Aimee W. Kao, Eric Verdin
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2019
Materias:	Geriatrics RC952-954.6
Acceso en línea:	https://doaj.org/article/fedb936c93fd4ed4a2abe901304bf02a
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spelling	oai:doaj.org-article:fedb936c93fd4ed4a2abe901304bf02a2021-12-02T14:18:31ZLifespan-increasing drug nordihydroguaiaretic acid inhibits p300 and activates autophagy10.1038/s41514-019-0037-72056-3973https://doaj.org/article/fedb936c93fd4ed4a2abe901304bf02a2019-10-01T00:00:00Zhttps://doi.org/10.1038/s41514-019-0037-7https://doaj.org/toc/2056-3973Abstract Aging is characterized by the progressive loss of physiological function in all organisms. Remarkably, the aging process can be modulated by environmental modifications, including diet and small molecules. The natural compound nordihydroguaiaretic acid (NDGA) robustly increases lifespan in flies and mice, but its mechanism of action remains unclear. Here, we report that NDGA is an inhibitor of the epigenetic regulator p300. We find that NDGA inhibits p300 acetyltransferase activity in vitro and suppresses acetylation of a key p300 target in histones (i.e., H3K27) in cells. We use the cellular thermal shift assay to uniquely demonstrate NDGA binding to p300 in cells. Finally, in agreement with recent findings indicating that p300 is a potent blocker of autophagy, we show that NDGA treatment induces autophagy. These findings identify p300 as a target of NDGA and provide mechanistic insight into its role in longevity.Tugsan TezilManish ChamoliChe-Ping NgRoman P. SimonVictoria J. ButlerManfred JungJulie AndersenAimee W. KaoEric VerdinNature PortfolioarticleGeriatricsRC952-954.6ENnpj Aging and Mechanisms of Disease, Vol 5, Iss 1, Pp 1-11 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	Geriatrics RC952-954.6
spellingShingle	Geriatrics RC952-954.6 Tugsan Tezil Manish Chamoli Che-Ping Ng Roman P. Simon Victoria J. Butler Manfred Jung Julie Andersen Aimee W. Kao Eric Verdin Lifespan-increasing drug nordihydroguaiaretic acid inhibits p300 and activates autophagy
description	Abstract Aging is characterized by the progressive loss of physiological function in all organisms. Remarkably, the aging process can be modulated by environmental modifications, including diet and small molecules. The natural compound nordihydroguaiaretic acid (NDGA) robustly increases lifespan in flies and mice, but its mechanism of action remains unclear. Here, we report that NDGA is an inhibitor of the epigenetic regulator p300. We find that NDGA inhibits p300 acetyltransferase activity in vitro and suppresses acetylation of a key p300 target in histones (i.e., H3K27) in cells. We use the cellular thermal shift assay to uniquely demonstrate NDGA binding to p300 in cells. Finally, in agreement with recent findings indicating that p300 is a potent blocker of autophagy, we show that NDGA treatment induces autophagy. These findings identify p300 as a target of NDGA and provide mechanistic insight into its role in longevity.
format	article
author	Tugsan Tezil Manish Chamoli Che-Ping Ng Roman P. Simon Victoria J. Butler Manfred Jung Julie Andersen Aimee W. Kao Eric Verdin
author_facet	Tugsan Tezil Manish Chamoli Che-Ping Ng Roman P. Simon Victoria J. Butler Manfred Jung Julie Andersen Aimee W. Kao Eric Verdin
author_sort	Tugsan Tezil
title	Lifespan-increasing drug nordihydroguaiaretic acid inhibits p300 and activates autophagy
title_short	Lifespan-increasing drug nordihydroguaiaretic acid inhibits p300 and activates autophagy
title_full	Lifespan-increasing drug nordihydroguaiaretic acid inhibits p300 and activates autophagy
title_fullStr	Lifespan-increasing drug nordihydroguaiaretic acid inhibits p300 and activates autophagy
title_full_unstemmed	Lifespan-increasing drug nordihydroguaiaretic acid inhibits p300 and activates autophagy
title_sort	lifespan-increasing drug nordihydroguaiaretic acid inhibits p300 and activates autophagy
publisher	Nature Portfolio
publishDate	2019
url	https://doaj.org/article/fedb936c93fd4ed4a2abe901304bf02a
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Lifespan-increasing drug nordihydroguaiaretic acid inhibits p300 and activates autophagy

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