Shikimic acid protects skin cells from UV-induced senescence through activation of the NAD+-dependent deacetylase SIRT1
Martínez-Gutiérrez, Alfredo (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Fernández-Duran, Irene (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Marazuela Duque, Anna (Institut d'Investigació Biomèdica de Bellvitge)
Simonet, Nicolas G.. (Institut d'Investigació Biomèdica de Bellvitge)
Yousef, Ibraheem (ALBA Laboratori de Llum de Sincrotró)
Martínez-Rovira, Immaculada (Universitat Autònoma de Barcelona. Departament de Física)
Martínez-Hoyos, Josefina (Mesostetic Pharma Group)
Vaquero, Alejandro (Institut d'Investigació Biomèdica de Bellvitge)

Date:	2021
Abstract:	UV radiation is one of the main contributors to skin photoaging by promoting the accumulation of cellular senescence, which in turn induces a proinflammatory and tissue-degrading state that favors skin aging. The members of the sirtuin family of NAD + -dependent enzymes play an anti-senescence role and their activation suggests a promising approach for preventing UV-induced senescence in the treatment of skin aging. A two-step screening designed to identify compounds able to protect cells from UV-induced senescence through sirtuin activation identified shikimic acid (SA), a metabolic intermediate in many organisms, as a bona-fide candidate. The protective effects of SA against senescence were dependent on specific activation of SIRT1 as the effect was abrogated by the SIRT1 inhibitor EX-527. Upon UV irradiation SA induced S-phase accumulation and a decrease in p16 INK4A expression but did not protect against DNA damage or increased polyploidies. In contrast, SA reverted misfolded protein accumulation upon senescence, an effect that was abrogated by EX-527. Consistently, SA induced an increase in the levels of the chaperone BiP, resulting in a downregulation of unfolded protein response (UPR) signaling and UPR-dependent autophagy, avoiding their abnormal hyperactivation during senescence. SA did not directly activate SIRT1 in vitro, suggesting that SIRT1 is a downstream effector of SA signaling specifically in the response to cellular senescence. Our study not only uncovers a shikimic acid/SIRT1 signaling pathway that prevents cellular senescence, but also reinforces the role of sirtuins as key regulators of cell proteostasis.
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	SIRT1 ; Senescence ; Human dermal fibroblasts ; UV irradiation ; Shikimic acid
Published in:	Aging (Albany NY), Vol. 13, Issue 9 (April 2021) , p. 12308-12333, ISSN 1945-4589

DOI: 10.18632/aging.203010
PMID: 33901008

26 p, 2.8 MB

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Research literature > UAB research groups literature > Research Centres and Groups (research output) > Health sciences and biosciences > Institut d'Investigació en Ciencies de la Salut Germans Trias i Pujol (IGTP) > Josep Carreras Leukaemia Research Institute
Research literature > UAB research groups literature > Research Centres and Groups (research output) > Experimental sciences > The ALBA Synchrotron
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Articles > Published articles