Research Paper Volume 13, Issue 9 pp 12308—12333
Shikimic acid protects skin cells from UV-induced senescence through activation of the NAD+-dependent deacetylase SIRT1
- 1 Chromatin Biology Laboratory, Josep Carreras Leukaemia Research Institute (IJC), Barcelona 08916, Badalona, Spain
- 2 Chromatin Biology Laboratory, Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Barcelona 08908, Spain
- 3 Mesostetic Pharma Group, Barcelona 08840, Viladecans, Spain
- 4 MIRAS Beamline, ALBA-CELLS Synchrotron, Barcelona 08290, Cerdanyola del Vallès, Spain
- 5 Ionizing Radiation Research Group, Physics Department, Universitat Autònoma de Barcelona (UAB), Barcelona 08193, Cerdanyola del Vallès, Spain
Received: September 18, 2020 Accepted: March 31, 2021 Published: April 26, 2021https://doi.org/10.18632/aging.203010
How to Cite
Copyright: © 2021 Gutiérrez et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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 p16INK4A 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.