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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 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.
Highlights
Skin aging is defined as the degenerative process by which structural and physiological alterations cause the impairment of skin biological functions [1,2,3]
Our work reveals a role for shikimic acid (SA) in preventing cellular senescence in human dermal fibroblasts (HDFs) and identifies SIRT1 as a key downstream effector of this function (Figure 5D)
Our evidences suggest that the signaling axis involving SA/SIRT1 contributes to maintenance of proteostasis
Summary
Skin aging is defined as the degenerative process by which structural and physiological alterations cause the impairment of skin biological functions [1,2,3]. The development of skin aging is associated with several changes at the molecular level, including the accumulation of DNA damage, genome instability, epigenetic dysregulation, extracellular matrix degradation, mitochondrial dysfunction, inflammation, loss of proteostasis, ER-stress and autophagy dysfunction Many of these alterations are directly associated with cellular senescence, one of the hallmarks of skin aging. Upon DNA damage, several pathways, including p53, p38-MAPK, NF-κβ and mTOR pathways, are activated to establish and maintain cellular senescence [10,11,12] These pathways are involved in cell cycle arrest and induction of a pro-inflammatory state (known as the senescence-associated secretory phenotype, SASP), among other processes, which is one of the major features of cell senescence. As none of the aforementioned senescence features is specific to senescence, the detection of more than one marker is required to confirm the senescent state [14]
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