Sirtuins, resveratrol and the intertwining cellular pathways connecting them

Sirtuins are a family of NAD⁺-dependent deacylases with numerous physiological and pathological implications, which lately became an attractive therapeutic target. Sirtuin-activating compounds (STACs) could be useful in disease prevention and treatment. Despite its bioavailability issues, resveratrol exerts a myriad of beneficial effects, known as the "resveratrol paradox". Modulation of sirtuins' expression and activity may, in fact, underlie many of resveratrol revered actions; however, the cellular pathways affected by modulating the activity of each sirtuin isoform, in different physio-pathological conditions, are not fully known. The purpose of this review was to summarize recent reports concerning the effects of resveratrol on the activity of sirtuins in different experimental settings, focusing on in vitro and in vivo preclinical studies. Most reports concern SIRT1, however recent studies dive into the effects initiated via other isoforms. Numerous cellular signaling pathways were reported to be modulated by resveratrol in a sirtuin-dependent manner (increased phosphorylation of MAPKs, AKT, AMPK, RhoA, BDNF, decreased activation of NLRP3 inflammasome, NF-κB, STAT3, upregulation of SIRT1/SREBP1c pathway, reduced β-amyloid via SIRT1-NF-κB-BACE1 signaling and counteracting mitochondrial damage by deacetylating PGC-1α). Thus, resveratrol may be the ideal candidate in the search for STACs as a tool for preventing and treating inflammatory and neurodegenerative diseases.