Therapeutic application of quercetin in aging-related diseases: SIRT1 as a potential mechanism

Abstract

Quercetin, a naturally non-toxic flavonoid within the safe dose range with antioxidant, anti-apoptotic and anti-inflammatory properties, plays an important role in the treatment of aging-related diseases. Sirtuin 1 (SIRT1), a member of NAD⁺-dependent deacetylase enzyme family, is extensively explored as a potential therapeutic target for attenuating aging-induced disorders. SIRT1 possess beneficial effects against aging-related diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), Depression, Osteoporosis, Myocardial ischemia (M/I) and reperfusion (MI/R), Atherosclerosis (AS), and Diabetes. Previous studies have reported that aging increases tissue susceptibility, whereas, SIRT1 regulates cellular senescence and multiple aging-related cellular processes, including SIRT1/Keap1/Nrf2/HO-1 and SIRTI/PI3K/Akt/GSK-3β mediated oxidative stress, SIRT1/NF-κB and SIRT1/NLRP3 regulated inflammatory response, SIRT1/PGC1α/eIF2α/ATF4/CHOP and SIRT1/PKD1/CREB controlled phosphorylation, SIRT1-PINK1-Parkin mediated mitochondrial damage, SIRT1/FoxO mediated autophagy, and SIRT1/FoxG1/CREB/BDNF/Trkβ-catenin mediated neuroprotective effects. In this review, we summarized the role of SIRT1 in the improvement of the attenuation effect of quercetin on aging-related diseases and the relationship between relevant signaling pathways regulated by SIRT1. Moreover, the functional regulation of quercetin in aging-related markers such as oxidative stress, inflammatory response, mitochondrial function, autophagy and apoptosis through SIRT1 was discussed. Finally, the prospects of an extracellular vesicles (EVs) as quercetin loading and delivery, and SIRT1-mediated EVs as signal carriers for treating aging-related diseases, as well as discussed the ferroptosis alleviation effects of quercetin to protect against aging-related disease via activating SIRT1. Generally, SIRT1 may serve as a promising therapeutic target in the treatment of aging-related diseases via inhibiting oxidative stress, reducing inflammatory responses, and restoring mitochondrial dysfunction.

Keywords: aging-related diseases; inflammatory response; mitochondrial dysfunction; oxidative stress; quercetin; sirtuin 1.

Graphical Abstract

Figure 1

Chemical formula of quercetin.

Figure 2

Mechanisms of quercetin on Alzheimer’s disease (AD). Quercetin exert neuroprotective effects against chronic AD by targeting SIRT1 to regulate cellular senescence and aging-related multiple cellular processes, including SIRT1/Keap1/Nrf2/HO-1 and PI3K/Akt/GSK-3β mediated oxidative stress, SIRT1/NF-κB mediated inflammatory response, SIRT1/PGC1α/eIF2α/ATF4/CHOP mediated mitochondrial damage, and SIRT1/FoxO mediated autophagy. CAT, catalase; GSH-Px, glutathione peroxidase; PI3K, phosphoinositide 3-kinase; GSK-3β, glycogen synthase kinase 3beta; iNOS, inducible nitric oxide synthase; TNF, tumor necrosis factor; TLR, toll-like receptors; PGC-1α, proliferator-activated receptor gamma coactivator 1alpha; AMPK, AMP-activated protein kinase; eIF2α, eukaryotic initiation factor 2 alpha; and ATF4, activating transcription factor 4.

Figure 3

Mechanisms of quercetin on attenuating Parkinson’s disease (PD). Quercetin is a potential therapeutic strategy for PD by targeting SIRT1. Developing therapies have shown that SIRT1/Nrf2/HO-1 mediated oxidative stress, SIRT1/NF-κB/NLRP3 pathway ameliorates neuroinflammation SIRT1-mediated PKD1/CREB phosphorylation and BDNF gene expression, regulates mitochondrial disorders in dopaminergic neurons and SIRT1-PINK1-Parkin mediated mitochondrial autophagy in the astrocytes to maintain mitochondrial function. ROS, reactive oxygen species; 5-HT, 5-hydroxytryptamine; CAT, catalase; GSH-Px, glutathione peroxidase; TNF, tumor necrosis factor; NLRP3, NOD-like receptor protein 3; IL-1β, interleukin-1 β; CREB, cAMP response element binding protein; MDA, malondialdehyde; BDNF, brain-derived neurotrophic factor; and GFAP, glial fibrillary acidic protein.

Figure 4

Mechanisms of quercetin in attenuating Huntington’s disease (HD). Quercetin plays neuroprotective role in HD by targeting SIRT1 to relieve aggregation of mHTT in patients, restore mitochondrial function, and reduce inflammation. UPS, ubiquitin-proteasome system; mHtt, Huntington’s protein; ROS, reactive oxygen species; TNF-α, tumor necrosis factor-α; and IL-1β, interleukin-1 β.

Figure 5

Mechanisms of quercetin on Depression. Quercetin act as an antidepressant by targeting SIRT1 to reverse depressive and anxiety-like behaviors and hippocampal neuroinflammation. The FoxG1/CREB/BDNF/Trkβ-catenin axis clarifies these mechanisms. FOXG1, Forkhead box transcription factor G1; CREB, cAMP response element binding protein; TrKβ, tyrosine receptor kinase A. SOD, superoxide dismutase; CAT, catalase; GSH-Px, glutathione peroxidase; TNF, tumor necrosis factor; IL-1β, interleukin-1 β; MDA, malondialdehyde; and BDNF, brain-derived neurotrophic factor.

Figure 6

Mechanism of quercetin on osteoporosis. Quercetin as a therapeutic strategy for the treatment of aging-related osteoporosis by targeting SIRT1, via antioxidant pathways, thereby inhibits osteoblast apoptosis, autophagy, and inflammatory responses. Runx2, related transcription factor 2; OSX, Osterix; OCN, osteocalcin; Cx43, connexin 43; RANKL, receptor activator of nuclear factor-kappa B ligand; TNF, tumor necrosis factor; IL-6, interleukin-6; IFN-γ, interferon γ; SOD, superoxide dismutase; CAT, catalase; GSH, glutathione; ALP, alkaline phosphatase; LC3, microtubule-associated protein light chain 3; OPG, osteoprotegerin; CTX-1, C-terminal telopeptide of type I collagen; P1NP, N-terminal propeptide of type I procollagen; TRAP, Tartrate-resistant acid phosphatase; Runx2, related transcription factor 2.

Figure 7

Mechanisms of quercetin on Myocardial ischemia (M/I) and reperfusion (MI/R). Quercetin is potential therapeutic drug that play roles in reducing MI/R injury via SIRT1/PI3K/Akt/Nrf2 mediated oxidative stress, SIRT1/PGC1α and HMGB1/TLR4/NF-κB mediated inflammatory response, and SIRT1/p38 MAPK mediated apoptosis pathways. MDA, malondialdehyde; SOD, superoxide dismutase; TNF-α, tumor necrosis factor-α; IL-1β, interleukin-1 β; iNOS, inducible nitric oxide synthase; GSH-Px, glutathione peroxidase; TLR4, toll-like receptor 4; and PGC-1α, proliferator-activated receptor gamma coactivator, 1alpha.

Figure 8

Mechanisms of quercetin on Atherosclerosis. Quercetin is an important target in the treatment of atherosclerosis by preventing endothelial cell damage via SIRT1/AMPK/Nrf2 mediated oxidative stress, SIRT1/PI3K/Akt/NF-κB and SIRT1/TLRs/MAPK mediated inflammatory response. TNF-α, tumor necrosis factor-α; AMPK, AMP-activated protein kinase; GSH-Px, glutathione peroxidase; MDA, malondialdehyde; NLRP3, NOD-like receptor protein 3; ox-LDL, oxidized low-density lipoprotein; and TLR4, toll-like receptor 4.

Figure 9

The mechanism of quercetin on diabetes. Quercetin play potential therapeutic roles in treating diabetes by targeting SIRT1 via PGC-1α/PPARα/Nrf2 mediated oxidative stress and SIRT1/NF-κB/NLRP3 mediated ferroptosis. SOD, superoxide dismutase; MDA, malondialdehyde; IL-6, interleukin-6; GST, glutathione S-transferases; PGC-1α, proliferator-activated receptor gamma coactivator; IRS-1, insulin receptor substrate-1; GSK3β, glycogen synthase kinase 3 beta.