Class: flavonol supplement
Alias(es): CAS# 117-39-5, 5,7,3′,4′-flavon-3-ol; Sophoretin; Meletin; Quercetine; Xanthaurine; Quercetol; Quercitin; Quertine; Bio-Quercetin; Flavin meletin
Background: Quercetin is a flavonoid found naturally in many fruits and vegetables, and most abundantly in onions, grapes, berries, cherries, broccoli, and citruses. Supplements can be taken to achieve much higher levels of quercetin than can be obtained from dietary sources. Quercetin is effective at restoring NAD levels, and targeting senescent cells of certain cell types whereas dasatinib, a synthetic senolytic drug, is effective at clearing senescent cells of other cell types. Thus, although they can be taken individually, quercetin is generally administered in combination with the prescription drug dasatinib (D+Q) in preclinical and clinical trials to achieve a broader senolytic effect. Although it is yet unknown whether D+Q can improve health and lifespan in aging humans, clinical trials will soon be underway (see section immediately below), and D+Q has shown promise in this regard in preclinical trials both in vitro in human cells and in vivo in mice and rats (see preclinical studies section). Lastly, it is important to consider that quercetin is considered Generally Recognized As Safe (GRAS) by the FDA and has been safely used at high doses in short-term (3 months) human clinical trials. However, there is limited data for long-term administration of quercetin in humans and toxicity studies in rats suggest that long-term administration of quercetin, especially at higher doses, may be toxic to the kidneys and carcinogenic.
Is there evidence it works in humans for aging?
Is there evidence it works in preclinical studies for aging?
Quercetin-only preclinical studies: When quercetin is used alone, it has been found to: restore NAD levels by inhibiting an NAD consuming enzyme (CD38), reduce senescent cell levels, oxidative stress, and inflammation, and improve bone repair. See table below for references and details.
Dasatinib+Quercetin (D+Q) preclinical studies: Benefits of D+Q for aging (as demonstrated in preclinical studies) include reduction of senescent cell burden and inflammatory markers, and improvements in cardiovascular health, gut microbiome, fatty liver disease, bone health and disc degeneration, strength and physical health, and cognitive health. See table below for references and details.
Maintaining NAD+ Homeostasis:
The figure above is from Escande et al., 2013. It shows the mechanism by which the senolytic drugs Apigenin and Quercetin improve NAD levels that have fallen due to aging. CD38 naturally causes low NAD+ levels within cells, which results in low sirtuin activity (nutrient sensing enzymes which have been linked to improved healthspan and lifespan when active). However, both Apigenin and Quercetin inhibit CD38’s NADase activity, leading to higher levels of NAD intracellularly.
The figure above is from a review by Martel et al., 2020. It shows the pathways inhibited by senolytic supplements, such as Quercetin, and drugs, such as Dasatinib, that lead to reduced viability of senescent cells and/or apoptosis of senescent cells.
Quercetin is known to selectively target senescent endothelial cells, the cells that line blood vessels, the heart, and lymph nodes, whereas the drug Dasatinib is known to target senescent pre-adipocytes. Thus, as mentioned earlier, dasatinib and quercetin have complimentary senolytic effects, enabling the targeting of a broader range of senescent cells than either alone, and are generally administered together in a combination known as D+Q. In fact, some senescent cell types, such as mouse fibroblast cells, do not respond to either D or Q alone, but are effectively cleared when the combination of D+Q is used.
Many of the benefits of D+Q for aging are due to this senolytic effect, which results in less systemic inflammation and damage by reducing levels of Senescence-Associated Secretory Phenotype (SASP). The mechanism by which D+Q removes senescent cells, while not affecting non-senescent cells, is by inhibiting certain Senescent Cell Anti-Apoptotic Pathways (SCAPs), which are upregulated by senescent cells to avoid apoptosis, programmed destruction that would otherwise be activated by the immune system in response to senescent cells’ inflammatory SASP. Several of the SCAPs inhibited by Quercetin are BCL-2/BCL-XL, PI3K/AKT, and p53/p21/serpine, whereas Dasatinib targets the ephrin/src tyrosine kinase pathway and dependence receptors. Different SCAPs are involved in different types of senescent cells, which explains why Quercetin and Dasatinib selectively target different cell types.
Are there known safety concerns?
There is no reported toxicity attributable to quercetin in human studies, but long-term data is limited.
In a 2018 human study involving treating idiopathic pulmonary fibrosis (IPF) patients (ages 55-84) with intermittent DQ (D:100 mg/day, Q:1250 mg/day, three-days/week over three-weeks), all patients were retained for the study course with no D+Q discontinuation. Although there was no placebo arm, the adverse events reported were consistent with previous placebo arms in trials for IPF, and there was only one serious adverse event (pneumonia and edema) which was completely resolved after hospitalization. There were no changes in laboratory tests to indicate any liver or kidney toxicity and pulmonary function did not change.
In male rats, there was some evidence of carcinogenicity.
In female rats, there was no evidence of carcinogenicity at all doses tested.
In male rats, kidney dysfunction (specifically the incidence of renal tubule hyperplasia and the severity of nephropathy) were increased in a dose-dependent manner.
1. Anand David, A. V., Arulmoli, R., & Parasuraman, S. (2016). Overviews of Biological Importance of Quercetin: A Bioactive Flavonoid. Pharmacognosy Reviews, 10(20), 84–89. https://doi.org/10.4103/0973-7847.194044
2. Zhu, Y., Tchkonia, T., Pirtskhalava, T., Gower, A. C., Ding, H., Giorgadze, N., Palmer, A. K., Ikeno, Y., Hubbard, G. B., Lenburg, M., O’Hara, S. P., LaRusso, N. F., Miller, J. D., Roos, C. M., Verzosa, G. C., LeBrasseur, N. K., Wren, J. D., Farr, J. N., Khosla, S., … Kirkland, J. L. (2015). The Achilles’ heel of senescent cells: From transcriptome to senolytic drugs. Aging Cell, 14(4), 644–658. https://doi.org/10.1111/acel.12344
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6. Escande, C., Nin, V., Price, N. L., Capellini, V., Gomes, A. P., Barbosa, M. T., O’Neil, L., White, T. A., Sinclair, D. A., & Chini, E. N. (2013). Flavonoid Apigenin Is an Inhibitor of the NAD+ase CD38. Diabetes, 62(4), 1084–1093. https://doi.org/10.2337/db12-1139
7. Song, S., Tchkonia, T., Jiang, J., Kirkland, J. L., & Sun, Y. (2020). Targeting Senescent Cells for a Healthier Aging: Challenges and Opportunities. Advanced Science, 7(23), 2002611. https://doi.org/10.1002/advs.202002611