By Willem Koert

 

In the eyes of biochemists, the man who discovered quercetin was also the discoverer of vitamin C. Albert Szent Gyorgyi, the Hungarian biochemist who in 1928 was the first modern scientist to isolate vitamin C from foods such as Hungarian bell peppers[1], discovered in the 1930s a group of ingredients in food that enhanced the effect of vitamin C.

Szent-Gyorgyi published a letter in 1936 in the prestigious scientific journal Nature, in which he described his experiments on a subject who suffered from leaky blood vessels due to a vitamin C deficiency.[2] Remedying that defect went considerably more smoothly by administering an extract from citrus fruits that contained other substances in addition to vitamin C than by administering purified vitamin C.

Citrus contained flavonoids, Szent-Gyorgyi discovered, which apparently stimulated the absorption of vitamin C. The biochemist half-seriously called that group of substances vitamin P. However, nutritional scientists have never considered flavonoids to be a vitamin.

A few years later, Szent-Gyorgyi would receive the Nobel Prize for his research into the biological properties of vitamin C.[3] [4] After the Second World War, the institute to which he was affiliated would intensively study flavonoids in food and discover that the average Westerner ingests somewhere between 50 and 100 milligrams of flavonoids. The most common flavonoids are quercetin [chemical structure below] and its analogs.

 

 

Cancer prevention

Quercetin belongs to the subgroup of flavonoids that biochemists call flavonols. In theory, the best dietary sources of quercetin analogs are lovage and capers, but the intake of those products is too small to carry much weight. In practice, onions and apples (with red skin) are the main sources of quercetin.

The exact function of flavonoids is still not fully known, but animal studies in the 1980s showed that quercetin supplementation could reduce the chance that laboratory animals actually developed cancer after exposure to carcinogens.[5] [6]

That research inspired the American oncologist and biologist Lee Wattenberg to write influential review articles, in which he launched the theory that the presence of substances such as quercetin in natural plant foods could protect against cancer by a diet containing as many unprocessed products as possible.[7] Wattenberg not only had in mind flavonoids such as quercetin, but also the sulfur-containing phytochemicals in cabbage vegetables and garlic, such as sulforaphane and alliin respectively.

Around the turn of the century, Wattenberg’s theories about natural substances in food that protect against cancer faded into the background. However, research into substances such as flavonoids such as quercetin continued.

 

Life extension

In 2012, German researchers from the Technische Universität München published an animal study in which they exposed the nematode Caenorhabditis elegans to four flavonoids. One of them was quercetin.[8] The researchers discovered that the administration of quercetin allowed the nematodes to live longer.

Initially, scientists suspected that substances such as quercetin could extend life and prevent disease by acting as an antioxidant. This was not the case, the Germans discovered. Antioxidants neutralize aggressive molecules in tissues that chemists call free radicals, thereby preventing those aggressive molecules from damaging cells. However, the Germans also conducted tests with genetically modified nematodes that produce extremely high levels of free radicals, and found that quercetin did not work in these test animals.

The mechanism of action of quercetin as a life extender is of a different order than the scavenging of free radicals, Chinese researchers discovered through further fundamental research with nematodes. In a study published in the International Journal of Molecular Sciences, they found that flavonols such as quercetin activate a key molecule called nuclear factor-erythroid 2 related factor-2 [Nrf-2] in humans.[9] In human cells, Nrf-2 acts as a kind of master switch when it comes to repair mechanisms and activation of antioxidant, detoxification and anti-inflammatory pathways.[10]

When the Nrf-2-switch flips, cells start with a major cleaning and the cell produces more peroxisomes. Peroxisomes can be described as a kind of molecular shredders. They break down molecules that no longer function properly due to damage. An increased yet controlled activity of peroxisomes makes aging cells function better.

 

Endurance

At the same time, quercetin also leads cells to construct more mitochondria.[11] Mitochondria are the parts of a cell that convert nutrients into energy. If people increase their physical activity, the production of mitochondria increases. This implies that quercetin in theory mimics the effect of exercise on a molecular level.[12]

This probably also explains why supplementation with several hundred milligrams of quercetin per day can improve the endurance of both laboratory animals[13] and humans[14]. According to meta-studies, although the performance enhancing effect of quercetin on humans is not large, and probably even too small to be relevant in real life, it is statistically significant.[15] [16]

 

Quercetin as an anti-viral

Another biological effect of quercetin supplementation, which may also be related to the activation of the Nrf-2 pathways, is antiviral in nature. Because quercetin mainly accumulates in the lungs,[17] this antiviral effect of quercetin is especially relevant when it comes to respiratory viruses.

In animal studies in which mice are subjected to intensive physical exertion, as a result of which their immune system is temporarily less active, the chance of illness and death as a result of exposure to a dangerous influenza virus was less if the test animals were given quercetin.[18] The human equivalent of the dose in these studies was approximately 80-100 milligrams per day.

In 2007, exercise scientists at Appalachian State University in the US published a human study in which cyclists had to cycle for three hours a day for 3 days in a row. If the test subjects also took 1000 milligrams of quercetin daily, this reduced their risk of infection with circulating cold and flu viruses.[19]

 

Optimal dose unknown

It is not exactly in which dose of quercetin is most suitable for anti-aging purposes. As long as that question has not been answered, some caution should be exercised when using quercetin as most scientists who study quercetin currently believe that the mechanism of action behind quercetin’s positive health effects is hormetic in nature.[20] This means that quercetin, when administered in the correct dosage, behaves like a mild toxin. In this dose, quercetin does not harm the organism, but it does activate a variety of defense mechanisms – such as the Nrf-2 pathway.

IncreaseLifespan has written about hormesis before. Like here.

From the above it’s clear that, although according to toxicological research quercetin in doses up to 1000 milligrams should not entail significant health risks, quercetin can indeed be toxic in very high concentrations. This may explain why mice live shorter when given such high doses of quercetin for life.[21]

A problem with substances such as quercetin is their low bio-availability. High doses are required to achieve biological effects. These lead to high peaks in the blood, in which the concentration of quercetin may even acquire toxic properties. Fortunately, those toxic peaks are short-lived.[22] The human metabolism neutralizes quercetin at lightning speed. But this also means that, even at high doses, quercetin will only have the desired hormetic effect for a limited time.

 

Enhanced bio-availability

The most convincing longevity effects of quercetin supplementation in the scientific literature relate to trials where researchers used quercetin preparations with increased bio-availability. Extreme doses were not necessary.

Scientists from the Chinese Academy of Sciences published an animal study in Protein Cell in which an extremely small dose of quercetin, in the form of such a preparation, was not able to extend the lifespan of mice, but it did ensure that the mice also were more often healthy in their last phase of life.[23] Older mice had better conditioned fur and were physically stronger thanks to supplementation.

If you want to slow down the aging process by using quercetin supplements, you may want to choose a reasonably dosed product with an increased bio-availability, such as a quercetin-phospholipid complex. According to animal studies[24] and human studies[25], the bio-availability of quercetin in such a form is significantly higher.

An extremely interesting property of quercetin is also that it increases the absorption of other phytochemicals – including another natural substance with a life-extending effect: resveratrol. For the life extension movement, resveratrol is perhaps even more interesting than quercetin.

But that is a topic for another blog.

 

 

References

[1] Banga I, Szent-Györgyi A. The large scale preparation of ascorbic acid from Hungarian pepper (Capsicum annuum). Biochem J. 1934;28(5):1625-8.

[2] Rusznyák S, Szent-Györgyi A. Vitamin P: Flavonols as Vitamins. Nature. 1936 July 4;138:27.

[3] Svirbely JL, Szent-Györgyi A. The chemical nature of vitamin C. Biochem J. 1932;26(3):865-70.

[4] Svirbely JL, Szent-Györgyi A. The chemical nature of vitamin C. Biochem J. 1933;27(1):279-85.

[5] Kato R, Nakadate T, Yamamoto S, Sugimura T. Inhibition of 12-O-tetradecanoylphorbol-13-acetate-induced tumor promotion and ornithine decarboxylase activity by quercetin: possible involvement of lipoxygenase inhibition. Carcinogenesis. 1983 Oct;4(10):1301-5.

[6] Verma AK, Johnson JA, Gould MN, Tanner MA. Inhibition of 7,12-dimethylbenz(a)anthracene- and N-nitrosomethylurea-induced rat mammary cancer by dietary flavonol quercetin. Cancer Res. 1988 Oct 15;48(20):5754-8.

[7] Wattenberg LW. Inhibition of carcinogenesis by minor dietary constituents. Cancer Res. 1992 Apr 1;52(7 Suppl):2085s-2091s.

[8] Grünz G, Haas K, Soukup S, Klingenspor M, Kulling SE, Daniel H, Spanier B. Structural features and bioavailability of four flavonoids and their implications for lifespan-extending and antioxidant actions in C. elegans. Mech Ageing Dev. 2012 Jan;133(1):1-10.

[9] He F, Ru X, Wen T. NRF2, a Transcription Factor for Stress Response and Beyond. Int J Mol Sci. 2020 Jul 6;21(13):4777.

[10] Zhu Y, Yang Q, Liu H, Song Z, Chen W. Phytochemical compounds targeting on Nrf2 for chemoprevention in colorectal cancer. Eur J Pharmacol. 2020 Nov 15;887:173588.

[11] Rayamajhi N, Kim SK, Go H, Joe Y, Callaway Z, Kang JG, Ryter SW, Chung HT. Quercetin induces mitochondrial biogenesis through activation of HO-1 in HepG2 cells. Oxid Med Cell Longev. 2013;2013:154279.

[12] De Sousa Lages A, Lopes V, Horta J, Espregueira-Mendes J, Andrade R, Rebelo-Marques A. Therapeutics That Can Potentially Replicate or Augment the Anti-Aging Effects of Physical Exercise. Int J Mol Sci. 2022 Sep 1;23(17):9957.

[13] Davis JM, Murphy EA, Carmichael MD, Davis B. Quercetin increases brain and muscle mitochondrial biogenesis and exercise tolerance. Am J Physiol Regul Integr Comp Physiol. 2009 Apr;296(4):R1071-7.

[14] Nieman DC, Williams AS, Shanely RA, Jin F, McAnulty SR, Triplett NT, Austin MD, Henson DA. Quercetin’s influence on exercise performance and muscle mitochondrial biogenesis. Med Sci Sports Exerc. 2010 Feb;42(2):338-45.

[15] Kressler J, Millard-Stafford M, Warren GL. Quercetin and endurance exercise capacity: a systematic review and meta-analysis. Med Sci Sports Exerc. 2011 Dec;43(12):2396-404.

[16] Pelletier DM, Lacerte G, Goulet ED. Effects of quercetin supplementation on endurance performance and maximal oxygen consumption: a meta-analysis. Int J Sport Nutr Exerc Metab. 2013 Feb;23(1):73-82.

[17] De Boer VC, Dihal AA, van der Woude H, Arts IC, Wolffram S, Alink GM, Rietjens IM, Keijer J, Hollman PC. Tissue distribution of quercetin in rats and pigs. J Nutr. 2005 Jul;135(7):1718-25.

[18] Davis JM, Murphy EA, McClellan JL, Carmichael MD, Gangemi JD. 3,3′,4′,5,7-pentahydroxyflavone reduces susceptibility to influenza infection following stressful exercise. Am J Physiol Regul Integr Comp Physiol. 2008 Aug;295(2):R505-9.

[19] Nieman DC, Henson DA, Gross SJ, Jenkins DP, Davis JM, Murphy EA, Carmichael MD, Dumke CL, Utter AC, McAnulty SR, McAnulty LS, Mayer EP. Quercetin reduces illness but not immune perturbations after intensive exercise. Med Sci Sports Exerc. 2007 Sep;39(9):1561-9.

[20] Calabrese EJ, Kozumbo WJ. The hormetic dose-response mechanism: Nrf2 activation. Pharmacol Res. 2021 May;167:105526.

[21] Jones E, Hughes RE. 3,3′,4′,5,7-pentahydroxyflavone, flavonoids and the life-span of mice. Exp Gerontol. 1982;17(3):213-7.

[22] Egert S, Wolffram S, Bosy-Westphal A, Boesch-Saadatmandi C, Wagner AE, Frank J, Rimbach G, Mueller MJ. Daily 3,3′,4′,5,7-pentahydroxyflavone supplementation dose-dependently increases plasma quercetin concentrations in healthy humans. J Nutr. 2008 Sep;138(9):1615-21.

[23] Geng L, Liu Z, Wang S, Sun S, Ma S, Liu X, Chan P, Sun L, Song M, Zhang W, Liu GH, Qu J. Low-dose 3,3′,4′,5,7-pentahydroxyflavone positively regulates mouse healthspan. Protein Cell. 2019 Oct;10(10):770-775.

[24] Zhang K, Zhang M, Liu Z, Zhang Y, Gu L, Hu G, Chen X, Jia J. Development of quercetin-phospholipid complex to improve the bioavailability and protection effects against carbon tetrachloride-induced hepatotoxicity in SD rats. Fitoterapia. 2016 Sep;113:102-9.

[25] Wang H, Cui Y, Fu Q, Deng B, Li G, Yang J, Wu T, Xie Y. A phospholipid complex to improve the oral bioavailability of flavonoids. Drug Dev Ind Pharm. 2015;41(10):1693-703.

[26] Jaisamut P, Wanna S, Limsuwan S, Chusri S, Wiwattanawongsa K, Wiwattanapatapee R. Enhanced Oral Bioavailability and Improved Biological Activities of a Quercetin/Resveratrol Combination Using a Liquid Self-Microemulsifying Drug Delivery System. Planta Med. 2021 Apr;87(4):336-46.

[27] Vesely O, Baldovska S, Kolesarova A. Enhancing Bioavailability of Nutraceutically Used Resveratrol and Other Stilbenoids. Nutrients. 2021 Sep 2;13(9):3095.