By lowering uric acid levels …

Can Quercetin Prevent Gout?
… and also reduces the risk factors for insulin resistance and diabetes

By Will Block

T oday, gout is an increasingly common lifestyle disease. According to the CDC, the prevalence of gout among US adults in 2007–2008 was 3.9% (8.3 million individuals) using nationally representative data from 2007–2008.1 The prevalence of gout among men was 5.9% (6.1 million), and the prevalence among women was 2.0% (2.2 million). While you might think that gout is a disease of the past, these figures are growing.

Hippocrates first identified gout in the fifth century BCE, although the condition was known in ancient Egypt some two millennia earlier.2 The cause of gout is a combination of bad diet, genetic factors, and kidney malfunction. It occurs more commonly in those who eat a lot of meat, drink a lot of beer, and are overweight. Men are more likely to get gout, but women become increasingly susceptible to gout after menopause.

Known as the disease of kings because in the past it affected only those wealthy enough to indulge in large amounts of alcohol and high purine foods (substances that could be broken down to form uric acid). Particularly high in purines are organ meat, liver, brains, and anchovies, along with shellfish, poultry, and even certain vegetables—including peas, mushrooms, and asparagus.

However, to learn more about gout it is worth noting some details about those who suffered (and suffer) from the past to the present. These include:

• Leonardo da Vinci, Italian painter, sculptor, architect and engineer

• King Henry VIII of England

• Sir Isaac Newton, English mathematician and physicist

• Benjamin Franklin, founding father

• Samuel Johnson, British author and poet

• Ludwig Van Beethoven, composer

• Charles Dickens, English novelist

• Ansel Adams, landscape photographer

• Sir Laurence Olivier, actor

• Anthony Burgess, writer and composer

• Luciano Pavarotti, Italian operatic tenor

• Dick Cheney, former Vice President

• Jim Belushi, comedian and actor

• Harry Kewell, professional soccer player

• Jared Leto, actor

Gout and Its Causes

Among subjects from the past, there appears to be a difference in attitude about food. Both da Vinci and Newton were interested in diet but didn’t eat a lot. Henry VIII, Johnson, and Franklin were gluttons and the first two drunkards as well.

What unites these four is lead poisoning, which may have played a role in their gout. da Vinci used lead-based paint and probably had a lot of lead in his body, even to the point of toxicity. As a pre-chemist, Newton pursued a belief in the transmutation of metals—trying to turn lead into gold (the Philosopher’s Stone). Following exhumation, the hair from Newton’s dead body was found to contain high levels of mercury and lead. He must have had considerable contact with these metals.

Henry VIII had lead poisoning caused by a pearl and lead ointment he used. And Franklin may also have suffered from lead poisoning due to his working with lead type (both hot and cold) in his printing career. The half-life of lead in adult human blood has been estimated to be from 28–36 days.


Gout is a rheumatic disease resulting
from deposition of uric acid crystals
(monosodium urate) in tissues and
fluids within the body.


Rome: The First Mass Distributor of Lead

During the Roman Empire wine consumption was associated with gout.3 In ancient Rome, lead poisoning was a disease common to the wealthy, which used lead extensively. In their cooking utensils urns, pots, and plumbing (also for lining the aqueducts), lead was ever-present. Moreover, it was significant in vessels used to concentrate grape juice into a syrup to preserve wine.

Known as sapa, this syrup was simmered slowly in the lead-lined vessel and then was mixed with wine in drinking vessels. The result was called plumbism. It is synonymous with lead poisoning, which is strongly associated with kidney malfunction.

In fact, plumbism reduces the excretion of uric acid and leads to elevated concentrations of uric acid in the blood leading to the formation of uric acid crystals in the joints and/or kidneys. These crystals increase the risk of insulin resistance, type 2 diabetes, and gout. Gout is a rheumatic disease resulting from deposition of uric acid crystals (monosodium urate) in tissues and fluids within the body. This process is caused by an over-production or under-excretion of uric acid—something that bad kidneys will do.

The Excruciating Pain of Gout

Acute gout typically manifests itself as an acutely red, hot, and swollen joint with excruciating pain. These acute gouty flare-ups respond well to treatment with oral anti-inflammatory medicines. Among the drugs used to treat gout is allopurinol. However, the allopurinol response is highly variable, with many users failing to achieve target serum uric acid levels. Recurrent bouts of acute gout can lead to a degenerative form of chronic arthritis called gouty arthritis.

Worldwide Increase in Obesity and Gout

Gout remains the most common form of inflammatory arthritis in Western countries, and is on the rise worldwide in countries such as China, New Zealand, and Taiwan, with a particularly high prevalence (~10%) in the aboriginal populations of these latter two countries. This is not surprising given the worldwide epidemic of obesity. Gout prevalence increased from 0.5 to 3% between 1960 and 2010 in the USA and other nations. That’s a 6-fold increase.


Daily supplementation of 500 mg
quercetin for 4 weeks significantly
reduces elevated plasma uric acid
concentrations in healthy males, thus
decreasing the risk for gout.


Lower Blood Uric Acid in Humans

Quercetin, a flavonoid found in high levels in onions, tea, and apples, inhibits xanthine oxidoreductase in vitro, the final step in intracellular uric acid production. This indicates that quercetin might be able to lower blood uric acid in humans. In a new report, researchers determined the effects of 4 weeks of oral quercetin supplementation on plasma uric acid, blood pressure and fasting glucose.4

This trial recruited twenty-two healthy males (19–60 years) with baseline plasma uric acid concentration in the higher, but still-healthy, range (339 (SD 51) μmol/l).


Just as resveratrol has been shown to
increase expression of PGC-1α, so
too did quercetin.


The intervention included one 500 mg quercetin tablet daily for 4 weeks, compared with placebo, with a 4-week washout period between treatments. The primary outcome was change in concentrations of plasma uric acid after 2 and 4 weeks; secondary outcome measures were changes in fasting plasma glucose, 24-h urinary excretion of uric acid and resting blood pressure. After quercetin treatment, plasma uric acid concentrations were significantly lowered by −26.5 μmol/l, without affecting fasting glucose, urinary excretion of uric acid or blood pressure. Daily supplementation of 500 mg quercetin for 4 weeks significantly reduces elevated plasma uric acid concentrations in healthy males, thus decreasing the risk for gout.

A recent study zeroed in on a common functional single nucleotide polymorphism (SNP) of ALDH2 as a genuine gout-associated SNP in the MYL2-CUX2 locus.5 If you have bad genes for gout, remember that elevated plasma uric acid concentration is a risk factor as well for insulin resistance and type 2 diabetes

Plus, there are many additional benefits attributed to quercetin.

Quercetin Prolongs Healthspan

Imagine living a very long time, but continuing to age and becoming more decrepit with the loss of function after function, all the while in relentless pain. Unfortunately, this is what many think when presented with the idea of a longer lifespan. But it doesn’t have to be that way, according to recent findings—especially an exemplary new study showing that healthspan may be prolonged.

In a recent “tour de force” scientific study, researchers at the Scripps Research Institute (SRI), the Mayo Clinic, and other institutions began with the assumption that the accumulations of senescent cells are associated with accelerated aging. Senescent cells stop dividing and secrete compounds that harm surrounding tissue structure and raise the odds of nearby cells also becoming senescent. Searching for ways to eliminate senescent cells in the body that have become destructive, the scientists found two compounds—a nutrient (quercetin) and a drug—that could induce cell suicide of senescent cells (separately and together), leading to improved cardiovascular function and exercise endurance, reduced osteoporosis and frailty, and extended healthspan in a species of mice that were developed to age rapidly. The researchers anticipate that the so-called senolytics will work in humans; thus this new therapy could truly be an “anti-aging” intervention.


Crucially, although often ignored,
the brain’s role in exercise tolerance
is paramount.


Quercetin Improves Exercise Tolerance

By increasing mitochondrial biogenesis in brain and muscle, quercetin enhances the motivation and willingness to exercise.

A study conducted at the University of South Carolina’s Arnold School of Public Health by a team of physiologists and exercise scientists, examined the effects of quercetin feedings in mice for 7 days.6 They paid special attention to markers of mitochondrial biogenesis in skeletal muscle and brain, and on endurance exercise tolerance. The mice were randomly assigned to three treatment groups: placebo, 12.5 mg/kg quercetin, or 25 mg/kg quercetin per day. The flavonoid was mixed with orange-flavored Tang® (“OJ for Astronauts”) or placebo (Tang only) daily via gavage for 7 days. Tang masks the taste of quercetin very well and contains vitamins (especially B3 and C), which may increase bioavailability. The human equivalence of the doses given the mice would be 76 mg and 152 mg per day, respectively, for a 75 kg (165 lb) person.

Following 7 days of treatment, the soleus muscle and brain tissues were analyzed for expression of PGC-1α and sirtuin 1, along with other markers.

As another measure of quercetin’s effects, some of the mice were given a treadmill performance run to fatigue test or were placed in activity wheel cages, where their voluntary activity (distance, time, and peak speed) was recorded. Interestingly, treadmill running is thought to be a better indicator of maximal running capacity as opposed to wheel running, which is greatly influenced by behavioral factors. Significantly, both treadmill and wheel running are strongly influenced by an increase in both muscle and brain mitochondria, although the brain is seldom mentioned in this context.

Just as resveratrol has been shown to increase expression of PGC-1α, so too did quercetin. Moreover, so too did quercetin increase the expressions of SIRT1 and mtDNA (mitochondrial DNA). Cytochrome c concentration was also increased. And all of these benefits occurred in skeletal muscle and brain tissue. Importantly, these marker changes of mitochondrial biogenesis were associated with an increase in both maximal endurance capacity (in which the mice were “forced” to go on) and wheel-running activity (in which the mice “volunteered” to go on).


One of the most pervasive aspects of
aging is the loss of strength. Anything
that safely increases our ability to stay
strong is of major importance.


The Effect of Brain on Brawn

As we have previously written, PGC-1α plays an important role in stimulating mitochondrial biogenesis after physiological demands such as exercise, or nutrients such as the flavonoid resveratrol. (See “Resveratrol Mimics Caloric Restriction,” in the April 2008 issue.) PGC-1α expression is emphatic in high-capacity mitochondrial systems, such as muscle fibers, where it helps regulate skeletal muscle fuel stores, an essential mechanism for endurance exercise capacity. Crucially, although often ignored, the brain’s role in exercise tolerance is paramount. What goes on in the metabolism of your brain has “important consequences for motivation, mood (e.g., vigor, fatigue, anxiety, depression), and central motor drive from the cortex, and increased brain mitochondrial activity could certainly enhance cerebral metabolism.”

PGC-1α activates mitochondrial biogenesis,which increases production of ATP, the universal energy molecule. This in turn allows for greater physiological demands caused by exercise and energy deprivation. When this happens, peak oxygen uptake increases and fatigue is diminished or is delayed during prolonged exercise.

After just 7 days of quercetin feeding, both PGC-1α and SIRT1 expression increased significantly in both skeletal muscle and brain (for both doses). However, while increases in muscle mtDNA (achieved in only the higher dose of quercetin) have been well-documented to enhance exercise tolerance, there is far less knowledge about the impact of these changes in the brain. The fact that the 12.5 mg/day quercetin feeding did not increase mtDNA may be attributed to the short feeding duration (more on this below). So while muscle mitochondrial biogenesis increases may be the most important factor responsible for increased endurance exercise tolerance in response to exercise training, the researchers show that the brain also plays an important role.

The Brain Dominates Human Exercise

The stimuli of the two paradigms of exercise (treadmill running and voluntary wheel running) are very different. Treadmill running is “forced” because, when the mice can no longer maintain the pace necessary to keep up with the moving belt, they are gently prodded by hand or mild electrical shock. Their fatigue arises primarily from peripheral limitations (e.g., cardiovascular system and muscle). On the other hand, voluntary wheel-running behavior is more centrally (i.e., involving the brain) influenced. This is more conducive to our own volitional exercise programs. Thus, while treadmill running is a better indicator of a mouse’s maximal running capacity, wheel running is strongly influenced by behavioral factors, as is the case for humans. Once again, while brain and muscle mitochondria are influential in exercise, rarely is the brain considered for the distinct role that it plays.

Suppressing the Neuroinhibitor Adenosine

A further point that the researchers made is that the benefits of the quercetin feedings increased voluntary activity during the feeding period as well as for 7 days after feeding was stopped. This extended response was probably due to the combined effects of quercetin and exercise on mitochondrial biogenesis. But with the plasma half-life of quercetin at 6–12 hours, there may be a supplementary explanation. That is—and this is especially important for humans—the motivation and willingness to exercise is driven more by brain factors.

Contributing to these brain factors—given that the quercetin-induced increase in maximum speed found on days 2–3 was far too short a time for sufficient change in mitochondrial capacity—may be the caffeine-like quality of quercetin. This entails quercetin’s ability to block the effect of the neuroinhibitor adenosine, the antagonism of which is partially responsible for caffeine’s psychostimulant and ergogenic effects. Consequently, in addition to enhancing mitochondrial biogenesis, quercetin may increase exercise tolerance through its activity as an adenosine receptor blocker in the brain.

Maintaining and Avoiding Loss of Strength

One of the most pervasive aspects of aging is the loss of strength. Anything that safely increases our ability to stay strong is of major importance. With this study, quercetin has entered a new arena of health benefits. Its apparent ability to enhance the effect of exercise on fitness, even without explicit training, may have important implication for not only athletic and military performance, but also for all “graduates” to greater knowledge. These benefits of quercetin may also extend to the prevention and treatment of chronic diseases, thereby extending the quality and quantity of our lives.

References

  1. Chandratre P, Roddy E, Clarson L, Richardson J, Hider SL, Mallen CD. Health-related quality of life in gout: a systematic review. Rheumatology (Oxford). 2013 Nov;52(11):2031-40.
  2. Geronikolou SA. Treatment of gout in a recently published 9th century manuscript of Rhazes. Vesalius. 2014 Winter;20(2):95-8.
  3. Bhattacharjee S. A brief history of gout. Int J Rheum Dis. 2009 Apr;12(1):61-3.
  4. Shi Y, Williamson G. Quercetin lowers plasma uric acid in pre-hyperuricaemic males: a randomised, double-blinded, placebo-controlled, cross-over trial. Br J Nutr. 2016 Mar 14;115(5):800-6.
  5. Sakiyama M, Matsuo H, Nakaoka H, Yamamoto K, Nakayama A, Nakamura T, Kawai S, Okada R, Ooyama H, Shimizu T, Shinomiya N. Identification of rs671, a common variant of ALDH2, as a gout susceptibility locus. Sci Rep. 2016 May 16;6:25360. doi: 10.1038/srep25360. PubMed PMID: 27181629; PubMed Central PMCID: PMC4867610.
  6. 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.

Quercetin Extends Lifespan in C. Elegans

Quercetin, caffeic- and rosmarinic acid exposure extended lifespan in the simple roundworm Caenorhabditis elegans. A recent comparative study uncovered basic common and contrasting underlying mechanisms: For all three compounds, life extension was characterized by hormetic dose response curves, but levels of heat-shock-protein genes expression were variable.1 Hormesis is a phenomenon characterized by low-dose stimulation and high-dose inhibition.

Quercetin and rosmarinic acid both suppressed bacterial growth; however, antibacterial properties were not the dominant reason for life extension. Exposure to quercetin, caffeic- and rosmarinic acid resulted in reduced body size, altered lipid-metabolism and a tendency towards a delay in reproductive timing; however, the total number of offspring was not affected.

An indirect dietary restriction effect, provoked by either chemo-repulsion or diminished pharyngeal pumping was rejected. Quercetin and Caffeic acid were shown to increase the antioxidative capacity in vivo and, by means of a lipofuscin assay, reduce the oxidative damage in the nematodes. Finally, it was possible to demonstrate that the life and thermotolerance-enhancing properties of caffeic- and rosmarinic acid both rely on certain genes in the case of caffeic acid. Taken together, hormesis, in vivo antioxidative/prooxidative properties, modulation of genetic players, as well as the re-allocation of energy all contribute to life extension.

Quercetin Prolongs Lifespan in Mice

Following up on how quercetin prolongs lifespan in higher species, researchers from several universities and aging research centers have noted that the health span of mice is enhanced by killing senescent cells using a transgenic suicide gene.2 A drug and a nutrient targeting the pro-survival networks in senescent cells selectively killed senescent cells.

Dasatinib, a cancer drug, eliminated senescent human fat cell progenitors, while quercetin was more effective against senescent human endothelial cells and mouse mesenchymal stem cells (multipotent connective tissue cells that can differentiate into a variety of cell types). In the study, of 46 agents tested, dasatinib and quercetin showed particular promise in clearing senescent cells.

References

  1. Pietsch K1, Saul N, Chakrabarti S, et al. Hormetins, antioxidants and prooxidants: defining quercetin-, caffeic acid- and rosmarinic acid-mediated life extension in C. elegans. Biogerontology. 2011 Aug;12(4):329–47.
  2. Zhu Y, Tchkonia T, Pirtskhalava T, et asl. The Achilles’ Heel of Senescent Cells: From Transcriptome to Senolytic Drugs. Aging Cell. 2015 Mar 9. doi: 10.1111/acel.12344. [Epub ahead of print].

From Durk Pearson & Sandy Shaw’s Life Extension News (see their May 2008 issue) we learn that …
Natural Metabolites of Dietary Quercetin Target and
Protect Macrophages from Becoming Foam Cells

A very interesting new paper provides experimental evidence to support a novel mechanism whereby dietary flavonoids protect against cardiovascular disease.1 The researchers used quercetin as a prime flavonoid as it is widely distributed in the human diet (onions are particularly rich in it, but it is also found in broccoli, apples, and other foods).

In the standard model of atherosclerosis (well supported by the evidence), macrophages enter the subendothelial linings of arteries, where they ingest modified LDL (especially oxidized LDL), becoming converted into foam cells, a major constituent of atherosclerotic lesions and a source of proinflammatory molecules that promote the development of these lesions. The authors found that pretreatment of RAW macrophages with quercetin-3-glucuronide (Q3GA), a major antioxidative quercetin metabolite, dose-dependently inhibited the accumulation of oxidized LDL in the cells.

Incredibly, the authors showed that Q3GA actually targeted and accumulated in the injured aorta of atherosclerotic plaques, primarily colocalizing with macrophage-derived foam cells—this was determined with an ingenious technique utilizing a monoclonal antibody that specifically bound to Q3GA. They showed that Q3GA dose-dependently downregulated the expression of two major scavenger molecules (SR-A and CD36) which are produced to remove excess cholesterol from foam cells, thus suggesting that the quercetin metabolite might prevent the development of foam cells and, hence, this might be a major source of quercetin’s (and other flavonoids’) protective effects against atherosclerosis. If you take our daily multi­nutrient supplement, at its recommended dosage (3 capsules 4 times a day), you get a daily total of 130 mg of quercetin, which is about three times as much as would be found in a natural vegetarian diet rich in quercetin.

Reference

  1. Kawai et al. Macrophage as a target of quercetin glucuronides in human atherosclerotic arteries. J Biol Chem. 283(14):9424-34 (2008).


Will Block is the publisher and editorial director of Life Enhancement magazine.

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