Reprinted with the kind permission of Life Extension.
By Christopher Wilson
If someone told you that taking a certain nutrient or drug could kill some of your cells, you might think it was a bad idea.
What few people understand is that as cells age, some of them degenerate into a population of poorly functioning senescent cells that accumulate throughout their body.1,2
There is no value to retaining these lingering senile cells. Their continued presence underlies a myriad of degenerative disorders. Senescent cells should be purged from the body!
The buildup of these dysfunctional senile cells contributes to decay of individual organs and greater susceptibility to disorders related to chronic inflammation.3,4
Pharmaceutical companies are developing technologies to remove or neutralize senile cells. They view this as a lucrative target of anti-aging research.6,7 The objective is to selectively remove senescent cells without damaging healthy cells.
Rather than wait for expensive drugs, scientists have discovered that the plant flavonoid quercetin has the unique ability to selectively remove old cells without harm to normal, actively dividing cells.8 This has the obvious potential for extending health span.
A number of studies suggest that low-cost quercetin may slow aging and reduce the risk of many age-accelerating processes—both by clearing senescent cells and via other beneficial mechanisms.9,10
WHAT YOU NEED TO KNOW
Quercetin Combats Aging at the Cellular Level
Scientists have identified a group of pro-inflammatory, aging cells (senescent cells) in various tissues and organs.
Certain kinds of these cells actively secrete substances that generate inflammation and accelerate aging of organs, which results in aging of the entire body and susceptibility to chronic, age-related disorders.
Quercetin, a naturally occurring nutrient, was recently shown to selectively “delete” dangerous senescent cells in laboratory studies, without harm to healthy, youthful cells.
This finding may help to explain quercetin’s known age-decelerating properties, which have contributed to reduction in diseases from the brain to the heart and lungs, to the intestinal tract and bones.
A true life-extending supplement regimen should include regular quercetin doses of 150 to over 500 mg per day. A dose of 150 mg may be sufficient for most people. One strategy might involve taking the higher dose range of quercetin (over 500 mg per day) for several months and then dropping back to a maintenance dose of 150 mg each day.
Aging Cells, Aging Organs, Aging Body
It might seem logical that our cells age at the same time as our body as a whole, but that is not the case.
Cells have varying life spans. Some cells live only briefly and replace themselves frequently, while others have longer life spans and are replaced only after weeks, months, or even years.11,12 The exact frequency of cell renewal depends on the tissue in which the cells are found.
In the presence of various detrimental stimuli (such as ultraviolet radiation, oxidation, and environmental toxins), some cells undergo changes to their DNA that results in old cells that won’t die when they’re supposed to.13,14 Scientists refer to these as senescent (senile) cells.
Senescent cells pose a significant health problem because many of them produce pro-inflammatory signaling molecules and protein-digesting enzymes that contribute to acceleration of age-related diseases.7,15
A healthy immune system can help remove senescent cells as part of its normal cellular housekeeping. This process is important in cancer prevention.7,16 As bodies age, the immune system itself begins to age via a process known as immune senescence. As a result, removal of senescent cells begins to fail. This leads to an acceleration of aging, and ultimately, an increase in the risk of most age-associated conditions, including cancer.16
By selectively eliminating senescent cells so that they do not “clog up” our body’s processes, it is possible to support or even regain youthful function in every organ and tissue. This was shown in a compelling fashion in a 2011 study from the Mayo Clinic, using a mouse model of rapidly accelerated aging similar to the disease progeria in humans.17
Progeria is a rare disease of accelerated aging. It is the result of a gene mutation that produces premature accumulation of senescent cells, and causes young children to age so rapidly that most die before age 15, commonly of atherosclerosis or other age-related processes.18,19
The Mayo researchers transplanted into the rapidly aging mouse model a specialized gene that selectively eliminated senescent cells.17 They found that, by removing senescent cells in tissues such as fat, skeletal muscles, and the eye, they could significantly delay onset of age-related disorders in those tissues. These included muscle loss, cataracts, and depletion of subcutaneous (under-the-skin) fat. Perhaps still more exciting, clearance of senescent cells even in late life slowed the progression of age-related disorders already in progress.
This study opened the door to the idea of senolytic (or “age-busting”) drugs. Testing this kind of gene transplantation therapy in humans is fraught with risks. A better, safer, and simpler solution was discovered in early 2015 by another group of scientists from several institutions, including the Mayo Clinic.8
SYNERGISTIC BENEFITS OF QUERCETIN + RESVERATROL
Polyphenols are versatile molecules found throughout the plant world, where they offer protection against the stresses imposed by extreme environments, UV radiation, and other factors.62 Recent studies have focused especially on the polyphenols quercetin and resveratrol, and on their synergistic effects when used together.
Resveratrol has important impacts on energy metabolism, and functioning of the tiny intracellular powerhouses called mitochondria.63-65 Resveratrol’s molecular effects are in some ways similar to those of profound calorie restriction, which has been found to extend life span in virtually every animal system in which it has been tested.66,67
Combining quercetin with resveratrol has been shown to have synergistic effects, meaning that the combination provides benefits that are greater than the simple sum of each nutrient’s effects together. Studies show that quercetin and resveratrol work together by multiple, complementary mechanisms.68-70
Delete Senescent Cells with Quercetin
The second Mayo study was carried out by researchers who recognized the threat of senescent cell accumulation. These scientists sought to correct this pathology in a simpler and safer way than gene transfers. They knew, from past research, that clearing away just 30% of senescent cells produced profound improvement in age-related signs and symptoms.8
The researchers turned to several compounds known to induce cellular suicide (known technically asapoptosis) preferentially in senescent cells, while leaving healthy cells untouched. They tested 46 different drugs and nutrients, and ended up with two candidates: a chemotherapy drug called dasatinib and quercetin, a well-studied nutrient found naturally in apples, onions, and other vegetables.20 Both compounds powerfully affect the cellular regulation systems that produce beneficial apoptosis, but dasatinib, unlike quercetin, has a wide range of serious toxic side effects.21-24
When human cell cultures were treated with either quercetin or dasatinib, the researchers found a sharp reduction in numbers of senescent cells. In this study, quercetin caused about a 50% reduction at the lowest two doses, with no effect on healthy cells.8 Dasatinib had similar effects when used alone.
In an animal study, the combination of the two compounds was still more effective. When administered to age-accelerated mice, the combination caused a significant reduction in a score of age-related symptoms, including hunched back, poor muscle function, tremors, loss of grip strength, gait abnormalities, urinary incontinence, and poor body condition. These effects were interpreted as an extension of the health span of the mice, both because of the delay in symptom onset and the reduction of their severity.8
Of course, no one is proposing that dasatinib, a powerful chemotherapy drug, be used to prevent human aging. This study shows that quercetin alone is just as effective at deleting dangerous senescent cells as the drug dasatinib, and that such deletion delays aging and promotes a longer health span.8
Like most natural supplements, quercetin appears to achieve its effects by multiple pathways. For example, quercetin activates a well-researched enzyme known as SIRT1, which is also activated by resveratrol.25Recent studies show that activated SIRT1 can suppress the pro-inflammatory signaling of senescent cells, thereby reducing their toxicity and potentially slowing aging.26 Numerous experiments have demonstrated that animals with experimentally increased SIRT1 activation live longer and experience fewer age-related disorders.27,28
Previous animal studies have shown that quercetin can extend life span. In one often-used model of aging using the roundworm Caenorhabditis elegans, quercetin treatment has been shown to prolong the mean life span by 16 to 23%.29-32
A wealth of evidence shows that quercetin acts by several mechanisms to delay aging, is safe, and is absorbed from the gastrointestinal tract after an oral dose.33,34 It is reasonable to examine quercetin’s effects as an age-decelerator in the human tissues most affected by aging, as we’ll now see.
HOW QUERCETIN ENHANCES EFFICACY OF RESVERATROL
Resveratrol has become a popular “anti-aging” supplement because of its beneficial effect on gene expression.71,72
Quercetin has been shown to make more resveratrol available to the body. It does this by reducing the rate of resveratrol degradation (sulfation) in the liver and enhancing its bioavailability.
When resveratrol is ingested, about 70% of it is absorbed from the intestine into the blood.73 The absorbed resveratrol is then transported to the liver. When the liver adds sulfate groups, there is some deactivation of the resveratrol.74
Since quercetin has favorable influences on the bioavailability of resveratrol, it makes sense to take these two nutrients together.75 Interestingly, while red wine is known to contain small amounts of resveratrol, it usually contains even more quercetin, meaning the health benefits associated with red wine may be due to both its resveratrol and quercetin content (along with other polyphenols).75.76
Quercetin Slows Cardiovascular Aging
Cardiovascular disease (heart attacks, congestive heart failure, and stroke) is the leading cause of death among older Americans.35 Finding a way to slow aging of the heart and blood vessels is a vital factor when seeking to significantly prolong human life. Quercetin has numerous properties that help to combat various factors involved in heart disease.
First, quercetin has the ability to relax blood vessels, an action that reduces the risk of heart attack and stroke.36 Scientists believe this is due in part to quercetin’s ability to fight oxidation. Oxidation in cells that line blood vessels reduces their ability to produce and respond to nitric oxide, a vital signaling molecule that helps control blood pressure by telling cells to dilate and relax.
Secondly, quercetin has been found to increase levels of an important enzyme called paraoxonase-2(PON2).34 Scientists now believe that this potent enzyme protects fat molecules from dangerous oxidation that can lead to atherosclerotic plaque formation and decreased blood flow.34 Indeed, animal studies demonstrate that supplementation withquercetin reduces markers of oxidation, while increasing heart weight (an indicator of good function in healthy animals), potentially improving the animals’ long-term health.37
The third way quercetin helps protect against heart disease is by counteracting the pro-clotting effect of platelets, a leading contributor to arterial blockage in the presence of plaque. In a study of healthy human volunteers, doses of a quercetin supplement at both 150 and300 mg were shown to decrease the clotting of platelets. This action has the potential to reduce the risk of stroke and heart attacks.20
Finally, quercetin directly opposes major components of metabolic syndrome (the combination of obesity, hypertension, glucose intolerance, insulin resistance, and lipid disturbances), a condition that vastly increases cardiovascular risk. When a group of overweight or obese subjects with features of metabolic syndrome received a daily 150 mg dose of quercetin for six weeks, mean fasting quercetin blood levels were boosted by nearly 4-fold.38 In this study, quercetin lowered systolic (top number) blood pressure and reduced levels ofoxidized LDL (bad) cholesterol, a contributor to atherosclerosis.
Another study evaluated healthy men who had a genetic variant that increases cardiovascular risk. A quercetin dose of 150 mg per day was used. After eight weeks, there were reductions in waist circumference, after-meal systolic blood pressure, and triglyceride levels. Beneficial increases in HDL (good) cholesterol were found in these men taking just 150 mg per day of quercetin.36
HOW SENESCENT CELLS IMPACT THE ENTIRE BODY
Troublesome senescent cells can be found throughout the body.17 Wherever those cells build up, they cause damage to that part of the body. These “retired cells” are responsible for increasing malfunctions in a once-vibrant body. For example:
In the immune system, senescent T cells have been found built up in the lymph nodes of older animals.54 These older cells are rich in memories of older threats, but are unable to “learn” about new threats, making them less effective, for example, against next year’s flu virus. 55
Senescent cells also affect skin integrity. The impaired skin and wound healing so commonly associated with aging may be related to an accumulation of senescent fibroblasts,56 which are all-purpose cells in the skin that are essential for producing new skin tissue.57
The most common form of arthritis, osteoarthritis, is due in part to the accumulation of old cartilage-producing cells (chondrocytes) in the joints.58 Joint stresses, such as overuse, produce chronic oxidative stress, which has been shown to hasten chondrocyte aging and accumulation of senescent cells.59
Senescent cells are also being explored as important targets for treating age-related brain disorders such as Alzheimer’s and Parkinson’s diseases.7 Brains of older animals have been shown to contain senescent cells that secrete highly inflammatory cytokines, and may contribute to growth of the age-associated brain tumor called glioma.60
Heart tissue from people with cardiovascular disease contains more senescent, rapidly aging cells than tissue from healthier, or younger, people. Interestingly, studies also show that, at least in heart tissue, some people may be born with a tendency for their cells to age more rapidly. In theory, this could explain why some people appear to be at higher risk for cardiovascular disease and death than others, despite having similar backgrounds in other ways.5
Smoking and air pollution promote chronic obstructive pulmonary disease (COPD). Senescent cells secreting highly inflammatory substances have recently been discovered in the lungs of smokers with chronic obstructive pulmonary disease, and are thought to promote the condition.16
Finally, senescent cells accumulating in liver tissue hasten loss of liver function.61 In addition, because these cells progress to form scar tissue, they may be involved in the advance of life-threatening liver cirrhosis from milder, earlier conditions such as non-alcoholic fatty liver disease (NAFLD).6
Clearly, senescent cells contribute to aging and disease in organs and tissues throughout the entire body. Fortunately, scientists have discovered a nutrient that selectively eliminates many such senescent cells. By doing so, it may be possible to support or even regain youthful function in every organ and tissue in the body.
Quercetin Protects Brain Cells
Scientists have determined that senescent, inflammation-generating cells accumulate in the brain during “normal” aging. This discovery has opened a new door to therapies aimed at preventing the decline associated with neurodegenerative diseases like Parkinson’s and Alzheimer’s. With quercetin’s ability to selectively delete senile cells in the brain, we can expect further advances in preventive neurology from this impressive natural flavonoid.
A great deal has already been discovered about quercetin’s ability to reduce the memory deficits and other features of neurodegenerative disorders by protecting brain cells’ structure and function.39
Studies show, for instance, that quercetin is absorbed in the blood after oral dosing, and is detectable soon thereafter in brain tissue.40 As a result, quercetin has been shown to help protect the brains of rats subjected to a high-stress environment.
In a study published in Free Radical Biology and Medicine, the rats initially developed oxidative stress in vital memory and movement centers of their brains as a result of the high-stress environment.40 However, when those same rats were supplemented with quercetin, the cognitive deficits they had experienced were reduced.
Oxidative stress and senescent cells are significant contributors to the gradual development of Alzheimer’s and Parkinson’s diseases, two common neurodegenerative consequences of aging.41-43 Quercetin has been shown to help battle both of these underlying issues.
In a rat model of Parkinson’s disease, quercetin or fish oil demonstrated valuable brain-protective properties. However, the combination of quercetin and fish oil produced even more protective benefits such as reducing behavioral impairment, improving production of the neurotransmitter dopamine, and rescuing ailing mitochondria.44
QUERCETIN DOSING SUGGESTIONS
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Quercetin is a low-cost dietary supplement that has health-promoting properties in the heart, brain, and other systems. Doses of 150 mg per day have demonstrated significant benefits in human studies and might be a good maintenance dose. Furthermore, higher dose amounts of 500 to 1,000 mg per day are generally recognized as safe based upon current data, especially over the short term, and thus higher dosing in this range may be considered based upon individual health needs. At the current time, little safety evidence exists to confidently support chronic daily dosing higher than 1,000 mg.
A prudent course to follow might be to take 500–800 mg per day of quercetin for three months to purge accumulated senile cells and then stay with a maintenance dose of 150 mg each day thereafter.
Note: For those individuals taking warfarin, please check with your physician if concomitantly taking high doses of quercetin.
Protection Against Environmental Toxins
Environmental toxins play a significant role in the development of neurodegenerative diseases. Parkinson’s disease, for example, is known to be promoted by exposure to PCBs (polychlorinated biphenyls, a class of environmental chemical toxins).45,46 PCBs damage brain cells that produce the neurotransmitter dopamine, which is deficient in Parkinson’s disease.47-49 Brain dopamine levels steadily decline as humans age past 45 years.50
One study demonstrated that quercetin reduces damage to dopamine-producing brain cells after rats are exposed to PCBs.39 Subsequent experiments demonstrated that quercetin protected the dopamine-producing cells by scavenging the destructive oxygen-free radicals induced by the toxin.39
In addition to memory loss, animals exposed to PCB also developed signs of anxiety. A separate study found that quercetin supplementation was able to reverse both the brain changes and the neurological deficits associated with PCB-induced anxiety.51
Further supporting quercetin’s ability to protect the brain from damaging toxins, a study published in Toxicology and Industrial Health found that supplementation with the nutrient reversed changes in the brains of rats previously exposed to a common industrial solvent called toluene. When the researchers examined microscopic evidence of the animals’ brains, they found that quercetin supplementation in fact led to structural improvements in brain architecture that had been damaged by the chemical. Amazingly, these improvements occurred even when quercetin was administered after the brain damage was done.52
Exposure to PCB weakens the blood-brain barrier, which allows PCB and other damaging toxins to leak into brain cells.53 However, researchers found that quercetin can protect brain cells against environmental toxins by stopping them from ever reaching the brain in the first place.53
SUPPRESSING HERPES IN THE BRAIN
Infection with herpes simplex virus 1 (HSV-1) is widespread and typically manifests outwardly as cold sore outbreaks on the mouth and/or lips. 78
What many people don’t know is that in approximately 70% of the population over 50 years old, the virus enters the brain and infects neurons.2 It is not known how many recurrent HSV-1 reactivation episodes occur in neurons before infection (Herpes Simplex Encephalitis) develops.79,80
A fascinating study published in 2015 reveals how quercetin or resveratrol may reduce viral propagation and/or counteract the effects of neuronal herpes infection.79
The scientists analyzed viral replication, neuronal viability, and neurodegenerative events during HSV-1 infection.
In this study, pretreatment of neurons with resveratrol or quercetin significantly reduced markers of damage associated with HSV-1 infection. The scientists concluded that their results could be potentially useful in reducing the risk of HSV-1 infection in neurons and the cellular damage associated with reactivation episodes.
The age-accelerating effects from chronic infections with herpes viruses such cytomegalovirus (CMV), herpes simplex I and II, herpes zoster and Epstein-Barr are increasingly being recognized, especially as it relates to disease.81,82
Chronic viral infection creates a sustained inflammatory response that is thought to contribute to increased cognitive impairment seen in preclinical and clinical Alzheimer’s disease.83-86 It is not yet possible to completely eradicate these chronic viruses, but this new study indicates that resveratrol or quercetin may at least mitigate their pathological impact.
The accumulation of pro-inflammatory senescent cells in the maturing body is an underlying factor behind premature aging. Research into this scientific arena provides a real-world opportunity to combat this degenerative mechanism.
Quercetin is a flavonoid found in many fruits and vegetables. It has recently been shown to remove dysfunctional cells without harming healthy ones.
Studies in animals and humans show that quercetin fights oxidative stress and inflammation, while beneficially modulating genes known to be involved in the aging process.
If you have any questions on the scientific content of this article, please call a Life Extension® Health Advisor at 1-866-864-3027.
PURGING SENESCENT CELLS: SCIENCE’S NEW ANTI-AGING STRATEGY
Scientists have now confirmed that an innovative life extension strategy of safely purging worn-out—or senescent—cells can increase longevity.
As we age, our bodies’ cells divide a finite number of times and eventually enter the state of senescence. These dysfunctional senescent cells cannot be turned back into functional, dividing cells, nor do they die, and appear to have some built-in survival mechanism. But the longer they hang around in the body the more they become deformed and chemically altered, pumping out destructive proteins that create inflammation. “We’ve seen them in every organ we’ve looked at,” says Judith Campisi, PhD, at the Buck Institute for Research on Aging.
Virtually all age-related diseases involve inflammation, and over time, the result of senescence-driven inflammation is a litany of disabling and deadly diseases.
Evidence now shows that it is possible to eliminate these nonfunctioning cells from the body, which can prevent or even reverse age-related diseases. In fact, Darren Baker, PhD, at the Mayo Clinic and colleagues have accomplished this in mice.
The Mayo team genetically engineered mice so that senescing cells would carry a tag marking them as targets for a drug capable of destroying them. By selectively removing the senescent cells, even at an advanced age, the drug delayed aging, inhibited muscle wasting, produced more youthful skin, and stalled onset of age-related diseases.
Dr. Campisi and her team have managed to stop senescent cells from producing pro-inflammatory toxins by using an existing drug known as rapamycin, which boosts life span in mice by 10%. But it weakens the immune system and raises the risk of diabetes. Campisi and other research groups are now seeking safer alternatives.
This raises another challenge. Any treatment targeting the inflammatory chemicals pumped out by senescent cells would need to be taken regularly, something difficult to justify in otherwise healthy people, no matter how safe the drug. A better option may be to clear out senescent cells altogether—but only periodically.
“Senescent cells accumulate slowly over time,” says Campisi. “You could take a drug to wipe them out every five years, for example.” Treatments could begin around age 50, which is when accumulated senescent cells start causing problems.
Earlier this year, a study on cells published in Aging Cell illustrated the effectiveness of two drugs, as well as quercetin, in removing senescent cells from different types of human cells. In this study, led by James Kirkland of the Mayo Clinic, senescent cells were essentially forced to commit suicide.
Scientists working specifically on the problem of senescent cells now believe that this approach may reverse multiple conditions of aging with just one senescent cell-purging agent, efficiently striking down every age-related disease with a single blow. “That’s the dream,” says Campisi. “It would revolutionize the way medicine is practiced.”
Animal studies show increased longevity with senescent cell removal. However, Campisi agrees that few scientists believe aging is caused entirely by senescent cells. But removing dangerous and inflammation-powering senescent cells from the body could translate into a state of slowed aging with none of the usual diseases linked to aging itself, diseases such as diabetes, cancer, mild cognitive impairment, Parkinson’s disease, heart problems, and osteoarthritis.
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