Sweep Away Senile Cells

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

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 as apoptosis) 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.²⁵ Recent 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 of oxidized 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

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

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.

Summary

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.

Editor's Note

Science continues to evolve, and new research is published daily. As such, we have a more recent article on this topic: Suppress Toxic Senescent Cell Secretions

References

1. Burton DG. Cellular senescence, ageing and disease. Age (Dordr). 2009 Mar;31(1):1-9.
2. Chen JH, Hales CN, Ozanne SE. DNA damage, cellular senescence and organismal ageing: causal or correlative? Nucleic Acids Res. 2007;35(22):7417-28.
3. Freund A, Orjalo AV, Desprez PY, Campisi J. Inflammatory networks during cellular senescence: causes and consequences. Trends Mol Med. 2010 May;16(5):238-46.
4. Karavassilis ME, Faragher R. A relationship exists between replicative senescence and cardiovascular health. Longev Healthspan. 2013;2(1):3.
5. Calhoun C, Shivshankar P, Saker M, et al. Senescent cells contribute to the physiological remodeling of aged lungs. J Gerontol A Biol Sci Med Sci. 2015 Jan 7.
6. Kim KH, Chen CC, Monzon RI, Lau LF. Matricellular protein CCN1 promotes regression of liver fibrosis through induction of cellular senescence in hepatic myofibroblasts. Mol Cell Biol. 2013 May;33(10):2078-90.
7. Chinta SJ, Woods G, Rane A, Demaria M, Campisi J, Andersen JK. Cellular senescence and the aging brain. Exp Gerontol. 2014 Oct 1.
8. Zhu Y, Tchkonia T, Pirtskhalava T, et al. The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs. Aging Cell. 2015 Mar 9.
9. Chondrogianni N, Kapeta S, Chinou I, Vassilatou K, Papassideri I, Gonos ES. Anti-ageing and rejuvenating effects of quercetin. Exp Gerontol. 2010 Oct;45(10):763-71.
10. Stefek M, Karasu C. Eye lens in aging and diabetes: effect of quercetin. Rejuvenation Res. 2011 Oct;14(5):525-34.
11. Gillooly JF, Hayward A, Hou C, Burleigh JG. Explaining differences in the lifespan and replicative capacity of cells: a general model and comparative analysis of vertebrates. Proc Biol Sci. 2012 Oct 7;279(1744):3976-80.
12. Spalding KL, Bhardwaj RD, Buchholz BA, Druid H, Frisen J. Retrospective birth dating of cells in humans. Cell. 2005 Jul 15;122(1):133-43.
13. James EL, Michalek RD, Pitiyage GN, et al. Senescent human fibroblasts show increased glycolysis and redox homeostasis with extracellular metabolomes that overlap with those of irreparable DNA damage, aging, and disease. J Proteome Res. 2015 Feb 26.
14. Kumar M, Seeger W, Voswinckel R. Senescence-associated secretory phenotype and its possible role in chronic obstructive pulmonary disease. Am J Respir Cell Mol Biol. 2014 Sep;51(3):323-33.
15. Lasry A, Ben-Neriah Y. Senescence-associated inflammatory responses: aging and cancer perspectives. Trends Immunol. 2015 Mar 20.
16. Sagiv A, Biran A, Yon M, Simon J, Lowe SW, Krizhanovsky V. Granule exocytosis mediates immune surveillance of senescent cells. Oncogene. 2013 Apr 11;32(15):1971-7.
17. Baker DJ, Wijshake T, Tchkonia T, et al. Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature. 2011 Nov 10;479(7372):232-6.
18. Gordon LB, Brown WT, Collins FS. et al. GeneReviews(R). Seattle WA: University of Washington, Seattle;1993.
19. Arancio W, Pizzolanti G, Genovese SI, Pitrone M, Giordano C. Epigenetic involvement in Hutchinson-Gilford progeria syndrome: a mini-review. Gerontology. 2014;60(3):197-203.
20. Hubbard GP, Wolffram S, Lovegrove JA, Gibbins JM. Ingestion of quercetin inhibits platelet aggregation and essential components of the collagen-stimulated platelet activation pathway in humans. J Thromb Haemost. 2004 Dec;2(12):2138-45.
21. Dudek AZ, Pang H, Kratzke RA, et al. Phase II study of dasatinib in patients with previously treated malignant mesothelioma (cancer and leukemia group B 30601): a brief report. J Thorac Oncol. 2012 Apr;7(4):755-9.
22. Fallahi P, Ferrari SM, Vita R, et al. Thyroid dysfunctions induced by tyrosine kinase inhibitors. Expert Opin Drug Saf. 2014 Jun;13(6):723-33.
23. Godinas L, Guignabert C, Seferian A, et al. Tyrosine kinase inhibitors in pulmonary arterial hypertension: a double-edge sword? Semin Respir Crit Care Med. 2013 Oct;34(5):714-24.
24. Latagliata R, Breccia M, Fava C, et al. Incidence, risk factors and management of pleural effusions during dasatinib treatment in unselected elderly patients with chronic myelogenous leukaemia. Hematol Oncol. 2013 Jun;31(2):103-9.
25. Zhao LR, Du YJ, Chen L, et al. Quercetin protects against high glucose-induced damage in bone marrow-derived endothelial progenitor cells. Int J Mol Med. 2014 Oct;34(4):1025-31.
26. Hayakawa T, Iwai M, Aoki S, et al. SIRT1 suppresses the senescence-associated secretory phenotype through epigenetic gene regulation. PLoS One. 2015;10(1):e0116480.
27. Bayod S, Guzman-Brambila C, Sanchez-Roige S, et al. Voluntary exercise promotes beneficial anti-aging mechanisms in SAMP8 female brain. J Mol Neurosci. 2015 Feb;55(2):525-32.
28. Mitchell SJ, Martin-Montalvo A, Mercken EM, et al. The SIRT1 activator SRT1720 extends lifespan and improves health of mice fed a standard diet. Cell Rep. 2014 Mar 13;6(5):836-43.
29. Duenas M, Surco-Laos F, Gonzalez-Manzano S, et al. Deglycosylation is a key step in biotransformation and lifespan effects of quercetin-3-O-glucoside in Caenorhabditis elegans. Pharmacol Res. 2013 Oct;76:41-8.
30. Pietsch K, Saul N, Menzel R, Sturzenbaum SR, Steinberg CE. Quercetin mediated lifespan extension in Caenorhabditis elegans is modulated by age-1, daf-2, sek-1 and unc-43. Biogerontology. 2009 Oct;10(5):565-78.
31. Surco-Laos F, Cabello J, Gomez-Orte E, et al. Effects of O-methylated metabolites of quercetin on oxidative stress, thermotolerance, lifespan and bioavailability on Caenorhabditis elegans. Food Funct. 2011 Aug;2(8):445-56.
32. Xue YL, Ahiko T, Miyakawa T, et al. Isolation and Caenorhabditis elegans lifespan assay of flavonoids from onion. J Agric Food Chem. 2011 Jun 8;59(11):5927-34.
33. Castilla P, Echarri R, Davalos A, et al. Concentrated red grape juice exerts antioxidant, hypolipidemic, and antiinflammatory effects in both hemodialysis patients and healthy subjects. Am J Clin Nutr. 2006 Jul;84(1):252-62.
34. Boesch-Saadatmandi C, Pospissil RT, Graeser AC, et al. Effect of quercetin on paraoxonase 2 levels in RAW264.7 macrophages and in human monocytes--role of quercetin metabolism. Int J Mol Sci. 2009 Sep;10(9):4168-77.
35. Coulter SA. Epidemiology of cardiovascular disease in women: risk, advances, and alarms. Tex Heart Inst J. 2011;38(2):145-7.
36. Pfeuffer M, Auinger A, Bley U, et al. Effect of quercetin on traits of the metabolic syndrome, endothelial function and inflammation in men with different APOE isoforms. Nutr Metab Cardiovasc Dis. 2013 May;23(5):403-9.
37. Goliomytis M, Tsoureki D, Simitzis PE, Charismiadou MA, Hager-Theodorides AL, Deligeorgis SG. The effects of quercetin dietary supplementation on broiler growth performance, meat quality, and oxidative stability. Poult Sci. 2014 Aug;93(8):1957-62.
38. Egert S, Bosy-Westphal A, Seiberl J, et al. Quercetin reduces systolic blood pressure and plasma oxidised low-density lipoprotein concentrations in overweight subjects with a high-cardiovascular disease risk phenotype: a double-blinded, placebo-controlled cross-over study. Br J Nutr. 2009 Oct;102(7):1065-74.
39. Bavithra S, Selvakumar K, Pratheepa Kumari R, Krishnamoorthy G, Venkataraman P, Arunakaran J. Polychlorinated biphenyl (PCBs)-induced oxidative stress plays a critical role on cerebellar dopaminergic receptor expression: ameliorative role of quercetin. Neurotox Res. 2012 Feb;21(2):149-59.
40. Ishisaka A, Ichikawa S, Sakakibara H, et al. Accumulation of orally administered quercetin in brain tissue and its antioxidative effects in rats. Free Radic Biol Med. 2011 Oct 1;51(7):1329-36.
41. Manayi A, Saeidnia S, Gohari AR, Abdollahi M. Methods for the discovery of new anti-aging products­—targeted approaches. Expert Opin Drug Discov. 2014 Apr;9(4):383-405.
42. Zhu Y, Armstrong JL, Tchkonia T, Kirkland JL. Cellular senescence and the senescent secretory phenotype in age-related chronic diseases. Curr Opin Clin Nutr Metab Care. 2014 Jul;17(4):324-8.
43. Prasad J, Baitharu I, Sharma AK, Dutta R, Prasad D, Singh SB. Quercetin reverses hypobaric hypoxia-induced hippocampal neurodegeneration and improves memory function in the rat. High Alt Med Biol. 2013 Dec;14(4):383-94.
44. Denny Joseph KM, Muralidhara. Combined oral supplementation of fish oil and quercetin enhances neuroprotection in a chronic rotenone rat model: relevance to Parkinson’s disease. Neurochem Res. 2015 May;40(5):894-905.
45. Corrigan FM, Murray L, Wyatt CL, Shore RF. Diorthosubstituted polychlorinated biphenyls in caudate nucleus in Parkinson’s disease. Exp Neurol. 1998 Apr;150(2):339-42.
46. Hatcher-Martin JM, Gearing M, Steenland K, Levey AI, Miller GW, Pennell KD. Association between polychlorinated biphenyls and Parkinson’s disease neuropathology. Neurotoxicology. 2012 Oct;33(5):1298-304.
47. Caudle WM, Richardson JR, Delea KC, et al. Polychlorinated biphenyl-induced reduction of dopamine transporter expression as a precursor to Parkinson’s disease-associated dopamine toxicity. Toxicol Sci. 2006 Aug;92(2):490-9.
48. Lee DW, Notter SA, Thiruchelvam M, et al. Subchronic polychlorinated biphenyl (Aroclor 1254) exposure produces oxidative damage and neuronal death of ventral midbrain dopaminergic systems. Toxicol Sci. 2012 Feb;125(2):496-508.
49. Lyng GD, Snyder-Keller A, Seegal RF. Polychlorinated biphenyl-induced neurotoxicity in organotypic cocultures of developing rat ventral mesencephalon and striatum. Toxicol Sci. 2007 May;97(1):128-39.
50. Knoll J. Deprenyl (selegiline): the history of its development and pharmacological action. Acta Neurol Scand Suppl. 1983;95:57-80.
51. Selvakumar K, Bavithra S, Ganesh L, Krishnamoorthy G, Venkataraman P, Arunakaran J. Polychlorinated biphenyls induced oxidative stress mediated neurodegeneration in hippocampus and behavioral changes of adult rats: anxiolytic-like effects of quercetin. Toxicol Lett. 2013 Sep 12;222(1):45-54.
52. Kanter M. Protective effects of quercetine on the neuronal injury in frontal cortex after chronic toluene exposure. Toxicol Ind Health. 2013 Aug;29(7):643-51.
53. Selvakumar K, Prabha RL, Saranya K, Bavithra S, Krishnamoorthy G, Arunakaran J. Polychlorinated biphenyls impair blood-brain barrier integrity via disruption of tight junction proteins in cerebrum, cerebellum and hippocampus of female Wistar rats: neuropotential role of quercetin. Hum Exp Toxicol. 2013 Jul;32(7):706-20.
54. Green-Johnson JM, Wade AW, Szewczuk MR. Regional accumulation of Pgp-1+ memory cells in senescent mucosal immune system. Reg Immunol. 1992 May-Jun;4(3):175-85.
55. Sharma S, Dominguez AL, Lustgarten J. High accumulation of T regulatory cells prevents the activation of immune responses in aged animals. J Immunol. 2006 Dec 15;177(12):8348-55.
56. Hameedaldeen A, Liu J, Batres A, Graves GS, Graves DT. FOXO1, TGF-beta regulation and wound healing. Int J Mol Sci. 2014;15(9):16257-69.
57. West MD, Pereira-Smith OM, Smith JR. Replicative senescence of human skin fibroblasts correlates with a loss of regulation and overexpression of collagenase activity. Exp Cell Res. 1989 Sep;184(1):138-47.
58. Martin JA, Buckwalter JA. The role of chondrocyte senescence in the pathogenesis of osteoarthritis and in limiting cartilage repair. J Bone Joint Surg Am. 2003;85-A Suppl 2:106-10.
59. Martin JA, Brown TD, Heiner AD, Buckwalter JA. Chondrocyte senescence, joint loading and osteoarthritis. Clin Orthop Relat Res. 2004 Oct (427 Suppl):S96-103.
60. Li L, Liu Y. Aging-related gene signature regulated by Nlrp3 predicts glioma progression. Am J Cancer Res. 2015;5(1):442-9.
61. Aravinthan A, Pietrosi G, Hoare M, et al. Hepatocyte expression of the senescence marker p21 is linked to fibrosis and an adverse liver-related outcome in alcohol-related liver disease. PLoS One. 2013;8(9):e72904.
62. Lattanzio V, Lattanzio VMT, Cardinali A. Role of phenolics in the resistance mechanisms of plants against fungal pathogens and insects (and references therein). In: Imperato F, ed. Phytochemistry: Advances in Research. Kerala, India: Research Signpost; 2006:23-67.
63. Ayub A, Poulose N, Raju R. Resveratrol improves survival and prolongs life following hemorrhagic shock. Mol Med. 2015;21(1):305-12.
64. Timmers S, Konings E, Bilet L, et al. Calorie restriction-like effects of 30 days of resveratrol supplementation on energy metabolism and metabolic profile in obese humans. Cell Metab. 2011 Nov 2;14(5):612-22.
65. Bitterman JL, Chung JH. Metabolic effects of resveratrol: addressing the controversies. Cell Mol Life Sci. 2015 Apr;72(8):1473-88.
66. Kane AE, Hilmer SN, Boyer D, et al. Impact of Longevity Interventions on a Validated Mouse Clinical Frailty Index. J Gerontol A Biol Sci Med Sci. 2015 Feb 22.
67. Lin Y, Yngve A, Lagergren J, Lu Y. A dietary pattern rich in lignans, quercetin and resveratrol decreases the risk of oesophageal cancer. Br J Nutr. 2014 Dec 28;112(12):2002-9.
68. Huang HL, Liu CT, Chou MC, Ko CH, Wang CK. Noni (Morinda citrifolia L.) Fruit Extracts Improve Colon Microflora and Exert Anti-Inflammatory Activities in Caco-2 Cells. J Med Food. 2015 Feb 4.
69. Mazue F, Delmas D, Murillo G, Saleiro D, Limagne E, Latruffe N. Differential protective effects of red wine polyphenol extracts (RWEs) on colon carcinogenesis. Food Funct. 2014 Apr;5(4):663-70.
70. Vargas JE, Filippi-Chiela EC, Suhre T, Kipper FC, Bonatto D, Lenz G. Inhibition of HDAC increases the senescence induced by natural polyphenols in glioma cells. Biochem Cell Biol. 2014 Aug;92(4):297-304.
71. Agarwal B, Campen MJ, Channell MM, et al. Resveratrol for primary prevention of atherosclerosis: clinical trial evidence for improved gene expression in vascular endothelium. Int J Cardiol. 2013 Jun 5;166(1):246-8.
72. Hsu SC, Huang SM, Chen A, et al. Resveratrol increases anti-aging Klotho gene expression via the activating transcription factor 3/c-Jun complex-mediated signaling pathway. Int J Biochem Cell B. 2014 Aug;53:361-71.
73. Carter LG, D’Orazio JA, Pearson KJ. Resveratrol and cancer: focus on in vivo evidence. Endocr Relat Cancer. 2014 Jun;21(3):R209-25.
74. Miksits M, Maier-Salamon A, Aust S, et al. Sulfation of resveratrol in human liver: evidence of a major role for the sulfotransferases SULT1A1 and SULT1E1. Xenobiotica. 2005 Dec;35(12):1101-19.
75. De Santi C, Pietrabissa A, Spisni R, et al. Sulphation of resveratrol, a natural compound present in wine, and its inhibition by natural flavonoids. Xenobiotica. 2000 Sep;30(9):857-66.
76. Careri M, Corradini C, Elviri L, et al. Direct HPLC analysis of quercetin and trans-resveratrol in red wine, grape, and winemaking byproducts. J Agric Food Chem. 2003 Aug 27;51(18):5226-31
77. Saleem TS, Basha SD. Red wine: A drink to your heart. J Cardio Res. 2010 Oct;1(4):171-6.
78. Arduino PG, Porter SR. Herpes Simplex Virus Type 1 infection: overview on relevant clinico-pathological features. J Oral Pathol Med. 2008 Feb;37(2):107-21.
79. Leyton L, Hott M, Acuna F, et al. Nutraceutical activators of AMPK/Sirt1 axis inhibit viral production and protect neurons from neurodegenerative events triggered during HSV-1 infection. Virus Res. 2015 Jul 2;205:63-72.
80. Available at: http://emedicine.medscape.com/article/1165183-overview#a5. Accessed September 3, 2015.
81. Kanapeckiene V, Kalibatas J, Redaitiene E, et al. The association between cytomegalovirus infection and aging process. Medicina (Kaunas, Lithuania). 2007;43(5):419-24.
82. Thompson MP, Kurzrock R. Epstein-Barr virus and cancer. Clin Cancer Res. 2004 Feb 1;10(3):803-21.
83. Faldu KG, Shah JS, Patel SS. Anti-Viral Agents in Neuro-degenerative Disorders: New Paradigm for Targeting Alzheimer’s Disease. Recent Pat Antiinfect Drug Discov. 2015 May 9.
84. Lovheim H, Gilthorpe J, Adolfsson R, et al. Reactivated herpes simplex infection increases the risk of Alzheimer’s disease. Alzheimers Dement. 2015 Jun;11(6):593-9.
85. Kristen H, Santana S, Sastre I, Recuero M, Bullido MJ, Aldudo J. Herpes simplex virus type 2 infection induces AD-like neurodegeneration markers in human neuroblastoma cells. Neurobiol Aging. 2015 Jun 18.
86. Bu XL, Yao XQ, Jiao SS, et al. A study on the association between infectious burden and Alzheimer’s disease. Eur J Neurol. 2014 Jun 9.