Health andAnti-AgingBenefits ofAged GarlicExtractby Carmia Borek, PhD

IntroductionGarlic has been used as

a medicinal remedy sinceantiquity to treat maladiesas well as prevent diseaseand enhance vigor. Modernscience and medicine havevalidated many of thetraditional uses of garlicand identified its health-promoting compounds. Mostof the benefits of garlic areattributed to its high contentof organosulfur compoundsand antioxidant activity,which protect againstoxidative damage by reactiveoxygen species (ROS)and offer other beneficialeffects.'^

Reactive Oxygen SpeciesReactive oxygen species (ROS)

that include free radicals areproduced internally in cells duringenergy production and increaseduring inflammation. Exposure toexternal sources of ROS comes fromexposure to pollutants, cigarettesmoke, radiation, some medicinaldrugs, and charcoal-broiled food.^Oxidative damage to DNA, proteins,and lipids affect a wide range ofmetabolic events that can triggerand /or exacerbate cardiovasculardiseases, neurodegenerativediseases, including Alzheimer'sdisease, cancer, and other age-related conditions.''^ Oxidativedamage increases with age," as dooxidative stress and fatigue.**

Garlic and Aged Garlic ExtractThe best way to combat

ROS-mediated aging and age-related diseases is to have a dietrich in antioxidants, includingphytochemicals with antioxidant

activity.'^^ Garlic is one of the mostpotent naturally occurring sourcesof antioxidant/phytochemicals.Yet many people avoid freshgarlic because of its lingeringpungent odor, due to volatileallicin that is produced uponcutting or macerating the bulb.Another deterrent is the abilityof allicin and the lipid solublecompounds produced from allicin,by a cascade of reactions, to causegastrointestinal disorders.-'

Enter odorless aged garlicextract (Kyolic), with highantioxidant activity and healthbenefits that are as effective oreven more so than those of freshgarlic.'-' Aged garlic extract (AGE)is manufactured by Wakunaga, byextraction and aging of organicfresh garlic for over 20 months. Theaging produces a rich content ofwater-soluble stable organosulfurcompounds such as S-allyl cysteine(SAC) and S- allyl mercaptocysteine(SAM) (unique to AGE), allixin, and

72 TOWNSEND LETTER - JULY 2007

other substances with importantbiological activity.'' The process,carried out at room temperature,also converts unstable volatileallicin and other harsh compoundsto beneficial stable substances andincreases the level of antioxidantswell beyond that of fresh garlic.'"S allyl cysteine, the most abundantorganosulfur compound in AGEhas a 98% bioavailability (i.e., it isreadily absorbed from the intestineto the circulation) and providesmost of AGE'S health benefits; SACis used for standardization of AGE.̂

Aged garlic extract is thechosen form of garlic in studies todetermine the medicinal benefits ofgarlic; AGE is manufactured underhigh quality control'" and contains"a standardized amount of SACthat can be measured in the bloodto monitor compliance."^ In wellover 400 scientific publications,AGE has been shown to counteractoxidative stress more effectivelythan fresh garlic and help preventcardiovascular disease, cancer,and neuronal death that leads toneurodegenerative diseases suchas Alzheimer's disease. AGE alsoboosts immunity, protects againstevents linked to diabetes, preventsradiation and drug toxicity, andacts as an anti-aging supplementhelping prevent fatigue and increaseendurance. Preclinical studies showthe potential of AGE to increasememory, learning, and longevity insenescence-prone models.'- Thisarticle reviews the effects of AGEin preventing age-related diseasesand aging, updating informationon the benefits of AGE that werediscussed in an earlier TownsendLefter article.'

Antioxidant Activity of AGEBesides the major water-

soluble organosulfur compoundsS-allyl cysteine and S-allylmercaptocysteine that havepowerful antioxidant activity,AGE contains other antioxidantsincluding allixin and smallamounts of selenium.'"' In addition,AGE increases cellular levels of

giutathione (GSH), one of thebody's most important intracellularantioxidants.^ In addition to playinga central role in quenching freeradicals, giutathione protectsagainst cataract formation,enhances immune function, acts asa detoxifying agent preventing drugtoxicity, prevents DNA damagethat can lead to cancer, and aidsin the elimination of heavy metals.Giutathione levels can quickly bedepleted when the body is exposedto high levels of oxidative stressduring times of illness, infection,trauma, or surgery. Thus, intakeof AGE and the potentiai increasein giutathione provide additionalantioxidant protection in diseaseprevention.

AGE and Cardiovascular DiseaseAged Garlic Extract has been

shown to modulate cardiovascularrisk factors in both clinical andpreclinical settings.""^'' AGE hasbeen shown to lower blood pressure,inhibit platelet aggregation andadhesion (thus helping preventblood clots), reduce LDLchoIesteroI(the bad cholesterol), and elevateHDL (the protective cholesterol);AGE prevents LDL oxidationthat is an exacerbating factor inathrogenesis.'" S ally! cysteineinhibits thecholesterol synthesizingenzyme HMA-CoA reductase by 30-40%,^' with an additive effect withlipid-lowering statins. AGE intakeis safe for patients on medicaltreatment with the anticoagulantwarfarin (coumadin), as shown in arandomized, double-blind, placebo-controlled clinical trial.^^

AGE has been found to reducesmoking-related oxidative damageand inhibit the production ofprostaglandins that are involvedin inflammation,'^-' shown to be amajor culprit in cardiovasculardisease (CVD), neurodegenerativediseases, and other age-relatedconditions. AGE reduces levelsof homocysteine, a risk factor forCVD as well as for dementia.^"'^In addition, AGE reduces thelevels of nuclear factor kappa B,

which are involved in oxidationand inflammation linked toatherosclerosis."

AGE, Microcirculation, andEndothelial Function

AGE has been shown to increaseblood flow, including micro-circulation," and protect endotheliaicells (cells that line blood vessels)from oxidative damage; improvedmicrocirculation is most importantin cases of diabetes where themicrovasculature is damaged,increasing the risk of CVD aswell as neurodegeneration. AGEalso increases the productionof an endothelial-relaxingfactor cellular nitric oxide thatimproves endothelial functionand helps reduce hypertension.'"In a randomized, double-blind,placebo-controlled trial, 15 menwith coronary artery disease weretreated with 2.4 grams of AGE aday for two weeks, or placebo.AGE treatment resulted in a 44%increase in endothelium function(dilation and increased blood fiow),compared to placebo, indicatingthat a short-term treatmentwith AGE can improve impairedendothelial function in men withcoronary artery disease treatedwith aspirin and a statin.^*

AGE has been found to inhibitthe progression of coronary arterycalcification, thus reducing therisk of heart attacks.''' Coronarycalcification, is nearly 100%specific for atheroscleroticplaques. Twenty-three patients,who were at high risk for heartdisease, received either 1200 mg/day AGE, for one year, or a placebo.As all patients were on statin andaspirin therapy, any improvementseen under the influence of AGEwould be an additional benefitto the statin treatment. Usinga non-invasive, electron-beam-computed tomography to measurecalcification. the investigatorsfound that in patients onplacebo, coronary artery plaquesprogressed at a rate of 22% a year,

TOWNSEND LETTER - JULY 2007 73

Aged Garlic Extract

while the addition of AGE to thediet reduced progression to 7.5%.AGE elevated HDL and decreasedLDL and triglycerides, as well ashomocysteine, as compared toplacebo."

AGE and the Heart-DementiaRisk Link

Recent evidence suggeststhat mid-life risk factors forcardiovascular disease, suchas high levels of cholesterol,hypertension, high homocysteine,and inflammation, are importantalso risk factors for forms ofdementia, including Alzheimerdisease (AD) and vasculardementia, which increase withage.'-̂ **

High Cholesterol andHypertension

High cholesterol andatherosclerosis that are high risk forCVD increase the risk of embolismand stroke (ischemic stroke), whenneurons die as they are deprivedof oxygen and nutrients; exposureto ROS formed when oxygen isreplenished (reperfusion) putsneurons at further risk of death,increasing the risk of dementia.^High cholesterol is also linked toincreased ROS-producing [beta]amyloid peptides (Abeta) in thebrain, the hallmark of Alzheimer'sdisease. Hypertension is anotherrisk factor for AD, linked to thedegeneration (atrophy) of thehippocampus, the center of learningand memory, and the amygdala."

AGE has been shown to protectagainst the consequences ofischemia and reperfusion'^ andreduce hypertension.'-' Recentpreclinical studies show thatAGE lowered blood pressureand increased flexibility of thearteries, increasing the levels ofblood vessel-relaxing factor nitricoxide more than raw garlic.'^ Thereduction of hypertension by

inhibiting atherosclerosis andincreasing blood vessel relaxationand circulation may serve well inprotecting the heart and the brain,preventing brain atrophy that leadsto AD.̂

AGE and HomocysteineElevated plasma homocysteine

(hyperhomocysteinemia) increasesthe risk of CVD" '̂' and is anindependent risk factor for strokeand dementia, including AD.'PIasmalevels of homocysteine increaseprogressively with age, posing aserious threat to aging individuals.The adverse vascular andneurotoxic effects of homocysteineare associated with oxidant stress;homocysteine impairs DNA repairin the hippocampus, sensitizingneurons to toxicity by the amyloidbeta peptides that are linked toAD.̂

Hyperhomocysteinemia iscaused largely by deficienciesin folate and vitamins B6and B12. AGE can preventhyperhomocysteinemia in folatedeficiency, protecting against thedamaging effects of homocysteine.While the antioxidant effects of AGEcan protect against ROS damageproduced by homocysteine,'^ AGEis now reported to elevate plasmaand liver folate levels in folatedeficiency and play an importantrole in the enzymatic reactions thatreduce homocysteine by convertingit to methionine.^'^

AGE and Brain FunctionAlzheimer's disease is associated

with extracellular plaques ofaggregated [ beta] -amyloidprotein (Abeta), intracellularneurofibrillary tangles containingtau protein, and a loss of neuronsin the hippocampus and otherareas of the brain. ROS producedby Abeta are thought to play a rolein neuronal death by programmedcell suicide (apoptosis) leading toneurodegenerative conditions.^

AGE and SAC have been shownin a number of studies to protect

against Abeta toxicity and celldeath.^"''^ Neurons exposed toAbeta showed a significant increasein ROS. Treatment with AGE andSAC suppressed the generationof the ROS and inhibited theenzymes caspases 3 and 12 thatare critical in inducing cell deathby apoptosis.•'""•'-

The potential of AGE as apotential protector against ADwas further shown in a recentpreclinical study, using an ADmodel. Researchers found thatAGE and SAC protected the brainagainst AD-associated events, withAGE being the more effective inpreventing beta amyloid peptides,neurofibrilar tangles composed ofabnormal tau protein, and inhibitinginflammation.-^^

Other Anti-AgingNeuroprotective Effects

Preclinical studies in models thatare genetically prone to early agingshow AGE or SAC prevented frontallobe degeneration associated withaging; improved learning; andmemory retention; extended lifespan; and enhanced the growthand branching of neurons fromthe hippocampus area, the brainarea associated with memory andcognition.-'*'•'''

AGE and CancerCancer Prevention

High intake of garlic has beenlinked to a dramatic reductionin gastrointestinal cancer inhumans, sometimes by 50%.'"'^Preclinical studies have shownthat AGE and its organosulfurcomponents inhibit the growth ofmany types of cancer.'^'"•^^•" Thecancer-preventive mechanisms ofthe antioxidant-rich AGE includeinhibition of ROS-induced DNAdamage, prevention of chemicalmodification of DNA by carcinogenicchemicals, increased detoxificationof carcinogens, increased immunityby boosting cancer-killing naturalkiller cells (NK cells),'- inhibitionof tumor growth-promoting

74 TOWNSEND LETTER - JULY 2007

vascularization (angiogenesis),^'modulation of immunity*^ and cellsignals''"modification of hormonalsupport/* and increased cancercell death by apoptosis.^ "̂ '"̂

AGE has been found to suppresscolorectal adenomas in humans.^^'"'In a year-long, double-blind,randomized clinical trial, patientswith pre-cancerous lesions ofthe colon (colorectal adenomas)received either a high AGE dose(2.4 mL/day) or a very low dose(0.16mL/day), as control. Theresults showed that in controls,the number of adenomas increasedcontinuously over the year, but inthe AGE group, AGE significantlysuppressed both the size andnumber of the colon adenomas,showing that AGE suppresses theprogression of pre-cancerous colonlesions and thus would preventthem from developing into fullblown colon cancer.'"'

AGE and Cancer TherapyAGE, SAC, and SAM have been

reported to inhibit the growthof a variety of human cancerceils including prostate, breast,erythroleukemia, and coloncancers,''^'" •'̂ •"̂ suggesting thatAGE, besides its cancer-preventiveeffects, has potential as an adjuvantin cancer therapy.

Preclinical studies have shownthat SAC and SAM reduce humanprostate cancer cell growth,decrease PSA, a characteristicmarker for prostate cancer, and cutthe production of testosterone bythe prostate cells, thus deprivingthem of a critical growth factor.'''''SAM dramatically inhibits thegrowth of human colon cells,disrupting and arresting mitosisand inducing death by apoptosis."^

AGE Prevents Drug ToxicityAs reviewed earlier,''^ AGE

protects against cardiototoxicity

Aged Garlic Extract

and liver toxicity induced bycarcinogens and by some drugsused in cancer therapy. AGEalso prevents liver toxicity byacetaminophen (e.g., Tylenol), apopular pain-killing medication.*"*

Gastrointestinal toxicityduring cancer treatment withmethotraxate (MTX) presents aproblem In therapy. Preclinicalstudies show that AGE protectsagainst MTX-induced toxicity in thesmall intestine"^ by preventing MTX-induced apoptosis,""* suggesting aprotective role for AGE during MTXcancer treatment by preventing thetoxic side effects to normal cells.

Kidney toxicity is an adverseside effect in gentamictn (GM)treatment, limiting the use of thisantibiotic. AGE and SAC and SAMwere found to protect the cellsagainst GM nephrotoxicity, without

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Aged Garlic Extract

interfering with the antibioticaction of GM; moreover, SACenhanced the antibiotic action ofGM, suggesting that AGE, rich SACand SAM may be co-administeredwith GM-treatment to ameliorateGM-induced nephrotoxicity andpossibly enhance its antibiotic

AGE, Cancer, ImmunityAged garlic extract has a wide

range of immuno-potentiatingeffects.'- '̂'̂ ''̂ A recent randomized,double-blind, placebo-controlledclinical trial underscored theefficacy of AGE in increasingimmunity. Patients with inoperablecancers of the digestive system(colorectal, pancreas, or livercancer) received AGE or placebo.Advanced stages of cancer areassociated with a decrease inimmune functions including adecline in Natural Killer (NK) cells.The results of the trial showed thatpatients who received AGE (500mg/day) for three months showeda significantly increase in NK cellcounts, compared to controls whoselevels of NK cells decreased/^

AGE, Endurance, and FatigueAging is associated with reduced

levels of energy, reduction inphysical endurance, and increasedfatigue. As seen in a number ofpreclinical studies and studieswith athletes, AGE provides help

on all fronts.'^ A new preclinicalstudy on endurance and fatiguefound that AGE ameliorates thevarious impairments linked tophysical fatigue following exerciseby improving aerobic glucosemetabolism, reducing oxidativestress, and promoting oxygensupply.**

AGE and DiabetesDiabetes is a disease

characterized by high glucoselevels (hyperglycemia); some ofthe pathological complicationsin diabetes arise from glucoseinteracting with proteins (glyca-tion). The glycation products,called Maillard reaction products,are accompanied by increased ROSand play a role in damaging variousorgans including eyes, bloodvessels, nerves, and kidneys. AGEand SAC, with their high antioxidantactivity, have anti-glycationactivity,'^' which would help preventpathological complications indiabetes. The potential therapeuticrole of AGE in diabetes is now beingtested in a clinical trial involvingpatient with type 2 diabetes.

AGE and Sickle Cell AnemiaSickle-ceil anemia is a hereditary

disorder with high risk of mortality.In the course of this genetic disease,small clusters, called Heinz bodies,are formed in the red blood cells(RBC) by oxidative damage to thehemoglobin molecules and damageto the RBC membrane. AGE, withits antioxidant activity, is effectivein reducing Heinz bodies.^^ Patients

Carmia Borek, PhD, is a Professor at Tufts UniversitySchool of Medicine in Boston, Massachusetts,Department of Public Health and Family Medicine. Dr.Borek's research has focused on the role of antioxidantsand nutraceuticals in health, prevention of disease,notably cancer, and aging. Dr. Borek has served asconsultant and on advisory boards at the NIH, NCI,and the National Institute of Aging, as well as in thepharmaceutical and food industries. Dr. Borek is anactive speaker in scientific and public forums and haspublished over 300 scientific articles and five books,including Maximize your Healthspan with Antioxidants: ABaby Boomer's Guide.

with sickle-cell anemia received adaily dose of 5 mL AGE. After fourweeks of treatment, the numberof Heinz bodies decreased signifi-cantly (58.9+/-20.0% at baselineto 29.8+/-15.3%), suggesting thatAGE may be considered a potentialtherapeutic agent to amelioratecomplications of sickle-cellanemia.

SummaryThe medicinal effects of

garlic have a long history. Freshgarlic, though an excellentcondiment, when taken in highdoses that provide medicinalbenefits may have unpleasantside effects, including lingeringodor on the breath and skin, andgastrointestinal disturbances. Agedgarlic extract, or Kyolic, an odorlessform of organic fresh garlic, hashealth benefits that are as effectiveas fresh garlic and often even moreso, being richer in antioxidantsthan are other garlic preparations,including the fresh bulb, andhigh in stable bioavailable, water-soluble organosulfur compounds,such as S allyl cysteine, which isused for standardization, and Sallyl mercaptocysteine, which isunique to AGE. To the wide rangeof health benefits of AGE discussedpreviously,''^ we can add recentfindings that underscore the healtheffects and add others found inpreclinical and clinical trials.These include cardioprotectiveand neuroprotective effects, anti-aging effects, potential preventionof complications in diabetes,amelioration of fatigue, potentialtherapeutic effects in sickle cellanemia, protection against toxicside effects from chemotherapyand antibiotic treatment, and newstudies on the cancer-preventiveand therapeutic effects of AGE.Taken daily in doses suggestedby the manufacturer (Wakunaga),AGE, as shown in over 400 scientificstudies, can help maintain goodhealth, protect the heart and brain,and help prevent aging symptoms,thus increasing quality of life.

76 TOWNSEND LETTER - JULY 2007

Notes1. Borek, C. The health benefits of aged garlic

extract. Townsend Letter August/September200-1.

2. Borek C. Antiuxidant health elfects of agedgarlic extract./A'u/r 2001: !31:I010S-IOi5S.

3. Amagase H. Clarifying the real bioactlveconstituents tif garlic./ Nuir 2006; 136: 716S-725S,

4. Kasuga S. Uda N, Kyo E, et al. Pharmacologicalactivities of aged garlic extract In comparisonwith other garlic preparations. J. Nutr2OO1;1.'JI: 108OS-I0a4S.

5. Borek C. Dietary antioxidants and humancancer. Integr Cancer Ther 2004 Dec;3(4):333-41.

6 Halllwell B. Role of free radicals In theneiirodeKeneratlve diseases; therapeuticImplications for antioxidant treatment. DrugsAging 2001:18:685-716..

7. Kowald A, Klrkwood TB. Accumulation oldefective mitochondria through delayeddegradation of damaged organelles and Itspossible rnle in ageing ol post-mitotic anddividing cells. J Theor Biol. 2000; 202:145-160.

H. Morihara N, Ushijima M, Kashimoto N,Sumioka I, Nishihama T. Hayama M, TakedaH. Aged garlic extract ameliorates physicallatigue. Biol Pharm Bull 2006; 29;9fi2-966-

!). Biirek C. Oarlic reduces dementia and heart-disease risk. J. Nutr. 2006; 136: 810S-812S.

10. Amagase H, Petesch BL, Matsuura H, Kasuga.S, Itakura Y. Intake of garlic and its bioactivecomponents, y^-ufr 200l;13I:955S-62S.

11. Weiss N. Ide N. Abahji, T, Nill L. et al. Agedgarlic extract improves homocysteine-induced endothelial dysfunction in macro-aiid mi< rorirruiation. J Nutr 2006; 136: 750S-754S.

12. Steiner M, Li W. Aged garlic extract, amodulator of cardiovascular disease risk[actors; a dose finding study of the effects ofAGE on platelet function. y/Vurr. 2001; 131;980S-9S4S.

13. Rahman K, Lowe GM. Garlic andcardiovascular disease; a critical review, J.Nutr 2006; 136; 736S-740S.

14. Budolf M. Aged garlic extract retardsprogression o( coronary artery calcification,yft'ufr 2006; 136: 741S-744S.

15. Yeh YY. Yeh SM. Homocysteine-loweringaction is another potential cardiovascularprotective factor of aged garlic extract. J Nutr2006; 136: 745S-749S.

16. Lau BHS. Suppression of LDL oxidation bygarlic compounds is a possible mechanismof cardiovascular health benefit. J Nutr.2006:136; 765S-768S.

17 Harauma A, Moriguchi T. Aged garlic extractimproves blood pressure in spontaneouslyhypertensive rats more safely than raw garlic.JA'ufr 2006; 136; 769S-773S.

18. Al-Qattan KK, Thomson M. Al-Mutawa'a S, Al-Haji-rl tJ, et al. Nitric oxide mediates the blood-pressure lowering effect of garlic in the raltwo-kidney, one-clip model of hypertension. JNutr. 2006: 136; 774S-776S-

19. Morihara N. Sumioka I. Ide N, MoriguchiT, et al. Aged garlic extract maintainscardiovascular honieostasJs in mice and rats.JNuIr 2006: 136; 777S-781S.

20. Aliison GL. Lowe GM, Rahman K. Aged garlicextract and its constituents inhibit plateletaggregation through multiple mechanisms. JNiilr 2()O6;I36:782S-788S.

21. Liu L, Yeh YY. S -Alk(en)yl cysteines of garlicinhibit cholesterol synthesis by deactivatingHMA-CoA reductase in cultured hepatocytes.JNutr. 2002:J32: II29-II34.

22. Macan H, Uyklmpang. R. Alconcel. M Takasu,J, Razon, R Amagase H. et al. Aged garlicextract may be safe for patients on warfarintherapy yA'ufr 2006; 136: 793S-795S.

23. Dillon SA, Lowe GM, Billington D. RahmanA. Dietary supplementation with agedgarlic extract reduces plasma and urineconcentration of 8-iso prostagiandinF(2alpha) in smoking and non-smoking menandwameii. JNutr 2002;132: 168-17L

24. Williams MJ. Sutherland WH, McCormlck MP,Yeoman DJ, de Jong SA. Aged garlic extractimproves endothelial function in men withcoronary artery disease. Phvtolher Res2005;19;314.

25. Haim M. Tanne D, Goldbourt U. Doolman R,et al. Serum homocysteine and long-term riskof myocardial Infarction and sudden deathin patients with coronary heart disease.Cardiology. 2O07;107;52-.56.

26. Yeh YY, Yeh SM, Homocysteine-loweringaction is another potential cardiovascularprotective factor of aged garlic extract. JNutr2006;I36;745S-749S.

27. Ide N, Lau BH. Garlic compounds minimizeintracellular oxidative stress and Inhibitnuclear factor-kappa b activation. J Nutr2001;13I;1020S-6S.

28. Ito Y, Ito M, Takagi N, Saito H, Ishige K.Neurotoxicity induced by amyloid beta-peptide and ibotenic acid in organotypichippocampal cultures: protection by S-ailyl~L-cysteine. a garlic compound. Brain Res.2003: 985:98-107.

29. KosugeY. Koen Y, Ishige K. Minami K. UrasawaH, Salto H, Ito Y. S-ally!-L-cysteine selectivelyprotects cultured rat hippocampal neuronsfrom amyloid beta-protein- and tunicamycin-induced neuronal death. Neuroscience.2003; 122:885-95.

30. Hereto J, Sugimoto M. Activation of caspase-3in beta-amyloid-induced apoptosis of culturedrat cortical neurons. Brain Res. 1999;842:311-23.

31 Jackson R, McNeil B, Taylor C. Holl G, RufID. Gwebu ET. Effect of aged garlic extract oncaspase-3 activity in vitro. Nut Neurosis. 2002;5:287-90.

32. Ito Y. S allyl cysteine, a garlic compound,selectively protects cultured hippocampalneurons from ER stress Induced neuronaldeath. Proceedings of the 2004 annualmeeting of the Korean Society of AppliedPfiarmachology; Neuroprotection andNeuroprotective Drugs, Seoul, Korea; 2004,

33. Chauhan NB. Effect of aged garlic extracton APP processing and tau phosphorylationin Alzheimer's transgenic model Tg2576. JElhnopharmacol. 2Q0e:im:3S5-94.

34. Nishiyama N, Moriguchi T, Morihara N, SaitoH, Ameliorative effect of S-allylcysteine. amajor thioallyl constituent in aged garlicextract, on learning deficits In senescence-accelerated mlce.JNutr 2001:13I:I093S-5S.

35. Moriguchi T, Saito H. Nishyama, N. Anti-agingeffect of aged garlic extract in the inbred brainatrophy mouse model. Clin Exp PharmacholandPhysiol. 1997; 24: 235-242,

36. Fleischauer AT. Arab L. Garlic and cancer:A critical review ot the epidemiologicalliterature. 7 A'u/r. 2001; 36: 1O32S-104OS.

37. Mllner JA. Preclinical perspectives on garlicand cancer. JAfufr 2006:136: 827S-831S.

38. Pinto JT, Krasnikov BF. Cooper AJL. Redox-sensltive proteins are potential targets ofgarlic-derived mercaptocysteine derivatives.JNutr 2006:136: 835S-841S.

39. Tanaka S, Haruma K, Kunihlro M, Nagata S,et al. Effects of aged garlic extract(AGE) oncolorectat adenQma:a double blind study.Hiroshima J MedSci. 2004:3-5:39-45.

Aged Garlic Extract40. Tanaka S, Haruma K. Yoshthara M, Kajlyama

G, Kira K, Amagase H, Chayama K, Agedgarlic extract has potential suppresslveeffecton colorectal adenomas In luimaiis. J Nutr2006:136: 821S-826S.

41. Kawaguchi N, Katsuki T. Hirata K, Sumi S\,Ishikawa H. Aged garlic extract Inhibitsanglogenesis and proliferation of coiorectalcarcinoma ceils. J Nutr 2006; 136: 842S-R46S.

42. Ishikawa H, Saeki T, Otanl T. Suzuki T, et al.Aged garlic extract prevents a decline of nkcell number and activity in patients withadvanced cancer. JA'u/r 2006; 136: 8lfiS-820S.

43. Kyo E. Uda N, KasugaS. Itakura,Y.Immunomodulatory effects ol aged garlicextract. 7 yV'ufr. 2001; 13I:IO75S-IO79S.

44. Pinto JT, Qlago C, Xing J, Suffoletto BP, et al-Alteration of prostate biomarker expressionand testosterone utilization i[i human LNCaPprostate carcinoma cells by garlif derivedS-allylmercaptocysteine. The h'ostate.2000:45:304-314.

45. Xiao D. Pinto JT, Gundersen GG. Welnstein IB.Effects of a series of organosulliir compoundson mitotic arrest and induction ol apoptosisIn colon cancer cells. Mol Cancer Ther2005;4;1388-98

46. Gwilt PR, et al. The effect o[ garlic extract onhuman metabolism of acetaminophen. CancerEpidemiol Bimarkers Prev. 1994:3; l.'i.')-60.

47. HorieT,AwazuS, Itakura Y, FuwaT. Alleviationby garlic of anti-tumor drug-Induced damageto the intestine. y/Vufr, 2001;131;1071S-4S.

48. Horie T. Li T, Ito K, Suml SI, Fuwa T. Agedgarlic extract protects against methotrexate-induced apoptotic cell injury of lEC-6 cells, JNutr 2006;136: 8615-863.S.

49. Velasco-Velazquez MA, Maldonado PD,Barrera D, Torres V et al. Aged garlic extractinduces proliferation and amelioratesgentamicin-induced toxicity in LLC-PKI cells.Phytother Res. 2006; Jan;20:76-8.

50. Pedraza-ChaverrI J. Barrera D, MaldonadoPD, Chirlno Yl. et al. S-allylmercaptocysteinescavenges hydroxyl radical and singletoxygen in vitro and attenuates gentamkhi-induced oxidative and nitrosative stress andrenal damage in vivo. BMC Clin Pharmacol.2004;4;5.

51. Ahmad MS, Ahmed N, Antigiycationproperties of aged garlic extract: possiblerole in prevention o( diabetic complications.JNutr 2006: 136: 796S-799S.

52. Takasu J. Uykimpang R, Sunga MA, AmagaseH, Nllhara Y. Aged garlic extract is a potentialtherapy lor sickle-cell anemia, J Nutr 2006Mar;136(3 Suppl):803S-805S.

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