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Ageing Research Reviews

2 (2003) 3956

Garlic and aging: new insights into an old remedyKhalid Rahman

School of Biomolecular Sciences, Liverpool John Moores University, Byrom Street, Liverpool L3 3AF, UK

Received 10 July 2002; accepted 12 July 2002

Abstract

There has been an impressive gain in individual life expectancy with parallel increases inage-related chronic diseases of the cardiovascular, brain and immune systems. These can causeloss of autonomy, dependence and high social costs for individuals and society. It is now acceptedthat aging and age-related diseases are in part caused by free radical reactions. The arrest of agingand stimulation of rejuvenation of the human body is also being sought. Over the last 20 yearsthe use of herbs and natural products has gained popularity and these are being consumed backedby epidemiological evidence. One such herb is garlic, which has been used throughout the historyof civilization for treating a wide variety of ailments associated with aging. The role of garlic inpreventing age-related diseases has been investigated extensively over the last 1015 years. Garlichas strong antioxidant properties and it has been suggested that garlic can prevent cardiovasculardisease, inhibit platelet aggregation, thrombus formation, prevent cancer, diseases associated withcerebral aging, arthritis, cataract formation, and rejuvenate skin, improve blood circulation andenergy levels. This review provides an insight in to garlics antioxidant properties and presentsevidence that it may either prevent or delay chronic diseases associated with aging. 2003 Elsevier Science Ireland Ltd. All rights reserved.

Keywords: Garlic; Aging; Chronic diseases; Antioxidants

1. Introduction

Medicinal herbs have been used in primary health care over many centuries before theadventof modernmedicine.Over thelast 20 years there hasbeen an international resurgenceof medicinal herbs in Western culture, especially in the USA which has coincided with thegreening issues and an enhanced interest in natural systems and the questioning of anover-dependence on synthetic drugs to maintain health. Similar trends have been observedin Europe and the growth rate of phytotherapeutics in Europe has been reported to be

Tel: + 44-151-231-2087; fax: + 44-151-298-2821. E-mail address: [email protected] (K. Rahman).

1568-1637/03/$ see front matter 2003 Elsevier Science Ireland Ltd. All rights reserved.PII: S1568-16 37(02 )0004 9-1

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40 K. Rahman/ Ageing Research Reviews 2 (2003) 3956

greater than that for pharmaceuticals ( Wills et al., 2000 ). Several epidemiological studieshave shown that a diet rich in plant foods may reduce the development of certain chronic

diseases such as cancer and atherosclerosis ( Keys, 1995 ); one such plant food is garlic.

2. Garlic

2.1. Historical perspective

Garlic ( Allium sativum) is believed to have originated in Central Asia and to date thegenus Allium comprises over 600 known species, which include Allium cepa (onion), Allium porrum (leek) and Allium schoenoprasum (chives). Thegenus Allium belongs to theAlliacaefamily. Garlic is used universally as a avoring agent, traditional medicine and a functional

food to enhance physical and mental health. The benecial effects of garlic consumptionin treating a wide variety of human diseases and disorders have been recorded and passeddown by many civilizations.

2.2. Composition of garlic

The general composition of garlic is shown in Table 1 . The majority of garlic (65%) iswater and the bulk of the dry weight is composed of fructose-containing carbohydrates,followed by sulfur compounds, protein, bre and free amino acids ( Lawson, 1996 ). Garlicalso contains high levels of saponins, phosphorus, potassium, sulfur, zinc, moderate levels

Table 1General composition of garlic

Component Amount (fresh weight; %)

Water 6268Carbohydrates (mainly fructans) 2630Protein 1.52.1Amino acids: common 11.5Amino acids: cysteine sulphoxides 0.61.9

-Glutamylcysteines 0.51.6Lipids 0.10.2Fibre 1.5

Total sulphur compounds a 1.13.5

Sulphur 0.230.37Nitrogen 0.61.3Minerals 0.7Vitamins 0.015Saponins 0.040.11

Total oil-soluble compounds 0.15 (whole)0.7 (cut)

Total water-soluble compounds 97

Taken from Lawson, 1996 .a Excluding protein and inorganic sulphate (0.5%).

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prominent presence in living beings. This free radical theory of aging is in good agreementwith another theory, the rate of living hypothesis, which inversely correlates metabolic

rate with life span ( Ku et al., 1993 ). It is generally accepted that reactive oxygen species(ROS) are generated in vivo and can cause cellular damage. The most important sources of ROS generation are mitochondrial electron transport, peroxisomal fatty acid metabolism,cytochrome P450 reactions and phagocytic cells (respiratory burst). However, in addition tothese four originators, numerous enzymes exist, capable of generating ROS under normaland pathological conditions. Based on Harmans (1956) assumptions, aging is a conse-quence of accumulation of ROS-induced damage to proteins and DNA in the mitochondriaand it has been frequently proposed that the major targets for free radical attack are themembranes of cells and the nuclear genome. The nuclear genome and mitochondrial DNAare especially vulnerable to the accumulation of free radical damage ( Barga and Herrero,2000 ) and aging results from the accumulated non-repaired damage caused by free radicals.

Over the last 1015 years the results of many studies have indicated that oxidative dam-age to human cells accumulates with age and is a major contributor to degenerative diseasesassociated with aging such as cancer, Alzheimers disease, cardiovascular disease and ner-vous system dysfunction ( Ames et al., 1993; Ambrosone et al., 1999; Christen, 200 0).On the transactional level, many studies suggest that the process of aging and the onsetof age-related diseases can be slowed, either through genetics or through dietary restric-tion (Prolla and Mattson, 2001 ). Unfortunately, genetic changes are unethical and dietaryrestriction is difcult and is unlikely to be followed by majority of elderly individuals.

Since it is well accepted that oxidative free-radical stress is an important contributorto the aging process and to many age-related diseases, the focus must be on reducingoxidative stress in vivo. This can be achieved by limiting exposure to outside oxidativeagents such as cigarette smoke and other environmental exposures such as UV sunlightetc. This is important because oxidative damage apparently increases with age and thusmay overwhelm the natural repair systems in the elderly ( Kowald and Kirkwood, 2000 ).The best way to neutralize free-radical mediated oxidative stress in the elderly is to ingestdiet rich in phytochemicals with antioxidant properties or to take dietary supplements of antioxidants. These are widely found in nature, especially in plant products and are anextremely diversied group of chemicals. One such naturally occurring antioxidant is garlicand its role in preventing diseases associated with old age is presented in this review. It mustbe remembered that any dietary supplement which can counteract oxidative stress has thepotential to extend life expectancy or improve the quality of life, whether or not it alters theaging process per se.

2.4. Garlic and cardiovascular disease

Epidemiological studies have identied a number of risk factors for the developmentof atherosclerosis which include elevated serum lipids (cholesterol and triglycerides), in-creased plasma brinogen and coagulation factors, increased platelet activation, alterationsin glucose metabolism and smoking ( Wood, 2001 ). However, the oxidative modicationof low-density lipoprotein (LDL) is now considered an important mechanism in the devel-opment of atherosclerosis ( Keaney, 2000 ). There is strong epidemiological evidence thatatherosclerosis-related conditions (coronary artery disease, ischemic stroke and peripheral

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K. Rahman/ Ageing Research Reviews 2 (2003) 3956 43

artery disease) all increase with age ( Gallotta et al., 1997 ) and its effects are mainly ev-ident in the muscular arteries e.g. coronary, carotid, femoral and iliac arteries as well as

the aorta. Aging causes the changes in the structure and function of the vessels that leadsto an increase in the incidence of certain cardiovascular diseases causing enhancement of both morbidity and mortality. When aging is associated with hypertension, these changesare increased. Aging also alters endothelial cells and hence the vascular tone regulation,reducing the endothelium-dependent relaxations, probably by a decrease in endothelialsynthesis or release of nitric oxide ( Marin and Rodriguez-Martinez, 1999 ). With increas-ing age, there is also an increase in vascular wall stiffening which is characterized byan increase of the collagen-elastin ratio and deposition of calcium and lipids within theblood vessels ( Robert, 1999 ). Enhanced oxidative stress with aging may also play an im-portant role in the increased prevalence of atherosclerosis in older individuals. Evidencefrom both in vitro and in vivo studies suggests that oxidation of LDL may contribute toearly atherosclerotic lesion formation ( Reaven and Witztum, 1996 ) and there is also acontinuous increase in LDL hydroxy fatty acids content with age in healthy, elderly indi-viduals ( Jira et al., 1996 ). A different type of lipoprotein aging can occur in conditionswhere lipoprotein removal from the plasma is delayed. This can then lead to a progres-sively more senescent form of circulating lipoprotein that is more susceptible to oxygenradical-induced modications ( Walzem et al., 1995 ). Oxidized LDL elicits pro-atherogenicproperties, these include increased smooth muscle proliferation ( Koba et al., 1999 ), cyto-toxicity to vascular endothelial cells, smooth muscle cells and broblasts ( Sevanian et al.,1995 ) together with theinductionof apoptoticcell death in vascularendothelial cells ( Napoliet al., 2000 ).

Garlic has been used to treat a variety of cardiovascular problems over the years. Variousgarlic extracts have been shown to reduce diet-induced hypercholesterolemia in rats andrabbits ( Bordia and Verma, 1980; Slowing et al., 2001 ). Aged garlic extract (GEX) supple-mentation has been shown to be effective in lowering plasma cholesterol and triglycerideand LDL-cholesterol in hyperlipidemic subjects ( Steiner et al., 1996 ) whilst it had no effectin normolipidemic subjects ( Rahman and Billington, 2000 ). In support of this, supplemen-tation with garlic powder preparations has also been reported to reduce plasma cholesterolin hypercholesterolemic subjects ( Kannar et al., 2001 ), however, some conicting data hasalso been reported ( Gardner et al., 2001 ). It is likely that garlic and its constituents lowerplasma cholesterol and triglycerides by inhibiting the key enzymes involved in cholesteroland fatty acid synthesis ( Liu and Yeh, 2001 ).

Platelet aggregation and subsequent thrombus formation is signicantly and efcientlydecreased by garlic and its constituents and rbrinolysis is also enhanced resulting in dis-

solution of clots and thrombi ( Bordia et al., 1998 ). At low intake (2.4g per day), sup-plementation with GEX has been shown to increase the threshold levels of collagen andepinephrine-induced platelet aggregation and platelet adhesion to brinogen in healthyindividuals ( Steiner and Li, 2001 ). This study also demonstrated that high intake (7.2gper day) of GEX increased the threshold level of ADP-induced platelet aggregation andplatelet adhesion to collagen and von Willebrand factor. More importantly, this inhibitionof ADP-induced platelet aggregation after dietary intervention with GEX (5 ml per day(equivalent to 1.5 g per day)) has also been observed in normolipidemic subjects in ourlaboratory ( Rahman and Billington, 2000 ).

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Fig.1. ADP-induced plateletaggregationin humans before andafter ingestionof agedgarlic extract(GEX). Plateletaggregation was initiated by the addition of various concentrations of ADP to platelet-rich plasma. Aggregationcurves were analyzed for : (A) the total percentage aggregation, and, (B) the initial rate of aggregation (%/min).Values are means SEM, n = 23. Signicantly different ( P < 0. 05) before and after ingestion of GEX.(reproduced from Rahman and Billington, 2000 ).

Aged garlic extract signicantly inhibited both the total percentage and the initial rateof platelet aggregation at concentrations of ADP up to 10 mol/l (Fig. 1A and B ). TheK M for ADP-induced platelet aggregation was approximately doubled after dietary supple-

mentation with GEX, where as the maximum rate of aggregation was unaffected. In otherstudies, dietary garlic oil has been shown to inhibit platelet aggregation induced by arachi-donic acid, adrenaline, collagen and calcium and has been shown to decrease the formationof the pro-aggregatory prostaglandin thromboxane-A 2 (TXA2) in platelets (measured asthromboxane-B 2) in coronary artery disease patients ( Bordia et al., 1998 ). In comparison,fresh garlic extracts have also been shown to inhibit cyclooxygenase activity in cell freesystems and in animal studies ( Thomson et al., 2000 ).

In vitro studies have identied that GEX improves microcirculation and blood propertiesby preventing lipid peroxidation and hemolysis in oxidized erythrocytes ( Moriguchi et al.,

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2001 ). This is supported by a study in which chronic garlic powder consumption was shownto attenuate age-related increases in aortic stiffness, thus protecting the elastic properties of

the aorta which are related to aging in humans ( Grogler-Breithaupt et al., 1997 ).A garlic extract has also been shown to modulate the production and function of both

endothelium-derived relaxing factor (NO) and constricting factors (endothelin-I) in rat-isolated pulmonary arteries ( Kim-Park and Ku, 2000 ) and reduce blood pressure in hyper-cholesterolemic subjects ( Steiner et al., 1996 ).

One of the most important biochemical properties of garlic is its antioxidant potential.The antioxidant actions of garlic and its constituents have been determined by their abil-ity to scavenge reactive oxygen species (ROS), inhibit lipid peroxide formation and LDLoxidation, and enhance endogenous antioxidant systems.

Aged garlic extract and its main constituents have been reported to scavenge the t -butylhydroperoxide radical andhence prevent lipid peroxidation of liver microsomes ( Imai et al.,1994 ). This study also reported that water extracts of raw and heat-treated garlic enhancedperoxidation of liver microsomes induced by t -butyl hydroperoxide whilst garlic powderextracts have demonstrated the ability to scavenge reactive species such as OH

and pe-

roxyl radicals ( Aruoma et al., 1997 ).Dietary supplementation with GEX for 7 days signicantly reduced the susceptibil-

ity of subsequently isolated LDL to Cu 2+ -mediated lipid peroxidation ( Munday et al.,1999; Steiner and Lin, 1998 ). Interestingly, in this study ingestion of raw garlic had nosignicant effect on the same parameters. Similar studies have also been performed usinggarlic powder extracts but the results are inconsistent.

Previous studies have reported that GEX increases intracellular glutathione (GSH) levelsin vascular endothelial cells by modulation of the GSH redox cycle specically increasingglutathione disulde (GSSG) reductase activity and superoxide dismutase (SOD) activity(Geng and Lau, 1997 ). This is supported by a study in which garlic supplementation pre-vented the increase in oxidative stressassociatedwith gentamicin-induced nephrotoxicity inrats. Oxidative stress was ameliorated by preserving superoxide dismutase and glutathioneperoxidase activities ( Pedraza-Chaverri et al., 2000 ). In vivo animal studies have been usedto investigate the effect of garlic oil supplementation on nicotine-induced lipid peroxida-tion in rats. Garlic oil supplementation reduced lipid peroxidation as assessed by numerousmethods in all major organs of the rat (heart, lung, liver and kidney). This decrease in lipidperoxidation was associated with an increase in activity of antioxidant enzymes (catalase,SOD and glutathione peroxidase) and increased levels of GSH ( Helen et al., 1999 ). If gar-lic is to be recommended as an antioxidant then its important that it is efcacy be provenin human clinical trials. There are no reported studies in the aging population in which

garlics efcacy has been tested. However, the data to date support the notion that garlicconsumption by the elderly may prevent or reduce diseases associated with oxidative stressand aging. We in our laboratory have investigated the effects of dietary supplementationwith GEXon theplasmaandurine concentrations of 8-iso-Prostaglandin F 2 (8-iso-PGF 2 )in smoking and non-smoking men and women. Its quantication in plasma and urine is asensitive and specic indicator of lipid peroxidation and, hence of oxidative stress in vivo.Dietary supplementation with GEX for 14 days reduced plasma and urine concentrations of 8-iso-Prostaglandin F 2 by 29% and 37% in non-smokers and by 35 and 48% in smokers.Fourteen days after cessation of dietary supplementation, plasma and urine concentrations

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of 8-iso-Prostaglandin F 2 returned to values not different from those before ingestionof GEX in both groups ( Fig. 2A and B ) (Dillon et al., 2002 ). No other changes in other

biochemical parameters were observed. In this study it was observed that the antioxidantcapacity of non-smokers was approximately twice that of smokers. More importantly theplasma antioxidant capacity of smokers had signicantly increased by 53% following sup-plementation with GEX for 14 days. Interestingly, the signicant difference observed in theplasma antioxidant capacity between non-smokers and smokers prior to ingestion of GEXwas reduced after 2 weeks of dietary supplementation. The plasma antioxidant capacityof non-smokers remained unaffected by the 2-week washout period. However, after the2-week washout period plasma antioxidant capacity decreased by 49% in smokers and wasnow similar to that prior to ingestion of GEX. ( Fig. 3). The results indicate that dietarysupplementation with garlic may reduce oxidative stress especially in the elderly as theytend to have a higher levels of this.

Garlic is a complex mixture of phytochemicals and its likely that they all interactsynergistically to provide it benecial effects, especially its antioxidant capacity. Dietaryavonoids are potent antioxidants and their consumption has resulted in signicantly re-duced susceptibility of isolated LDL to lipid peroxidation ( Avriam et al., 2000 ). Intake of avonoids has also been inversely correlated with risk of mortality from coronary arterydisease (Geleijnse et al., 1999 ) and it is likely that some of the benecial effects of garlicare due to its contents of avonids such as apigenin, myricetin and quercetin ( Miean andMohamed, 2001 ).

2.5. Garlic and cancer

Carcinogenesis is a complicated, multi-stage process; a small population of abnormalcells is generated and then increases in abnormality as a result of a series of mutations andchanges in the patterns of gene expression. Factors predisposing to malignancy include,inherited traits, environmental agents, diet, and the risk of cancer increases with age ( Amesand Shigenaga, 1992 ). It is well established that oxidative insults to DNA can lead tomutations in crucial genes, which ultimately may lead to cancer ( Ames and Shigenaga,1992 ) and that potent antioxidants and nutrients from fruits and vegetables may be able toquell the effects of oxidative DNA damage in the aged, in addition to lowering the overallrisk of cancer ( Block, 1991 ).

Epidemiological studies have shown that enhanced garlic consumption is closely relatedwith reduced cancer incidence ( Bianchini and Vainio, 2001 ). Many studies have reportedthe anti-cancer effects of garlic. For example, diallyl disulde (DADS) is an oil-soluble

organosulfur compound found in garlic and is reported to have anticancer properties againstboth hormone-dependent and-independent breast cancers andmay hormonize with polyun-saturated fattyacids whichareknown as modulators ofbreastcancercell growth.( Nakagawaet al., 2001 ). In support of this, other recent studies have also indicated that derivatives of garlic can inhibit proliferation of a human prostate cancer cell line and a human breastcancer cell line ( Pinto and Rivlin, 2001 ). Garlic also inhibits the proliferation of humancolon, lung and skin cancer cells and induces apoptosis of human colon tumor cells byincreasing intracellular calcium concentrations ( Sundaram and Milner, 1996a , Sundaramand Milner, 1996b ). In another study a recently identied Se compound in natural garlic

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Fig. 2. Plasma and urine concentrations of 8-iso-PGF 2 in smoking and non-smoking subjects before and after

GEX consumption. (A) Plasma total concentration of 8-iso-PGF 2 . Signicant difference ( P < 0. 05) is indicatedby from control (non-smokers) and from day 0. (B) Urine concentration of 8-iso-PGF 2 . Signicant difference(P < 0 . 05) is indicated by from control (non-smokers), from day 0 and from day 14. Values for both aremeans SEM, n = 10.

Fig.3. Antioxidant capacityof plasmain non-smokersand smokersbefore andafter GEXconsumption.Antioxidantcapacity is expressed as ascorbate equivalent antioxidant units ( mol/l). Values are means SEM, n = 10.Signicant difference ( P < 0. 05) is indicated by from control (non-smokers), from day 0 and from day 14.

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and selenised garlic, gamma-glutamyl- Se-methylselenocysteine has been shown to be acancer chemopreventative agent ( Dong et al., 2001 ). Garlic can also detoxify carcinogens

by stimulation of cytochrome P450 enzymes, antioxidant activity or sulfur compound bind-ing. Other studies have demonstrated a direct toxic effect of garlic on sarcoma and gastric,colon, bladder and prostate cancer cells in tissue culture. It is likely that this effect of garlicis obtained by the ability of garlic to prevent the suppression of the immune response whichis associated with increase risk of malignancy ( Lamm and Riggs, 2001 ). In support of thisGEX has been shown to inhibit both early and late stages of carcinogenesis, resulting in in-hibition of tumor growth in many tissues, including colon, mammary glands, skin, stomachand oesophagus ( Milner, 2001 ). Aged garlic extract exerts its cancer-inhibitory action indifferent and complementary ways, due to the variety of compounds present in the extractsuch as water and lipid-soluble organosulfur compounds, phenolic compounds, notably al-lixin, saponins and selenium. Thus, the anticarcinogenic action of GEX, which contains allof these compounds is broad in scope ( Borek, 2001 ) and GEX is effective in blocking amyriad of chemically induced tumors. Garlic can also inhibit carcinogenesis by modulatingcarcinogen metabolism and decreasing carcinogen binding to DNA and it may also preventROS-induced DNA damage since garlic has strong antioxidant properties. Thus, GEX hasalso shown to inhibit DNA adduct formation in mammary cells ( Milner, 1996 ).

The elderly population is exposed to a life time of UV-radiation which can cause DNAdamage and it is well established that inhibition of UV-and ionizing radiation carcino-genesis can be reduced by the intake of antioxidants ( Borek, 1997 ). Garlic being a strongantioxidant provides radioprotective effects by its ability to scavenge free radicals, and en-hance scavenging systems in the cell, including glutathione, SOD, catalase and glutathioneperoxidase ( Wei and Lau, 1998 ). This is supported by a study in which GEX was shownto protect bald mice from UV-light induced skin carcinogenesis ( Reeve et al., 1993 ) andallixin, a avonoid present in garlic inhibited tumor promotion in a multistep in vivo car-cinogenesis skin tumor model and in vitro ( Nishino et al., 1990 ). Aged garlic extract isalso reported to inhibit nuclear factor- B which is a transcription factor that is regulated bythe redox state of the cell and implicated in the inducible expression of a variety of genesinvolved in oxidative stress and cellular responses to stress. It can be activated by mitogens,bacteria and viruses and by ROS producing agents such as UV, ionizing radiation, hydrogenperoxide and tumor necrosis factor (Borek, 2001 ). The collective evidence presented heresupports the notion that consumption of garlic by the elderly population may either preventor reduce the incidence of cancer. This is supported by a study by Smith et al. (1999) inwhich they showed that supplementation with fruit and vegetable extracts, which are richin antioxidants, may decrease DNA damage in the peripheral lymphocytes in the elderly

population.

2.6. Garlic and cerebral function

The impressive gain in individual life expectancy is overshadowed by the loss of mentalfunction in old age. Decrements in motor function and decrements in memory are two mainbehavioral parameters that are altered in senescence in both humans and animals. Thesechanges occur even in the absence of specic age-related neurodegenerative diseases, butthese could contribute to the changes. Primary degenerative brain disease and diseases

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related to cerebral vascular disturbances are the leading cause of disability in old age andcancause loss of autonomy, dependence andhigh socialcosts for individualsandthesociety.

Cognitive impairment reduces an individualsability to function independentlyand the mostdevastating consequence of cognitive impairment occurs when it progresses to clinicaldementia. Hence, prevention and treatment of disorders leading to mental impairment haveemerged as major challenge of the modern health care system.

Numerically the most important sub-type of dementia is Alzheimers disease (AD), fol-lowedby vasculardementia(VD) ( Launer, 2000 ). There is increasingevidence thatoxidativestress is involved in cerebral aging anddementia and that free-radical reactionsgenerated byoxidation may contribute to both vascular and AD pathology. The brain is a good substratefor oxidation: it is a large consumer of oxygen and a major component of cell membranes,polyunsaturated fatty acids, are highly susceptible to lipid peroxidation and the brain alsohas areas rich in pro-oxidant iron. Furthermore, the brain is low in anti-oxidant substances,which could stop the free-radical chain reactions, which canalso interact with other proteinsresulting in glycation and other Maillard reactions. Together, these processes disturb cellstructure and function, inactivate proteins, damage mitochondria and DNA, cause collagencross linking and damage the arterial system ( Kristal and Yu, 1992 ). Evidence for oxidativeprocesses in AD comes from experimental and neuropathologic studies ( Markesbery andCarney, 1999; Yves, 2000 ). Briey, activated reactions may result from -amyloid toxicity,activated microglial cells, defects in energy metabolism and altered capacity to inactivatefree radicals.

Oxidative stress may also mediate the damage in vascular dementia. There is a largebody of research describing mechanisms that generate free radicals in vessels and howthese free radicals contribute to atherosclerosis which in turn leads to cerebral ischemiaand reperfusion ( Hall and Braughler, 1989 ), which in turn generate new free radicals. Inaddition, elevated blood pressure leads to endothelial damage, dysregulation of nitric oxideproduction andgenerationof free radicals which canthen lead to tissuedamageand neuronaldeath. Cognitive impairment results if the damage is localized in regions or the interfacebetween regions important for cognition.

Since antioxidants are thought to play a role in stopping free-radical chain reactions,interventions with antioxidants may help to reduce or prevent the incidence or progressionof dementing diseases. Thus, garlic, a strong antioxidant may have a role to play in reducingcerebrovascular disease in the elderly.

Several epidemiological studies in elderly people have revealed a correlation betweenantioxidants and cognitive performance ( Stahelin, 1999 ). This epidemiological evidenceis supported by a number of laboratory investigations including experiments with garlic.

Allixin, a component of garlic was found to promote the survival of neurons derived fromvarious regions of the brain and also increased the number of branching points per axon inhippocampal neurons ( Moriguchi et al., 1997a ). In another study by the same authors, usinga senile dementia model in mice it has been shown that GEX prevented atrophic changes inthe frontal brain, improved learning abilities and memory retention and increased longevityin the senescence-acceleratedmouse ( Moriguchiet al., 1997b ). This senescence-acceleratedmouse (SAM) model is particularly useful, as it has been shown to exhibit both morpho-logical and neurological impairments observed in normal aging ( Potier et al., 1993 ). Otherstudies have found that SAM supplemented with GEX displayed both increased lifespan

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and improved learning as assessed by active and passive avoidance tests ( Moriguchi et al.,1994 ). This protection by GEX was found to be most predominant in the frontal brain areas,

thus likely contributing to the observed improvements in cognitive and behavioral tasks.While a direct protective effect cannot be dismissed, the benecial effects promoted bygarlic could also be attributed to improved antioxidant activity within brain regions, whichpotentially could result in reduction in membrane lipid peroxidation. Thus, protection of neuronal cells from free-radical damage by garlic may improve certain brain functions.

In addition to antioxidant activity, changes in the immune response may contribute to anumber of age-related impairments in cognitive performance. In support of this, in thymec-tomised mice supplemented with GEX, it has been shown that GEX displays a markedimprovement in a number of markers of immune function, thus GEX may be exerting someprotective effects in SAM through immunomodulatory mechanisms ( Youdim and Joseph,2001 ).

Free-radicaldamageandinammatory processeslinked to enhancedlevelsof eicosanoids,play an important role in cerebral ischemia-reperfusion injury. Using a rat model, GEX andits components showeda dose-related attenuation of ROS production andinhibition of braindamage caused by ischemia-reperfusion, reducing post-ischemia edema ( Numagami et al.,1996 ). Garlic being a strong antioxidant may also protect against age-related maculopathyand cataract formation in the elderly as a reduced prevalence of nuclear cataract and antiox-idant potential has been reported ( Cumming et al., 2000 ). The role of garlic in preventingcerebral aging and dementia is well supported by other studies which have indicated thatphytochemicals displaying antioxidant properties can improve neurological dysfunctions(Youdim and Joseph, 2001; Deschamps et al., 2001 ).

2.7. Garlic and other anti-aging properties

The arrest of aging and stimulation of rejuvenation of the human body is being investi-gated intensively andgarlic has also been investigated for this purpose. The Hayick systemof cellular aging in culture has been used to test the anti-aging effects of garlic on long-termgrowth characteristics, morphology and macromolecular synthesis of human skin brob-lasts. This study has shown that garlic has some youth-preserving, anti-aging and benecialeffects on human broblasts in terms of maximum proliferative capacity andmorphologicalcharacteristics ( Svendsen et al., 1994 ). Garlic may also have a protective role to play in re-versing certain clinical features of cutaneous aging (i.e. ne lines and wrinkles) as has beenshown for other nutraceuticals and antioxidants ( Murad and Tabibian, 2001 ). It has beenshown to increase perfusion in healthy volunteers as judged by an increase in erythrocyte

ow velocity which was mainly due to vaso dilation in both arterial and venous vessels(Wohlrab et al., 2000 ). In addition, the administration of alliin and volatile S-containingcompounds in garlic have shown to enhance thermogenesis by increasing norepinephrinesecretion via -adrenergic action in an animal model ( Oi et al., 1998 ). Aged garlic extracthas also been shown to modify the function of mast cells, basophils and activated T lym-phocytes which play a leading role in allergic cascade reactions including inammation(Kyo et al., 1997 ) and it has been also suggested that garlic may prevent bacteria-causedfood poisoning ( Sasaki et al., 1999 ). Aging is associated with a decline in immune function,which is believed to be responsible for the high prevalence of rheumatic, malignant, and

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infectious diseases in the elderly. It is well known that older adults are at risk of malnutritionwhich may contribute to an increased risk of infection and this may be increased in immune

senescence ( Castle, 2000 ). Thus, garlic consumption may be benecial by the elderly asit has strong antioxidant properties since it is known that antioxidants can modulate theimmune system ( Fuente and Victor, 2000 ).

The glutathione redox system is a major component of overall antioxidant defenses inthe cells. It is irreversibly consumed in the detoxication of electrophilic metabolites andxenobiotics and is a very efcient free-radical scavenger and protects cells from the toxiceffects of reactive oxygencompounds. The elderly have lowerconcentrations of glutathionein plasma, whole blood and gastric mucosa indicative of impaired antioxidant defenses.It has also been shown that there is a higher incidence of age-related chronic illnesses inelderly individuals with lower than normal blood glutathione concentrations compared withelderly individuals withnormal concentrations( Langet al.,2000 ). Cataractsand retinopathyhave been linked directly to impaired glutathione status and aged garlic extract has beenshown to increase cellular glutathione in a variety of cells including those in normal liverand mammary tissue and thus consumption of garlic may enhance glutathione levels andprovide protection from chronic diseases associated with old age.

2.8. Summary and future directions

The summary of the possible role of garlic in preventing age-related diseases is shownin Table 2 . The accumulated knowledge over the last few years suggests that intake of garlic by humans may either prevent or decrease the incidence of major chronic diseasesassociated with old age such as atherosclerosis, stroke, cancer, immune disorders, cerebralaging, arthritis and cataract formation. The majority of the diseases associated with old ageare initiated by free radicals. Garlic has strong antioxidant properties and epidemiologicalstudies support the fact that diets rich in antioxidants may prevent some of the abovementioned chronic diseases. Thus, garlic is reported to decrease serum cholesterol andtriglyceride levels, inhibit platelet aggregation and increase blood circulation. Garlic mayalso prevent cancer, boost the immune system and prevent cerebral aging, arthritis andcataract formation. It may also promote general health by preventing pre-mature aging of the skin and increases glutathione and energy levels. Thus, garlic can be benecial if takenby the elderly, in either preventing or reducing chronic diseases associated with old age.

The principal sources of dietary recommendations have historically failed to address theunique needs of the aging population. The use of herbal medicines in the Western worldis now a signicant factor in modern health care and conrmation of their efcacy will

stimulate rapid and continued growth in the herbal market. However, mechanisms of actionof herbs and phytochemicals need to be established in vitro; and in vivo. The rapid growthin the use of garlic requires that standardized preparations are available with the backingof safety and efcacy data and that studies are conducted in which the active constituentsof garlic are known. At the moment the studies have been conducted using fresh garlicand a host of different garlic preparations. Further controlled human clinical trials arerequired with garlic especially in the elderly. These studies need to take in to account thebioavailability, metabolism of the bioactive components of garlic and their interactions withdrugs commonly taken by older people. This will help the modern and elderly consumer and

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Table 2Summary of the role of garlic in preventing age-related diseases

meet their expectations of product safety, efcacy and reliability. This can only be achievedby a more collaborative approach by all the different health professionals with an interestin the prevention by garlic of chronic diseases associated with old age.

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