Review Article Lycopene Deficiency in Ageing and Cardiovascular...

Review ArticleLycopene Deficiency in Ageing and Cardiovascular Disease

Ivan M Petyaev

Lycotec Ltd Granta Park Campus Cambridge CB21 6GP UK

Correspondence should be addressed to Ivan M Petyaev ykb75035aolcom

Received 19 June 2015 Revised 11 November 2015 Accepted 16 November 2015

Academic Editor Vibha Rani

Copyright copy 2016 Ivan M Petyaev This is an open access article distributed under the Creative Commons Attribution Licensewhich permits unrestricted use distribution and reproduction in any medium provided the original work is properly cited

Lycopene is a hydrocarbon phytochemical belonging to the tetraterpene carotenoid family and is found in red fruit and vegetablesEleven conjugated double bonds predetermine the antioxidant properties of lycopene and its ability to scavenge lipid peroxylradicals reactive oxygen species and nitric oxide Lycopene has a low bioavailability rate and appears in the blood circulationincorporated into chylomicrons and other apo-B containing lipoproteins The recent body of evidence suggests that plasmaconcentration of lycopene is not only a function of intestinal absorption rate but also lycopene breakdown via enzymatic andoxidative pathways in blood and tissues Oxidative stress and the accumulation of reactive oxygen species and nitric oxide mayrepresent a major cause of lycopene depletion in ageing cardiovascular disease and type 2 diabetes mellitus It has been shownrecently that low carotenoid levels and especially decreased serum lycopene levels are strongly predictive of all-causemortality andpoor outcomes of cardiovascular disease However there is a poor statistical association between dietary and serum lycopene levelswhich occurs due to limited bioavailability of lycopene from dietary sources Hence it is very unlikely that nutritional interventionalone could be instrumental in the correction of lycopene and carotenoid deficiency Therefore new nutraceutical formulations ofcarotenoids with enhanced bioavailability are urgently needed

1 Introduction

Lycopene is a polyunsaturated hydrocarbon phytochemicalpresent in red fruit and vegetables (papayas tomatoes redpeppers watermelons etc) and belongs to the tetrater-pene carotenoid family [1] Ingestion of products containingcooked tomato accounts for about 80 of daily dietary intakeof lycopene in the developed world [2 3] Despite significantindividual disparities the average consumption of lycopenevaries between 5 and 7mgday in the western world [4] Dueto its distinctive ability to neutralize free radicals lycopeneis believed to confer measurable protection against canceratherosclerosis diabetes and some inflammatory diseases[5 6] Indeed a growing body of epidemiological evi-dence suggests that lycopene consumption is associated withdecreased risk of various chronic diseases while lycopenealso demonstrates significant antioxidant activity in a numberof in vitro and in vivo systems [7] The multiple biologicaleffects of lycopene are predetermined by the unique chemicalstructure of the compound and its particular physicochemi-cal properties

2 Physical and Chemical Properties

Lycopene is a 40-carbon atom acyclic fat-soluble compoundcontaining 13 linearly aligned double bonds 11 of thembeing conjugated It occurs in nature as an all-trans-isoformoften referred to as all-E-lycopene [8] Thermal process-ing as well as intestinal digestion of raw tomato productsfacilitates cis-isomerization of lycopene [9] In the humanbody lycopene is represented predominantly by various cis-isomers (referred to as (Z)-lycopene) suggesting that cis-transformation is essential for efficient intestinal absorption[10] cis-isomerization can also be initiated by exposure oflycopene to heat light and oxygen although this can eventu-ally cause irreversible degradation of the lycopene moleculeto a number of small end products [8] C=O bonds arechromogenic and confer a distinctive red color to lycopenecrystals Double bonds are essential to the antioxidant prop-erties of lycopene which are a major functional feature of thecompound Amongst the different carotenoids lycopene hasthe highest 1O

2quenching ability exceeding the antioxidant

properties of carotene by at least twofold [11] (Z)-isomers

Hindawi Publishing CorporationOxidative Medicine and Cellular LongevityVolume 2016 Article ID 3218605 6 pageshttpdxdoiorg10115520163218605

2 Oxidative Medicine and Cellular Longevity

Lycopene turnover

Lycopene degradation products

Lycopene

SR-B1

Intestinal epithelium

VLDL

LYMPH

Portal blood

VLDL

LDL

LDLLDL

LDL

Nucleus

LDL

Figure 1

have the greatest antioxidant activity in scavenging lipidperoxyl radicals [8 11]

3 Bioavailability and Absorption

Bioavailability of lycopene and other carotenoids is poorlyunderstood and studied It has been shown recently thatstructural localization of lycopene in the chloroplasts of fruitand vegetables is an important factor limiting bioavailabilityof lycopene from dietary sources since chloroplasts have highresistance to gastric and intestinal digestion [10] Thus foodmatrix structure predetermines significantly the bioavailabil-ity of lycopene A significant portion of dietary lycopeneis excreted from the human body in undigested form andthere is no immediate absorption peak in plasma lycopenelevel after a single tomato meal However there is a clearcumulative lycopene absorption spike in the plasma of vol-unteers after a 5-day ingestion period of lycopene-containingproducts [12] As shown in Figure 1 the ingested portion oflycopene released from the food matrix becomes solubilizedand emulsified inside the intestinal lumen and is transportedwith scavenger receptor class B type 1 protein (SR-B1) viathe epithelium of small intestine [13] Lycopene distributionamong tissues is very selectiveThe testes adrenals liver andprostate have the highest lycopene concentration while otherorgans are known to have much lower lycopene content [14]Plasma lipoproteins aremajor delivery vehicles of carotenoidsand lycopene in the human body [15]

Therefore it is very likely that the differences in lycopenetissue levels are related to variation in tissue expression oflipoprotein receptors and cholesterol transporters

4 Daily Requirements

There is no consensus on recommended daily dose oflycopene since carotenoids are considered to be nonessential

micronutrients In the industrialized European countriesdaily intake of lycopene varies from 07mg (Finland) to13mg (Germany) while a much higher range (37ndash161mg)is reported for the United States [16] Higher intake oflycopene at daily dosage up to 100mg has no side effectsin volunteers [17] No evidence of toxicity of lycopene hasbeen obtained from in vivo studies using laboratory animals[18] Clinical studies usemoderate amounts of lycopene rarelyexceeding 10mg per day However in animal experimentsdaily supplementation up to 200mgkg has been reported[19] Therefore low toxicity and high tolerance of lycopeneopen the door to various options in the design of lycopenesupplementation protocols

5 Lycopene in Blood

Factors influencing blood levels of lycopene represented inhumans by cis-isoforms are not well understood as yetAmong these is geographic location of individuals and healthstatus as well as a number of sociodemographic factors It hasbeen reported [20] thatmedian lycopene concentration in theplasma of the general population of the USA is 059 120583molL(range 007ndash179) whereas average lycopene concentrationin the Scandinavian countries in particular Finland seemsto be lower minus016 plusmn 011 120583molL A very recent study [21]defines world regions with low and high levels of lycopeneconsumption Surprisingly Northern and Western Europealong with Central Africa and the Middle East represent thegeographical areas with the lowest lycopene consumption asopposed to the Asian countries which display the highestlevel of lycopene consumption in the world attributed tohigh intake of fruit and vegetables [21] It is also knownthat age and plasma lipid levels (LDL total cholesterol andtriglycerides) are inversely correlated to blood lycopene level[20 22] Lower lycopene values are reportedly associatedwithbeing unmarried of lower income and an older nonwhitemale [20]

Oxidative Medicine and Cellular Longevity 3

6 Lycopene Depletion

Recent developments in molecular medicine reveal that theplasma level of lycopene and other carotenoids is a function ofintestinal absorption rate as well as lycopene utilization in thereactions of biological oxidation in tissues The antioxidantproperties of lycopene and its ability to scavenge lipid peroxylradicals are attributed to the eleven conjugated double bondsbetween its carbon atoms When double bonds are oxidizedand broken by reactive oxygen and reactive oxygen speciesthe lycopene molecule undergoes irreversible nonenzymaticdegradation leading to the formation of various oxida-tive metabolites such as 2-apo-58-lycopenal-furanoxidelycopene-565101584061015840-diepoxide lycopene-58-furanoxide andlycopene-58-epoxide isomers [23 24] On the other handlycopene level in blood and tissues can be significantlyaffected by enzymatic degradation leading to the formationof different end products In particular enzymatic cleavage oflycopene by lipoxygenase is accompanied by accumulation of3-keto-apo-13-lycopenone and 15151015840-apo-lycopenal amongother minor cleavage products [24] Depletion of lycopeneas well as formation of lycopene oxidative metabolites canbe reproduced in cell-free plasma specimens and isolatedlipoproteins by introducing into the medium enzymaticsystems generating reactive nitrogen species [25]

Taken together these results suggest that oxidative stressas well as hyperactivity of the endogenous enzymes responsi-ble for generation of reactive oxygen species and nitric oxidemay deplete lycopene reserves in human cells and tissues

7 Lycopene Deficiency in Ageing

Plasma lycopene level can become significantly reduced dur-ing the process of ageing Older individuals show statisticallylower lycopene concentration values in blood as compared toyoungermatching individuals with similar ethnic and dietarybackground [26] Intestinal absorption of carotenoids is acomplex multistage process which requires a fully intact andfunctioning gastrointestinal epithelium and subset of variousenzymes [27] Acute and chronic gastritis and abnormalgastric acid secretion as well as deviations in intestinalenzyme spectrum during ageing are considered to be majorcauses of reduced intestinal carotenoid absorption in olderindividuals [28] Moreover depleted levels of lycopene andother carotenoids in older individuals are believed to reflectage-related changes in the intestinal microbiota which reg-ulates bioavailability of carotenoids and polyphenols in thelarge intestine [29] Although additional research to explainthe causes and mechanisms of lycopene deficiency in ageingis required it is clear now that correction of carotenoiddeficiency in older individualsmay have an enormous impacton their health status Recent DNA microarray analysisreveals that lycopene supplementation prevents transcrip-tional activation of genes implemented in the process ofageing in multiple strains of mice [30] This antagonizingaction was as effective as the effect of well-known SIRT-1 activators such as starvation and resveratrol Moreoverlycopene has recently been shown to suppress activation ofthemTORAMPKcascade amajormetabolic pathway linked

to ageing [31] These cutting-edge observations help us tounderstand the multiple clinical and experimental reportsrevealing the effects of lycopene on a variety of health con-ditions associated with ageing There are numerous pieces ofclinical evidence suggesting that lycopene supplementationprevents osteoporosis and incidence of bone fractures [3233] improves pulmonary function [34] delays skin ageing[35] and enhances physical performance in elderly patients[36] The set of clinical consequences of lycopene deficiencyis greatly enlightened by the solid body of clinical evidencerevealing the crucial role of lycopene in maintaining prostatehealth and its ability to prevent prostate cancer in elderlymales [37 38]

8 Lycopene and Cardiovascular Disease

Cardiovascular disease (CVD) remains a leading cause ofmortality and disability around the world There is a massivebody of epidemiological results suggesting that Mediter-ranean countries have a lower rate of CVD mortality whencompared to other regions ofWestern Europe and the UnitedStates [39] The reduced rate of CVD mortality can beexplained at least in part by the dietary culture of theMediterranean region which includes consumption of largeamounts of fruit and vegetables Tomato-based products rep-resent an essential element of the Mediterranean diet whichmotivates many researchers to search for the link betweenlycopene consumption and occurrence of CVD Epidemio-logical studies provide indisputable evidence supporting thedirect role of lycopene in prevention of CVD As has beenrecently confirmed in the FraminghamHeartOffspring Study[40] there is a strong inverse association between lycopeneintake and incidence of myocardial infarction angina pec-toris and coronary insufficiency Low plasma lycopene levelswere reported by many researchers in hypertension myocar-dial infarction stroke and atherosclerosis [41 42] Less con-vincing results and a more complex landscape emerge whenthe data from interventional studies on lycopene use in CVDpatients are analyzed There are multiple conflicting reportson how lycopene administration affects the progression ofCVD and its outcomes [43 44] However there is a certaindegree of reproducibility in scientific reports describing thereduction of cholesterol (LDL and total) upregulation ofHDL [45] decrease in carotid artery intima-media thickness[46] and lowering of both plasma markers of oxidativedamage [44] and postprandial oxidative stress [47] in patientstreated with lycopene Nevertheless the effect of lycopeneon progression of CVD remains a controversial topic inmodern medical science and requires further well-designedclinical studies The experimental approach brings muchmore certainty regarding the beneficial role of lycopene inCVDThere are multiple and reproducible reports describingnormalization of endothelial nitric oxide synthase activityand nitric oxide level in coronary arteries [48] inhibitionof the mevalonate pathway of cholesterol biosynthesis [49]improvement of endothelial function and attenuation ofinflammatory damage [50] as well as improvements inlipoprotein profile and their turnover [48] in different animalmodels of CVD These changes may represent a molecular


basis for lycopene action in CVD Significant discrepancies inthe outcomes of clinical and experimental studies verifyingthe effect of lycopene on CVD can be explained in ouropinion by significant fluctuations in preexisting levels oflycopene in the blood of subjects enrolled on clinical trialswhereas lycopene concentration in the blood of experimentalanimals kept on standardized diets tends to stay in a similarrange However individual variations in plasma lycopenelevel in general populations may have a significant impacton public health As recently shown [51] low serum lycopeneand total carotenoid levels predict all-cause mortality as wellas poor outcomes and rapid progression of CVD in the adultpopulation of the USA The majority of individuals even indeveloped countries have astonishingly decreased levels oflycopene and total carotenoids in the blood which translatesinto higher stroke risk [52] Decreased alpha-carotene andlycopene concentrations in the blood have recently beenproposed as possible criteria for prognosis of public healthsince they are inversely associated with CVD mortality ina highly significant manner [53] Although carotenoids areconsidered nonessential micronutrients there have beensome recent attempts to declare desirable plasma concen-tration levels of carotenoids for public health As recentlyproposed there are 5 cut-off levels for plasma carotenoidlevels [54] According to the results ofmeta-analysis a plasmacarotenoid level lt1 120583M translates into a very high risk ofhealth consequences Moderate health risk is proclaimed tobe associated with carotenoid concentration in the range 15ndash25 120583M Values for carotenoid concentration from 25ndash4 120583Msuggest a moderate risk whereas carotenoid concentrationsover 4 120583M are proposed to have the lowest risk of healthconsequences According to the same report over 95 of theUS population falls into themoderate or high risk category ofthe carotenoid health index

9 Conclusion

Recent advances in medical and analytical chemistry haveallowed pinpointing of multiple nonalimentary diseases andpathological conditions associated with micronutrient defi-ciencies It has been increasingly recognized that healthconditions associated with oxidative stress (ageing CVD andtype 2 diabetes mellitus) are accompanied by significant devi-ations in plasma and tissue levels of many important nutri-ents in particular lycopene and other carotenoids [55 56]

Lycopene is the most powerful antioxidant from thetetraterpene carotenoid family its anti-radical propertiesbeing mediated by eleven conjugated double bonds betweencarbon atoms Lycopene is essential in scavenging lipid per-oxyl radicals reactive oxygen species andnitric oxide Recentadvances in molecular science reveal that the interaction oflycopene with reactive oxygen species leads to irreversiblenonenzymatic degradation of lycopene and formation ofvarious oxidative lycopene metabolites There is also a newlyidentified enzymatic pathway of lycopene degradation thatresults in the formation of several end products excretedfrom the human body Thus health conditions accompa-nied by long-lasting oxidative stress may cause lycopenedepletion and require constant and efficient replenishment of

carotenoids in the antioxidant ldquobasketrdquo of human cells and tis-sues However lycopene from dietary sources has extremelylow absorption and bioavailability rate It appears in the bloodcirculation incorporated into chylomicrons and other apo-Bcontaining lipoproteins and requires a sophisticated systemof intestinal absorption and distribution among the tissuesTherefore plasma concentration of lycopene needs to beconsidered as an integral value reflecting both the intestinalabsorption rate of carotenoids and the intensity of lycopenebreakdown via enzymatic and oxidative pathways in bloodand tissues

There is alarming prevalence of lycopene and carotenoiddeficiency in older individuals and CVD patients as well aswidespread carotenoid deficiency in the general populationas revealed by latest research This illustrates the necessityfor a well-designed nutritional strategy and new nutraceu-tical products capable of normalizing plasma lycopene andcarotenoid levels in an efficient manner However it is veryunlikely that nutritional intervention alone will be sufficientin the correction of carotenoid deficiency There is a poorstatistical association between dietary and serum lycopenelevels which can be explained by the limited bioavailabil-ity of lycopene from dietary sources As shown recentlyplasma concentration of lycopene but not dietary intake oflycopene correlates with predisposition to stroke [53] It issuggested that even a high intake of lycopene-containing foodproducts may not affect the health outcomes of lycopeneand carotenoid deficiency in the general population There-fore new nutraceutical formulations of carotenoids andlycopene with enhanced bioavailability are urgently neededIn recent years new formulations of lycopene and othercarotenoids with increased bioavailability have been createdusing microemulsifying protocols andor nanodelivery sys-tems [57 58] Their implementation could be a milestonedevelopment in the prevention and treatment of the healthconsequences of lycopene and carotenoid deficiency in thegeneral population

Conflict of Interests

The author declares that there is no conflict of interestsregarding the publication of this paper

References

[1] R M C Bojorquez J G Gallego and P S Collado ldquoFunctionalproperties and health benefits of Lycopenerdquo Nutricion Hospita-laria vol 28 no 1 pp 6ndash15 2013

[2] N E Moran J W Erdman Jr and S K Clinton ldquoCom-plex interactions between dietary and genetic factors impactlycopenemetabolism anddistributionrdquoArchives of Biochemistryand Biophysics vol 539 no 2 pp 171ndash180 2013

[3] V Bohm ldquoLycopene and heart healthrdquoMolecular Nutrition andFood Research vol 56 no 2 pp 296ndash303 2012

[4] X D Wang ldquoLycopene metabolism and its biological signifi-cancerdquo The American Journal of Clinical Nutrition vol 96 no5 pp 1214Sndash1222S 2012

[5] G Riccioni B Mancini E Di Ilio T Bucciarelli and NDrsquoOrazio ldquoProtective effect of lycopene in cardiovascular


diseaserdquo European Review for Medical and PharmacologicalSciences vol 12 no 3 pp 183ndash190 2008

[6] H-E Khoo K N Prasad K-W Kong Y Jiang and A IsmailldquoCarotenoids and their isomers color pigments in fruits andvegetablesrdquoMolecules vol 16 no 2 pp 1710ndash1738 2011

[7] S Xianquan J Shi Y Kakuda and J Yueming ldquoStabilityof lycopene during food processing and storagerdquo Journal ofMedicinal Food vol 8 no 4 pp 413ndash422 2005

[8] H Jackson C L Braun and H Ernst ldquoThe chemistry of novelxanthophyll carotenoidsrdquo The American Journal of Cardiologyvol 101 no 10 supplement pp S50ndashS57 2008

[9] A R Moise S Al-Babili and E T Wurtzel ldquoMechanisticaspects of carotenoid biosynthesisrdquo Chemical Reviews vol 114no 1 pp 164ndash193 2014

[10] R M Schweiggert R E Kopec M G Villalobos-Gutierrez etal ldquoCarotenoids are more bioavailable from papaya than fromtomato and carrot in humans a randomised cross-over studyrdquoBritish Journal of Nutrition vol 111 no 3 pp 490ndash498 2014

[11] N J Engelmann S K Clinton and J W Erdman ldquoNutritionalaspects of phytoene and phytofluene carotenoid precursors tolycopenerdquo Advances in Nutrition vol 2 no 1 pp 51ndash61 2011

[12] J M Fielding K G Rowley P Cooper and K OrsquoDealdquoIncreases in plasma lycopene concentration after consumptionof tomatoes cookedwith olive oilrdquoAsia Pacific Journal of ClinicalNutrition vol 14 no 2 pp 131ndash136 2005

[13] E Reboul ldquoAbsorption of vitamin A and carotenoids by theenterocyte focus on transport proteinsrdquo Nutrients vol 5 no9 pp 3563ndash3581 2013

[14] N E Moran J W Erdman and S K Clinton ldquoComplex inter-actions between dietary and genetic factors impact lycopenemetabolism and distributionrdquo Archives of Biochemistry andBiophysics vol 539 no 2 pp 171ndash180 2013

[15] I H K Dias M C Polidori L Li et al ldquoPlasma levels of HDLand carotenoids are lower in dementia patients with vascularcomorbiditiesrdquo Journal of Alzheimerrsquos Disease vol 40 no 2 pp399ndash408 2014

[16] M Porrini and P Riso ldquoWhat are typical lycopene intakesrdquoJournal of Nutrition vol 135 no 8 pp 2042Sndash2045S 2005

[17] A Shao and J N Hathcock ldquoRisk assessment for thecarotenoids lutein and lycopenerdquo Regulatory Toxicology andPharmacology vol 45 no 3 pp 289ndash298 2006

[18] D Jonker C F Kuper N Fraile A Estrella and C RodrıguezOtero ldquoNinety-day oral toxicity study of lycopene fromBlakeslea trispora in ratsrdquo Regulatory Toxicology and Pharma-cology vol 37 no 3 pp 396ndash406 2003

[19] S K Gupta D Trivedi S Srivastava S Joshi N Halder andS D Verma ldquoLycopene attenuates oxidative stress inducedexperimental cataract development an in vitro and in vivostudyrdquo Nutrition vol 19 no 9 pp 794ndash799 2003

[20] S T Mayne B Cartmel F Silva et al ldquoPlasma lycopeneconcentrations in humans are determined by lycopene intakeplasma cholesterol concentrations and selected demographicfactorsrdquo Journal of Nutrition vol 129 no 4 pp 849ndash854 1999

[21] M M Murphy L M Barraj J H Spungen D R Hermanand R K Randolph ldquoGlobal assessment of select phytonutrientintakes by level of fruit and vegetable consumptionrdquo BritishJournal of Nutrition vol 112 no 6 pp 1004ndash1018 2014

[22] R Re G D Mishra C W Thane and C J Bates ldquoTomatoconsumption and plasma lycopene concentration in peopleaged 65 y and over in a British national surveyrdquo EuropeanJournal of Clinical Nutrition vol 57 no 12 pp 1545ndash1554 2003

[23] L Muller P Goupy K Frohlich O Dangles C Caris-Veyratand V Bohm ldquoComparative study on antioxidant activity oflycopene (Z)-isomers in different assaysrdquo Journal of Agriculturaland Food Chemistry vol 59 no 9 pp 4504ndash4511 2011

[24] A L D A Ferreira K-J Yeum RM Russell N I Krinsky andG Tang ldquoEnzymatic and oxidative metabolites of lycopenerdquoJournal of Nutritional Biochemistry vol 14 no 9 pp 531ndash5402003

[25] D L Graham M Carail C Caris-Veyrat and G M Loweldquo(13Z)- and (9Z)-lycopene isomers are major intermediates inthe oxidative degradation of lycopene by cigarette smoke andSin-1rdquo Free Radical Research vol 46 no 7 pp 891ndash902 2012

[26] R D Semba K V Patel L Ferrucci et al ldquoSerum antioxidantsand inflammation predict red cell distribution width in olderwomen the Womenrsquos Health and Aging Studyrdquo Clinical Nutri-tion vol 29 no 5 pp 600ndash604 2010

[27] L Davidsson andMHaskell ldquoBioavailability ofmicronutrientsstable isotope techniques to develop effective food-based strate-gies to combat micronutrient deficienciesrdquo Food and NutritionBulletin vol 32 supplement 1 pp S24ndashS30 2011

[28] S Akhtar A Ahmed M A Randhawa et al ldquoPrevalence ofvitamin A deficiency in South Asia causes outcomes andpossible remediesrdquo Journal of Health Population and Nutritionvol 31 no 4 pp 413ndash423 2013

[29] T Bohn ldquoDietary factors affecting polyphenol bioavailabilityrdquoNutrition Reviews vol 72 no 7 pp 429ndash452 2014

[30] S-K Park K Kim G P Page D B Allison R Weindruchand T A Prolla ldquoGene expression profiling of aging in multiplemouse strains identification of aging biomarkers and impact ofdietary antioxidantsrdquoAgingCell vol 8 no 4 pp 484ndash495 2009

[31] J A Menendez J Joven G A Aragones et al ldquoXenohormeticand anti-aging activity of secoiridoid polyphenols present inextra virgin olive oil a new family of gerosuppressant agentsrdquoCell Cycle vol 12 no 4 pp 555ndash578 2013

[32] S M Sacco M-N Horcajada and E Offord ldquoPhytonutrientsfor bone health during ageingrdquo British Journal of ClinicalPharmacology vol 75 no 3 pp 697ndash707 2013

[33] S Sahni M T Hannan J Blumberg L A Cupples D P KielandK L Tucker ldquoInverse association of carotenoid intakes with4-y change in bone mineral density in elderly men and womenthe Framingham Osteoporosis studyrdquo The American Journal ofClinical Nutrition vol 89 no 1 pp 416ndash424 2009

[34] R D Semba S S Chang K Sun S Talegawkar L Ferrucciand L P Fried ldquoSerum carotenoids and pulmonary functionin older community-dwelling womenrdquo Journal of NutritionHealth and Aging vol 16 no 4 pp 291ndash296 2012

[35] S K Schagen V A Zampeli E Makrantonaki and C CZouboulis ldquoDiscovering the link between nutrition and skinagingrdquo Dermato-Endocrinology vol 4 no 3 pp 298ndash307 2012

[36] N Alipanah R Varadhan K Sun L Ferrucci L P Fried and RD Semba ldquoLow serum carotenoids are associatedwith a declinein walking speed in older womenrdquo Journal of Nutrition Healthand Aging vol 13 no 3 pp 170ndash176 2009

[37] S Mariani L Lionetto M Cavallari et al ldquoLow prostateconcentration of lycopene is associated with development ofprostate cancer in patients with high-grade prostatic intraep-ithelial neoplasiardquo International Journal of Molecular Sciencesvol 15 no 1 pp 1433ndash1440 2014

[38] M M Shen and C Abate-Shen ldquoMolecular genetics of prostatecancer new prospects for old challengesrdquo Genes and Develop-ment vol 24 no 18 pp 1967ndash2000 2010


[39] E Garcıa-Fernandez L Rico-Cabanas R Estruch R EstruchA Bach-Faig and A Bach-Faig ldquoMediterranean diet andcardiodiabesity a reviewrdquoNutrients vol 6 no 9 pp 3474ndash35002014

[40] P A Jacques A Lyass J M Massaro R S Vasan and R BDrsquoAgostino Sr ldquoRelation of lycopene intake and consumptionof tomato products to incident cardiovascular diseaserdquo BritishJournal of Nutrition vol 110 no 3 pp 545ndash551 2013

[41] T Wolak and E Paran ldquoCan carotenoids attenuate vascularagingrdquoVascular Pharmacology vol 59 no 3-4 pp 63ndash66 2013

[42] G Riccioni N DrsquoOrazio N Palumbo et al ldquoRelationshipbetween plasma antioxidant concentrations and carotid intima-media thickness the asymptomatic carotid atherosclerotic dis-ease in manfredonia studyrdquo European Journal of CardiovascularPrevention and Rehabilitation vol 16 no 3 pp 351ndash357 2009

[43] MM Ciccone F CorteseM Gesualdo et al ldquoDietary intake ofcarotenoids and their antioxidant and anti-inflammatory effectsin cardiovascular carerdquo Mediators of Inflammation vol 2013Article ID 782137 11 pages 2013

[44] J Chen Y Song and L Zhang ldquoEffect of lycopene supple-mentation on oxidative stress an exploratory systematic reviewand meta-analysis of randomized controlled trialsrdquo Journal ofMedicinal Food vol 16 no 5 pp 361ndash374 2013

[45] P Palozza A Catalano R E Simone M C Mele and A Cit-tadini ldquoEffect of lycopene and tomato products on cholesterolmetabolismrdquo Annals of Nutrition and Metabolism vol 61 no 2pp 126ndash134 2012

[46] Z-Y Zou X-R Xu X-M Lin et al ldquoEffects of lutein andlycopene on carotid intimandashmedia thickness in Chinese sub-jects with subclinical atherosclerosis a randomised double-blind placebo-controlled trialrdquo British Journal of Nutrition vol111 no 3 pp 474ndash480 2014

[47] B Burton-Freeman J Talbot E Park S Krishnankutty and IEdirisinghe ldquoProtective activity of processed tomato productson postprandial oxidation and inflammation a clinical trial inhealthy weight men and womenrdquoMolecular Nutrition and FoodResearch vol 56 no 4 pp 622ndash631 2012

[48] G Vilahur J Cubedo T Padro et al ldquoIntake of cooked tomatosauce preserves coronary endothelial function and improvesapolipoprotein A-I and apolipoprotein J protein profile in high-density lipoproteinsrdquo Translational Research vol 166 no 1 pp44ndash56 2015

[49] P M Tricarico G Kleiner E Valencic et al ldquoBlock ofthe mevalonate pathway triggers oxidative and inflammatorymolecular mechanisms modulated by exogenous isoprenoidcompoundsrdquo International Journal ofMolecular Sciences vol 15no 4 pp 6843ndash6856 2014

[50] J Zou D Feng W-H Ling and R-D Duan ldquoLycopenesuppresses proinflammatory response in lipopolysaccharide-stimulated macrophages by inhibiting ROS-induced traffickingof TLR4 to lipid raft-like domainsrdquo Journal of NutritionalBiochemistry vol 24 no 6 pp 1117ndash1122 2013

[51] M D Shardell D E Alley G E Hicks et al ldquoLow-serumcarotenoid concentrations and carotenoid interactions predictmortality in US adults theThird National Health andNutritionExamination Surveyrdquo Nutrition Research vol 31 no 3 pp 178ndash189 2011

[52] Y Ito M Kurata K Suzuki N Hamajima H Hishida and KAoki ldquoCardiovascular disease mortality and serum carotenoidlevels a Japanese population-based follow-up studyrdquo Journal ofEpidemiology vol 16 no 4 pp 154ndash160 2006

[53] X Li and J Xu ldquoDietary and circulating lycopene and strokerisk a metaanalysis of prospective studiesrdquo Scientific Reportsvol 4 p 5031 2014

[54] M S Donaldson ldquoA carotenoid health index based on plasmacarotenoids and health outcomesrdquo Nutrients vol 3 no 12 pp1003ndash1022 2011

[55] B Kaur and J Henry ldquoMicronutrient status in type 2 diabetesa reviewrdquo Advances in Food and Nutrition Research vol 71 pp55ndash100 2014

[56] S C Montgomery S M Streit M L Beebe and P J MaxwellldquoMicronutrient needs of the elderlyrdquo Nutrition in ClinicalPractice vol 29 no 4 pp 435ndash444 2014

[57] A Ascenso S Pinho C Eleuterio et al ldquoLycopene from toma-toes vesicular nanocarrier formulations for dermal deliveryrdquoJournal of Agricultural and Food Chemistry vol 61 no 30 pp7284ndash7293 2013

[58] W Faisal T Ruane-OrsquoHora C M OrsquoDriscoll and B TGriffin ldquoA novel lipid-based solid dispersion for enhancingoral bioavailability of Lycopenemdashin vivo evaluation using a pigmodelrdquo International Journal of Pharmaceutics vol 453 no 2pp 307ndash314 2013

Submit your manuscripts athttpwwwhindawicom

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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014


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OncologyJournal of



Oxidative Medicine and Cellular Longevity


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The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

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Journal of

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Gastroenterology Research and Practice


Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom


Lycopene turnover

Lycopene degradation products

Lycopene

SR-B1

Intestinal epithelium

VLDL

LYMPH

Portal blood

VLDL

LDL

LDLLDL

LDL

Nucleus

LDL

Figure 1

have the greatest antioxidant activity in scavenging lipidperoxyl radicals [8 11]

3 Bioavailability and Absorption

Bioavailability of lycopene and other carotenoids is poorlyunderstood and studied It has been shown recently thatstructural localization of lycopene in the chloroplasts of fruitand vegetables is an important factor limiting bioavailabilityof lycopene from dietary sources since chloroplasts have highresistance to gastric and intestinal digestion [10] Thus foodmatrix structure predetermines significantly the bioavailabil-ity of lycopene A significant portion of dietary lycopeneis excreted from the human body in undigested form andthere is no immediate absorption peak in plasma lycopenelevel after a single tomato meal However there is a clearcumulative lycopene absorption spike in the plasma of vol-unteers after a 5-day ingestion period of lycopene-containingproducts [12] As shown in Figure 1 the ingested portion oflycopene released from the food matrix becomes solubilizedand emulsified inside the intestinal lumen and is transportedwith scavenger receptor class B type 1 protein (SR-B1) viathe epithelium of small intestine [13] Lycopene distributionamong tissues is very selectiveThe testes adrenals liver andprostate have the highest lycopene concentration while otherorgans are known to have much lower lycopene content [14]Plasma lipoproteins aremajor delivery vehicles of carotenoidsand lycopene in the human body [15]

Therefore it is very likely that the differences in lycopenetissue levels are related to variation in tissue expression oflipoprotein receptors and cholesterol transporters

4 Daily Requirements

There is no consensus on recommended daily dose oflycopene since carotenoids are considered to be nonessential

micronutrients In the industrialized European countriesdaily intake of lycopene varies from 07mg (Finland) to13mg (Germany) while a much higher range (37ndash161mg)is reported for the United States [16] Higher intake oflycopene at daily dosage up to 100mg has no side effectsin volunteers [17] No evidence of toxicity of lycopene hasbeen obtained from in vivo studies using laboratory animals[18] Clinical studies usemoderate amounts of lycopene rarelyexceeding 10mg per day However in animal experimentsdaily supplementation up to 200mgkg has been reported[19] Therefore low toxicity and high tolerance of lycopeneopen the door to various options in the design of lycopenesupplementation protocols

5 Lycopene in Blood

Factors influencing blood levels of lycopene represented inhumans by cis-isoforms are not well understood as yetAmong these is geographic location of individuals and healthstatus as well as a number of sociodemographic factors It hasbeen reported [20] thatmedian lycopene concentration in theplasma of the general population of the USA is 059 120583molL(range 007ndash179) whereas average lycopene concentrationin the Scandinavian countries in particular Finland seemsto be lower minus016 plusmn 011 120583molL A very recent study [21]defines world regions with low and high levels of lycopeneconsumption Surprisingly Northern and Western Europealong with Central Africa and the Middle East represent thegeographical areas with the lowest lycopene consumption asopposed to the Asian countries which display the highestlevel of lycopene consumption in the world attributed tohigh intake of fruit and vegetables [21] It is also knownthat age and plasma lipid levels (LDL total cholesterol andtriglycerides) are inversely correlated to blood lycopene level[20 22] Lower lycopene values are reportedly associatedwithbeing unmarried of lower income and an older nonwhitemale [20]












9 Conclusion







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Review Article Lycopene Deficiency in Ageing and Cardiovascular...

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