inclusilver european personalised nutrition strategy · the sacn concluded that the dietary...

This project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 731349

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–EuropeanPersonalisedNutritionStrategy–HelenGriffiths,MoniqueRaats,DominickBurton,ChloeWilmot

UniversityofSurrey


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1. Introduction

Foodchoiceschangewithageandareinfluencedbymanyfactorsincludingchangingtaste,budgetaswellaslifestyle.Superimposedonfoodchoicefactors,arenutritionalrequirements;thesealsochangewithage.

Thisreviewgatherstogetherevidencethatmayinformdecision-makingtosupportnutritionforolderadults.Itincludesevidenceonnutritionalrequirementsforpeopleovertheageof65yearsweretheyaredifferentfromadultsingeneralandconsiderswhetherornottheserequirementsarebeingmet;theassociationbetweenlowernutrientlevelsandhealthoutcomesisconsideredforolderadults,althoughbecauseofthedesignofthesestudies,theevidencecannotimplythatrestoringanutrientlevelthatisdeficientinolderadultswillimprovehealthoutcomes;andfinallyweconsidertheeffectsofdietsthataresupplementedwithparticularnutrientswithininterventiontrialsonage-associatedhealthoutcomes.

Inundertakingthereview,weconsiderednutritionalevidenceaboutpeopleovertheageof65years.Historically,themajorityofstudieshaveincludedpeopleuptotheageof79years.In19601.4%ofEuropeanswereover80andreached4.1%in2010.By2060,11.5%ofEuropeansarepredictedtobeabove80yearsofage1.In2012,healthylife-expectancyforEuropeanmenwasfor61.2healthyyearsandforEuropeanwomenwas61.9healthyyears.Thereisa10yearvarianceacrossEuropeinhealthylifeyearsformencomparingWesternEurope(64years)withEasternEurope(54years).Thenumbersofandageswhenolderpeoplerequireandreceivecarevariesaccordingly.Veryfewnutritionalstudiesfocusonthepopulationover80yearsofageandonthoselivingincarehomes;wehaveidentifiedtheage-groupsandwhethertheyareindependentlylivinginthesectionsbelow.

2. Nutritionalrequirementschangewithage

Itisdifficulttogeneraliseabouttheenergyrequirementsofolderadultsbecauseofthevariationinhealthandmobility.Nevertheless,ittherequirementsarelikelytobethesameasyoungeradultsduringgoodgeneralhealthandwhenmobilityismaintained.However,intheoldestadultsandforthosewhohavemuchlessmobility,itishighlylikelythattheirphysicalactivitylevelswillbelower;consequentlytheirenergyrequirementwillbelower.TheScientificAdvisoryCommitteeonnutritionintheUKhasestimatedenergyrequirementsbasedonaverageage,sizeandmobility(Figure1)2.Thechangeinrequirementismoststrikingovertheageof65yearsandmostlikelyrelatestoslowermetabolismandlossofmuscle.

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Figure1.GenderandageeffectsonEstimatedAverageenergyrequirementsatcurrentmeanheightandBMI(22.5Kg/m2;2)

1Eurostat.ExtractedJune2017.Population structure and ageing 2ScientificAdvisoryCommitteeonNutritionDietaryReferenceValuesforEnergy2011


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AsimilarpictureisdescribedbyEFSAfortheEuropeanpopulationandseptuagenarianmenwithaveryphysicallyactivelifestylecouldhaveanenergyrequirementupto11.9MJ/d3.

IntheUK,totaldailyenergyintakeisestimatedas9.8MJ/dfortheaveragemanaged65-74ordroppingto9.6MJ/dforamanmorethan75years.Forwomen,totaldailyenergyintakeisestimatedas9.86MJ/ddroppingto9.6MJ/drespectively.

Ifenergyintakeismaintainedwithreducingenergyexpenditure,bodyfataccumulatesaroundtheorgansofthebody,withmuchlessinthesubcutaneousfatdeposits.Visceralbodyfatincreasestheriskfordiseasesliketype2diabeteswhichincreasesinprevalencewitholderadults.

Macronutrientrequirementsinpeopleover65years

Thedietaryproteinintakethatisneededbypeopleofdifferentagestomeettheirnitrogenbalancehasbeendiscussedextensivelyinthepublishedliterature.Thesafelimitforproteinintaketakesintoaccountthestudiesthathavelookedatwhetherrenalfunctioniscompromisedbyhighproteinintakeinolderadultsandthosethatareconcernedwithdelayingage-associatedmuscle-loss,sarcopenia,byincreasingdietaryproteintopromotemusclesynthesis.

TheWorldHealthOrganisationrecommends0.75gproteinperKgbodyweightperdayforolderadultsandisnothigherthanforadultsunder65yearsofage4.ThepopulationReferenceIntakesforproteinreportedbyEFSAare0.83g/dforadultsovertheageof60years3.

Somerecentstudiesthatuseadifferentmethodtostudyproteinrequirement,havesuggestedthattherecommendationcouldbeincreasedbyafurther25%inolderadultsandthereareanumberofstudiesthatareinvestigatingwhetherparticulartypesofdietaryproteinarebettertoincreasetherateofaminoacidaccretionintomuscle.

Carbohydratesareamajorenergysourceinthedietthataremadeupofthesameconstituents,carbon,hydrogenandoxygen,butcanbehaveinverydifferentwaysinthebody.The“free”sugars,mono-anddi-saccharides,provideareadyburstofenergy.Highintakeoffreesugarshasbeenassociatedwithincreasedriskforobesityandtype2diabetes.TheWHOextendedthedefinitionoffreesugarstoincludemonosaccharidesanddisaccharidesthatareaddedtofoodsandbeveragesbythemanufacturer,cookorconsumerandincludesugarsthatarenaturallypresentinhoney,syrupandfruitjuices(WHO,2015).TheUKgovernmentcommissionedaSACNreportofcarbohydratesandhealththatalsoreportedin20155.

TheSACNconcludedthatthedietaryreferencevaluefortotalcarbohydrateintakeofanaverageadultshouldbe50%oftotaldietaryenergyanddietaryintakeoffreesugarsshouldnotexceed5%oftotalenergy.Theaveragepopulationintakeofdietaryfibre6foradultsshouldbe30g/day.

FatsareamajorsourceofenergyforthebodyandalsoareimportanttocarrycertainvitaminsinthebloodsuchasvitaminA,D,EandK,andsomeothernutrientssuchascarotenoidswhichareonlysolubleinfat.Dietaryfatsarefoundinthreemajortypes;triglycerides,sterolssuchascholesterolandsmalleramountsofphospholipid.

Foradults,overallintakefordietaryfatinallitsformsshouldnotexceed35%oftotalenergyintake.

3https://www.efsa.europa.eu/sites/default/files/assets/DRV_Summary_tables_jan_17.pdf4WHO/FAO.ReportofaJointExpertConsultation.Proteinrequirementsofadults,includingolderpeople,andwomenduringpregnancyandlactation.Geneva(Switzerland):WHOPress;2007(UNUreport05123054).5https://www.gov.uk/government/uploads/system/uploads/attachment_data/file/445503/SACN_Carbohydrates_and_Health.pdf6Fibre=carbohydratesthatarenotdigestedandnotabsorbedinthesmallintestineandarepolymersofthreeormoresubunits;andlignin


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Fattyacidsaretheconstituentoftriglyceridesandcanbegroupedintosaturated,monounsaturatedandpolyunsaturatedfattyacids.Manyofthesefattyacidscanbesynthesisedbythebodybuttwopoly-unsaturatedfattyacids(n-3andn-6)cannotbemadeefficientlyandareconsideredtobeessential.Theessentialn-3fattyacidisα-linolenicacidandtheessentialn-6fattyacidislinoleicacid.Then-3fattyacidsareconsideredtobeanti-inflammatoryandhavebeenthefocusofmanystudiesthathavesupplementedwithothern-3fattyacidssuchaseicosapentaenoicacid(EPA)anddocosohexaenoicacid(DHA).InstituteofMedicineGuidelineshavedefinedadequateintakesofn-3essentialfattyacidsandtheydonotdifferforadultsbetweenagegroups7.

TheInstituteofMedicinestatethatinsufficientinformationisavailabletoestablisharecommendeddailyintakeforn-3fattyacidsbutadequateIntake(AI)levelsareconsideredtobe1.6g/dformenand1.1gperdayforwomen.EFSAreportAIsof4%and0.5%oftotalenergyforLAandALArespectively3.

Trans-fattyacidsareproducedduringfoodprocessingandhavebeenassociatedwithnegativehealthoutcomes8.TheUKScientificAdvisoryCommitteeonNutritionrecommendsthataverageintakesoftransfattyacidsshouldnotexceed2%offoodenergy.

Micronutrientrequirementsinpeopleover65years

Thereferenceintakesforvitaminsdonotincreasewithagealthoughforsomee.g.forniacin,thereisaminorreductioninrequirementsbetweenyoungandolderadultsovertheageof50.Table1describesvitaminrequirementsforUKolderadultpopulations.ThedataiswascollatedbytheBritishNutritionFoundation9in2016.AttheEuropeanlevel,informationisavailableforadultsingeneralovertheageof18yearsbutnotforolderadults.

Gender Thiaminmg/d

Riboflavinmg/d

Niacinmg/d

VitB6mg/d

VitB12μg/d

Folateμg/d

VitCmg/d

VitAμg/d

Male 0.9 1.3 16 1.4 1.5 200 40 700Female 0.8 1.1 12 1.3 1.5 200 40 600

Table2–EuropeanFoodSafetyAgencyPopulationReferenceIntakes(PRIs)andAdequateIntakes(AIs)forvitaminsinadults

Gender Thiaminmg/d

Biotinmg/d

Niacinmg/d

VitB6mg/d

VitB12μg/d

Folateμg/d

VitCmg/d

VitAμg/d

Male 0.1 40 1.7 1.7 4 330 110 750Female 0.1 40 1.7 1.6 4 330 95 650AcomprehensivereviewofvitaminDintakeinolderadultswasincludedintheUKSACNreportonvitaminDandhealth10andconcludeswitharecommendedintakeof10μgdailyintakeformenandwomenintheUKover50yearsofage.Currently,intheUKtheaverageintakefromthedietaloneis3.3µgi.e.1/3oftherequirement.Forthosetakingsupplements,themeandailyintakeswere5.1µgvitaminDformenand5.2µgforwomen.Thisisapproximately50%oftherecommendedintakeforvitaminD.Itisclearthatthoseonlowerincomesandpeoplewhoarelivingincarehomesalsohavelowerintakes;incarehomes,meandailyvitaminDintakeformenwas3.9µgandwas3.4µgforwomenfromallsources.Similarrequirementsare7https://ods.od.nih.gov/factsheets/Omega3FattyAcids-HealthProfessional/#h2InstituteofMedicine,FoodandNutritionBoard.Dietaryreferenceintakesforenergy,carbohydrate,fiber,fat,fattyacids,cholesterol,protein,andaminoacids(macronutrients).Washington,DC:NationalAcademyPress;2005.8https://www.bda.uk.com/foodfacts/TransFats.pdf9https://www.nutrition.org.uk/attachments/article/234/Nutrition%20Requirements_Revised%20Oct%202016.pdf10https://www.gov.uk/government/uploads/system/uploads/attachment_data/file/537616/SACN_Vitamin_D_and_Health_report.pdf


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alsoanticipatesforotherNorthernEuropeancountries,however,inFrance,vitaminDrequirementsarelowerinanticipationofefficientproductionintheskinthroughUVexposure.

PopulationReferenceIntakes(PRIs)andAdequateIntakes(AIs)forvitaminshavebeenreportedbytheEuropeanFoodSafetyAgencyforadultsingeneralratherthanforolderadultsspecifically.

Table3.DietaryreferencevaluesforvitaminD(μg/day)inEuropeancountriesforolderadults(adaptedfromSpiroandButtriss11)

Country AU BE FR IE ES CH TU NL UK EC IOM WHOVitaminDrequirement

20 15 5 20 10 20 10 20 10 10 10-15

10-15

TheNIHrecommendsanintakeof15mg(22.4IU)vitaminEperdayforadultsbutdoesnotspecifyanyage-dependencyinrequirements12.

ApartfromthemanystudiesthathaveconsistentlyshownthatvitaminDintaketendstobelowinolderadults,othervitaminintakerequirementsappeartobeadequatelymetthroughahealthybalanceddiet.

NutritionalintakemineralrequirementsforolderadultsintheUKhasbeenreportedbytheBritishNutritionFoundationandaresummarisedinTable3.

Table4.UKReferenceNutrientIntakesforMineralsforolderadults

gender calcium phosphorous magnesium sodium potassium iron zinc copper selenium iodineMen50+years

700mg/d

550mg/d 300mg/d 1600mg/d

3500mg/d

8.7mg/d

9.5mg/d

1.2mg/d

75μg/d 140μg/d

Women50+years

700mg/d

550mg/d 270mg/d 1600mg/d

3500mg/d

8.7mg/d

7.0mg/d

1.2mg/d

60μg/d 140μg/d

IntakesforpotassiumandmagnesiumaresignificantlyreducedinUKolderadultpopulationswhoarelivingindependently.Intakesofthesetwomineralsarealsolowerinolderadultswhoarelivingincare.TheUKreferencenutrientintakeforironisthesameinoldermenandwomen,andthisrepresentsareductionintherequirementforwomenwhoarepost-menopausal.

Table5.EFSAPopulationReferenceIntakes(PRIs)andAdequateIntakes(AIs)forminerals

gender calcium phosphorous magnesium manganese potassium iron Zinc* copper selenium iodineMen 950

mg/d550mg/d 350mg/d 3mg/d 3500

mg/d11mg/d

9.4-16.3mg/d

1.6mg/d

70μg/d 150μg/d

Women 950mg/d

550mg/d 300mg/d 3mg/d 3500mg/d

11mg/d

7.5-12.7mg/d

1.3mg/d

70μg/d 150μg/d

*Variesaccordingtophytate

11https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4288313/12https://ods.od.nih.gov/factsheets/VitaminE-Consumer/


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Ingeneral,EFSAreferenceintakesformineralsaremarginallyhigherthanthespecificUKdatabutthesedatarepresentadultpopulationsasawholeandarenotreferencesforolderadults.

Phytochemicals

Thepreviousreviewshavefocussedonessentialnutrientsthatarefoundwithinfoodandforwhichknownfunctionshavebeenascribed.Foodoffersabenefitthatgoesbeyondtheindividualnutrientsbecauseofinteractionsbetweendifferentcomponentsandbecausetheratesofnutrientreleasefromdifferentfoodswillvary.Theconsumptionofphytochemicalssuchascarotenoidsandpolyphenolsthatarefoundwithinwholefruitsandvegetablesmayalsohavebeneficialeffectsonhealth.Asthesearenotconsideredessential,referenceintakelevelsarenotrequired.Anumbersofstudieshaveconsideredtheassociationbetweenphytochemicalintakeandhealthoutcomes,andthereareanumberofexamplesofdietaryinterventionstudiesthathaveincludedphytochemicals.PhytochemicalsareimportantcomponentsintheMediterraneandietandtheircontributiontooverallnutritionalqualityofnutsisreviewed13.

Foodversusnutrientenrichment

Nutrientsinthedietinteractinthewaythattheyareabsorbed.Forexamples,foodsthatarerichinphytateswillimpedezincabsorptionandforiron,absorptionisalsoinhibitedbyvitaminCandcalcium.Ironbioavailabilityforvegetariansisestimatedatbetween33-66%ofthatfornon-vegetarians.Othernutrientsactpositivelytogetherfortheirphysiologicalactivity;forexampleBvitaminswithfolateforDNAsynthesis;vitaminCandEforantioxidantfunction;andvitaminDandcalciumforbonehealth.Indeed,oneofthelimitstotheepidemiologicalassociationstudiesthatwehavereviewedinsection2isthattheytendtoreporttheassociationbetweenonenutrientandhealthoutcomesbutofcourse,thissinglenutrientismostlikelytohavebeenconsumedaspartofamixeddiet;othercomponentsinthedietactingeitheraloneorincombination,maycontributetoanoverallimprovementinhealth.Associationstudiesareretrospective,thereforeonlyindicativeandcanbehighlyvariable.Thestrongestevidenceforthevalueofanutrientordietforhealthoutcomesisachievedbyinterventionstudiesthataredesignedtotesttheeffectofnutrientordietonaspecificallydefinedhealthoutcomeinaprospectiveway.

Personalisednutritionforolderadults

Movingforwardfromgeneralisednutrientrequirementstopersonalisednutritioncaninvolvemanydifferentvariables.Theolderadultpopulationisveryheterogeneousandwillbeinfluencedintheirpersonalchoicesbymanydifferentfactors.Theconceptofconveniencemayoutweighnutritionalvalueforexampleinonepopulationwhereasanothermaybemotivatedtotryprotein-enriched,functionalfoodproducts.Understandingconsumerbehaviourwillbeanimportantfactorforthesuccessofpersonalisednutrition.

Arecentstudyhashighlightedhowpersonalisingnutritionatanindividuallevel,usingfoodsthatarereadilyavailable,canresultineffectivelifestylechangesthatincreasetheintakeofessentialnutrientssuchasfolate14.

Foractiveandhealthyolderadults,adequateenergyintakeandabalanceddietprovidingmacronutrientswithintherecommendedrangeswillmostlikelymeetthemajorityoftheirnutritionalneeds.Therewillbeseasonalityinrequirements,forexamplevitaminCintakebydietistypicallyhigherduringthesummermonthswhenmorefreshfruitandvegetablesareavailablebutcorrespondinglylowinthewinter.

13BrJNutr.2015Apr;113Suppl2:S79-93.doi:10.1017/S000711451400325014https://academic.oup.com/ije/article-abstract/46/2/578/2622850/Effect-of-personalized-nutrition-on-health-related


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Conversely,ironintakeandproteinistypicallyistypicallylowerduringthesummeraslessredmeatisconsumed.

Geographyandethnicityalsoplayanimportantpartinthenutritionalintakepatternsofotherwisehealthyolderadults,withPakistanimenandwomenlivingintheUKtypicallyconsuminglesscalcium15andhighlightaspecificcalciumrequirementforhealth.ThecapacitytomakevitaminDfromsunlightisalsoaffectedbyskinpigmentation.However,theprevalenceofvitaminDdeficiencyinolderadultslivinginEuropeaccordingtoethnicityisunclear,casesofricketswererecordedinmuchgreaterfrequencyinchildrenofSouthAsian,MiddleEasternorsub-SaharanAfricanbackground.IncreasingvitaminDintakeisbeingincreasinglyrecognisedasanimportantpublichealthgoal.Theaforementionedevidencepointstoethnicityasafactorinpersonalisednutrition.

Peoplewithlongtermconditionssuchashighbloodpressure,highcholesterolandtype2diabeteswhichincreaseinprevalenceinolderadults,havedietaryrequirementsforfoodsthatarelowerinfat,saltandrefinedsugars.Therearecertaingenotypesthatincreaseriskforthesemetabolicdiseases.Inthenearfuture,ariskcalculationbasedongenotypeforsuchlong-termconditionsislikelytoemergethatwouldencourageapersonalisednutritionapproachtoreducediseaserisk.OneofthefirstEuropeanstudiesthatusedgenomicinformationtoadviseindividualsontheirpersonalriskprofileandtodevelopanappropriateonnutritionalprogrammehasnowconcluded.Thestudyidentifiedthatpersonalisednutritionadviceresultedinparticipantsselectingamuchhealthierdiet,irrespectiveofwhetherthegenomicinformationwasused.Thissuggeststhatpersonalisednutritioncouldbeasustainablewaytoimprovehealth16.

Animportantconsiderationinfoodsforadultswithpoororalhealthanddentalproblemsistominimisemealsthatrequirechewingwhilemaintainingfibrousandproteincontent.Proteinenrichedfoodshavebeensuccessfullyusedinthehospitalsettingbutcost,tasteandscepticismfromconsumershasnothelpedwithwideruptake.

Nutritionalhealthmaybeaffectedbydrugtreatmentsthataffectappetite,absorptionandmetabolism.Conversely,somefoodsalsoaffectdrugmetabolism,mostnotablygrapefruitthatimpairstheactivityofacytochromep450metabolisingenzymesandsoincreasesbloodconcentrationsofdrugs.Thesefactorsareaddressedindrugsafetynotesthataccompanymedicines.

Theaforementioneddataassumesthatabsorptionofnutrientsisalsounaffectedalthoughifanindividualhasphysiologicalchangeswithageinge.g.ingastricacidsecretion,theabsorptionofBvitaminsmaybeimpairedhenceintakerequirementsmaybehigher.Inthiscase,thestateofanindividual’shealthwillimpactontheirpersonaldietaryrequirements.TheclinicalpractitionerwillassesswhetherthisisthecaseonapersonalisedbasisifanindividualpresentswithsymptomsofBvitamindeficiency.Inthiscase,themotivationtoincreaseaspecificnutrientwouldbehealth-relatedviaapharmacistratherthanlifestylechoicedependent.

Nevertheless,healthyolderadultsdoexperienceanage-relateddeclineinmanyphysiologicalsystemswithoutthedevelopmentofovertdisease.Thesystemsaffectedbyageincludetheimmunesystem,musculo-skeletalsystem,brainandmetabolicsystem.Theoutcomesofdecliningfunctionatthesystemslevelincludeincreasedsusceptibilitytoinfectionandtodevelopstrongvaccinationresponses,increasedriskoffallsandfractures,decliningcognitionandweightgain.Wehavereviewedtheevidenceforwhetheradequateorenrichednutritionassociateswithbetterphysiologicalsystemsfunctionsinpopulationsof

15http://onlinelibrary.wiley.com/doi/10.1046/j.1365-277X.2003.00461.x/epdf16https://clinicaltrials.gov/show/NCT01530139


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healthyolderadults(Section3)andprovideastateoftheartreviewofevidencesupportingdietaryenrichmentorsupplementationonhealthyolderadults(section2).

Overall,successinadoptingpersonalisednutritioninanolderadultpopulationwillbetheresultofintegratingdifferentapproachestoimproveddietaryintakeofnutrients.Theseshouldtakeintoaccountanypersonalmonitoringdevicesthatanindividualhasforexistinghealthconditionse.g.forbloodsugarandbloodpressure,wearablesthatmonitoractivityandmobileappsthatoffercoaching.Togetherthesecouldhelptointegratelifestyleandmedicalvariablestoimprovetheperceivedimportanceofdietandcompliancewithhealthynutrition.


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Section2Systematicreviewofnutritionalinterventionstudiesinolderadults

Thefollowingsectiondescribesafocussedsystematicreviewofthoseclinicalstudiesthathavedeterminedhealthoutcomemeasuresinolderadultsfollowingnutrientordietaryenrichmentorsupplementationinordertounderstandanyvalueofnutritionforgeneralhealthandwell-being.ThereviewwasconductedinJulyandAugust2017.Alldatawasreviewedbytwopeopleindependently.

Searchstrategy

Bibliographicdatabasesweresearchedforrandomised,placebo-controlledtrialsinvestigatingtheeffectofnutrientsonhealthoutcomesinolderadults.Thesearchwasconductedbycombination(usingBooleanoperators)ofthesearchtermsintable2.1.Thefollowingdatabasesweresearched:PubMed,CochraneLibrary,WebofKnowledge,Controlled-TrialswebsiteandScienceDirect.Theexclusioncriteriawereasfollows:populationage<65years;animalstudies;andstudiesofindividualswithdiseaseonlyandnotofhealthycontrols.

Table2.1.Searchstrategyforsystematicreviews

Agecategory Food Outcomeolderadult vitaminA frailtyelderly thiamin musclestrengthseptuagenarian riboflavin immuneresponseoctogenarian niacin lifespannonagenarian folate longevitycentenarian dietary-protein cognitionpensionage, omega3fattyacid falls,

retirementage,polyunsaturatedfattyacid fractures

Geriatricmonounsaturatedfattyacid dentalhealth

seniorcitizen, iron infectionOAP, calcium bodyweightoldage magnesium potassium vitaminB6 vitaminB12 vitaminC vitaminD vitaminE fibre zinc MULTIVITAMINS


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Dataextraction

Forinvestigationoftheeffectsofnutrientsonhealthoutcomes,wefocussedonmeasuresofphysiologicalsystemsthatdeclinewithageratherthaneffectsonovertexistingdisease.TheageingsystemsthatweincludedasoutcomesinoursearchesaredescribedinTable1.Weextractedmeasuresoffunctionatbaselineandattheendofthenutritionalinterventionforboththecontrolandtreatmentgroups.Thefollowingparticipantcharacteristicswerenotedaspossibleconfounders:nutrientformandamountordoseconsumed,studyduration,numberofparticipantspergroup,participantagerange.Themethodologicalqualityofstudieswasassessedtoeliminatebiasbydropoutrateandcompliancewerepossible.Thethresholdlimitssetforthecriticalappraisalwerethatstudiesshouldberandomisedcontrolledtrials,withacontrolgroupandsingleblinding.Inadditionbothcomparatorgroupsmusthavebeensubjectedtoidenticaltreatmentanalysis.ThosestudiesmeetingtheinclusioncriteriaarelistedintheTables2.2etc.

Macronutrients

Fibreinterventionstudies;effectsonolderadulthealthoutcomes

Onestudyonfibresupplementationinolderadultsthatmetinclusioncriteriawasidentified(Table2.2).Thereportedinterventionoutcomewasweightgain.Thestudynotedthatfibretreatmentswereeffectiveandreportednoincreaseinmeanbodyweightsfollowingfibreintervention(Baghurstetal,1985).Onestudyinhealthymenshowedthatincreasedfibreintakemaintainedbodyweight.

Proteininterventionstudies;effectsonolderadulthealthoutcomes

Fourstudiesthatfocusedondietaryproteinenrichmentwereidentified;oneofthestudiesrecruitedamalepopulationonlywithallstudiesusingage-groupsgreaterthan65years(Table2.3).Interventionoutcomeofthesestudiesincludemuscleloss,musclegainandskeletalmusclehypertrophy,physicalperformancefrailty.Onestudyconcludedthatadditionalproteinintakewasrequiredtoallowmusclemassgainduringexercisetraining in frail elderly people (Tieland et al, 2012b). Another study reported that timed proteinsupplementation immediatelybeforeandafterexercisedoesnot furtheraugment the increase in skeletalmuscle mass and strength after prolonged resistance-type exercise training in healthy elderly men whohabitually consume adequate amounts of dietary protein (Verdijk et al, 2009). Dietary proteinsupplementation improvedphysicalperformance,butdidnot increaseskeletalmusclemass infrailelderlypeople (Tieland et al, 2012a). Finally, a study on frailty reported that protein-energy supplementationadministeredtofrailolderadultswithlowsocioeconomicstatusshowedevidenceofreducingtheprogressionoffunctionaldecline(KimandLee,2013).Insummary,threeoutoffourstudiesshowedpositiveoutcomesofproteinsupplementationonfunctionalmusclestrengthormusclemassgain in frailolderadults.Onestudyinhealthymeanshowednoeffectofproteinsupplementationonmusclemassstrength.

Omega-3fattyacidinterventionstudies;effectsonolderadulthealthoutcomes

Twelvestudiesinvolvingomega-3supplementationwereidentifiedasmeetinginclusioncriteria,oneofwhichfocusedonafemalepopulation,twoonmaleonlypopulationsandtheremainderweremixedgender(Table2.4).Sixofthestudiesrecruitedpatientsfromupwardsof50-64years.Theinterventionoutcomesrelevanttoourstudywerecognitionandall-causemortality.Onestudyhasyettoreport.Sixsmallerstudies(<100peopleanalysedineachstudy)ofomega-3fattyacidsupplementationinolderpeoplewereidentified;threestudiesrecruitedpeoplewithMCIandallfocusedoncognitionastheinterventionoutcome.Theinterventionhadpositiveimpactsoncognitionincludingimprovedlearningandmemoryinallcases(Boetal2015,Tokudaetal,2015,Strikeetal,2010,Leeetal,2011,Randanellietal,2012,Nilsonnetal2012).Onelargestudywith


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485participants,showedabenefit forcognitiveperformanceforpeopleof55years (Yurko-Mauro,2011).However,inthreeotherlargerstudiesomega-3fattyacidsupplementationnosignificanteffectsoncognitivedeclineover3yearsinelderlypeoplewithorwithoutmemorycomplaintswereobserved(Andrieuetal,2017,vandeRestetal,Dangour2010).ThesefindingsareconsistentwithasystematicreviewbyJiaoetalin2014andtheCochranesystematicreview(Sydenham,Dangouretal.2012)whichconcludedthattheavailabletrialsshowed no benefit of omega-3 PUFA supplementation on cognitive function in cognitively healthy olderpeople.

InaNorwegianpopulationatriskforcardiovasculardisease,astatisticallysignificantreductiononall-causemortalitywasobservedfollowingthreeyearsofomega-3supplementation(Einviketal,2010).

Insummary,inhealthyolderadultsthreeoffourlargeomega3interventionstudiesshowedneitherbenefitnor riskoncognitionandone large interventionstudyshowedpositivebenefit.A reduction inall-causemortality formenwithcardiovasculardisease riskwasobserved inone largeomega-3supplementationstudy.

Micronutrients

VitaminB6,B12andfolateinterventionstudies;effectsonolderadulthealthoutcomes

EightvitaminB12studiesinelderlypersonsthatmettheinclusioncriteriaforthisreviewwereidentified.Oneof the studies included vitamin B6, one study included omega-3 fatty acids and two included folatesupplementation (Table 2.5). Seven of the studieswere conducted on subject aged 65+,with one studyrecruiting participants from the age of 60;men andwomen participated in all studies. The interventionoutcomes were cognition, brain atrophy, bone mineral density, fractures, immune function and physicalperformance. TwoofthefourstudiesfocusedontheimpactofvitaminB12onbrainatrophyorcognitionreportedbeneficialsignificanteffects;andbothalsoincludedomega-3fattyacidsupplements(Walkeretal,2012)andonealso includevitaminB6supplementation(Jernerenetal,2015).Athird largestudyof2919participantsdidnotdescribeanycognitiveimprovementfromvitaminB12supplementationinhealthyolderadults(vanderZwaluwetal,2014).OtherstudiesconcludedthatvitaminB12supplementationhasnoimpactonbonemineraldensity,fractures,physicalperformanceandimmunefunctioninolderadults(Ennemanetal,2015,Wijngaardenetal,2014,Swartetal,2015,vanDijketal,2016).Insummary,inhealthyolderadultstwoofthreelargevitaminB12combinedwithomega-3fattyacidinterventionstudiesshowedbenefitoncognitionandonelargeinterventionstudyshowednoeffect.Noadverseoutcomeswerenoted.

VitaminCinterventionstudies;effectsonolderadulthealthoutcomes

ThreevitaminCsupplementationstudiesinelderlypersonswereidentifiedasmeetingtheinclusioncriteriafocusedonsubjectsagedmorethan60years(Table2.6).Onestudyrecruitedonlymaleparticipants. Theinterventionoutcomesmeasuredwerecognition,acuterespiratoryinfectionsandphysicalperformance.Withregard to cognition, vitaminC intakedidnot enhance cognitiveperformance in elderly personswithmildcognitiveimpairment(Naeinietal,2013).VitaminCwasshowntosignificantlyimproverespiratoryfunctionin thepresenceofacuterespiratory infection in individualswith lowvitaminCconcentrations (Huntetal,1994).HighdosageofvitaminCandEsupplementationwasshowntobluntcertainmuscleadaptationstostrengthtraininginelderlymen(Bjornsenetal,2015).Insummary,olderadultswithlowplasmavitaminCshowed benefit from supplementation whereas high dose supplementation with vitamin C and E hadnegativeeffectsonmuscletraining.


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VitaminDinterventionstudies;effectsonolderadulthealthoutcomes

Thirteen vitaminD supplementation studies in elderly personswere identified (Table 2.7). Twelveof thethirteenstudiesusedsubjectsaged65+andonerecruitedpeopleolderthan60yearsofage.Threeofthestudiesrecruitedwomanonlyandonestudiedmenonly.Theinterventionoutcomesrelevanttothisstudywerecognition,falls,musclestrengthandfractures.OfthefourstudiesfocusedonvitaminDintakeandfalls,twosuggestedsuchinterventionwaseffectiveatreducingfalls(Imaokaetal,2016,Flickeretal,2005)andtwostudiessuggestvitaminDsupplementationwasnoteffective(Burleighetal,2007,Lathametal,2003).All four studies focusedon vitaminD intake and the incidenceof fractures; this didnotdemonstrate anypositiveimprovements(Lawetal,2006,Salovaaraetal,2010,Meyeretal,2002,RECORDtrialgroup,2005).Of the four studies focusedon the impactof vitaminD supplementationonmuscle strength, two studiessuggesteditwasinsufficientforimprovingmusclestrength(Kennyetal,2003,Janssenetal,2009),whereastwostudiessuggestedapositiveresponse(Moreira-Pfrimeretal,2009,Pfeiferetal,2008).OnestudyfoundnoassociationbetweenvitaminDtreatmentandtheincidenceofcognitiveimpairment(Rossometal,2012).Insummary,fouroutoffourteenvitaminDinterventionstudiesinolderadultsshowedpositivebenefitonhealthoutcomesandtenotherstudiesshowednobenefitandnoincreasedrisk.

VitaminEinterventionstudies;effectsonolderadulthealthoutcomes

FourvitaminEsupplementationstudiesinelderlypersonwereidentified(Table2.8).Threeofthefourstudiesusedsubjects65+yearsold,onestudywasconductedonmalesubjectsonlyandonestudyfocusedonfemalesonly.Theinterventionoutcomesincludedcognitionandimmunefunction.Inthepresenceoffishoil,vitaminEwasshowntoimproveimmunefunction(Wuetal,2006),whereasanotherstudyreportedthattherewasnoclearindicationofimprovedimmuneresponses(Parketal,2002).AstudyonriskforpneumoniaconcludedthatalthoughtheevidenceforthebenefitfromvitaminEtoreduceriskofpneumoniaisstrong,theoverallfindingsarecomplex(Hemila,2016).AnotherstudyreportedthatvitaminEdidnotprovidecognitivebenefitsinhealthyolderwomanafterfouryearsoffollow-up(Kangetal,2006).Insummary,twooutoffourvitaminEinterventionstudiesinolderadultsshowedpositivebenefitonimmunefunctionandtwootherstudiesshowednobenefitandnoincreasedriskforhealthoutcomes.

Multivitamininterventionstudies;effectsonolderadulthealthoutcomes

Fivestudiesthatfocusedonmultivitaminsupplementationinhealthyolderadultswereidentifiedasmeetingthestudyinclusioncriteria(Table2.9).Twostudiesrecruitedfemalesonly.Interventionoutcomesmeasuredincludecognition,nutritionandbonedensityandimmunefunction.Twostudiesoncognitionconcludedthatmultivitaminsupplementationhadnoimpactoncognitiveperformance(Woltersetal,2005,Harrisetal,2015)whereas another study suggested that combinedmultivitamins, mineral and herbal formulamay benefitworkingmemoryinelderlywomanatriskofcognitivedecline(Macphearsonetal,2012).Astudyfocusedonbonemineraldensityconcludedthatsupplementationhadapositiveeffectonbonedensity(Griegeretal,2009).Astudytoinvestigateimmunefunctioneffectsofmultivitaminandmulti-mineralsupplementationofolder people living at home did not show any improvement in self-reported infection related morbidity(Avenelletal,2005).Insummary,threeoutoffivemulti-vitamininterventionstudiesinolderadultsdidnotshowbenefitsorrisksfromsupplementation.Otherstudiessuggestsimprovedmemoryandbonedensityinatriskpopulation.

Calciuminterventionstudies;effectsonolderadulthealthoutcomes

Ninecalciumsupplementationstudiesinelderlypersonswereidentifiedasmeetingthestudycriteria,fourofwhichwerecombinedwithvitaminDsupplementation(Table2.10).Sixoftheninestudiesusedsubjectsaged65+and threeof theninewere conductedon femaleparticipantsonly. The interventionoutcomeswere


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concernedwith bonemineral density (BMD), dementia, dental health and fractures. Two of the studiessuggestthatcalciumsupplementationmayhaveapositiveimpactonBMD(Dawson-HughesandHarris,2002,Nakamura et al, 2012). Three studies investigating the impact of combined calcium and vitamin Dsupplementationondentalhealthgenerallyfoundpositiveoutcomesregardingtoothloss,dentalplaqueandperiodontalhealth(Kralletal,2001,Adegboyeetal,2013,Garciaetal,2011).Theimpactofcalciumintakeonfractureswaslessconsistent.Noevidenceofreducedriskoffractureswasreportedinonestudyfocusedoncalcium/vitaminDintake,areductioninfractureriskwasobservedinanotherinvestigation,whereasthethird study stated that the relationship between calcium intake and fracture susceptibility is complex(Porthouseetal,2005,Bischoff-Ferrarietal,2008,Choetal,2008).Finally,onestudyconcludedthatcalciumsupplementation may increase the risk of developing dementia in elderly woman (Kern et al, 2016). Insummary,sixoutofninestudiesshowedpositiveoutcomesofcalciumsupplementationforavarietyofhealthmeasures;onestudysuggestedacomplexeffect;anotherstudydescribednobenefit;andonestudysuggestedrisk.

Potassiuminterventionstudies;effectsonolderadulthealthoutcomes

Threestudiesfocusedonpotassiumsupplementationinelderlypersonswereidentifiedasmeetingthestudycriteria,twoofwhichwerebasedonafemalecohortonly(Table2.11).Onlyonestudyrecruitedanage-groupof65+whiletheothertwoselectedparticipantsover55yearsofage. The interventionoutcomeofthesestudieswere bonemetabolism and calcium balance. One study reported that treatmentwith potassiumcitrateforthreemonthsinanall-femalecohortreducedboneresorption(Marangelloetal,2004),whereasanothertwo-yearstudy,alsowithagroupofwomanconsistingof276participantsagedbetween55-65didnot find evidence that potassium citrate reduced bone turnover or increased bone mineral density(MacDonaldetal,2008).Thethirdstudyfocusedoncalciumbalanceconcludedthatpotassiumcitratehasthe potential to improve skeletal health (Mosely et al, 2013). In summary, the effects of potassiumsupplementationonbonehealthonolderadultsisvariedbuttherewasnoevidencefornegativeeffects.

Magnesiuminterventionstudies;effectsonolderadulthealthoutcomes

Threestudiesonmagnesiumsupplementationinelderlypersonswereidentifiedasmeetingthestudycriteria(Table2.12). Twoofthethreestudieswereconductedonparticipantsaged65+andonerecruitedpeoplebetween51and85years.Onestudyrecruitedonlyfemales.Outcomesmeasuresrelevanttothisreportwerebonemineraldensity,muscleperformance,glucosehandlingandimmunefunction.Dailymagnesiumoxidesupplementationimprovedphysicalperformanceinhealthyelderlywoman(Veroneseetal,2014).Inanotherstudy, correctionof a lowerythrocytemagnesium concentration associatedwith improvementof glucosehandling (Paolisso et al, 1992). Finally,magnesium supplementationwas shown to reduce inflammation(Nielsonetal,2010).Insummary,magnesiumsupplementationinhealthyolderadultsimprovedthehealthoutcomesstudiedhere.

Ironinterventionstudies;effectsonolderadulthealthoutcomes

Onestudywhich investigated ironsupplementation inelderlypersonswas identifiedasmeetingthestudycriteria, which was in combination with 5-aminolevulinic acid (Table 2.13). Combined iron and 5-aminolevulinic acid intake augmented exercise efficiency and thereby improved interval-walking training(Masukietal,2015).Insummary,magnesiumsupplementationinhealthyolderadultsimprovedphysicalhealth.


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Seleniuminterventionstudies;effectsonolderadulthealthoutcomes

Sevenstudiesfocusedonseleniumsupplementationwereidentifiedinolderadultswereidentifiedasmeetingthereportcriteria,withonlytwostudiesusingagegroups65+;allstudiesrecruitedparticipantsover50yearsofage(Table2.14).Interventionoutcomesmeasuredincludedimmunefunction,mood,thyroidfunctionandmortality. Regarding thyroid function,one study reported that selenium intakedoesnot improve thyroidfunctioninanelderlyUKpopulation(Raymanetal,2008)andanotherstudysuggeststhatseleniumintakeonlyminimally anddosedependently affects thyroid function (Winther et al, 2015). A study focusedonimmunityfoundthatseleniumintakecanhavebothbeneficialanddetrimentaleffectsoncellularimmunitytoflu thatwas affectedby the formof selenium, supplemental dose anddeliverymatrix (Ivory et al, 2017).Anotherstudysuggeststhatintakeofselenium-enrichedyeastresultsinanimmunostimulatoryresponseinelderlyhumans(Peretzetal,1991).Afive-yearlongsupplementationstudyreportednoimpactonplasmacholesterolconcentrations inanelderlypopulationconsistingof492participantsagedbetween60and74(Coldetal,2015).Inanotherstudyconsistingof501individualsagedbetween60-74years,noevidencewasfound to suggest that selenium treatment improves mood or quality of life (Rayman et al, 2006).SupplementationwithSeleniumandCoenzymeQ10wasshowntoreducecardiovascularmortalityinelderlywithlowseleniumstatus(Alehagenetal,2016). Insummary,seleniumsupplementationinhealthyolderadults does not exert consistent effects and attention should be paid to the form inwhich selenium isavailable.

Zincinterventionstudies;effectsonolderadulthealthoutcomes

Onestudyonzincsupplementationconductedonagroupof5055-87-year-oldmenandwomanfor12months(Table 2.15). It reported that the incidenceof infectionwas significantly lower following supplementationsuggestinganimprovementinimmunefunction(Prasadetal,2007).

Dietenrichmentinterventions

Thesearchstrategywasdesignedtoinvestigatespecificdietarynutrienteffectsinolderadults.Somepreviousstudieshaveconsideredawidercontextofdietanddietaryenrichmentinolderadults.Themostsignificantof these studies is the PREDIMED study; in a healthy older adult population, a Mediterraneandietsupplementedwitholiveoilornuts isassociatedwith improvedcognitive function, immunefunction,boneandhealth(Valls-Pedret,Sala-Vilaetal.2015,Casas,Sacanellaetal.2016,Savanelli,Barreaetal.2017).AMediterraneandiet is considered todeliver thenutrientbalance thatpromotesgoodhealthoutlined inSection1andpointstotheimportanceofdietforpositivehealthoutcomes.


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References

Casas,R.,E.SacanellaandR.Estruch(2016)."TheImmuneProtectiveEffectoftheMediterraneanDietagainstChronicLow-gradeInflammatoryDiseases."Endocrine,Metabolic&ImmuneDisordersDrugTargets14(4):245-254.Savanelli,M.C.,L.Barrea,P.E.Macchia,S.Savastano,A.Falco,A.Renzullo,E.Scarano,I.C.Nettore,A.ColaoandC.DiSomma(2017)."PreliminaryresultsdemonstratingtheimpactofMediterraneandietonbonehealth."JTranslMed15(1):81.Sydenham,E.,A.D.DangourandW.-S.Lim(2012)."Omega3fattyacidforthepreventionofcognitivedeclineanddementia."CochraneDatabaseofSystematicReviews(6).Valls-Pedret,C.,A.Sala-Vila,M.Serra-Mir,D.Corella,R.delaTorre,M.A.Martinez-Gonzalez,E.H.Martinez-Lapiscina,M.Fito,A.Perez-Heras,J.Salas-Salvado,R.EstruchandE.Ros(2015)."MediterraneanDietandAge-RelatedCognitiveDecline:ARandomizedClinicalTrial."JAMAInternMed175(7):1094-1103.

Retrospective,epidemiologicalstudiesoftheeffectsof


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SECTION3Systematicreviewofepidemiologicalstudiesofnutrientsandhealthoutcomesinolderadults

Thefollowingsectiondescribesafocussedsystematicreviewofthoseepidemiologicalstudiesthathavedeterminedhealthoutcomemeasuresinolderadultslivingindependentlyandwithoutdiseaseinordertounderstandanyassociationsbetweennutritionandgeneralhealthandwell-being.ThereviewwasconductedinJulyandAugust2017.Alldatawasreviewedbytwopeopleindependently.

Searchstrategy

Bibliographicdatabasesweresearchedforstudiedreportingtherelationshipsbetweennutrientsandhealthoutcomesinindependent-living,healthyolderadults.Thesearchwasconductedbycombination(usingBooleanoperators)ofthesearchtermsintable2.1.Thefollowingdatabasesweresearched:PubMed,CochraneLibrary,WebofKnowledgeandScienceDirect.Theexclusioncriteriawereasfollows:populationage>65years;animalstudies;andstudiesofindividualswithdiseaseonlyandnotofhealthycontrols.

Table3.1.Searchstrategyforsystematicreviews

Agecategory Food Outcomeolderadult vitaminA frailtyelderly thiamin musclestrengthseptuagenarian riboflavin immuneresponseoctogenarian niacin lifespannonagenarian folate longevitycentenarian dietary-protein cognitionpensionage, omega3fattyacid falls,

retirementage,polyunsaturatedfattyacid fractures

Geriatricmonounsaturatedfattyacid dentalhealth

seniorcitizen, iron infectionOAP, calcium bodyweightoldage magnesium potassium vitaminB6 vitaminB12 vitaminC vitaminD vitaminE fibre zinc MULTIVITAMINS


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Dataextraction

Forinvestigationanyassociationbetweennutrientsandhealthoutcomes,wefocussedonmeasuresofphysiologicalsystemsthatdeclinewithageratherthaneffectsonovertexistingdisease.TheageingsystemsthatweincludedasoutcomesinoursearchesaredescribedinTable3.1.Thefollowingparticipantcharacteristicswerenotedaspossibleconfounders:follow-upduration,numberofparticipantspergroup,participantagerangeandgender.ThosestudiesmeetingtheinclusioncriteriaarelistedintheTables3.2etc.

Macronutrients

Fibre

Twostudiesondietaryfibrewereidentifiedasmeetingtheinclusioncriteriaforthisreview,oneofwhichwasstudiedwithproteinintake.Thesetwostudiesfocusedonfrailtyanddentalhealth.Onestudyconcludedthatcarbohydrate,fat,protein,anddietaryfibreshowednoconsistentassociationswithfrailtystatus(Shikanyetal, 2013). The other study reported that only fruits that were good to excellent sources of fibre wereassociatedwithlowerriskofprogressionofABL,probingpocketdepth,andtoothloss(Schwartzetal,2012).Thelaststudyhighlightsthedifficultyininterpretingretrospectivestudies;itispossiblethatpoordentalhealthmayhavecontributedtoolderpeopleselectedfewer“hard”orfibrousfoodstoeatratherthanthefibreitselfofferinganybenefitforprogressionofperiodontitis.

Limitedepidemiologicalstudiesoffibreintakehavebeenreportedforolderadults.Apossiblebenefitexistsfordentalhealthandnoriskswereidentified.

Protein

Sixteenstudieswereidentifiedwhichfocusedontherelationshipbetweendietaryproteinintakeandhealthoutcomes. Normal protein intake varies between 15-35% of the energy intake. Nine of the studies usedpopulations >65yrs and 6 studied all-female cohorts. Outcomemeasures included fractures, bodyweight,proteinintake,bonemineraldensity,infection,frailty,musclemass/strength.Thefivestudiesfocusedontherelationshipbetweenproteinintakeandfractureincidenceallagreedthatacorrelationexistedbetweenlowproteinintakeandfractureoccurrence(Wengreenetal,2004,Misraetal,2011,Mungeretal,1999,Martinez-Ramirezetal,2011,Frassettoetal,2000).Onestudyreportedthateach20%increaseinproteinintakewasassociatedwithasignificantlyhigherbonemineraldensity(BMD),fortotalbodyandhip(Beasleyetal,2014),whereasanotherstudyconcludedthatbonemineraldensitywasnotsignificantlyassociatedwiththeratioofanimal tovegetableprotein intake(Sellmeyeretal,2001). Investigatinganyrelationshipbetweenproteinintakeandbodyweight,onestudyreportedthatinthetotalpopulation,proteinintakewasassociatedwithhigher percent body fat, but in the subgroup with intermediate BMI and stable weight, there was noassociationbetweenproteinintakeandpercentbodyfat(Vinknesetal,2011).Anotherstudyreportedthata1%increaseincarbohydrateandproteinconsumptionwasassociatedwitha14%and16%lowerlikelihoodofbeingobese(Tyrovovlasetal,2011).

With regard to the relationshipbetweenprotein intakeand frailty, one study reported that subjectswithhigherproteinintakehadlowerriskoffrailty(Kobayashietal,2013).Insupportofthis,anotherstudyreportedthata20%increaseinuncalibratedproteinintake(%kcal)wasassociatedwitha12%lowerriskoffrailty,whilea 20% increase in calibratedproteinwas associatedwith a 32% lower risk of frailty (Beasley et al, 2010).Similarly,afurtherstudyconcludedthatdietwithacombinationofhighproteinandhightotalantioxidantcapacity isstronglyassociatedwith lowprevalenceof frailtyamongoldJapanesewomen(Kobayashietal,2017).


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Investigatingmusclestrength/mass,onestudyreportedthatnotmeetingtherecommendeddietaryproteinintakewas associatedwith significantly lower appendicular leanmass at baseline (Scott et al, 2010) andanotherreportedthatgreaterproteinintakewasassociatedwithlessage-relateddecreaseingripstrength(McLeanetal,2015).Itwasreportedthatmalnutritionandinadequateproteinintakewereverycommonandassociatedwithpoordentalhealthamongolderpeoplewithmultipledisabilities inassisted living facilities(Saarela et al, 2014). Finally, a study on infection incidence concluded that a lower protein intake wasindependentlyassociatedwithhospitalisationduetoinfection(Whametal,2015).

Insummary,higherprotein intakewasassociatedwithlowerriskforfrailty, improvedbonedensityandstrengthbuttherewasnoconsistentrelationshipbetweenproteinintakeandbodymass.Lowerproteinintakewasassociatedwithnegativehealthoutcomes.

N-3fattyacidsandPUFA

Cognition

SixteenstudieswereidentifiedthatfocusedonN-3fattyacid/PUFAintakeandmettheinclusioncriteriaofthisreview.Elevenwereconductedon65+yearsorusedameangroupagegreaterthan65years.Allstudiesexcept one (male only)were ofmixed gender populations.Health outcomemeasureswere cognition (9),fracturerisk(3),dentalhealth(2)musclestrength(2).

Higher omega-3 fatty acid/PUFA intake was associated with positive health outcomes in several studies.Seafoodconsumptionwasassociatedwithslowerdeclineinsemanticmemoryandperceptualspeed(VandeRestetal,2016). Anotherstudyreportedthatconsumptionof leanfriedfishhadnoprotectiveeffectbutconsumptionoffattyfishmorethantwiceperweekwasassociatedwithareductioninriskofdementiaby28%andAlzheimer’sdiseaseby41%incomparisontothosewhoatefishlessthanoncepermonth(Huangetal,2005).Fishconsumershadsignificantlylesscognitivedeclineoverfiveyearsthandidnon-consumers(VanGelderetal,2007). Anotherstudy reported that low intakeofEPAandDHAwerepredictorsofcognitiveimpairment and were negatively associated with cognitive function, assessed by the Mini Mental StateExamination(Gonzalezetal,2010).HigherglobalcognitivefunctionwasalsoreportedtobeassociatedwithhigherlevelsofserumEPAandDHA+EPAaftercontrollingforconfounders(Nishihiraetal,2016).PlasmaEPAhasalsobeenassociatedwithaslowerdeclineintheBentonVisualRetentionTestinApoEe4carriersanddepressivesubjects(Samierietal,2011).AfurtherstudyconcludedthatMontrealCognitiveAssessmenttestscoreswererelatedtofishservings(Bruttoetal,2015). Finally,therewassignificantassociationbetweenreported fish consumption and a verbal language score (Dangour et al, 2009). High fish consumptionassociatedwithlesscognitiveimpairmentandslowercognitivedecline.

Fractures

Inastudyofassociationsbetweenfish-oilconsumptioninearlylife,midlife,andlatelifewithosteoporoticfracture risk, in the highest tertile of omega–3 fatty acid consumers (daily) a decreased fracture riskwasobservedinmenthatalmostreachedsignificanceinwomen(Harrisetal,2015).Onestudyreportedinverseassociationswithvegetableconsumption,fishconsumptionandpolyunsaturatedlipidintakewithhipfracture,whereassaturatedlipidintakewaspositivelyassociatedwithhipfracturerisk(Benetouetal,2011).AthirdstudyreportednostatisticallysignificantassociationbetweenintakesoftotalPUFA,totaln-3PUFA,totaln-6PUFA,n-6/n-3PUFAratioorindividualPUFAsandhipfracturerisk;however,womenwithlowintakesoftotalPUFA,n-6PUFAandlinoleicacidwereatincreasedriskoffractures(Virtanenetal,2012).


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Dentalhealth

Two relevant studies were retrieved. They reported that a high dietary n-6:n-3 PUFA intake ratio wasassociatedwitha greaternumberofperiodontaldiseaseevents (Iwasaki et al, 2011); similarly a lowDHAintakewasassociatedwithmoreperiodontaldiseaseevents(Iwasakietal,2010).

Musclestrength

Tworelevantstudieswereretrieved.Onestudyconcludedthathigherconcentrationsof totalPUFAswereassociatedwithlargermusclesizeandwithgreaterkneeextensionstrength(Reindersetal,2014).Asecondstudyconcludedthatthemostimportantdietaryfactorinrelationtogripstrengthwasfattyfishconsumption(Robinsonetal,2008).

Insummary,fishconsumption(particularlyoilyfishrichinomega-3fattyacids)associatedpositivelywithmusclestrength,dentalhealthandcognitivefunction.Inaddition,twoofthreestudiessuggestthatdailyfishconsumptionassociateswithreducedfracturerisk,particularlyinmen.

MUFA

Four studies were identified thatmet the inclusion criteria of this review and evaluated the relationshipbetweenmonounsaturatedfattyacids(MUFA)andhealthoutcomes.Twoofthefourstudieswereconductedwitholderpeopleof65+yearsandonefocusedonfemales.Measuredhealthoutcomesincludedcognition,fracturerisk,and longevity. OnestudyreportedthatMUFAintakewas inverselyassociatedwithcognitivedecline(Naqvietal,2011);asecondstudyreportedthattheoddsratioformildcognitive impairmentwasreducedinthosewithhighvegetableintakeandwithhighmono-pluspolyunsaturatedfattyacidtosaturatedfattyacidratio(Robertsetal,2010).Astudyonfracturesreportedthatadose-dependentincreaseinriskofhipfractureswasassociatedwithhigherintakesoftotalfat,animalfat,saturatedfattyacidsandMUFA(Zengetal,2015).HigherMUFAintakewasassociatedwithanincreasedchanceofsurvivalinolderadults(Solfrizzietal,2005).

Insummary,MUFAintakewasassociatedwithpositivehealthoutcomesinthreeoffourstudies.

VitaminA

ThreestudiesonvitaminAwereidentifiedthatmettheinclusioncriteriaofthisreview;twoincludedanall-femalepopulationand lookedat relationships inpeopleover50yearsofage.Healthoutcomesmeasuredwerefractureincidenceanddentalhealth.Inrelationtofractureincidence,onestudyconcludedthattherewasnosignificantassociationbetweenvitaminAintakeandtheriskoffracturebutthatthosewithinhighestquintileforvitaminAintakeandwithlowvitaminDintakeweremorelikelytohaveincreasedfracturerisk(Caire-Juveraetal,2009).AsecondstudyreportedthatusersofsupplementscontainingvitaminAhada1.18-fold increased risk of incident hip fracture compared with non-users, but there was no evidence for anincreasedriskofallfracturesamongsupplementusers(Limetal,2004).Regardingoralhealth,thosewithlowerHealthyEatingIndexscoresandsignificantlylowervitaminAintakeweremorelikelytohavepoororalhealth(Baileyetal,2004).

In summary,highest vitaminA intakewasassociatedwith increased risk for fracture,particularlywhencombinewithlowvitaminDintwoofthreestudies.PoororalhealthassociatedwithlowvitaminAintake.


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VitaminB12

EightstudiesthatfocusedonvitaminB12andmettheinclusioncriteriaofthisreviewwereidentified.Fiveofthese studieswere conducted on cohorts older than 65 years and all studiedmixed gender populations.Outcomesassessedwerecognition, fracturesandmortality. Regardingcognition,onestudyreportedthatpeopleover50withmildcognitiveimpairmentandwithlow-normalvitaminB12showedasignificantlypoorerlearningabilityandrecognitionperformancethanthosewithhigh-normalvitaminB12concentrationintheblood(Kobeetal,2016).Similarly,itwasalsoconcludedthatcognitiveimpairmentwasrelatedtolowbloodvitaminB12inaBrazilianpopulation(Martinho,TinocoandRibeiro,2015).LowvitaminB12concentrationswereidentifiedin13%ofolderpeopleandwereassociatedwithmemoryimpairmentanddepression(Hinetal,2006).AnotherstudyconcludedthattheratesofdementiaordeclineassociatedwithhomocysteineforthoseinthelowestandhighesttertilesofvitaminB12,respectively,weresignificantlyhigherandlowerthantheriskforthoseinthemiddletertile(Haanetal,2007).However,afurtherstudyfoundnoevidenceforavitaminB12-relatedmemorydeficitalthoughcognitiveprocessingspeedwaslower(Jelicic,JonkerandDeeg,2010).

Regarding fractures, one study reported that plasma vitamin B12 and B6 concentrations were inverselyassociated with hip fracture risk (McLean et al, 2008), with a second study reporting that osteoporosisoccurredmoreamongwomenwhoseB12statuswasmarginalordeficientthaninwomenwithanormalstatus(Dhonukshe-Ruttenetal,2002).

Inrelationtomortality,findingssuggestedthatinpatientsatnutritionalriskwhowereadmittedtohospitalandgivensupplements,thosewithhighvitaminB12hadincreasedmortalityandalongerlengthofstay(LOS)thanthosewithnormalconcentrations(median25days)versus23days,andelevatedvitaminB12wasanindependentpredictorofLOS(Cappelloetal,2017).

In summary, low vitamin B12 in the blood associated with poor cognitive performance and increasedfracturerisk.ThesestudiesdidnotconsidervitaminB12intake;absorptionfromthedietmaybeimpairedwithage.

VitaminC

FourstudieswereidentifiedwhichinvestigatedvitaminCandmettheinclusioncriteriaofthisreview.Healthoutcomesrelatedtocognition,infectionandmusclestrength.Allstudieswereconductedonsubjectsgreaterthan65yearsofage,withtwostudiesbeingundertakenonfemalepopulations.Investigatingcognition,onestudyconcludedthatconsumptionofvitaminCsupplementswasassociatedwithalowerprevalenceofmoreseverecognitiveimpairment(Paleologous,CummingandLazarus,1998),withanotherstudysuggestingthatoverall, long-termvitaminC intakeswerenotconsistently related tocognition (Devoreetal,2012). Withregardtoinfection,itwasconcludedthatserumvitaminC(measuredasascorbate)concentrationwasstronglyinversely related to fibrinogen, factor VIIC and acute phase proteins but not to self-reported respiratorysymptoms(KhawandWoodhouse,1995).PlasmavitaminCconcentrationwasalsoreportedtobepositivelycorrelatedwithhandgripstrength,lengthoftimestandingononelegwitheyesopenandwalkingspeed,andinverselycorrelatedwithbodymassindex(Saitoetal,2011).

Insummary,vitaminCintakeandbloodconcentrationswerenotassociatedwithhealthrisksand50%ofstudiesshowedbenefit;oneonstrengthandtheotheroncognition.

VitaminD

AtotalofonehundredstudiesthatfocusedonvitaminDandmettheinclusioncriteriaofthisreviewwereidentified.Seventy-onestudiesspecificallyexamineddata fromthoseabove65years. Thirty-twoof these


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studieswereconductedonfemalesonlyandelevenwereundertakenonamale-onlycohort.Healthoutcomewerecomprisedoffractures(30),cognition(15),frailty(16),musclestrength(14),bodyweight(6),falls(6)longevity(6),vitaminDlevels(2)dentalhealth(2)andinfection(2).

Fractures:Twenty-fouroutofthirtystudiesreportedaninverseassociationbetweenvitaminDandfractureincidence.EithersubjectswithhigherlevelsofvitaminDhadreducedincidenceoffracturesormoreoften,acorrelationbetweenlowvitaminD levelsandincreasefractureoccurrencewasevident(seeTable). Threestudies reported no obvious correlation between vitamin D levels and fracture risk (Garnero et al, 2007,Shinkovetal,2016,Steingrimsdottiretal,2014).Conclusionsfromfiveotherstudiesweremorecomplex.AstudycombinedwithvitaminK1reportedthata50%higherriskofhipfracturewasobservedinsubjectswithbothlowvitaminK1andvitaminD,butnoincreasedriskwasobservedinthegroupslowinonevitaminonly(Finnes et al, 2016). The same finding was reported by Dahl et al (2015). Similarly, looking at fractureincidence,lowvitaminK1and25(OH)Dwereindependentlyandsynergisticallyassociatedwiththeriskofhipfracture(Torbergsenetal,2015).AnotherreportshowedthatserumvitaminDwasalinearpredictorofmajorosteoporoticfractureandsignificantquadraticpredictorofhipfractureinthetotalsampleandamongthosewith<10yearsoffollow-up,butitwasnotrelatedtoriskoffractureamongthosewith>10yearsoffollow-up(Lookeretal,2013).Cauleyetal(2010)concludedthatvitaminDlevelswereunrelatedtonon-spinefracturesbutadecreaseinvitaminDwasassociatedwithincreasedriskofhipfracture.Age,height,weight,bodymassindex,fatmass,leanbodymass,waistcircumference,serumvitaminD,parathyroidhormone,andexercisewere also reported to be related to bonemineral density (Yang and Kim, 2015). Finally, the relationshipbetweenbaselinevitaminDandfractureriskwasdescribedasbeingU-shaped,withincreasedfractureriskinmenwitheitherloworhighserumvitaminDlevels(Bleicheretal,2014).

Cognition: FourteenofthefifteenstudiesreportedanassociationbetweenvitaminD levelsandcognitiveperformance.EithersubjectswithhigherlevelsofvitaminDwerelesslikelytohavecognitiveimpairmentorwithlowvitaminDlevelwereassociatedwithincreasedcognitiveimpairment(Wilkinsetal,2006,Annweileretal,2012,Milmanetal,2014,Bartalietal,2014,Pernaetal,2014,Jordeetal,2015,Breitlingetal,2012,Llewellynetal,2011,Llewellynetal,2010,Wilkinsetal,2009,Annweileretal,2016,Cheietal,2014,Seamansetal,2010,Milleretal,2010).OnestudyreportedthatthoseinthelowestandhighestvitaminDquartileshad an increased risk of impaired prevalent but not incident global cognitive functioning or decline infunctioningcomparedwiththoseinthemiddlequartiles(Granicetal,2015).

Frailty:SixteenoftheseventeenstudiesreportedaninversecorrelationbetweenvitaminDlevelsandfrailty,withlowvitaminDlevelsbeingassociatedwithfrailty(Shardelletal,2012,Pabstetal,2015,Gutierrez-Robledoetal,2015,Shardelletal,2009,Hiranietal,2013,Alvarez-Riosetal,2015,Trevisanetal,2017,Wongetal,2013,Vogtetal,2015,Tajaretal,2012,Butaetal,2016,Smitetal,2012,Wilhelm-Leenetal,2010,Changetal,2010,Schottkeretal,2014).LessablepatientsreportedlyhadsignificantlylowervitaminDlevelsinanotherstudy(Skalska,GalasandGrodzicki,2012).OnestudyreportedaU-shapedassociationatbaselinewasseenbetween25(OH)Dlevelandoddsoffrailty,withthelowestriskamongthosewithmid-rangeplasmavitaminDlevels20.0–29.9ng/ml(Ensrudetal,2010).

Musclestrengthandfalls:TenofthefifteenstudiesshowedasignificantcorrelationbetweenlowvitaminDlevelsandmusclestrength,withlowerlevelsassociatingwithpoorstrength(Gerdhemetal,2005,Houstonetal,2007,Mastagliaetal,2011,Iolasconetal,2015,Zambonietal,2002,Birdetal,2013,Inderjeethetal,2007,Gumieiroetal,2015,Salminenetal,2015,Pramyothinetal,2009).Fivestudiesreportednoassociation.Onesuchstudyconcludedthatfewsubjectshad25-hydroxyvitaminDconcentrations<30nmol/Landthatabovethisconcentration,therewasnodoseeffectrelationwithphysicalperformanceexceptforsingle-legstands(Chuangetal,2016).AsecondstudyreportedthattherewerenodifferencesintheGCSCompositeScale,aglobalmeasureofphysicalfunction,betweenthosewithhigherandlower25(OH)Dconcentrations(Haslam


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etal,2014).Afurtherstudyreportedthatnosignificantrelationshipbetweenbalance,gaitspeedandgripstrength, and serum25-OHDwas detected (Mathei et al, 2013). A fourth study concluded that althoughphysical performancedeclinedover time, thiswas not associatedwith baseline vitaminD (Houston et al,2012).ThiswasechoedbyChanetal(2012)whoreportedthatserum25OHDlevelswerenotassociatedwithbaselineor4-yearchange inphysicalperformancemeasuresandskeletalmusclemass.Fiveoutof thesixstudiesexaminingassociationbetweenvitaminDandfallsincidencereportedaninversecorrelation(Steinetal,1999,Lloydetal,2009,Rothenbacheretal,2014,Shimizuetal,2015andFlickeretal,2003).OnestudyhoweverreportedthatuseofvitaminDsupplementswasnotassociatedwithanymeasuresofneuromuscularfunction,changeinneuromuscularfunction,orfallrates(Faulkneretal,2006).

Longevity: Four of the six studies identified a correlation between low serum vitamin D and increasedmortality(Buchebneretal,2016,Sembaetal,2009,Kimetal,2015,Sameforsetal,2014).TwofurtherstudiesreportednoassociationbetweenvitaminDlevelsandall-causemortality(Cawthonetal,2010,Eatonetal,2011).

BodyWeight:FiveoutofthesixstudiesreportedacorrelationbetweenlowvitaminDlevelsandincreasedbodyweight,withthreeofthesestudiesincludingarelationshiptosarcopenia(Seoetal,2012,Hwangetal,2012,Huoetal,2016,Ohetal,2016,Sohletal,2015).OnlyonestudyconcludedthatvitaminDlevelswerenotassociatedwithoverallweightchangeorbodyfatloss(Vogtetal,2016).

DentalHealth:Ofthetwostudiesidentified,onereportedthatmenwithmoresevereperiodontaldiseasehavelowervitaminDlevelsandthatvitaminDlevelsacrossallperiodontitisgroupsareconsideredtobelow(Schulze-Spate et al, 2015). The second study concluded that there were no statistically significantassociationsfoundbetweenbaselinevitaminDlevelsandchangeinperiodontaldiseasemeasures,overallorinasubset (n=442)ofwomenwithstablevitaminDconcentrations (changeof<±20nmol/L) (Millenetal,2014).

Infection:Ofthetwostudiesidentified,onereportedthataftermultivariableadjustments,thesubjectsinthelowestserumvitaminDtertile(8.9-33.8nmol/L)hada2.6-foldhigherriskofdevelopingpneumoniacomparedwith the subjects in the highest tertile (50.8-112.8nmol/L) (Aregbesola et al, 2013). The second studyconcludedthatinmultivariableanalyses,aserumvitaminDlevelof<15ng/mLwasassociatedwithahigherriskofhospitalizationwithaninfectionbutnotofhospitalizationwithoutaninfection(Kempkeretal,2016).

Insummary,70%of100studiesreportedbenefitsofhighervitaminDlevelsforhealthoutcomes(orlowervitaminandpoorhealthoutcomes).ThehighestconcentrationsofvitaminDmayassociatewithincreasedprevalenceofcognitiveimpairment,fracturesandfrailty.VitaminKandvitaminDassociatesynergisticallywithbonehealth.

VitaminE

FourstudiesonvitaminEthatmettheinclusioncriteriaofthisreviewwereidentified.Allstudiedpeopleolderthan65yearsandonewasanall-femalepopulation.Healthoutcomesmeasuredwerecognition,dentalhealthandfractures.Withregardtocognition,onestudyconcludedthatparticipantswithplasmavitaminElevelsinthebottomtertile(<26umol/L)hadasignificantlyhigherprobabilityofbeingdementedandsufferingfromcognitiveimpairmentcomparedtothoseinthehighestvitaminEtertile(>32.93umol/L)(Cherubinietal,2005).Anothercognitionstudyreportedthatlowerriskofcognitiveimpairmentwasobservedinpeoplewithhigherlevelsofy-tocopherol,B-tocotrienolandtotaltocotrienols(Mangialascheetal,2013).WithregardtodentalhealthhigherintakeofvitaminEassociatedwithreducedperiodontaldiseaseseverityincommunity-dwellingolderJapanese(Iwasakietal,2012).AreportonfracturerecoveryidentifiedhighervitaminEconcentrations


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inpeoplewhowererecoveringfromhipfracturesthanincontrols,buttheywerehadhighercognitiveandphysicalfunctionthanthecontrolgroup(D'Adamoetal,2011).

Insummary,lowvitaminEintake/bloodconcentrationwasrelatedtopoorhealthoutcomesinolderadults.

Thiamin

Onestudythatfocusedonthiaminwasidentifiedasmeetingtheinclusioncriteriaforthisreview;theaverageageofthosestudiedwas83years.Cognitivestatusdidnotdifferaccordingtothiaminstatusbutthiamine-deficientsubjectsrepresentedalargerproportionofAlzheimer’spatients(Pepersacketal,1998).

Insummary,inhealthyolderadultsthiaminestatuswasnotassociatedwithcognitivefunction

Riboflavin

Twostudiesthatfocusedonriboflavinwereidentifiedasmeetingtheinclusioncriteriaforthisreview;thehealthoutcomewasfracturerisk.Lowriboflavinintakealonewasnotassociatedwithfractureriskandbonemineraldensity(Yazdanpanahetal,2007butasmall,butsignificantassociationwasfoundbetweenvitaminB6andriboflavinintakeandbaselineBMDofthefemoralneck(Yazdanpanahetal,2007).

Insummary,thereisaweaklinkbetweenbonehealthandriboflavinwithvitaminB6intake.

Calcium

Nineteenepidemiologicalstudiesthatfocusedoncalciumwereidentifiedasmeetingtheinclusioncriteriaforthisreview;onestudyinvestigatedcalciumcombinedwithzincandanotherwithprotein.FurtherstudieswithvitaminDandcalciumhavebeenconsideredpreviously.Fiveof thestudiesusedagegroupsof65+years,fourteenstudiesincludedpeopleover50yearsandonestudyincludepeopleaged41-79years.Tenstudieswereconductedonfemalepopulationsonlyandonestudyrecruitedanall-malecohort.Outcomesassessedincluded sarcopenia, cognitive function, bone mineral density, fractures, periodontitis, osteoporosis andmortality.

Two studies investigated the relationship between calcium intake and cognition; one study reported thatcognitive declinewas associatedwith elevated serum calcium (>1.29mmol/L; Tilvis et al, 2004) whereasanotherstudyconcludedthatcognitionincreasedwithcalciumuptoapoint(datacouldnotbeextractedfromthesource)andthencognitiondecreasedascalciumfurtherincreased(Emsleyetal,2000).Anotherstudyreportedthatdailycalciumintakewassignificantlylowerinsubjectswithsarcopeniathaninthosewithout(Seoetal,2013).

Fourteenstudiesinvestigatedtheassociationbetweencalciumandoutcomesrelatedtobonemineraldensity(BMD),fracturesandosteoporosis.Onestudyconcludedthatbonediseasewasassociatedwithalackofdairyproductsorcalciumsupplementation(Wangetal,2017),whilstanotherstudyreportedthatcalciumintakewasnotassociatedwithosteoporosisdiagnosisorfracture(Fardelloneetal,2009).FourstudiesreportedapositivecorrelationbetweenBMDandcalciumintakewherelowercalciumintakeswerelinkedtofractures(FormosaandXuereb-Anastasi,2016,Wlodareketal,2012,Radavelli-Bagatinietal,2014,Cauleyetal,2004).TworeportssuggestedthatdailydairycalciumintakeisnotassociatedwithBMD;infemoralneckBMD(VandenBergetal,2014)andpeoplewhoweregenerallyosteoporoticandosteopenic(Leeetal,2007).Urinarycalciumwas reported tobenegatively associatedwith trochanter, total femurand spineBMD (Ilichet al,2009).

Consideringtherelationbetweencalciumandbonefractures,onestudyreportedthatcalciumintakewasnotrelatedtotheriskoffractureinwomen,however,dailycalciumintakesabove1gassociatedwithlowerrisks


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inmen(Cooper,BarkerandWickham,1988).Khanetal(2015)concludedthatforoldermenandwomen,calciumintakesofupto1348mg/dfromfoodwereassociatedwithdecreasedrisksforfracture,non-fatalCVD,strokeandall-causemortality.

Finally,astudyonperiodontitisconcludedthatintakesoftotaldairycalcium,calciumfrommilkandfermentedfoodswereinverselyassociatedwithperiodontitisbutnon-dairycalcium,calciumfromcheeseandotherdairyfoodintakeswerenot(Adegboyeetal,2012).

Insummary,75%ofstudiesshowedanassociationbetweenhighercalciumintakeandbonehealth.Onestudyshowedthatlowcalciumintakeassociatedwithage-relatedmuscleloss.Twostudiesreportedthathigherbloodionisedcalciumwasassociatedwithpoorcognitionalthoughitisnotclearwhetherthiswasrelatedtohigherintakeorotherpathology.

CalciumandVitaminD

FivestudiesthatfocusedoncalciumandvitaminDwereidentifiedasmeetingtheinclusioncriteriaforthisreview,fourstudiedanall-femalecohort.HealthoutcomesincludedBMD,fracturesandcognition.OnestudyreportedthatlowvitaminDintakewasassociatedwithamorepronouncedrateoffractureandthathigherlevelsofcalciumintakedidnotfurtherreducetheriskoffracturesofanytype,orofosteoporosis(Warensjoetal,2011).AnotherstudyreportedthathighercalciumandvitaminDintakessignificantlyreducedtheoddsof osteoporosis but not the 3-year risk of fracture in Caucasian women (Nieves et al, 2008). OtherinvestigationsconcludedthatwomenconsumingvitaminD≥12.5g/dfromfood/supplementshada37%lowerriskofhipfracturethandidwomenconsuming<3.5g/d,buttotalcalciumintakewasnotassociatedwithhipfracture risk (Feskanich, Willett and Colditz, 2003). A further study reported that no dose–responseassociationbetweencalciumintakeandfractureriskwasfoundandthatvitaminDintakewasnotassociatedwithfracturerisk(Michaelssonetal,2003).

Regardingcognition,neitherserumionizedcalciumnor25-hydroxyvitaminDwasreportedtobeassociatedwithcognitivefunction(Tolppanen,WilliamsandLawlor,2011).

Insummary,fouroffivestudiesdidnotobserveanyassociationbetweenpoorhealthoutcomesascribedtolowvitaminDwhencalciumwasincreased.

Folate

Fivestudiesthat focusedonfolatewere identifiedasmeetingthe inclusioncriteria for this review,oneofwhichalsoinvestigatedvitaminD.Allstudiedpeopleover65years.Outcomemeasureswerecognition,fallsand dental health. All three studies of the relationship between folate and cognition reported positiveassociationswithcognition.OneofthesestudiesreportedthatcognitiveimpairmentanddementiadecreasedwithincreasingRBCfolateconcentration(Ramosetal,2005),anotherthathigherplasmafolateconcentrationsareassociatedwithbetterglobalcognitivefunction(Lauetal,2007)andthethirdconcludedthatmenhadincreasedcognitiveimpairmentandthiswasassociatedwithlowerserumfolate(Lee,ShaharandRajab,2009).Regardingfallsitwasreportedthatserumfolatewasnegativelyassociatedwiththenumberoffallsandinthosewithprescribedmedicationsitwastheonlyprotectivefactoragainstfalls(Shaharetal,2008).Astudyon dental health concluded that a low serum folate levelwas independently associatedwith periodontaldiseaseinolderadults(Yuetal,2007).

Insummary,allstudiesshowedassociationsbetweenlowfolateandpoorhealthoutcomesorhigherfolateandimprovedhealthoutcomes.


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FolateandVitaminB12

TwelvestudiesthatfocusedonfolateandvitaminB12wereidentifiedasmeetingtheinclusioncriteriaforthisreview.Tenofthetwelvestudiedpeopleolderthan65years,twostudiedall-femalepopulationsandonestudiedmales only. Health outcomesmeasured included cognition (11) and fracture incidence (1). Fivestudiesoncognitionreportedthatfolatewassignificantlycorrelatedwithcognition,butvitaminB12wasnot(Ravagliaetal,2005,Tettamantietal,2006,Agnew-Blaisetal,2015,Fengetal,2006,Mooijaartetal,2005).Onestudyreportedthatsubjectsinthelowestfolatetertilehadsignificantlyhigheradjustedoddsratiosformildcognitiveimpairmentanddementia(Quadrietal,2004)andanotherthatdietaryfolatewasaprotectiveagainstadeclineinverbalfluency(Tuckeretal,2005).OnlyplasmafolatelevelwaspositivelyassociatedwiththeMMSE-KCandBostonNamingTest inanotherstudy(Kimetal,2002). Onestudyreportedthathighervitaminlevelswerenotassociatedwitheitherinitialcognitiveperformanceorsubsequentcognitivedecline(Kang, IrizarryandGrodstein,2006). Anotherstudyconcludedthathigh folate intakewasassociatedwithfasterrateofcognitivedecline(Morrisetal,2005).Similarly,whenserumfolatewaslow,increasingthefolateconcentrationassociatedwithbetter cognitiveperformanceespeciallywhenvitaminB12 levelswere low,however, when folate was high and vitamin B12 was high, further increasing folate was associated withincreasedtheriskforimpairedcognitivefunction(Castillo-Lancellottietal,2014).

Asinglestudyfocusedonfracture incidencereportedthatparticipants inthe lowestserumfolatequartile(~9.3nmol/L)hadanincreasedriskoffracturethandidthoseinhigherquartilesbutnodose-relatedprotectiveeffectforincreasingserumfolatelevelswasfound(Ravagliaetal,2005).ThissamestudyalsoconcludedthatnoindependentassociationwasfoundforserumvitaminB12.

Insummary,lowfolatebutnotB12associatedwithpoorhealthoutcomesbutthatincreasingfolateinthosewithalreadyhighfolateandB12levelsassociatedwithpoorhealthoutcomes.

Iron

Six studies that focused on iron were identified as meeting the inclusion criteria for this review; healthoutcomesrelatedtoimmunity,anaemia,cognitionandbodyweightwereidentified.Regardingbodyweight,itwasreportedthatlowerserumFelevelswererelatedtotheinflammationlinkedwithhigherBMI(Oldewage-Theron, Egal,Grobler, 2014). Also, serum ferritinwas significantly correlatedwith the various indexes ofadiposity,suchasthehepaticfatcontent(negativeassociation),visceralandsubcutaneousfat(Iwasakietal,2005).Anotherstudyreportedthattheinfluenceofhighstorage-ironlevelsimpairedimmunityandincreasedtheprevalenceofobesityandabdominalfatness(Kouris-Blazosetal,1996).Itwasconcludedinanotherstudythat vegetarians' low serum ferritin levelmay reduce the risk ofmetabolic syndrome in postmenopausalwomen(KimandBae,2012).AstudyoncognitionconcludedthatMini-MentalStateExaminationscoresweremoderatelyandsignificantlycorrelatedwithironlevelsandtransferrinsaturation(Yavuzetal,2012).Astudyrelated to anaemia reported that iron deficiency anaemia was associated with positive urine culture forbacteriuria(Buttaetal,2014).

Insummary,highironconcentrationsrelatedtopoorhealthoutcomesinolderadultsbutthatlowironalsorelatedtopoorimmunefunctionandcognition.

Magnesium

Threestudiesthat focusedonmagnesiumwere identifiedasmeetingthe inclusioncriteria forthisreview;healthoutcomesweremetabolism,BMDandfractureincidence.Astronginverserelationshipbetweenserummagnesiumand thepresenceofmetabolic syndromewas reportedandas thenumberof componentsofmetabolic syndrome increased,magnesium levels decreased (Evangelopoulos et al, 2008). In relation to


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fractureincidence,itwasreportedthatBMI,serummagnesium,calciumandalbuminweresignificantlylowerin femaleswhenBMDwas lower (Saitoetal,2004). Riskof lower-armorwrist fractureswas reported toincreasewithhighermagnesiumintake,howeveritwasnotedthatthesewomenweremoreactiveandatahigherriskoffalls(Orchardetal,2014).

Insummary,intwoofthreestudies,lowmagnesiumassociatedwithpoorhealth.

Mixedvitamin/nutrientintake

Fifteenstudieswereidentifiedwhichinvestigatedmulti-vitaminintakeornutrient-richdiets,withtenstudyingagegroupsof65+yearsandtwostudyingall-femalepopulations.Healthoutcomeswerefrailty,bodyweight,obesity, fracture risk,dentalhealthandcognition. With regard todentalhealth,one study reported thatintake of non-starch polysaccharides, protein, calcium, non-haem iron, niacin, and vitamin C intakeweresignificantly lower inedentatesubjectscomparedwithdentatesubjects (Sheihametal,2001). Inanotherstudy, itwasalsoreportedthatsubjectswhohadat least5teethhadhighercarbohydrateandvitaminB1intakethanthosewhohad4orlessteeth(Suzukietal,2006).

Cognition: differences in cognitive functioning were related to specific nutrient intakes; protein, fibre,eicosapentaenoic acid, niacin and vitamin B6 (Guligowska et al, 2016). Another study concluded thatassociationsbetweenlifestyleandcognitionexisted,includingPUFAandvitaminB2,withfatintake,vitaminsA,B2,B3,C,fibreandvegetablesbeingassociatedwithdepression(Wooetal,2006).Athirdstudyreportedthatfemalesubjectswithpoorcognitivefunctionhadsignificantlylowerintakesofcereals,vegetables,fruits,milk,spicesandalso,protein,fat,calcium,iron,vitaminA,thiamin,riboflavinandniacinthanthoseofanormalcognition(Leeetal,2001). Malesubjects inthesamestudywithpoorcognitivefunctionhadsignificantlylowerintakeoffruits,fibre,andvitaminCthannormalsubjects.AfourthstudyconcludedthattheprevalenceoflowvitaminsB12,B6,folateandniacinwere6.7%,5.3%,1.3%and26.7%respectivelyandthattherewasnosignificantdifferenceamonggroupedintotertilesofcognition(Paulionis,KaneandMeckling,2005).

Fracture incidence: after adjustment, dose-dependent inverse associations were observed between thedietaryintakeofvitaminC,vitaminE,β-carotene,andSeandantioxidantscoreandtheriskofhipfracture(Sunetal,2014)butnosignificantassociationwasobservedbetweendietaryZnoranimal-derivedvitaminAintakeandhipfracturerisk. Asecondstudyconcludedthata“nutrient-dense”patternrichincalciumandphosphorous, iron,vitaminsB includingB12,vitaminsCandE,alcohol,proteins,andunsaturatedfatswasassociatedwitha19% lowerriskofwrist fractures (Samierietal,2013). Thesamestudyreportedthata“south-westernFrench”dietarypatternrich incalcium,phosphorous,vitaminsDandB12,retinol,alcohol,proteins,andfats-includingunsaturatedfats;poorinvitaminsC,E,andK,carotenes,folates,andfibres;wasrelatedtoa33%lowerriskofhipfractures.

Frailty:onestudyconcludedthatdailyenergyintake≤21kcal/kgwassignificantlyassociatedwithfrailtyandafteradjustingforenergyintake,alowintakeofprotein;vitaminsD,E,C,andfolate;andhavingalowintakeofmorethanthreenutrientsweresignificantlyandindependentlyrelatedtofrailty(Bartalietal,2006). Asecondstudyreportedthatwomeninthelowestquartileofserumcarotenoids,a-tocopherol,and25(OH)Dhadanincreasedriskofbecomingfrailandthatthenumberofnutritionaldeficiencieswasassociatedwithanincreased risk of becoming frail, after adjustment (Semba et al, 2006). A third study concluded that frailwomenweremorelikelytohaveatleast2deficienciesandthattheoddsratiosofbeingfrailweresignificantlyhigher for those participants whose concentrations were in the lowest quartile for total carotenoids, a-tocopherol,25(OH)D,andvitaminB6(Michelonetal,2006).OnestudyfocusedonaMediterraneandietandfrailtyonamixed-sexpopulationaged60yearsandgreaterconcludedthattheriskoffrailtywasinverselyassociatedwithfishandfruitconsumption(Leon-Munozetal,2014).


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Bodymass:Withregardtobodyweight,itwasreportedthatlowintakeofprotein,vitaminD,calciumandvitaminCwassignificantlyassociatedwithlossofmuscleinmen,butnotwomen(Ohetal,2015).Afurtherstudy concluded thatnooverall associationwas seenbetweenpatternsofnutrient intakeandabdominalobesityinbothgenders(Kosakaetal,2013).

Insummary,proteinandmicronutrient-lowdietsassociatewithpoorhealthoutcomesandhigherproteinandmicronutrientintakesassociatewithgoodhealthoutcomes.


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