Plant bioactives as natural panacea against age induced diseases nutraceuticals and functional lead

Plant Bioactives

as Natural Panacea

against Age-Induced Diseases: Nutraceuticals and Functional Lead Compounds for Drug Development

Kanti Bhooshan Pandey

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PlantBioactivesasNaturalPanacea AgainstAge-inducedDiseases

NutraceuticalsandFunctionalLeadCompoundsforDrug Development

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DrugDiscoveryUpdate

PlantBioactivesas NaturalPanacea AgainstAge-induced Diseases

NutraceuticalsandFunctionalLead CompoundsforDrugDevelopment

Editedby

KantiBhooshanPandey

CSIR-CentralSalt&MarineChemicalsResearchInstitute,Bhavnagar, Gujarat,India

MaitreeSuttajit

ThaiVegetarianAssociation,Changpuak,ChiangMai,Thailand

SeriesEditor

ChukwuebukaEgbuna

Elsevier

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Listofcontributors

SutasineeApichai DepartmentofPharmaceuticalSciences,FacultyofPharmacy, ChiangMaiUniversity,ChiangMai,Thailand;CenterofExcellencefor InnovationinAnalyticalScienceandTechnologyforBiodiversity-based EconomicandSociety(I-ANALY-S-T_B.BES-CMU),ChiangMaiUniversity, ChiangMai,Thailand

BavaniArumugam DepartmentofBiomedicalScience,FacultyofMedicine, UniversitiMalaya,KualaLumpur,Malaysia

SambeAshaDevi LaboratoryofGerontology,DepartmentofZoology,Bangalore University,Bangalore,Karnataka,India

PinarAtukeren IstanbulUniversity-Cerrahpasa,FacultyofPharmacy,Cerrahpasa MedicalFaculty,DepartmentofMedicalBiochemistry,Istanbul,Turkey

YaseminAydin DepartmentofBiology,FacultyofScience,IstanbulUniversity, Istanbul,Turkey

RatanaBanjerdpongchai DepartmentofBiochemistry,FacultyofMedicine,Chiang MaiUniversity,ChiangMai,Thailand

WittayaChaiwangyen DivisionofBiochemistry,SchoolofMedicalSciences, UniversityofPhayao,Phayao,Thailand

SuphachaiCharoensin

DivisionofNutritionandDietetics,SchoolofMedical Sciences,UniversityofPhayao,Phayao,Thailand

YengChen DepartmentofOral&CraniofacialSciences,FacultyofDentistry, UniversityofMalaya,KualaLumpur,Malaysia

IkennaChikeokwu DepartmentofPharmacognosy,FacultyofPharmaceutical Sciences,EnuguStateUniversityofScienceandTechnology(ESUT),Agbani, EnuguState,Nigeria

OradaChumphukam DivisionofBiochemistry,SchoolofMedicalSciences, UniversityofPhayao,Phayao,Thailand

YaseminUlkuDikbasan

DepartmentofBiology,InstituteofGraduateStudiesin Sciences,IstanbulUniversity,Istanbul,Turkey

PracheeDubey GovernmentG.I.College,Malwan,Fatehpur,UttarPradesh,India

UchennaEstellaOdoh DepartmentofPharmacognosyandEnvironmentalMedicines, FacultyofPharmaceuticalScences,UniversityofNigeria,Nsukka,Nigeria

GeetikaGarg DepartmentofZoology,SavitribaiPhulePuneUniversity,Pune, Maharashtra,India

ManisekaranHemagirri InstituteforResearchinMolecularMedicine (INFORMM),UniversitiSainsMalaysia,USM,PulauPinang,Malaysia

NapapanKangwan DivisionofPhysiology,SchoolofMedicalSciences,University ofPhayao,Phayao,Thailand

JagatR.Kanwar DepartmentofBiochemistry,AllIndiaInstituteofMedical Sciences(AIIMS),Bilaspur,HimachelPradesh,India

ArpitaKonar CSIR-InstituteofGenomics&IntegrativeBiology,NewDelhi,Delhi, India

PrachyaKongtawelert DepartmentofBiochemistry,FacultyofMedicine,Chiang MaiUniversity,ChiangMai,Thailand

PimpisidKoonyosying OxidativeStressResearchCluster,Departmentof Biochemistry,FacultyofMedicine,ChiangMaiUniversity,ChiangMai, Thailand;ClusterofHighValueProductfromThaiRiceandPlantforHealth, ChiangMaiUniversity,ChiangMai,Thailand

UmahRaniKuppusamy DepartmentofBiomedicalScience,FacultyofMedicine, UniversitiMalaya,KualaLumpur,Malaysia

SuparnaMandal LaboratoryofGerontology,DepartmentofZoology,Bangalore University,Bangalore,Karnataka,India

Theodoramba DepartmentofPharmacognosy,FacultyofPharmaceuticalSciences, EnuguStateUniversityofScienceandTechnology(ESUT),Agbani,EnuguState, Nigeria

MohammadMurtazaMehdi DepartmentofBiochemistry,Schoolof BioengineeringandBiosciences,LovelyProfessionalUniversity,Phagwara, Punjab,India

ChukwumaMichealOnyegbulam DepartmentofPharmacognosyand EnvironmentalMedicines,FacultyofPharmaceuticalScences,Universityof Nigeria,Nsukka,Nigeria

LonginusC.Odoh DepartmentofAccountancy,UniversityofNigeria,Nsukka, Nigeria

BanuOrtaYilmaz DepartmentofBiology,FacultyofScience,IstanbulUniversity, Istanbul,Turkey

BishnuKumarPandey DepartmentofPhysics,SPMCollege,Universityof Allahabad,Prayagraj,Allahabad,UttarPradesh,India

KantiBhooshanPandey CSIR-CentralSalt&MarineChemicalsResearchInstitute, Bhavnagar,Gujarat,India

NarisaraParadee OxidativeStressResearchCluster,DepartmentofBiochemistry, FacultyofMedicine,ChiangMaiUniversity,ChiangMai,Thailand

ThanawatPattananandecha DepartmentofPharmaceuticalSciences,Facultyof Pharmacy,ChiangMaiUniversity,ChiangMai,Thailand;CenterofExcellence forInnovationinAnalyticalScienceandTechnologyforBiodiversity-based EconomicandSociety(I-ANALY-S-T_B.BES-CMU),ChiangMaiUniversity, ChiangMai,Thailand

KomsakPintha DivisionofBiochemistry,SchoolofMedicalSciences,University ofPhayao,Phayao,Thailand

PeraphanPothacharoen DepartmentofBiochemistry,FacultyofMedicine,Chiang MaiUniversity,ChiangMai,Thailand

TreetipRatanavalachai DepartmentofPreclinicalSciences(Biochemistry),Faculty ofMedicine,ThammasatUniversity,Pathumthani,Thailand

SyedIbrahimRizvi DepartmentofBiochemistry,UniversityofAllahabad, Allahabad,UttarPradesh,India

ObinnaSabastineOnugwu DepartmentofPharmacognosy,Facultyof PharmaceuticalSciences,EnuguStateUniversityofScienceandTechnology (ESUT),Agbani,EnuguState,Nigeria

NidhiSachan CellandNeurobiologyLaboratory,DepartmentofBiochemistry, InstituteofScience,BanarasHinduUniversity,Varanasi,UttarPradesh,India; ToxicogenomicsandPredictiveToxicologyLaboratory,SystemsToxicologyand HealthRiskAssessmentGroup,CSIR-IndianInstituteofToxicologyResearch (CSIR-IITR),VishvigyanBhawan,Lucknow,UttarPradesh,India

ChalermpongSaenjum DepartmentofPharmaceuticalSciences,Facultyof Pharmacy,ChiangMaiUniversity,ChiangMai,Thailand;CenterofExcellence forInnovationinAnalyticalScienceandTechnologyforBiodiversity-based EconomicandSociety(I-ANALY-S-T_B.BES-CMU),ChiangMaiUniversity, ChiangMai,Thailand

SreenivasanSasidharan InstituteforResearchinMolecularMedicine(INFORMM), UniversitiSainsMalaysia,USM,PulauPinang,Malaysia

Shanmugapriya InstituteforResearchinMolecularMedicine(INFORMM), UniversitiSainsMalaysia,USM,PulauPinang,Malaysia

RavichandraShivalingappa DivisionofBiology,IndianInstituteofScience EducationandResearch,Tirupati,AndhraPradesh,India

EwaSikora LaboratoryofMolecularBasesofAging,NenckiInstituteof ExperimentalBiology,PolishAcademyofSciences,Warsaw,Poland

PadmanabhSingh CentreofAdvancedStudy,DepartmentofZoology,Instituteof Science,BanarasHinduUniversity,Varanasi,UttarPradesh,India;Departmentof Zoology,IndiraGandhiNationalTribalUniversity,Amarkantak,Madhya Pradesh,India

PrabhakarSingh DepartmentofBiochemistry,FacultyofScience,VeerBahadur SinghPurvanchalUniversity,Jaunpur,UttarPradesh,India

SandeepSingh DepartmentofBiochemistry,UniversityofAllahabad,Allahabad, UttarPradesh,India;HadassahBiologicalPsychiatryLaboratory,HadassahHebrewUniversityMedicalCenter,Jerusalem,Israel

BrijeshSinghChauhan CellandNeurobiologyLab oratory,Departmentof Biochemistry,InstituteofScience,BanarasHinduUniversity,Varanasi, UttarPradesh,India

xviii Listofcontributors

BhagavathiSundaramSivamaruthi InnovationCenterforHolisticHealth, Nutraceuticals,andCosmeceuticals,FacultyofPharmacy,ChiangMaiUniversity, ChiangMai,Thailand

SomdetSrichairatanakool OxidativeStressResearchCluster,Departmentof Biochemistry,FacultyofMedicine,ChiangMaiUniversity,ChiangMai, Thailand;ClusterofHighValueProductfromThaiRiceandPlantforHealth, ChiangMaiUniversity,ChiangMai,Thailand

SaripellaSrikrishna CellandNeurobiologyLaboratory,Departmentof Biochemistry,InstituteofScience,BanarasHinduUniversity,Varanasi, UttarPradesh,India

BungornSripanidkulchai FacultyofPharmaceuticalSciences,KhonKaen University,KhonKaen,Thailand

ShailendraKumarSrivastava SamHigginbottomUniversityofAgriculture, Technology&Sciences,Prayagraj,Allahabad,UttarPradesh,India

MaitreeSuttajit DivisionofNutritionandDietetics,SchoolofMedicalSciences, UniversityofPhayao,Phayao,Thailand;ThaiVegetarianAssociation, Changpuak,ChiangMai,Thailand

M.K.Thakur CentreofAdvancedStudy,DepartmentofZoology,Instituteof Science,BanarasHinduUniversity,Varanasi,UttarPradesh,India

SubramanianThangaleela BehaviouralNeuroscienceLaboratory,Departmentof AnimalScience,SchoolofLifeSciences,BharathidasanUniversity, Tiruchirappalli,TamilNadu,India

BrahmKumarTiwari DepartmentofParamedicalSciences,SGTUniversity, Gurugram,Haryana,India

OrawanWanachewin DepartmentofBiochemistry,FacultyofMedicine,Chiang MaiUniversity,ChiangMai,Thailand

BuseYilmaz

DepartmentofBiology,InstituteofGraduateStudiesinSciences, IstanbulUniversity,Istanbul,Turkey

Preface

Extendinglifespan/healthyaginghasbeenthegreatestwishofhumanssince evolution.Inthepastfewdecades,significantadvanceshavebeenseenin theexplorationoftheagingprocess,itscellularbiology,andbiomarkersof aging,whichhaveprovidedspecifictargetsthatcanbeleveragedforpossibleaginginterventions.Thereisnodoubtthataginginterventionismore complicatedthanfindingthecureforotherdiseases,sincetheagingprocess ishighlyheterochronic.Inaddition,variationsintheoriesexplainingthe agingprocess,thestrategiesbeingexercisedforanagingcure,or/andthe promotionofhealthyagingarealsohighlydiverse.However,interveningin agingisalwaysthenextfrontierincontemporarycureandwillremaintobe ofhigherimportancesinceagingnotonlyaffectsthelifestyleoftheindividualsadverselybutalsobringsdependencyonothersandcostlymedical expenses.

Althoughtheavailabilityofadvancedagecarefacilitieshasdelayedthe developmentandprogressionofagingcomplications,stillitisnotfeasiblefor alargegroupofthepopulationduetohighcosts.Inaddition,sideeffectsassociatedwiththesesyntheticremedieshaverestrictedtheirfrequentandsafe use.Insuchascenario,asustainablecurewithno/leastsideeffectsistheneed ofthehourtocombattheanticipatedfutureburdenofage-dependent complications.

Bioactivesfromplantsofferremar kablefeaturesincomparisonwith traditionalsyntheticmedicines whichendowbothadvantagesandchallengesfordrugdiscovery.Enormouss caffolddiversity,structuralcomplexity,andhighernumbersofH- bondacceptors/donorsprovidehigher molecularrigiditytothesebioactiv escomparedwithsyntheticcompounds, thesecharacteristicsarevaluableind rugdiscoverytacklingprotein-proteininteractions.

Thepresentbookisacomprehensivedescriptionoftheantiagingpotentialofplant-derivedbioactivecompounds,naturallypresentinfoodsand beverages,anditprovidesanupdateonaginginterventionbasedonnatural compounds,whichmaybeutilizedinplant-baseddrugdiscoveryagainstan agingandassociatedcomplications.Writtenbyaglobalteamofexperts,this bookmaybeanidealresourceforresearchersinthisarea.Thisbookhas22 chapters.Chapter1extendsanexpertopiniononagingprinciplesandinterventionalperspectives.Chapters2and22discussanti-agingstrategiesand

thepossibilityofplantbioactivesinantiagingdrugdiscoveryandthechallengesinvolved.Recently,plantpolyphenolshavegainedglobalinterestin aginginterventionduetotheirstrongantioxidativeandimmunomodulatory effects.However,scatteredandcontradictoryliteraturechallengestheconcurringresults.Chapter8exploresmoreonthistopic.Thebookalsocontainsdedicatedchapters9,12,and13onvariousantiagingmechanismsof actionofdifferentpolyphenols.

Neurologicalimpairmentsincludingcognitivedysfunctionareoneofthe majorcomplicationsduringaging,whichcompromisethehealth/lifespansas wellasthequalityoflifeofolderpopulationssignificantly.Chapters10,11, and17specificallydealwiththetherapeuticeffectsofplantbioactivesin counteractingneuroproblemsamongtheelderly.Chapter4focusesonthe advancesmadeindecipheringtheroleofgrapeseedsandgreenteabioactivesinmaintainingglucosehomeostasisinbloodandthebrainduringaging andattenuatingage-associateddisorders.Theimmunomodulatoryroleof plantbioactivesrelevanceinagingisincorporatedinChapter5.

Functionalfoodsrichinbioactivecompoundsarerecentlygainingmuch attentioninpromotinghealthandenhancinglifespan.Keepingthisrationale inminddedicatedChapters14,15,and21areincludedinthebook,which discussestheeffectivenessoffunctionalfoodsinpreventivecognitive impairmentsandimprovingbonehealthintheelderlyandrealisticresultsin clinicaltrialsinagingintervention.

Nanotechnologicalapproachestoenhancementofbioavailability,targeted deliveryandpreventionofbiotransformation,andmajorconcernsassociated withplantbioactivestodrugdevelopmentarediscussedinChapter19. Chapter20hasbeenincorporatedinthebooktobetterunderstandtheeffects ofdietarypatternsandassociatedbioactivesonagingandlongevityindifferentcontinentsoftheworld.Inadditiontotheestablishedcompounds,the antiagingpotenciesofnovelbioactivesarediscussedinChapter18, highlightingthereality,promises,andchallengesinapplyingthemasnutraceuticalorfunctionalanti-agingmolecules.Dietaryrestriction,vegetarian diet,andtheirrelationshipwithagingareexploredinChapter16.

Nutrigenomicsstudiesareimportantinunderstandingtheinteractionof nutrition/foodbioactiveswithlongevitygenes.Chapters3and6discusslongevitygenesandtheirinteractionwithplantbioactives,whichishelpfulin drugdiscovery.Recently,hormesisisintroducedincounterbalancingthe progressiveshrinkageofthehomeodynamicspace,whichistheultimate causeofaging.Chapter7dealswiththehormeticeffectsofplantbioactives inpromotinghealthyagingandlongevity.

Thisbookprovidescutting-edgeupdatedinformationandfutureperspectivesonplantbioactivesasemergingsourcesofleadcompoundsfornew drugdiscoveryagainstagingandrelateddiseases,whichofferpossiblehope forhealthandlongevity.

Preface xxi

WeextendourthankstoallourcontributorswhoprovideduswithsplendidchaptersinthisfieldandElsevier,Inc.formakingeveryefforttopublish thisbook,whenalargegroupofpopulationworldwideisconcernedwiththe age-associatedhealthissues.

KantiBhooshanPandey MaitreeSuttajit

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Agingprinciplesand interventionalperspectives

EwaSikora

LaboratoryofMolecularBasesofAging,NenckiInstituteofExperimentalBiology,Polish AcademyofSciences,Warsaw,Poland

1.1Themessageofgeroscience

Agingischaracterizeddemographicallybyincreasedmortalityanddecreased reproductivesuccesswithadvancingage.Sincetheforceofselection declineswithage,aging,accordingtothenotmutuallyexclusiveevolutionarytheories,evolvesduetomutationaccumulation(mutationaccumulation theory)orasabenefittotheearlylifefitness(antagonisticpleiotropytheory) (Flatt&Partridge,2018).

Agingisaseeminglyuniversalbiologicalphenomenon,whichbegins aftersexualmaturityandgraduallyleadstoadeclineinvariousfunctioning (althoughtheexamplesofanimalsthatdolivewithoutcharacteristicsymptomsofdecreasingfunctionalityandreproductionhavebeendescribedand arecategorizedasnegligiblesenescence)(Finch,2009).Withage,thecharacteristicfunctionalchanges,knownasbiological“hallmarks”ofaging, occuratboththemolecularandcellularlevels.Recently,nineindicative hallmarksthatrepresentcommondenominatorsofagingindifferentorganisms,withspecialemphasisonmammalianaging,havebeenproposed. Namely,genomicinstability,telomereattrition,epigeneticalterations,lossof proteostasis,deregulatednutrient-sensing,mitochondrialdysfunction,cellular senescence,stemcellexhaustion,andalteredintercellularcommunication. Accordingtotheauthorswhoproposedthesehallmarks:“amajorchallenge istodissecttheinterconnectednessbetweenthecandidatehallmarksand theirrelativecontributiontoaging,withthefinalgoalofidentifyingpharmaceuticaltargetstoimprovehumanhealthduringagingwithminimalsideeffects”(Lo ´ pez-Ot´ınetal.,2013).

Thesamegoalofimprovingagingconditionswaspursuedbyotherleadersofbiogerontology,whoassumedthatagingisthemainriskfactorfor manygeriatricsyndromes(GSs)andage-relateddiseases(ARDs),suchas

PlantBioactivesasNaturalPanaceaagainstAge-InducedDiseases.

DOI: https://doi.org/10.1016/B978-0-323-90581-7.00002-5 © 2023ElsevierInc.Allrightsreserved.

sarcopenia,osteoporosis,frailty,cardiovasculardiseases,metabolicsyndrome,osteoarthritis,neurodegenerativediseases,andsomecommoncancers,suchasbreast,prostate,andcoloncancers.Manyofthemolecularand biochemicalmechanismsthatdeterminetherateofagingwerealsounder investigationinlaboratoriesthatfocusedsolelyonindividualchronicdiseases.Thuscollaborationsbetweenscientistsworkingonagingandchronic diseaseshavebecometheneedofthehour.Accordingly,aninterdisciplinary scienceattheinterfaceofnormalagingandchronicdiseasewascreatedand termed“geroscience.”Geroscienceseesagingastheprimarycauseofmany chronicdiseasesoflaterlife.Thusthepremiseunderlyinggeroscienceisthat bytargetingagingwecanpreventordelaymultiplechronicdiseasesand deathsimultaneously(Kennedyetal.,2014).Indeed,invariousexperimental interventionsinlaboratorymodels,itispossibletoslowandpartiallyreverse thefeaturesofaging(Childsetal.,2015).Thebasicmechanismssharedby agingandARDs/GSshavebeenidentifiedas“sevenpillars,”whichinclude adaptationtostress,lossofproteostasis,stemcellexhaustion,metabolism derangement,macromoleculardamage,epigeneticmodifications,andinflammation(Kennedyetal.,2014).Thegoalofgeroscienceistopromotehealthy aging;however,itisgoodtorealizethathealthspanandlonglifespan(longevity)areintimatelyrelated,asindividualswholiveexceptionallylong tendtobehealthyformuchoftheirlives(Franceschietal.,2018).Onthe otherhand,increasedlifeexpectancyobservedduringthepastfewcenturies (althoughdisturbedrecentlybytheCOVID-19pandemic(Maroisetal., 2020))resultedinincreasedmorbidityanddisabilityinoldandveryoldpeople(Chengetal.,2020).

Agingistheresultofacontinuousinteractionbetweenanindividual’s “geneticmakeup”andenvironmentalfactors,characterizedbylifelongdamageaccumulationandprogressivelossoftissueandorganfunctionality (Kirkwood,2017).Indeed,longevityhasheritablecomponents,however, theirinfluencehasbeenoverestimatedforalongtime,andisnowthoughtto benomorethan10%(Melzeretal.,2020).AlsoARDshaveaheritability component,butitdependsverymuchonthetypeofdisorder(Tenesa& Haley,2013).Nonetheless,relativelylowheritabilityofthedurationoflifespanstrengthensthelong-lastingassumptionthatagingisaplasticprocess, whichcanbemodifiedbylifestyleandenvironment(Kirkwood,2017).Thus prolongingnotonlylifespanbut,firstofall,healthspan,ispossible,since accordingtogeroscience(letusrepeat)both“physiological”and“pathological”agingsharethesamebasicmolecularandcellularmechanisms,and shouldbeconsideredasthesameprocessbutoccurringwithadifferentrate dependingondiversegeneticbackgroundandlifestyle(Franceschietal., 2018).Fromtheplethoraofanimalandhumandatacollectedsofar,it emergesthatthereareseveralcommonmolecularandcellulartargets,which atleastpartiallyoverlapwithcommonaginghallmarks,andwhichcanbe modifiedbylifestyle.Theseincludespecialdiets,food,nutrition,physical 2

activity,andpharmacologicalapproach.Someofthebeneficialinterventions andtheirtargetsarebrieflyreviewedbelow.

1.2Rejuvenationbydiet

AnoldChineseproverbsays:showmewhatyoueatandI’lltellyouwho youare.Itcanbeparaphrasedasfollows:showmewhatandhowyoueat, andIwilltellyouwhatageyouare.Wemeanthebiologicalage,whichis differentfromthecalendarage.Eachofushasourownaginghistoryreflectingourgeneticbackgroundandlifestyle.Thematteristofollowtherulesof life,whichwillallowustodieyoungaslateaspossible.Epidemiological, clinical,andpreclinicalstudiesactuallyshowedthatwhatweeatandhow muchweconsumecontributestodeterminingourhealthspan(Ekmekcioglu, 2020).Manipulationofanutritionallybalanceddiet,whetherbyalteringthe caloricintakeormealtiming,canleadtoadelayintheonsetandprogressionofdiseasesandincreaselifeinmostorganisms(DiFrancescoetal., 2018).

Thebeneficialeffectsofcaloricrestriction(CR)onlifespanhavebeen discoveredmorethanacenturyago(Osborneetal.,1917).Later,thepositiveeffectofCRonhealthspanandlifespanhasbeendocumentedinmany modelorganisms,suchasyeast, Caenorhabditiselegans, Drosophilamelanogaster,mice,andprimates,pointingtothestrongevolutionaryconservationofthecommonmechanismsconnectingfoodintaketolongevity(De Cabo&Mattson,2019).CRinvolvesa20% 40%reductionincalorie intakewithoutcausingmalnutrition.Also,inhumans,datafromobservationalandrandomizedclinicaltrialsindicatethatCRelicitsthesame mechanismsandbeneficialeffectsasinanimalmodelsoflongevity. ModerateCRinhumansamelioratesmultiplemetabolicandhormonalfactorsthatareimplicatedinthepathogenesisoftype2diabetes,cardiovascular diseases,cancer,andneurologicaldisorders,theleadingcausesofmorbidity, disability,andmortality(Dorlingetal.,2020;Mostetal.,2017).

Foodprovidesuswithnutrientsandenergynecessaryforgrowth,reproduction,andthesustainenceoflife.Moreover,nutrientsregulatemanyprocessesonthemolecular,cellular,andorganismallevelsviaso-callednutrient signalingpathways,whichinfluencetheagingprocess.Genetic,pharmacological,ordietaryinterventionstargetingnutrientsignalingpathwayshave beenshowntoattenuateaginginmanyorganisms(Johnson,2018).Theinsulin/insulin-likegrowthfactor1(IGF-1)signalingpathway(ILS)wasthefirst definedgeneticpathwayregulatingagingandARDsinmodelorganisms (Kenyon,2011).Additionalplayershavesincebeenidentified,suchas mTOR(mechanistictargetofrapamycin),AMPK(50 AMP-activatedprotein kinase),andsirtuins,asrobustmediatorsoftheprotectiveeffectsofdietary restriction(Johnson,2018).Allthesesignalingpathwaysaresomehow interconnected.

4 PlantBioactivesasNaturalPanaceaagainstAge-InducedDiseases

ThemaincomponentofILSisIGF-1,ananabolichormonemainlyproducedintheliverandlocallyexpressedinperipheraltissues.Inmammals, IGF-1isunderthecontrolofgrowthhormone(GH)fromthepituitaryand secretionofGH/IGF-1isessentialfornormalgrowthandforthemaintenanceofanabolicprocesses.DownstreamofIGF-1areforkheadboxtranscriptionfactors(FOXOs).CRnegativelyregulatesILS,thusprolonging lifespaninmodelorganisms(Yuetal.,2021).mTORisanutrient-sensing threonine-serinekinasethatintegratesextra-andintracellularsignalsfrom nutrients,growthfactors,andvariousstresses.TORcomplexI(TORC1)is rapamycin-sensitiveandisthecentralelementoftheTORsignalingnetwork. TORC1activityinfluencestranscription,mRNAtranslation,autophagy, metabolismandcellsurvival,proliferation,sizeandgrowth,andmanyother processes.StudiesinlaboratorymodelssupportthenotionthattheTORsignalingnetworkmodulatesaging(Kapahietal.,2010).

AMPKisakeyregulatorofenergyinthecell,whichallowsthecell/ organismtosurviveevenwithadeficitofATP.Downstreammediatorsof AMPKsignalingincludemTOR,aminocyclopropane-1-carboxylicacid (ACC1),glucosetransporter1(GLUT1)/GLUT4,p53,autophagyactivating kinase1/2(ULK1/2),peroxisomeproliferator-activatedreceptor-gamma coactivator-1(PGC1-),FOXOs,whicharecomponentsofthecentralmetabolicactivitiesintheagingprocess.Thusthekinaseregulatesglucoseconsumption,cellproliferation,autophagy,andsynthesisofproteinsandfatty acids;alltheseprocessesarecloselyrelatedtolongevity(Morgunova& Klebanov,2019).

Sirtuinsarethefamilyofproteinsalsotermedtheproteinsofyouthas theirleveldeclineswithage.Inhumans,thefamilyconsistsofsevenmembers(SIRT1 7)thatpossesseithermono-ADPribosyltransferaseordeacetylaseactivity.Althoughsomedataputinquestionthedirectinvolvementof sirtuinsinextendingthehumanlifespan,itwasdocumentedthataproper lifestyleincludingphysicalactivityanddietcaninfluencehealthspanvia increasingthelevelofsirtuins.Sirtuinsinfluencetheactivityofmanymoleculesandsignalingpathwaysinvolvedintheprocessofsenescence,suchas FOXO,NF-κB,TOR,p53,andDNAdamage/repair(Grabowskaetal., 2017).ThusCRseemstobearelativelywell-recognizedmeansofinfluencingatleastseveralmolecularmechanismsinvolvedinmetabolism,redirectingitintoatrackthatfavorshealthspan.Itseemsthatbeneficialeffectsof moderate,butnotsevereCR,havebeenwelldocumentedinpreclinicaland clinicalstudies.ThequestioniswhyCRcannotbeimplementedasaroutine inthehumanlifestyle?Theanswerseemstobeascomplicatedastheworld welivein.However,justconsideringhumannature,itseemsthatkeeping permanentfooddisciplineintheobesogenicWesternworldisextremelydifficult.Moreover,studiesinmiceandnonhumanprimateshaverevealedthat theeffectofCRonlifespanextensionisnotuniversal(Ingram&deCabo, 2017).CRregimens,sex,age,andgeneticbackgroundcontributetothe

outcomesregardinghealthandsurvivalinmice,thushighlightingthecomplexitiesoftranslationofCRintohumans(Mitchelletal.,2016).Moreover, chronicCRhasbeenreportedtoexertadverseeffectsonanumberofmouse strains(includingshortenedlifespan)(Liaoetal.,2010).Furthermore,itis difficulttopredicthowCR,inwhichdailycaloricintakeistypically decreasedby15% 40%,mayaffectthephysicalandmentalconditionof oldpeople,whoarealreadymuchmorevulnerableintheseaspectsthan youngindividuals.

ThishasraisedinterestinalternativefeedingregimensthatmayrecapitulateatleastsomeofthebeneficialeffectsofCRbycontrollingfeedingfastingpatternswithoutadrasticreductionincaloricintake(DeCabo& Mattson,2019;Fantietal.,2021;Mattsonetal.,2014).Noveltherapeutic strategies,focusedprimarilyondietaryinterventions,havebeenproposed: time-restrictedeating,altereddiet,intermittentfasting(IF),andperiodic fasting/fasting-mimickingdiet(FMD)(Fantietal.,2021).Theyarefocused alsoonreducingobesity,butanelevatedBMIresultsinmanypathologies, whichshortenlifespan(Mattsonetal.,2014).Indeed,animalsundergoing differenttypesoffastingcanlivelongerthanthosethateateveryday adlibitum.Inmice,FMDrejuvenatestheimmunesystem,reducescancer incidence,promoteshippocampalneurogenesis,improvescognitiveperformance,andprolongshealthspan.Inhumans,FMDcausedbeneficialchanges inriskfactorsofARDs(Brandhorstetal.,2015).Bothinanimalsand humans,differentdietprotocolspromotehealthbenefits,includingresistance todiabetes,cancers,cardiovascular,andneurodegenerativediseases(Fanti etal.,2021).

Mechanistically,duringfasting ,similartoCR,theratioofAMPto ATPisincreasedandAMPKisactivated ,triggeringrepairandinhibition ofanabolicprocesses.AcetylcoenzymeA(CoA)andNAD 1 serveas cofactorsforepigeneticmodifierssuc hassirtuins.Sirtuinsdeacetylate FOXOsandPGC-1 α,whichresultsintheexpressionofgenesinvolvedin stressresistanceandmito chondrialbiogenesis( Mattsonetal.,2018 ). Sincesirtuin1deacetylatesseveral cytoplasmicproteins,suchasAMPdependentkinase,theresultingAMPKautophagy-relevantgeneproducts maybemajoractivatorsofautophagy.Thishasbeendocumentedby usinganaturalproduct,resveratrol,presentingrapesandredwine,which isadirectsirtuin1activator( Madeoetal.,2010 ).Severalothersmall molecules,whicharesirtuins’regul ators,arealreadyinclinicaltrials ( Daietal.,2018 ).

NutrientstarvationtriggersdownregulationoftheILSsignalingpathway andreductionofcirculatingaminoacids,whichrepresstheactivityof mTOR,resultingininhibitionofproteinsynthesisandalsostimulationof autophagy.mTORisanegativeregulatorofautophagy.Indeed,thereis accumulatingevidencethatbothfastingandCRhavearoleintheupregulationofautophagy(Bagherniyaetal.,2018).Autophagyisaprocesswhereby

6 PlantBioactivesasNaturalPanaceaagainstAge-InducedDiseases

cellularmaterialisdegradedinalysosome-dependentmannerandrecycled. Autophagyisanevolutionarilyconservedphysiologicalprocesswithafundamentalroleduringdevelopment,differentiation,andsurvival,essentialfor homeostasisineukaryoticcells(Dudkowskaetal.,2021).Severaltypesof autophagycanbedistinguisheddependingonthemechanismsoftheuptake ofcytosolicmaterialbylysosomes(Yim&Mizushima,2020).Themostfrequentlyobservedtypeofautophagyismacroautophagy(hereinreferredtoas autophagy),whichischaracterizedbytheformationofautophagosomes, theirfusionwithlysosomes,andcargodegradation(Mizushima&Komatsu, 2011).Thusthespecificstagesofautophagyareinduction,formationofthe isolationmembrane(phagophore),formationandmaturationoftheautophagosome,and,finally,fusionwiththelysosometoformtheautolysosome (Nakamura&Yoshimori,2018).Moreover,theso-calledselectiveautophagy,whichmeansdegradationofspecificorganelles,suchasmitochondria (mitophagy),lysosomes(lysophagy),ormolecules(lipophagy,aggrephagy), canbedistinguished(Hansenetal.,2018).Autophagy,whichcanbe inhibitedatanystageleadingtotheaccumulationofundigesteddefective moleculesandorganelles,contributestoage-relateddisorders,suchasneurodegenerativediseases,heartdiseases,andcancer.Ontheotherhand,active autophagyisconsideredtocontributetoahealthylifespanandlongevity (Nakamura&Yoshimori,2018).Thusrestoring/activationofautophagy maybearationalstrategyforhealthspan(Rubinszteinetal.,2011).Indeed, itwasdocumentedthatsometissuesmaybenefitfromautophagyactivation inlongevitymodels,astissue-specificoverexpressionofsingleautophagy genesissufficienttoextendlifespan.Moreover,selectivetypesofautophagy maybecrucialforlongevitybyspecificallytargetingdysfunctionalcellular componentsandpreventingtheiraccumulation(Hansenetal.,2018). Themostspectacularnaturalcompound,polyaminespermidine,hasbeen recentlyshowntopromoteautophagyandlongevity.Externaladministration ofspermidineprolongsthelifespanofyeasts,flies,andwormsinan autophagy-dependentfashionandspermidine-mediatedtranscriptionof autophagy-relevantgenesmayaccountfortheobservedinductionofautophagy(Madeoetal.,2019).

BesidessomedoubtsconcerningCRdescribedabove,itseemsthattheso farcollecteddatastronglysupportbeneficialeffectsonthehealthspanofany kindofdietrestrictionandmanymechanismsinvolvedinthisprocesshave beenelucidated.However,toimplementanydietrestriction,peoplerequire strongmotivation,discipline,changingtheorganizationoflife,givingup habitsandfavoritefoods.Itcanalsonegativelyinfluencesociallifeandrelationshipwithothers.Thusmanynutraceuticalsandpharmacological approaches(besidesthosedescribedabove),thatmimictheeffectsofdiet restrictionwithouttheneedtosubstantiallyalterfeedingandsocialhabits, havebeenproposedandmorestudiesareinprogress.Theyarebriefly describedbelow.

1.3Antiagingmoleculesmimickingdietrestrictions

Variousorganiccompoundshavebeenshowntomodulateagingpathwaysin amannersimilartoCRandIFandare,therefore,referredtoasCRmimetics (Marteletal.,2021).Someofthem,namelyresveratrolandspermidine,have alreadybeenmentioned.Thebest-knownotherexamplesofcompoundsthat canbeclassifiedasCRmimeticsarerapamycin,metformin,andcurcumin.

Rapamycinisamacrolidecompoundinitiallyisolatedfrom Streptomyces bacteriaandusedtopreventorgantransplantrejectionduetoitsimmunosuppressiveeffects.RapamycininhibitsmTOR.Treatmentwithrapamycin extendslifespanandimproveshealthmarksininvertebratesandmice (Johnsonetal.,2013).Duetosomeserioussideeffectsofrapamycin,such asincreasedrisksofcataracts,infections,andinsulinresistance,thehopeis inderivativescalledrapalogs.First-generationrapalogs,suchaseverolimus andsirolimus,havebeenapprovedtopreventorganrejectionorforcancer treatment.Second-andthird-generationcompoundsarecurrentlybeing investigatedinpreclinicalandclinicalstudies(e.g.,NVP-BEZ235,OSI-027, andRapaLink-1)(Boutoujaetal.,2019).

Metformin,initiallyderivedfrombiguanidesisolatedfromFrenchlilac, isawidelyprescribedantidiabeticdrugthathasbeenfoundtoattenuatehallmarksofaging(Kulkarnietal.,2020).Moreover,itwasshowntoimprove insulinsensitivitythroughvariousmechanismsthatincludeinhibitionof complexIoftheelectrontransportchain,activationofAMPKandautophagy,inducedglucagon-likepeptide-1(GLP-1)secretion,andmodulationof thegutmicrobiota.Inrandomizedtrials,metforminnotonlypreventedthe onsetofdiabetesbutimprovedcardiovascularriskfactors(Knowleretal., 2002).Epidemiologicalstudieshavesuggestedthatmetforminusemight alsoreducetheincidenceofcancerandneurodegenerativediseases(Barzilai etal.,2016)andretrospectiveanalysisofpatientswithdiabeteswhoreceived metforminshowedincreasedlifespanincomparisontoindividualswithout diabetes(Bannisteretal.,2014).Dueinparttoitsrelativelysafeprofileand evidenceindicatingthatmetforminmayreducemortalityinhumans,this drugwillbethefirstCRmimetictobetestedtodelaysignsofagingand chronicdiseaseinhealthyhumansaspartoftheTargetingAgingwith Metformin(TAME)clinicaltrial(Kulkarnietal.,2020).

Curcuminisaphytochemicalbelongingtopolyphenols.Polyphenolsare afamilyofsecondarymetabolitespresentinleaves,bark,vegetables,fruits, herbs,andmanyhigherplants.Theyareinvolvedinthechemicalprotection ofplants,alsoplayanimportantroleinplantreproductionandgrowth,and arethemostcommonbioactivenaturalproducts(DelBoetal.,2019).As curcumincaninteractwithmanyreceptors(e.g.,EGFR,CXCR4),growth factors(e.g.,EGF,TGF),kinases(e.g.,MAPK,FAK),transcriptionfactors (e.g.,NF-KB,STAT1 5),enzymes(e.g.,DNApol,COX2),adhesionmolecules(e.g.,ICAM-1,VCAM-1),apoptoticregulators(e.g.,survivin,Bcl-2),

8 PlantBioactivesasNaturalPanaceaagainstAge-InducedDiseases

proinflammatorycytokines(e.g.,interleukin(IL)-8,tumornecrosisfactor (TNF)),andotherproteins(e.g.,p53,cyclinB1),itcanevokeabroadcellularresponse.Furthermore,curcuminup-anddownregulatesdifferentRNAs andtakespartinepigeneticalterationsbyinhibitingDNAmethyltransferases andregulatinghistonemodificationsviaeffectsonhistoneacetyltransferases andhistonedeacetylases.Thuscurcuminaffectsdiversebiologicalprocesses, suchastheredoxstate,inflammation,proliferation,migration,apoptosis, woundhealing,and,therefore,improvesmemory,postponesaging(inmodel organisms),andARDssuchasatherosclerosis.Therearemanycomprehensivereviewsconcerningthebeneficialeffectsofcurcuminonhealthspanand someofthemcomefromourlaboratory(Bielak-Zmijewskaetal.,2019; Salviolietal.,2007;Sikoraetal.,2010).Duetoallthosepropertiesofcurcumin,ithasbeenusedinavastnumberofclinicaltrialsasadrugoradjuvantinthetreatmentofvariousdiseases(Salehietal.,2019).Recently, curcuminhasbeenclassifiedasaweaksenolytic(Yousefzadehetal.,2018). However,theseriousobstacleinclassifyingcurcuminasapanaceaforaging andARDsisitslowbioavailability,whichresearchersaretryingtoovercomebydesigningcurcuminnano-formulations(Mahjoob&Stochaj,2021). However,itisworthytonotethatnotonlycurcuminbutalsootherdietary restrictionmimetics(includingphytochemicals),anddietaryrestrictionby themselves,areconsideredashormetics.Hormeticagentsproducea biphasic,hormeticresponseonphysiologicalfunctions,inwhichbeneficial effectsareobservedatlowdoses,whereasdetrimentaleffectsareproduced athighdoses.Thusitcannotbeexcludedthatincreasedbioactivitymay relatetounpredictedharmfuleffects(Marteletal.,2019).

1.4Cellularsenescenceandsenotherapy

Agingismanifestedontheorganismallevel.MostARDsaffecttheentire system.However,thebasicbuildingandfunctionalblocksofmulticellular organismsarecells.Althoughdependingontheorgan,thecellshavevery specializedfunctions,theyalsohavethesamebasalpropensities,namely divisions,differentiation,programmedcelldeath,autophagy,andsenescence. Thesepropensitiesarechangingduringlifespan.Withage,whentheperiod ofgrowthisfinished,therearefewerproliferating,differentiating,anddying cells,butmoresenescentcellsandcellswithdysregulatedautophagy.By modulatingautophagyandcellsenescence,whicharetosomeextentinterconnected,itispossibletoprolonghealthspan.Recently,atotallynew approach,thatissenotherapy,hasbeenproposed(reviewedin(Sikoraetal., 2019)).Itreliesontheassumptionthattheburdenofsenescentcellsincreasingwithage,despitesomebeneficialproperties,isresponsibleforagingand ARDs(Farretal.,2017;Sikoraetal.,2011).Accordingly,selectivekillers ofsenescentcellswereidentified(Zhuetal.,2015).

Originally,cellularsenescencewasdescribedasaprocessofproliferation cessationcausedbyexhaustionofcelldivisionpotentialduetotelomereerosion(replicativesenescence).Later,itappearedthatoncogeneactivation (oncogene-inducedsenescence—OIS)andvariousformsofstress(stressinducedprematuresenescence—SIPS)canstopcelldivisionsandleadtothe manifestationofothercellularsenescencemarkers,suchasincreasedlevel ofcellcycleinhibitors,p16andp21,DNAdamage,chromatinrearrangements,decreasedleveloflaminB1,increasedgranularity,andenlargedcell size(Bielak-Zmijewskaetal.,2018;Gorgoulisetal.,2019).Moreover,the senescentphenotypehasrecentlybeenassignedtoproliferation-noncompetent,post-mitoticcells(Sikoraetal.,2021;VonZglinickietal.,2021). Senescentcellsarealive,metabolicallyactive,resistanttoapoptosis,but havedisturbedproteostasis(Sabathetal.,2020).Senescentcellssecretealot offactors,includingcytokines,growthfactors,andmetalloproteinases,which arecommonlydescribedasasenescence-associatedsecretoryphenotype (SASP)(Freundetal.,2010).SASPparticipatesingeneratingthestateof low-gradechronicinflammation,calledinflammaging,althoughoriginally inflammagingwasstrictlyconnectedwithimmunosenescence(Franceschi etal.,2000).

InflammagingislinkedtoARDsandGSssuchascancer,type2diabetes, cardiovasculardiseases,neurodegenerativediseases,andfrailty(Franceschi &Campisi,2014).Otherfactorsthatcontributetoinflammaginginclude obesityandchangesinthepermeabilityoftheintestinalbarrierassociated withthetranslocationofbacterialproducts(Fransenetal.,2017).

Interestingly,dietaryrestrictionreducesinflammatorybiomarkers (Fontana,2009).Onthebasisofthesefindings,inflammagingisnowconsideredtobeabiomarkerforacceleratedagingandoneofthehallmarksof agingbiology.Senescentcellsaccumulatewithageand,togetherwith inflammaging,areconsideredtobethemainculpritofagingandARDs(Di Miccoetal.,2021;Sikoraetal.,2014;Sikoraetal.,2019).Inaseminal paperbyBakeretal.(Bakeretal.,2011),ithasbeenshownthatbygenetic manipulationinamousemodelitispossibletoclearsenescentcells,thus postponingtheagingprocess.Duringthepastdecade,thenumberofpreclinicalstudiesusinggeneticandpharmacologicalapproacheshasincreaseddramatically.Thesestudiesprovedthattargetingsenescentcellsresultsin alleviationofmanyaging-relateddisorders,suchasosteoarthrosis,liverstenosis,kidneyandpulmonarydysfunction,heartstroke,cognitiveimpairment, Parkinson’sandAlzheimer’sdisease,physicalweakness,andmanyothers (Childsetal.,2017;Pignoloetal.,2020;Tchkoniaetal.,2021).Moreover, pharmacologicaltreatmentbysenolyticsappearedtobeeffectiveasanantiagingstrategyandpreliminaryevidencecomingfromclinicaltrialsshows thatsenolyticscanbeappliedalsoforhumantreatmentgivingthepromise ofhealthspan(Kirklandetal.,2017;Kirkland&Tchkonia,2020).Sofarthe mosteffectivesenolyticsapprovedforuseinhumansaredasatinib,whichis

ananticancerdrug,appliedtogetherwithanaturalcompound,quercetin (Justiceetal.,2019).However,manyotherpotentialsenolyticsarecurrently testedinagrowingnumberoflaboratories.Furthermore,theemergenceof senomorphic(orhemostatic)compounds(Shortetal.,2019),whichtarget molecularpathwaysresponsibleforSASP,isobserved.Thus,collectively, senotherapeuticsareanewclassofdrugsandnaturalproductsthatconsistof senolyticsandsenomorphics(Lagoumtzi&Chondrogianni,2021). Moreover,thereisapossibilitytoreducetheburdenofsenescentcellsindirectlybyimprovingimmunecellfunction.Functionalimmunecells,includingNKcells,macrophages,andTcells,canremovesenescentcells. However,astheimmunesystemages,theabilitytoclearsenescentcells diminishes.Thereforeitisconceivabletousethesamemechanismsthatthe immunesystemdoestotargetotherthreats,toeliminatesenescentcells. Severalsuchapproacheshavebeenrecentlyimplementedandarebeing reviewed(Ovadya&Krizhanovsky,2018).Thusthemaingoalofsenotherapeuticsistoeliminateordelaytheadverseeffectsofcellularsenescence and,consequently,theprocessofagingandage-relatedpathologies (Lagoumtzi&Chondrogianni,2021).

1.4.1Senolytics

Senescentcellsareresistanttoapoptosis.Usingbioinformaticsapproaches basedontheRNAandproteinexpressionprofilesofsenescentcells,five senescent-cellantiapoptoticpathways(SCAPs)wereidentified:BCL-2/BCLXL,PI3K/AKT/ceramidemetabolicnetwork,MDM2/p53/p21/serpineelements,ephirins/dependencereceptors/tyrosinekinases,andhypoxia-inducible factor(HIF-1α)pathway.TherequirementofSCAPsforsenescentcellviabilitywasverifiedbyRNAinterferencestudies,inwhichkeyproteinsin thesepathwayswerereduced(Kirkland&Tchkonia,2017;Zhuetal.,2015). Knocking-downexpressionoftheseproteins(Achilles’heels)causedthe deathofsenescentbutnotofnonsenescentcells(Zhuetal.,2015).Sincethe discoveryofthefirstfiveSCAPs,anotheronewasidentified,namelythe HSP-90-dependentpathway(Fuhrmann-Stroissniggetal.,2017).This approachwassubsequentlyusedtoidentifyputativesenolytictargets (reviewedby(Kirklandetal.,2017)).Thefirsttwosenolytics,namelyquercetinanddasatinib,weredescribedin2015(Zhuetal.,2015).Tillthistime varioussenotherapystrategieshavebeendevelopedusingacombinationof invitromodelsofsenescenceandinvivoanimalmodels(DiMiccoetal., 2021).

Manynaturalagentsknownmainlyfromtheiranticanceractivityand influencingmanysignalingpathwaysarenowknownassenolytics. Quercetin’sactionincludesestrogenreceptorsignaling,mTOR,NF-K,PI3k/Akt, p53/p21/serpine,andHIF-1α pathways(Reyes-Farias&Carrasco-Pozo,2019). Fisetin,similarto quercetin,isanaturalflavonoidthatimpactsPI3K/AKT/mTOR,