Serum eicosapentaenoic acid to arachidonic acid ratio is associated with cardio-healthy exceptional longevity

Abstract

1. IntroductionLong-chain ω-3 polyunsaturated fatty acids, (PUFAs)eicosapentaenoic acid (EPA; 20:5(n-3)) and docosahexaenoic acid(DHA; 22:6(n-3)) are associated with coronary heart disease (CHD)[1]. Specifically, high serum levels of EPA and DHA as well as reducedconcentrations of the ω-6 PUFA arachidonic acid (AA; 20:4(n-6)) areassociated with lower CHD risk [2] and a higher EPA/AA ratio portendsadecreasedriskofacutemyocardialinfarction(AMI)andsuddencardi-ac death [3]. The biological effects of ω-3 PUFAs on the cardiovascularsystem involve, among numerous pathways, transformation to bioac-tivemetabolites,alterationofphysicalandchemicalpropertiesofcellu-lar membranes, modulation of membrane channels and proteins,regulation of gene expression, or changes in eicosanoid profiles [1].Owing to the limited ability of humans to synthesize EPA, the DietaryGuidelines for Americans recommend obtaining them from marineoils or supplements [4]. However, some controversy exists with recentevidence not supporting a strong cardiovascular benefitofomega-3PUFA consumption [5]. The potential preventive effect of ω-3 PUFAsalso varies depending on the dosages employed and the characteristicsof selected patients [6].Ingeneral,threemajorpointsduringthecourseofhumanagingcanbe identified: 60 years old (the average age of onset of major age-associated diseases), 80 years old (average life expectancyin the West-ern world), and 100 years old (exceptional longevity [EL]). People whoreach EL may be further divided into three subgroups: 1) ‘survivors’—those who survive to become centenarians in spite of the onset ofmajor age-associated diseases, including CHD, at an age comparable tothe general population, i.e. at the age of 60 years (thus characterizedby a long lifespan but a short healthy lifespan); 2) ‘delayers’—thosewho develop age-related diseases much later than the control popula-tion, i.e. at the age of 80 years instead of 60 years (therefore having along healthy lifespan), and 3) ‘dodgers’ or healthy centenarians —those who fail to develop age-related illnesses naturally throughouttheir lifespan [7]. The question as to whether PUFAs may be associatedwith EL — especially in CHD-free centenarian ‘dodgers’—remainsopen. With the intent of gaining insights into the CHD and longevity-predictivevalueofbloodPUFAs,wecomparedunderacase–controlde-signtheEPA/AAratioamongCHD-freecentenarian‘dodgers’andyoun-ger adults with or without CHD.2. MethodsThe study complied with the tenets of the Declaration of Helsinki andwas approved by the local ethics committee. Written informed consentwasobtainedfromallparticipants.Thefollowingthreegroupsofsubjectswere analyzed: CHD-free centenarian ‘dodgers’, patients who experi-encedAMIatlessthan40yearsofage,andapparentlyhealthyyoungcon-trols(Table1).Theparticipants'ageswerede finedbythedatesofbirthasstatedonidentitycards.AllsubjectswereCaucasianwhitesascertainedtobe of Italian descent (Northern Italy, mainly from Lombardy and Pied-mont). The sample has been previously described [8].Thecentenarian‘dodgers’wereascertainedmainlyviageneralprac-titionersinthecommunity.Thehistoryofpastandcurrentdiseaseswasaccuratelycollected,checkingthecentenarians'medicaldocumentationand their current drug therapy. Accordingly, all of them were ‘dodgers’