biostudies-literatureManoharan MSIntramural NIH HHSNCATS NIH HHSNIDCR NIH HHSNIA NIH HHSNIAID NIH HHSNHLBI NIH HHSUnited States Air Force (DoD)U.S. Department of Veterans AffairsNIH HHSNIGMS NIH HHSCSRD VAe70063https://www.ebi.ac.uk/biostudies/studies/S-EPMC12266754biostudies-literatureUnknown24(7)Human aging presents an evolutionary paradox: while aging rates remain constant, healthspan and lifespan vary widely. We address this conundrum via salutogenesis-the active production of health-through immune resilience (IR), the capacity to resist disease despite aging and inflammation. Analyzing ~17,500 individuals across lifespan stages and inflammatory challenges, we identified a core salutogenic mechanism: IR centered on TCF7, a conserved transcription factor maintaining T-cell stemness and regenerative potential. IR integrates innate and adaptive immunity to counter three aging and mortality drivers: chronic inflammation (inflammaging), immune aging, and cellular senescence. By mitigating these aging mechanisms, IR confers survival advantages: At age 40, individuals with poor IR faceAging cellThe 15-Year Survival Advantage: Immune Resilience as a Salutogenic Force in Healthy Aging.PMC12266754T32DE014318IP1 CX000875R21GM147800UM1 TR004538HHSN268201500001CIP1 CX000875-01A1T32 DE014318K23 AG066933K23AG066933COVID19-8100-01R37 AI0463261UM1TR004538R37AI046326R21 GM147800ZIA AI001202ZIA HG200374ZIA HG200373Z01 AI000825ZIA HG200371FA8650-17-2-6816AAI20042-001HHSN268201500001ICarrillo AGrigsby SLester CSPascual-Guardia SLouder ATovar EJMedlin LZhang NPolk PBMunro SBReichelderfer RLBolan-Reding SNSanchez-Reilly SRatcliffe TADickerson JSanchez MEArellanes AGrassmuck SRudd TEscalante MStewart EWalker MJewell PBanfield ABOkulicz JFHanson JSanders THo TTNambiar AAgnew JMaldonado RFarrar RColazo RHe WSchmit DQuitta RFWinter CAVarela CJLawler ACLewis HVBriggs HAnzueto AHarper NSmith AMBranum APJabur AFeldman DLee MEscamilla VAbdalla MIBraddy SDoanne JSoni NDhami CRenz EMGaitan AARoss JHinojosa CDePaul SADanaher PJVenticinque SGMcElligott NAdebayo YLevine SMNassery DGarza MAFoy JDPreston KJNicholson SVeloso MCJo GGoel MClark RAPhillips REMoreno JBarnett CBenavides RJohnson TBPatterson MYabes JMSTVHCS Center for Personalized MedicineBirdwell AAdams SGBradford SFlores DWang EBarker JDeLeon KSMeunier JASouth Texas Veterans Health Care System (STVHCS) COVID‐19 Clinical teamO'Rorke JRamirez LJOakman KMarin-Corral JGarza MMurray CButler CRPadgett CPeters JIDiaz NGSTVHCS COVID‐19 Vaccine teamTam WSSalehi MNoronha MSegal LNFlynn JFreeman MTrinh HDPugh JARestrepo MINathanson RVillanueva MSTVHCS COVID‐19 Convalescent care teamHopkins TJiva KRangel MGarcia JGoyal VKMorneau KPandranki LHecht JMMang HMartinez CMader MBalmes MTyler AREscamilla CWallace AMartinez YMelby PWickizer SKarekatt SVillegas LWallace MAngel LHaywood AMireles MAndampour KZentner KHAhuja SKWinter LAPerez GLPomager MABible VHussain ANSchindler KCWilliamson ASehgal RTMoreira AGCadena Zuluaga JAMuetz JSolorzano CVillalpando JAPerez RPaleracio EManoharan MSTripathy DKadhume RVasquez AYunes AJimenez FGomez JProud KCHarris BMata CAli SElbel SGilman SMainor CFord DRobinson EAnstead GTrammell Velasquez SALee GCDacus JJGalley SfalseThe 15-Year Survival Advantage: Immune Resilience as a Salutogenic Force in Healthy Aging.Human aging presents an evolutionary paradox: while aging rates remain constant, healthspan and lifespan vary widely. We address this conundrum via salutogenesis-the active production of health-through immune resilience (IR), the capacity to resist disease despite aging and inflammation. Analyzing ~17,500 individuals across lifespan stages and inflammatory challenges, we identified a core salutogenic mechanism: IR centered on TCF7, a conserved transcription factor maintaining T-cell stemness and regenerative potential. IR integrates innate and adaptive immunity to counter three aging and mortality drivers: chronic inflammation (inflammaging), immune aging, and cellular senescence. By mitigating these aging mechanisms, IR confers survival advantages: At age 40, individuals with poor IR face2025-01-01T00:00:00Z2025 Jul2026-03-27T15:18:03.904Z2025-08-23T03:08:54.331ZS-EPMC122667544026435710.1111/acel.70063