Programmatic Adaptive Failure in Myeloid Cells: A Novel Mechanism Linking Frailty to Accelerated Epigenetic Aging

Programmatic Adaptive Failure in Myeloid Cells: A Novel Mechanism Linking Frailty to Accelerated Epigenetic Aging | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Programmatic Adaptive Failure in Myeloid Cells: A Novel Mechanism Linking Frailty to Accelerated Epigenetic Aging Tian Wang, Ting Wang, Jia Wang, Jinghuan Li This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8715723/v1 This work is licensed under a CC BY 4.0 License Status: Under Revision Version 1 posted 10 You are reading this latest preprint version Abstract Background Frailty is a hallmark of accelerated biological aging, yet the causal pathways and cellular-molecular mechanisms driving the vicious cycle of "frailty-inflammation-aging" remain unclear. Methods This study employed a multi-level integrative analysis: 1) validation of associations and inflammatory mediation based on the NHANES cohort; 2) establishment of causal chains using two-step Mendelian randomization (including mediation analysis); 3) identification of mechanistic modules through weighted gene co-expression networks and single-cell deconvolution; 4) construction of the AI clinical decision-making system FIRE-AI, integrating inflammatory thresholds, molecular scores, and network pharmacology results. Results Frailty accelerated aging (17.2% mediated by inflammation). Mendelian randomization established the causal chain "frailty → neutrophilia → accelerated aging" (mediation effect 0.309). The BLUE module was found to exhibit a functional paradox—both anti-frailty/anti-inflammatory and pro-neutrophilic proliferation. Single-cell analysis revealed that this paradox originates from the functional differentiation of the module in macrophages (protective clearance) and progenitor cells (myeloid proliferation), manifesting as a systemic decoupling of "clearance intent" and "metabolic support." Based on these findings, the original theory of "Programmatic Adaptive Failure" was proposed, and the POAM score and FIRE-AI decision system were developed, completing the translational loop from mechanism to clinical application. Conclusion This study establishes systemic inflammation as a significant mediator in frailty-driven aging and discovers a novel myeloid-based "Programmatic Adaptive Failure" mechanism. Our work provides both a new theoretical framework for understanding inflammaging and a translatable toolkit (POAM score & FIRE-AI) for stratifying risk and guiding targeted interventions to break the frailty-inflammation-aging cycle. Biological sciences/Computational biology and bioinformatics Health sciences/Diseases Biological sciences/Immunology Health sciences/Medical research Frailty Biological Aging Inflammation Mendelian Randomization Macrophage Lysosomal Function Drug Repurposing Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 Figure 9 Figure 10 Figure 11 Figure 12 Figure 13 Figure 14 Full Text Additional Declarations No competing interests reported. Supplementary Files S1File.docx S1Figure.tiff Cite Share Download PDF Status: Under Revision Version 1 posted Editorial decision: Revision requested 24 Mar, 2026 Reviews received at journal 24 Mar, 2026 Reviews received at journal 18 Mar, 2026 Reviewers agreed at journal 16 Mar, 2026 Reviewers agreed at journal 14 Mar, 2026 Reviewers agreed at journal 14 Mar, 2026 Reviewers invited by journal 12 Mar, 2026 Editor assigned by journal 12 Mar, 2026 Submission checks completed at journal 02 Feb, 2026 First submitted to journal 27 Jan, 2026 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8715723","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":606198026,"identity":"8fb98390-a159-4b14-884b-99bc635cc4d1","order_by":0,"name":"Tian Wang","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA8UlEQVRIiWNgGAWjYBAC+8NAgrENSDAzNj4AUjIMDGz4tbAxw7SwNzcbMDAY8BDWwgDTwnO8TYI4LezMzx4wttnlyUcktlV8bPvDw8/elsDwo2IbHoexmRswbksuNryR2HZzZpsBj2TPsQOMPWdu4/OLmQTjNubEjTMS227zArUY3EhvYGZsw6eF/RtQSz1YSzGRWniAtvw7nDif52AbM0RL2gFCWsokEs8dT9zA3tgsOeOcMcgvCQfx+oX/+DaJj23VifOb2R9++FAmJwcMMcMHPypwawGDBCA2OIAkcACrMnQg30CUslEwCkbBKBiJAAAQLVHQC9v8EQAAAABJRU5ErkJggg==","orcid":"","institution":"Hebei Medical University","correspondingAuthor":true,"prefix":"","firstName":"Tian","middleName":"","lastName":"Wang","suffix":""},{"id":606198028,"identity":"5d106103-0e50-4526-9164-eebe13fc83af","order_by":1,"name":"Ting Wang","email":"","orcid":"","institution":"Yan'an University","correspondingAuthor":false,"prefix":"","firstName":"Ting","middleName":"","lastName":"Wang","suffix":""},{"id":606198030,"identity":"db2db623-1549-4102-8f7b-01a2da9cfcb4","order_by":2,"name":"Jia Wang","email":"","orcid":"","institution":"Tianjin First Hospital","correspondingAuthor":false,"prefix":"","firstName":"Jia","middleName":"","lastName":"Wang","suffix":""},{"id":606198032,"identity":"5359a7d8-90ea-475c-b712-b4a202b304c0","order_by":3,"name":"Jinghuan Li","email":"","orcid":"","institution":"Hebei Medical University","correspondingAuthor":false,"prefix":"","firstName":"Jinghuan","middleName":"","lastName":"Li","suffix":""}],"badges":[],"createdAt":"2026-01-28 03:23:12","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8715723/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8715723/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":104732233,"identity":"d043e186-63a3-49a9-99d3-8aac28f3845e","added_by":"auto","created_at":"2026-03-16 14:42:44","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":767552,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eAssociation of Frailty Index (FI) and Inflammatory Burden Index (IBI) with DunedinPACE: Results from Hierarchical Linear Regression Model.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eModel 1: crude; Model 2: Adjust: age, ethnic, sex, educational attainment, country of birth, PIR; Model 3: Adjust: age, ethnic, sex, educational attainment, country of birth, PIR, smoking status, drinking status.\u003c/p\u003e\n\u003cp\u003eModel 4A: Model 3 + IBI (Assessing the direct effect of FI).\u003c/p\u003e\n\u003cp\u003eModel 4B: Model 3 + FI (Assessing the independent effect of IBI).\u003c/p\u003e\n\u003cp\u003eCI: Confidence Interval. PIR: poverty-to-income ratio. FI: Frailty Index. IBI: Inflammatory Burden Index.\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-8715723/v1/4ecf16cc86b1014f12ce5ac8.png"},{"id":104732220,"identity":"e0ca7d76-b158-4e47-8015-53ce4b889a28","added_by":"auto","created_at":"2026-03-16 14:42:42","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":95616,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eAssociation of Frailty Index (FI) with Inflammatory Burden Index (IBI).\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eModel 1: crude; Model 2: Adjust: age, ethnic, sex, educational attainment, country of birth, PIR; Model 3: Adjust: age, ethnic, sex, educational attainment, country of birth, PIR, smoking status, drinking status.\u003c/p\u003e\n\u003cp\u003eCI: Confidence Interval. PIR: poverty-to-income ratio. FI: Frailty Index.\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-8715723/v1/f9ceda5d0e9bc3068f352f4f.png"},{"id":104732263,"identity":"f177ba8c-4ab7-4bb1-bd62-ea7118ea3065","added_by":"auto","created_at":"2026-03-16 14:42:58","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":585193,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eNon-Linear Associations among Frailty, Inflammation, and the Pace of Epigenetic Aging.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e(A) Frailty Index (FI) vs. DunedinPACE. (B) FI vs. Inflammatory Burden Index (IBI). (C) IBI vs. DunedinPACE.\u003c/p\u003e\n\u003cp\u003eSolid lines represent predicted values from restricted cubic spline models; shaded areas indicate 95% confidence intervals.\u003c/p\u003e","description":"","filename":"Figure3.png","url":"https://assets-eu.researchsquare.com/files/rs-8715723/v1/4537d2a4fdb19e4ec10bbc1f.png"},{"id":104732274,"identity":"34ee6bab-0fe6-4caf-ba1e-dcbf3ef103a2","added_by":"auto","created_at":"2026-03-16 14:43:04","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":277416,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eThreshold Effect Analysis of the Relationship between Inflammatory Burden Index (IBI) and DunedinPACE.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"Figure4.png","url":"https://assets-eu.researchsquare.com/files/rs-8715723/v1/1a8685fe0cc95f94dcba1761.png"},{"id":104732242,"identity":"d59fbc99-b64d-4639-9b51-1291a6061bb2","added_by":"auto","created_at":"2026-03-16 14:42:53","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":5568857,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eForest Plots of Subgroup Analyses.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e(A) Association between FI and DunedinPACE across subgroups. (B) Association between FI and IBI across subgroups. (C) Association between IBI and DunedinPACE within the Low-IBI stratum (IBI \u0026lt; 1.496). (D) Association between IBI and DunedinPACE within the High-IBI stratum (IBI ≥ 1.496). Squares represent point estimates (β); horizontal lines represent 95% CIs. The dashed vertical line indicates the null (β=0). P-int denotes the P-value for interaction.\u003c/p\u003e","description":"","filename":"Figure5.png","url":"https://assets-eu.researchsquare.com/files/rs-8715723/v1/c348da4a55a830de0e5e1829.png"},{"id":104732312,"identity":"36cafd8a-4bfe-4d69-946f-6603e652b261","added_by":"auto","created_at":"2026-03-16 14:43:12","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":228607,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eMediation of the Frailty-Aging Relationship by Systemic Inflammation.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"Figure6.png","url":"https://assets-eu.researchsquare.com/files/rs-8715723/v1/a83f9af8a881b6ec301ee551.png"},{"id":104732264,"identity":"a4fa9756-0c7b-4d7d-9361-c94c8f67fb8b","added_by":"auto","created_at":"2026-03-16 14:42:59","extension":"png","order_by":7,"title":"Figure 7","display":"","copyAsset":false,"role":"figure","size":2008929,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eGenetic Evidence for Neutrophil-Mediated Frailty-to-Aging Pathway.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e(A) Fl → Neutrophil Count. (B) Neutrophil Count POAM. (C) Sensitivity Analysis Across Different MR Methods.\u003c/p\u003e","description":"","filename":"Figure7.png","url":"https://assets-eu.researchsquare.com/files/rs-8715723/v1/fc831d1d07e54e1a743a3795.png"},{"id":104732268,"identity":"36537eeb-a8c6-460b-b653-37c884d5d31a","added_by":"auto","created_at":"2026-03-16 14:43:01","extension":"png","order_by":8,"title":"Figure 8","display":"","copyAsset":false,"role":"figure","size":3057749,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eWGCNA Analysis.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e(A) Module Eigengene Expression Patterns Across Samples. (B) Module Connectivity Analysis. (C) Soft Threshold Power Selection for WGCNA. (D) Module Preservation Analysis. (E) Module-Trait Correlation Heat map.\u003c/p\u003e","description":"","filename":"Figure8.png","url":"https://assets-eu.researchsquare.com/files/rs-8715723/v1/b4df039546c44358abde4b15.png"},{"id":104732248,"identity":"09b170c2-b81d-4756-80e5-d1c85c3e74a4","added_by":"auto","created_at":"2026-03-16 14:42:57","extension":"png","order_by":9,"title":"Figure 9","display":"","copyAsset":false,"role":"figure","size":700919,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eMendelian Randomization Analysis of BLUE Module.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e(A) BLUE Module MR Results Across Phenotypes. (B) Sensitivity Analysis Results.\u003c/p\u003e","description":"","filename":"Figure9.png","url":"https://assets-eu.researchsquare.com/files/rs-8715723/v1/f9dc3efd51413f9d10a39c98.png"},{"id":104732270,"identity":"8ee80133-53d0-436e-9c71-97cc0d3cdacd","added_by":"auto","created_at":"2026-03-16 14:43:02","extension":"png","order_by":10,"title":"Figure 10","display":"","copyAsset":false,"role":"figure","size":2112016,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eCellular Deconvolution of BLUE Module.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e(A) BLUE Module Cell-Type Specificity. (B) Myeloid Lineage Developmental Trajectory. (C) Transcription Factors Regulating BLUE Module. (D) BLUE Module Pathway Enrichment.\u003c/p\u003e","description":"","filename":"Figure10.png","url":"https://assets-eu.researchsquare.com/files/rs-8715723/v1/7b28e1cfd2cc7a485bbd759d.png"},{"id":104732309,"identity":"6a396272-0ff8-4dab-b476-e488c68f46b3","added_by":"auto","created_at":"2026-03-16 14:43:10","extension":"png","order_by":11,"title":"Figure 11","display":"","copyAsset":false,"role":"figure","size":2496894,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eThe Paradox of Non-Productive Activation in Myeloid Cells.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e(A) Pathway Enrichment Reveals Intent-Capability Disconnect. (B) The Paradox of Non-Productive Activation in Myeloid Cells. (C) The Paradox of Failed Compensation. (D) Metabolic-Clearance Imbalance Across Samples.\u003c/p\u003e","description":"","filename":"Figure11.png","url":"https://assets-eu.researchsquare.com/files/rs-8715723/v1/450c06bbcc7660f30ec13c3a.png"},{"id":104732266,"identity":"97b7ba9a-80f4-4f1c-a6b1-ece20e662327","added_by":"auto","created_at":"2026-03-16 14:43:01","extension":"png","order_by":12,"title":"Figure 12","display":"","copyAsset":false,"role":"figure","size":1467100,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSystemic Aging Mapping Visualization\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e(A) BLUE Module as a Convergence Hub for Core Aging Hallmarks. (B) Pathway-Level Evidence for Aging Hallmark Associations.\u003c/p\u003e","description":"","filename":"Figure12.png","url":"https://assets-eu.researchsquare.com/files/rs-8715723/v1/98b3bfba00c21bf19263b4e0.png"},{"id":104732244,"identity":"5bf2eddc-be30-4ac8-8efe-42116442bfdf","added_by":"auto","created_at":"2026-03-16 14:42:54","extension":"png","order_by":13,"title":"Figure 13","display":"","copyAsset":false,"role":"figure","size":1318844,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eTheoretical Synthesis.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e(A) Research Pipe line: From Discovery to Translation. (B) Integrated Mechanistic Model: A Vicious Cycle \u0026amp;Targe table Compensation.\u003c/p\u003e","description":"","filename":"Figure13.png","url":"https://assets-eu.researchsquare.com/files/rs-8715723/v1/daee11ef9dc7e28d50ecd59b.png"},{"id":104732283,"identity":"21f0cdc8-0638-4e64-bf79-a7458294780c","added_by":"auto","created_at":"2026-03-16 14:43:06","extension":"png","order_by":14,"title":"Figure 14","display":"","copyAsset":false,"role":"figure","size":1181742,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eTarget-to-Compound Mapping for BLUE Module Drug Discovery.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e(A) Compound Information Summary. (B) Target Priority Assessment.\u003c/p\u003e","description":"","filename":"Figure14.png","url":"https://assets-eu.researchsquare.com/files/rs-8715723/v1/75315cc9bc8331e69ddaf798.png"},{"id":104732386,"identity":"79245e77-c9d2-4d13-96fd-abdc58ad9180","added_by":"auto","created_at":"2026-03-16 14:43:54","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":3869537,"visible":true,"origin":"","legend":"","description":"","filename":"Manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8715723/v1_covered_482729f0-7029-4d2b-a292-e9ac6c68962f.pdf"},{"id":104732240,"identity":"194d8ee3-33de-4fd5-a31b-8edaf0230cf2","added_by":"auto","created_at":"2026-03-16 14:42:53","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":22171,"visible":true,"origin":"","legend":"","description":"","filename":"S1File.docx","url":"https://assets-eu.researchsquare.com/files/rs-8715723/v1/b1059b0639172bfa08219cbf.docx"},{"id":104732241,"identity":"5ae47179-e12c-4879-906a-d15771543654","added_by":"auto","created_at":"2026-03-16 14:42:53","extension":"tiff","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":351355,"visible":true,"origin":"","legend":"","description":"","filename":"S1Figure.tiff","url":"https://assets-eu.researchsquare.com/files/rs-8715723/v1/02c35c9c28c49135c74403a6.tiff"}],"financialInterests":"No competing interests reported.","formattedTitle":"Programmatic Adaptive Failure in Myeloid Cells: A Novel Mechanism Linking Frailty to Accelerated Epigenetic Aging","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"npj-aging","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"Learn more about [npj Aging](https://www.nature.com/npjamd/)","snPcode":"41514","submissionUrl":"https://submission.springernature.com/new-submission/41514/3","title":"npj Aging","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"NPJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Frailty, Biological Aging, Inflammation, Mendelian Randomization, Macrophage, Lysosomal Function, Drug Repurposing","lastPublishedDoi":"10.21203/rs.3.rs-8715723/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8715723/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFrailty is a hallmark of accelerated biological aging, yet the causal pathways and cellular-molecular mechanisms driving the vicious cycle of \"frailty-inflammation-aging\" remain unclear.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study employed a multi-level integrative analysis: 1) validation of associations and inflammatory mediation based on the NHANES cohort; 2) establishment of causal chains using two-step Mendelian randomization (including mediation analysis); 3) identification of mechanistic modules through weighted gene co-expression networks and single-cell deconvolution; 4) construction of the AI clinical decision-making system FIRE-AI, integrating inflammatory thresholds, molecular scores, and network pharmacology results.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFrailty accelerated aging (17.2% mediated by inflammation). Mendelian randomization established the causal chain \"frailty → neutrophilia → accelerated aging\" (mediation effect 0.309). The BLUE module was found to exhibit a functional paradox—both anti-frailty/anti-inflammatory and pro-neutrophilic proliferation. Single-cell analysis revealed that this paradox originates from the functional differentiation of the module in macrophages (protective clearance) and progenitor cells (myeloid proliferation), manifesting as a systemic decoupling of \"clearance intent\" and \"metabolic support.\" Based on these findings, the original theory of \"Programmatic Adaptive Failure\" was proposed, and the POAM score and FIRE-AI decision system were developed, completing the translational loop from mechanism to clinical application.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study establishes systemic inflammation as a significant mediator in frailty-driven aging and discovers a novel myeloid-based \"Programmatic Adaptive Failure\" mechanism. Our work provides both a new theoretical framework for understanding inflammaging and a translatable toolkit (POAM score \u0026amp; FIRE-AI) for stratifying risk and guiding targeted interventions to break the frailty-inflammation-aging cycle.\u0026nbsp;\u003c/p\u003e","manuscriptTitle":"Programmatic Adaptive Failure in Myeloid Cells: A Novel Mechanism Linking Frailty to Accelerated Epigenetic Aging","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-03-16 14:40:40","doi":"10.21203/rs.3.rs-8715723/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-03-24T15:01:21+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-03-24T07:40:51+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-03-18T10:09:01+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"250639448854500661788530795676999228872","date":"2026-03-16T13:20:49+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"337246393355351384358316225090350747168","date":"2026-03-14T16:12:12+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"80874231757741677550534875362617618073","date":"2026-03-14T16:09:04+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-03-12T15:53:18+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-03-12T15:21:43+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-02-02T09:31:30+00:00","index":"","fulltext":""},{"type":"submitted","content":"npj Aging","date":"2026-01-28T03:05:50+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"npj-aging","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"Learn more about [npj Aging](https://www.nature.com/npjamd/)","snPcode":"41514","submissionUrl":"https://submission.springernature.com/new-submission/41514/3","title":"npj Aging","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"NPJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"abc2659e-12ec-42aa-9e6e-4599da3ab270","owner":[],"postedDate":"March 16th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"in-revision","subjectAreas":[{"id":64512615,"name":"Biological sciences/Computational biology and bioinformatics"},{"id":64512616,"name":"Health sciences/Diseases"},{"id":64512617,"name":"Biological sciences/Immunology"},{"id":64512618,"name":"Health sciences/Medical research"}],"tags":[],"updatedAt":"2026-05-15T14:55:14+00:00","versionOfRecord":[],"versionCreatedAt":"2026-03-16 14:40:40","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8715723","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8715723","identity":"rs-8715723","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}