{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T02:55:17Z","timestamp":1789095317188,"version":"build-2803163510"},"reference-count":46,"publisher":"Public Library of Science (PLoS)","issue":"10","license":[{"start":{"date-parts":[[2024,10,17]],"date-time":"2024-10-17T00:00:00Z","timestamp":1729123200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"UC San Diego Academic Senate"},{"name":"National Institute of Health","award":["NIH grant AG083015"],"award-info":[{"award-number":["NIH grant AG083015"]}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>The mechanism that triggers the progressive dysregulation of cell functions, inflammation, and breakdown of tissues during aging is currently unknown. We propose here a previously unknown mechanism due to tissue autodigestion by the digestive enzymes. After synthesis in the pancreas, these powerful enzymes are activated and transported inside the lumen of the small intestine to which they are compartmentalized by the mucin\/epithelial barrier. We hypothesize that this barrier leaks active digestive enzymes (e.g. during meals) and leads to their accumulation in tissues outside the gastrointestinal tract. Using immune-histochemistry we provide evidence in young (4 months) and old (24 months) rats for significant accumulation of pancreatic trypsin, elastase, lipase, and amylase in peripheral organs, including liver, lung, heart, kidney, brain, and skin. The mucin layer density on the small intestine barrier is attenuated in the old and trypsin leaks across the tip region of intestinal villi with depleted mucin. The accumulation of digestive enzymes is accompanied in the same tissues of the old by damage to collagen, as detected with collagen fragment hybridizing peptides. We provide evidence that the hyperglycemia in the old is accompanied by proteolytic cleavage of the extracellular domain of the insulin receptor. Blockade of pancreatic trypsin in the old by a two-week oral treatment with a serine protease inhibitor (tranexamic acid) serves to significantly reduce trypsin accumulation in organs outside the intestine, collagen damage, as well as hyperglycemia and insulin receptor cleavage. These results support the hypothesis that the breakdown of tissues in aging is due to autodigestion and a side-effect of the fundamental requirement for digestion.<\/jats:p>","DOI":"10.1371\/journal.pone.0312149","type":"journal-article","created":{"date-parts":[[2024,10,17]],"date-time":"2024-10-17T17:30:33Z","timestamp":1729186233000},"page":"e0312149","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":3,"title":["Aging by autodigestion"],"prefix":"10.1371","volume":"19","author":[{"given":"Frank A.","family":"DeLano","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Geert W.","family":"Schmid-Sch\u00f6nbein","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2024,10,17]]},"reference":[{"issue":"2","key":"pone.0312149.ref001","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1016\/j.cell.2022.11.001","article-title":"Hallmarks of aging: An expanding universe","volume":"186","author":"C Lopez-Otin","year":"2023","journal-title":"Cell"},{"issue":"8","key":"pone.0312149.ref002","doi-asserted-by":"crossref","first-page":"931","DOI":"10.1016\/j.jacc.2019.11.061","article-title":"Mechanisms of Vascular Aging, A Geroscience Perspective: JACC Focus Seminar","volume":"75","author":"Z Ungvari","year":"2020","journal-title":"J Am Coll Cardiol"},{"issue":"3","key":"pone.0312149.ref003","doi-asserted-by":"crossref","first-page":"676","DOI":"10.14336\/AD.2019.0315","article-title":"A Microcirculatory Theory of Aging.","volume":"10","author":"K. Jin","year":"2019","journal-title":"Aging Dis."},{"issue":"14","key":"pone.0312149.ref004","doi-asserted-by":"crossref","DOI":"10.1172\/JCI158448","article-title":"3rd, Ferrucci L. Connecting aging biology and inflammation in the omics era","volume":"132","author":"KA Walker","year":"2022","journal-title":"J Clin Invest"},{"issue":"8","key":"pone.0312149.ref005","doi-asserted-by":"crossref","first-page":"837","DOI":"10.1016\/j.jacc.2021.12.017","article-title":"Inflammation, Aging, and Cardiovascular Disease: JACC Review Topic of the Week","volume":"79","author":"L Liberale","year":"2022","journal-title":"J Am Coll Cardiol"},{"key":"pone.0312149.ref006","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1146\/annurev.bioeng.8.061505.095708","article-title":"Analysis of inflammation","volume":"8","author":"GW Schmid-Sch\u00f6nbein","year":"2006","journal-title":"Annu Rev Biomed Eng"},{"key":"pone.0312149.ref007","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1016\/j.ejphar.2017.03.050","article-title":"DNA damage-dependent mechanisms of ageing and disease in the macro- and microvasculature","volume":"816","author":"AV Shah","year":"2017","journal-title":"Eur J Pharmacol"},{"key":"pone.0312149.ref008","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.freeradbiomed.2013.02.011","article-title":"Reactive oxygen species and the free radical theory of aging","volume":"60","author":"SI Liochev","year":"2013","journal-title":"Free Radic Biol Med"},{"issue":"7\u20138","key":"pone.0312149.ref009","doi-asserted-by":"crossref","first-page":"817","DOI":"10.1007\/s00011-022-01598-8","article-title":"Photoaging: UV radiation-induced inflammation and immunosuppression accelerate the aging process in the skin","volume":"71","author":"A Salminen","year":"2022","journal-title":"Inflamm Res"},{"issue":"12","key":"pone.0312149.ref010","article-title":"Ionizing Radiation-Induced Brain Cell Aging and the Potential Underlying Molecular Mechanisms.","volume":"10","author":"QQ Wang","year":"2021","journal-title":"Cells"},{"issue":"2","key":"pone.0312149.ref011","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1111\/acel.12306","article-title":"Aging and radiation: bad companions","volume":"14","author":"L Hernandez","year":"2015","journal-title":"Aging Cell"},{"issue":"6","key":"pone.0312149.ref012","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1016\/8756-3282(95)00370-3","article-title":"Aging and matrix microdamage accumulation in human compact bone","volume":"17","author":"MB Schaffler","year":"1995","journal-title":"Bone"},{"issue":"5","key":"pone.0312149.ref013","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1097\/SHK.0000000000000544","article-title":"Autodigestion: Proteolytic Degradation and Multiple Organ Failure in Shock","volume":"45","author":"AE Altshuler","year":"2016","journal-title":"Shock"},{"issue":"4","key":"pone.0312149.ref014","first-page":"289","article-title":"Inflammation and the autodigestion hypothesis","volume":"16","author":"GW Schmid-Sch\u00f6nbein","year":"2009","journal-title":"Microcirculation"},{"issue":"3","key":"pone.0312149.ref015","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1097\/SHK.0b013e318240b59b","article-title":"Disruption of the mucosal barrier during gut ischemia allows entry of digestive enzymes into the intestinal wall","volume":"37","author":"M Chang","year":"2012","journal-title":"Shock"},{"issue":"6","key":"pone.0312149.ref016","doi-asserted-by":"crossref","first-page":"e40087","DOI":"10.1371\/journal.pone.0040087","article-title":"Breakdown of mucin as barrier to digestive enzymes in the ischemic rat small intestine.","volume":"7","author":"M Chang","year":"2012","journal-title":"PLoS One."},{"issue":"1","key":"pone.0312149.ref017","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1038\/s41598-019-57106-2","article-title":"Intestinal barrier function is maintained with aging\u2014a comprehensive study in healthy subjects and irritable bowel syndrome patients.","volume":"10","author":"E Wilms","year":"2020","journal-title":"Sci Rep."},{"issue":"6","key":"pone.0312149.ref018","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1080\/07315724.2018.1545611","article-title":"Elevated Resting and Postprandial Digestive Proteolytic Activity in Peripheral Blood of Individuals With Type-2 Diabetes Mellitus, With Uncontrolled Cleavage of Insulin Receptors.","volume":"38","author":"AE Modestino","year":"2019","journal-title":"J Am Coll Nutr."},{"issue":"5\u20136","key":"pone.0312149.ref019","first-page":"337","article-title":"Proteolytic receptor cleavage in the pathogenesis of blood rheology and co-morbidities in metabolic syndrome. Early forms of autodigestion","volume":"52","author":"R Mazor","year":"2015","journal-title":"Biorheology"},{"issue":"2","key":"pone.0312149.ref020","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1111\/j.1365-2818.1978.tb01174.x","article-title":"Two rapid and simple methods used for the removal of resins from 1.0 micron thick epoxy sections","volume":"112","author":"MH Maxwell","year":"1978","journal-title":"J Microsc"},{"issue":"37","key":"pone.0312149.ref021","doi-asserted-by":"crossref","first-page":"14767","DOI":"10.1073\/pnas.1209721109","article-title":"Targeting collagen strands by photo-triggered triple-helix hybridization","volume":"109","author":"Y Li","year":"2012","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"12","key":"pone.0312149.ref022","doi-asserted-by":"crossref","first-page":"7668","DOI":"10.1074\/jbc.274.12.7668","article-title":"Sequence dependence of the folding of collagen-like peptides. Single amino acids affect the rate of triple-helix nucleation","volume":"274","author":"MS Ackerman","year":"1999","journal-title":"J Biol Chem"},{"issue":"2","key":"pone.0312149.ref023","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1161\/HYPERTENSIONAHA.107.104356","article-title":"Proteinase activity and receptor cleavage: mechanism for insulin resistance in the spontaneously hypertensive rat","volume":"52","author":"FA DeLano","year":"2008","journal-title":"Hypertension"},{"issue":"2","key":"pone.0312149.ref024","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1007\/s10439-013-0891-6","article-title":"The autodigestion hypothesis for shock and multi-organ failure","volume":"42","author":"GW Schmid-Sch\u00f6nbein","year":"2014","journal-title":"Ann Biomed Eng"},{"issue":"3","key":"pone.0312149.ref025","doi-asserted-by":"crossref","first-page":"262","DOI":"10.1097\/SHK.0b013e31825b1717","article-title":"Impaired small-bowel barrier integrity in the presence of lumenal pancreatic digestive enzymes leads to circulatory shock","volume":"38","author":"EB Kistler","year":"2012","journal-title":"Shock"},{"issue":"3","key":"pone.0312149.ref026","doi-asserted-by":"crossref","first-page":"296","DOI":"10.1097\/01.shk.0000235139.20775.7f","article-title":"Pancreatic enzymes generate cytotoxic mediators in the intestine","volume":"27","author":"AH Penn","year":"2007","journal-title":"Shock"},{"issue":"4","key":"pone.0312149.ref027","doi-asserted-by":"crossref","first-page":"H1779","DOI":"10.1152\/ajpheart.00902.2007","article-title":"The intestine as source of cytotoxic mediators in shock: free fatty acids and degradation of lipid-binding proteins","volume":"294","author":"AH Penn","year":"2008","journal-title":"Am J Physiol Heart Circ Physiol"},{"issue":"4","key":"pone.0312149.ref028","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1038\/bjc.1972.33","article-title":"Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics","volume":"26","author":"JF Kerr","year":"1972","journal-title":"Br J Cancer"},{"issue":"14","key":"pone.0312149.ref029","doi-asserted-by":"crossref","first-page":"2701","DOI":"10.1111\/febs.13575","article-title":"Cell death at the intestinal epithelial front line","volume":"283","author":"ME Delgado","year":"2016","journal-title":"FEBS J"},{"issue":"5","key":"pone.0312149.ref030","doi-asserted-by":"crossref","first-page":"e00109","DOI":"10.1002\/phy2.109","article-title":"Removal of luminal content protects the small intestine during hemorrhagic shock but is not sufficient to prevent lung injury","volume":"1","author":"AE Altshuler","year":"2013","journal-title":"Physiol Rep"},{"issue":"5","key":"pone.0312149.ref031","doi-asserted-by":"crossref","first-page":"e96655","DOI":"10.1371\/journal.pone.0096655","article-title":"Transmural intestinal wall permeability in severe ischemia after enteral protease inhibition.","volume":"9","author":"AE Altshuler","year":"2014","journal-title":"PLoS One."},{"key":"pone.0312149.ref032","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1007\/978-1-4939-2272-7_3","article-title":"Getting across the cell membrane: an overview for small molecules, peptides, and proteins.","volume":"1266","author":"NJ Yang","year":"2015","journal-title":"Methods Mol Biol."},{"issue":"2","key":"pone.0312149.ref033","doi-asserted-by":"crossref","first-page":"114","DOI":"10.3181\/00379727-206-43728","article-title":"Enterokinase.","volume":"206","author":"NS Mann","year":"1994","journal-title":"Proc Soc Exp Biol Med"},{"issue":"169","key":"pone.0312149.ref034","doi-asserted-by":"crossref","first-page":"169ra11","DOI":"10.1126\/scitranslmed.3005046","article-title":"Pancreatic digestive enzyme blockade in the intestine increases survival after experimental shock","volume":"5","author":"FA DeLano","year":"2013","journal-title":"Sci Transl Med"},{"issue":"5","key":"pone.0312149.ref035","doi-asserted-by":"crossref","first-page":"1707","DOI":"10.1016\/S0002-9440(10)63729-7","article-title":"Pancreatic trypsin increases matrix metalloproteinase-9 accumulation and activation during acute intestinal ischemia-reperfusion in the rat","volume":"164","author":"HS Rosario","year":"2004","journal-title":"Am J Pathol"},{"issue":"4","key":"pone.0312149.ref036","doi-asserted-by":"crossref","first-page":"682","DOI":"10.1016\/j.jmb.2005.05.018","article-title":"Pancreatic trypsin activates human promatrix metalloproteinase-2","volume":"350","author":"RI Lindstad","year":"2005","journal-title":"J Mol Biol"},{"issue":"455","key":"pone.0312149.ref037","doi-asserted-by":"crossref","DOI":"10.1126\/scitranslmed.aah6324","article-title":"Cleavage of the leptin receptor by matrix metalloproteinase-2 promotes leptin resistance and obesity in mice.","volume":"10","author":"R Mazor","year":"2018","journal-title":"Sci Transl Med."},{"issue":"6","key":"pone.0312149.ref038","doi-asserted-by":"crossref","first-page":"1194","DOI":"10.1016\/j.cell.2013.05.039","article-title":"The hallmarks of aging","volume":"153","author":"C Lopez-Otin","year":"2013","journal-title":"Cell"},{"key":"pone.0312149.ref039","doi-asserted-by":"crossref","first-page":"12","DOI":"10.3389\/fcvm.2018.00012","article-title":"Source of Chronic Inflammation in Aging.","volume":"5","author":"F Sanada","year":"2018","journal-title":"Front Cardiovasc Med"},{"key":"pone.0312149.ref040","doi-asserted-by":"crossref","first-page":"14913","DOI":"10.1038\/ncomms14913","article-title":"Molecular level detection and localization of mechanical damage in collagen enabled by collagen hybridizing peptides","volume":"8","author":"JL Zitnay","year":"2017","journal-title":"Nat Commun"},{"issue":"3","key":"pone.0312149.ref041","doi-asserted-by":"crossref","first-page":"619","DOI":"10.1083\/jcb.147.3.619","article-title":"Degraded collagen fragments promote rapid disassembly of smooth muscle focal adhesions that correlates with cleavage of pp125(FAK), paxillin, and talin.","volume":"147","author":"NO Carragher","year":"1999","journal-title":"J Cell Biol"},{"issue":"2\u20133","key":"pone.0312149.ref042","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1016\/j.bbamcr.2004.04.007","article-title":"Focal adhesion regulation of cell behavior","volume":"1692","author":"MA Wozniak","year":"2004","journal-title":"Biochim Biophys Acta"},{"issue":"31","key":"pone.0312149.ref043","doi-asserted-by":"crossref","first-page":"19525","DOI":"10.1074\/jbc.273.31.19525","article-title":"Cleavage of the cytoplasmic domain of the integrin beta3 subunit during endothelial cell apoptosis","volume":"273","author":"J Meredith","year":"1998","journal-title":"J Biol Chem"},{"key":"pone.0312149.ref044","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1146\/annurev-nutr-122319-034601","article-title":"Calorie Restriction and Aging in Humans","volume":"40","author":"EW Flanagan","year":"2020","journal-title":"Annu Rev Nutr"},{"issue":"6598","key":"pone.0312149.ref045","doi-asserted-by":"crossref","first-page":"1192","DOI":"10.1126\/science.abk0297","article-title":"Circadian alignment of early onset caloric restriction promotes longevity in male C57BL\/6J mice","volume":"376","author":"V Acosta-Rodriguez","year":"2022","journal-title":"Science"},{"issue":"6","key":"pone.0312149.ref046","doi-asserted-by":"crossref","first-page":"344","DOI":"10.1016\/j.tig.2015.04.005","article-title":"Repairing organs: lessons from intestine and liver","volume":"31","author":"H Gehart","year":"2015","journal-title":"Trends Genet"}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0312149","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,10,17]],"date-time":"2024-10-17T17:30:49Z","timestamp":1729186249000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0312149"}},"subtitle":[],"editor":[{"given":"Hualin","family":"Fu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2024,10,17]]},"references-count":46,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2024,10,17]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0312149","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,10,17]]}}}