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AGEs form when sugars or their metabolites react with proteins. Associated with a myriad of age\u2010related diseases, AGEs accumulate in many tissues and are cytotoxic. To date, efforts to limit glycation pharmacologically have failed in human trials. Thus, it is crucial to identify systems that remove AGEs, but such research is scanty. Here, we determined if and how AGEs might be cleared by autophagy. Our<jats:italic>in vivo<\/jats:italic>mouse and<jats:italic>C<\/jats:italic>.<jats:italic>elegans<\/jats:italic>models, in which we altered proteolysis or glycative burden, as well as experiments in five types of cells, revealed more than six criteria indicating that p62\u2010dependent autophagy is a conserved pathway that plays a critical role in the removal of AGEs. Activation of autophagic removal of AGEs requires p62, and blocking this pathway results in accumulation of AGEs and compromised viability. Deficiency of p62 accelerates accumulation of AGEs in soluble and insoluble fractions. p62 itself is subject to glycative inactivation and accumulates as high mass species. Accumulation of p62 in retinal pigment epithelium is reversed by switching to a lower glycemia diet. Since diminution of glycative damage is associated with reduced risk for age\u2010related diseases, including age\u2010related macular degeneration, cardiovascular disease, diabetes, Alzheimer's, and Parkinson's, discovery of methods to limit AGEs or enhance p62\u2010dependent autophagy offers novel potential therapeutic targets to treat AGEs\u2010related pathologies.<\/jats:p>","DOI":"10.1111\/acel.13257","type":"journal-article","created":{"date-parts":[[2020,11,4]],"date-time":"2020-11-04T19:36:45Z","timestamp":1604518605000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":41,"title":["Autophagic receptor p62 protects against glycation\u2010derived toxicity and enhances viability"],"prefix":"10.1111","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1924-9231","authenticated-orcid":false,"given":"Gemma","family":"Aragon\u00e8s","sequence":"first","affiliation":[{"name":"Laboratory for Nutrition and Vision Research USDA Human Nutrition Research Center on Aging Tufts University Boston MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kalavathi","family":"Dasuri","sequence":"additional","affiliation":[{"name":"Laboratory for Nutrition and Vision Research USDA Human Nutrition Research Center on Aging Tufts University Boston MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Opeoluwa","family":"Olukorede","sequence":"additional","affiliation":[{"name":"Laboratory for Nutrition and Vision Research USDA Human Nutrition Research Center on Aging Tufts University Boston MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah G.","family":"Francisco","sequence":"additional","affiliation":[{"name":"Laboratory for Nutrition and Vision Research USDA Human Nutrition Research Center on Aging Tufts University Boston MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carol","family":"Renneburg","sequence":"additional","affiliation":[{"name":"Laboratory for Nutrition and Vision Research USDA Human Nutrition Research Center on Aging Tufts University Boston MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caroline","family":"Kumsta","sequence":"additional","affiliation":[{"name":"Sanford Burnham Prebys Medical Discovery Institute La Jolla CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Malene","family":"Hansen","sequence":"additional","affiliation":[{"name":"Sanford Burnham Prebys Medical Discovery Institute La Jolla CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shun","family":"Kageyama","sequence":"additional","affiliation":[{"name":"Department of Physiology Juntendo University School of Medicine Bunkyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masaaki","family":"Komatsu","sequence":"additional","affiliation":[{"name":"Department of Physiology Juntendo University School of Medicine Bunkyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1123-6743","authenticated-orcid":false,"given":"Sheldon","family":"Rowan","sequence":"additional","affiliation":[{"name":"Laboratory for Nutrition and Vision Research USDA Human Nutrition Research Center on Aging Tufts University Boston MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan","family":"Volkin","sequence":"additional","affiliation":[{"name":"Laboratory for Nutrition and Vision Research USDA Human Nutrition Research Center on Aging Tufts University Boston MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Workman","sequence":"additional","affiliation":[{"name":"Laboratory for Nutrition and Vision Research USDA Human Nutrition Research Center on Aging Tufts University Boston MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenxin","family":"Yang","sequence":"additional","affiliation":[{"name":"Laboratory for Nutrition and Vision Research USDA Human Nutrition Research Center on Aging Tufts University Boston MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5170-1868","authenticated-orcid":false,"given":"Paula","family":"Daza","sequence":"additional","affiliation":[{"name":"Departamento Biolog\u00eda Celular. Facultad de Biolog\u00eda Universidad de Sevilla Sevilla Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6131-3033","authenticated-orcid":false,"given":"Diego","family":"Ruano","sequence":"additional","affiliation":[{"name":"Departamento de Bioqu\u00edmica y Biolog\u00eda Molecular. Facultad de Farmacia Universidad de Sevilla Sevilla Spain"},{"name":"Instituto de Biomedicina de Sevilla (IBiS Hospital Universitario Virgen del Roc\u00edo\/Consejo Superior de Investigaciones Cient\u00edficas\/Universidad de Sevilla Sevilla Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7933-4489","authenticated-orcid":false,"given":"Helena","family":"Dominguez\u2010Mart\u00edn","sequence":"additional","affiliation":[{"name":"Departamento de Bioqu\u00edmica y Biolog\u00eda Molecular. Facultad de Farmacia Universidad de Sevilla Sevilla Spain"},{"name":"Instituto de Biomedicina de Sevilla (IBiS Hospital Universitario Virgen del Roc\u00edo\/Consejo Superior de Investigaciones Cient\u00edficas\/Universidad de Sevilla Sevilla Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0741-6338","authenticated-orcid":false,"given":"Jos\u00e9 Antonio","family":"Rodr\u00edguez\u2010Navarro","sequence":"additional","affiliation":[{"name":"Servicio de Neurobiolog\u00eda Departamento de Investigaci\u00f3n Hospital Ram\u00f3n y Cajal Instituto Ram\u00f3n y Cajal de Investigaciones Sanitarias Carretera de Colmenar Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xue\u2010Liang","family":"Du","sequence":"additional","affiliation":[{"name":"Albert Einstein College of Medicine Bronx NY USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael A.","family":"Brownlee","sequence":"additional","affiliation":[{"name":"Albert Einstein College of Medicine Bronx NY USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8390-1581","authenticated-orcid":false,"given":"Eloy","family":"Bejarano","sequence":"additional","affiliation":[{"name":"Laboratory for Nutrition and Vision Research USDA Human Nutrition Research Center on Aging Tufts University Boston MA USA"},{"name":"School of Health Sciences Universidad CEU Cardenal Herrera Valencia Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Allen","family":"Taylor","sequence":"additional","affiliation":[{"name":"Laboratory for Nutrition and Vision Research USDA Human Nutrition Research Center on Aging Tufts University Boston MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2020,11,4]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0210474"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1080\/15548627.2020.1725404"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1091\/mbc.E11-10-0844"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1111\/acel.12777"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.exer.2018.08.017"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncb2934"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.126128"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M110.100420"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2018.08.014"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0114964"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.RA118.002275"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-018-0162-7"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1111\/acel.12109"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neurobiolaging.2015.02.025"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1111\/acel.12327"},{"issue":"7","key":"e_1_2_9_17_1","doi-asserted-by":"crossref","first-page":"441","DOI":"10.14348\/molcells.2017.0115","article-title":"Crosstalk and Interplay between the Ubiquitin\u2010Proteasome System and Autophagy","volume":"40","author":"Ji C. 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