{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T16:42:08Z","timestamp":1790959328653,"version":"4.1.0"},"reference-count":76,"publisher":"Public Library of Science (PLoS)","issue":"6","license":[{"start":{"date-parts":[[2021,6,17]],"date-time":"2021-06-17T00:00:00Z","timestamp":1623888000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["HL136969S"],"award-info":[{"award-number":["HL136969S"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"name":"McGovern Scholar Funds"},{"name":"The Bob Hazel Casey Endowment of University of Texas Health Science Center-McGovern Medical School"},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["HL146442"],"award-info":[{"award-number":["HL146442"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["HL149714"],"award-info":[{"award-number":["HL149714"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["HL148151"],"award-info":[{"award-number":["HL148151"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["HL150032"],"award-info":[{"award-number":["HL150032"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["HL136969"],"award-info":[{"award-number":["HL136969"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["HL136969"],"award-info":[{"award-number":["HL136969"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosbiology.org"],"crossmark-restriction":false},"short-container-title":["PLoS Biol"],"abstract":"<jats:p>Hypoxia drives aging and promotes age-related cognition and hearing functional decline. Despite the role of erythrocytes in oxygen (O<jats:sub>2<\/jats:sub>) transport, their role in the onset of aging and age-related cognitive decline and hearing loss (HL) remains undetermined. Recent studies revealed that signaling through the erythrocyte adenosine A2B receptor (ADORA2B) promotes O<jats:sub>2<\/jats:sub> release to counteract hypoxia at high altitude. However, nothing is known about a role for erythrocyte ADORA2B in age-related functional decline. Here, we report that loss of murine erythrocyte\u2013specific ADORA2B (e<jats:italic>Adora2b<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup>) accelerates early onset of age-related impairments in spatial learning, memory, and hearing ability. <jats:italic>eAdora2b<jats:sup>-\/-<\/jats:sup><\/jats:italic> mice display the early aging-like cellular and molecular features including the proliferation and activation of microglia and macrophages, elevation of pro-inflammatory cytokines, and attenuation of hypoxia-induced glycolytic gene expression to counteract hypoxia in the hippocampus (HIP), cortex, or cochlea. Hypoxia sufficiently accelerates early onset of cognitive and cochlear functional decline and inflammatory response in e<jats:italic>Adora2b<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> mice. Mechanistically, erythrocyte ADORA2B-mediated activation of AMP-activated protein kinase (AMPK) and bisphosphoglycerate mutase (BPGM) promotes hypoxic and metabolic reprogramming to enhance production of 2,3-bisphosphoglycerate (2,3-BPG), an erythrocyte-specific metabolite triggering O<jats:sub>2<\/jats:sub> delivery. Significantly, this finding led us to further discover that murine erythroblast ADORA2B and BPGM mRNA levels and erythrocyte BPGM activity are reduced during normal aging. Overall, we determined that erythrocyte ADORA2B\u2013BPGM axis is a key component for anti-aging and anti-age\u2013related functional decline.<\/jats:p>","DOI":"10.1371\/journal.pbio.3001239","type":"journal-article","created":{"date-parts":[[2021,6,17]],"date-time":"2021-06-17T17:26:14Z","timestamp":1623950774000},"page":"e3001239","update-policy":"https:\/\/doi.org\/10.1371\/journal.pbio.corrections_policy","source":"Crossref","is-referenced-by-count":29,"title":["Erythrocyte adenosine A2B receptor prevents cognitive and auditory dysfunction by promoting hypoxic and metabolic reprogramming"],"prefix":"10.1371","volume":"19","author":[{"given":"Qingfen","family":"Qiang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7289-8102","authenticated-orcid":true,"given":"Jeanne M.","family":"Manalo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yujin","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anren","family":"Song","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander Q.","family":"Wen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Y. Edward","family":"Wen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Changhan","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Cui","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8566-7119","authenticated-orcid":true,"given":"Travis","family":"Nemkov","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie A.","family":"Reisz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8795-5851","authenticated-orcid":true,"given":"George","family":"Edwards III","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2100-0280","authenticated-orcid":true,"given":"Fred A.","family":"Perreira","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rodney E.","family":"Kellems","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudio","family":"Soto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2258-6490","authenticated-orcid":true,"given":"Angelo","family":"D\u2019Alessandro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8059-6179","authenticated-orcid":true,"given":"Yang","family":"Xia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2021,6,17]]},"reference":[{"issue":"1","key":"pbio.3001239.ref001","first-page":"323","article-title":"Disability incidence and functional decline among older adults with major chronic diseases","volume":"19","author":"JHJBG Fong","year":"2019"},{"issue":"1","key":"pbio.3001239.ref002","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1186\/s13690-019-0375-8","article-title":"The age-performance relationship in the general population and strategies to delay age related decline in performance","volume":"77","author":"G Berthelot","year":"2019","journal-title":"Archives of Public Health"},{"issue":"4","key":"pbio.3001239.ref003","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1001\/jamainternmed.2013.1868","article-title":"Hearing loss and cognitive decline in older adults","volume":"173","author":"FR Lin","year":"2013","journal-title":"JAMA Intern Med"},{"issue":"4","key":"pbio.3001239.ref004","doi-asserted-by":"crossref","first-page":"737","DOI":"10.1016\/j.cger.2013.07.002","article-title":"Normal cognitive aging","volume":"29","author":"CN Harada","year":"2013","journal-title":"Clin Geriatr Med"},{"issue":"10","key":"pbio.3001239.ref005","doi-asserted-by":"crossref","first-page":"576","DOI":"10.1038\/s41574-018-0059-4","article-title":"Inflammaging: a new immune\u2013metabolic viewpoint for age-related diseases","volume":"14","author":"C Franceschi","year":"2018","journal-title":"Nat Rev Endocrinol"},{"issue":"3","key":"pbio.3001239.ref006","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1016\/j.tips.2013.12.004","article-title":"Small molecule SIRT1 activators for the treatment of aging and age-related diseases","volume":"35","author":"BP Hubbard","year":"2014","journal-title":"Trends in Pharmacological Sciences"},{"key":"pbio.3001239.ref007","author":"A Gerald","year":"2017","journal-title":"Brain Glucose Metabolism: Integration of Energetics with Function"},{"issue":"10","key":"pbio.3001239.ref008","doi-asserted-by":"crossref","first-page":"587","DOI":"10.1016\/j.tins.2013.07.001","article-title":"Sugar for the brain: the role of glucose in physiological and pathological brain function","volume":"36","author":"P Mergenthaler","year":"2013","journal-title":"Trends in Neurosciences"},{"issue":"7","key":"pbio.3001239.ref009","doi-asserted-by":"crossref","first-page":"465","DOI":"10.18632\/aging.100782","article-title":"Hypoxia metabolism in ageing","volume":"7","author":"A Valli","year":"2015","journal-title":"Aging"},{"issue":"7444","key":"pbio.3001239.ref010","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1038\/nature11986","article-title":"Succinate is an inflammatory signal that induces IL-1\u03b2 through HIF-1\u03b1","volume":"496","author":"GM Tannahill","year":"2013","journal-title":"Nature"},{"issue":"3","key":"pbio.3001239.ref011","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1016\/j.stem.2018.01.020","article-title":"Macrophage-Derived Extracellular Succinate Licenses Neural Stem Cells to Suppress Chronic Neuroinflammation","volume":"22","author":"L Peruzzotti-Jametti","year":"2018","journal-title":"Cell stem cell"},{"key":"pbio.3001239.ref012","doi-asserted-by":"crossref","first-page":"1745","DOI":"10.3389\/fimmu.2017.01745","article-title":"Aging, Obesity, and Inflammatory Age-Related Diseases","volume":"8","author":"D Frasca","year":"2017","journal-title":"Front Immunol"},{"issue":"11","key":"pbio.3001239.ref013","doi-asserted-by":"crossref","first-page":"2313","DOI":"10.1016\/j.jprot.2011.06.005","article-title":"Oxidative stress, inflamm-aging and immunosenescence","volume":"74","author":"ES Cannizzo","year":"2011","journal-title":"J Proteome"},{"issue":"6\u20137","key":"pbio.3001239.ref014","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1016\/j.exger.2009.04.006","article-title":"Age-related expression of adenosine receptors in brain from the senescence-accelerated mouse","volume":"44","author":"CA Castillo","year":"2009","journal-title":"Exp Gerontol"},{"issue":"8","key":"pbio.3001239.ref015","doi-asserted-by":"crossref","first-page":"1629","DOI":"10.1038\/sj.bjp.0703736","article-title":"Modification of adenosine modulation of synaptic transmission in the hippocampus of aged rats","volume":"131","author":"AM Sebasti\u00e3o","year":"2000","journal-title":"Br J Pharmacol"},{"issue":"1","key":"pbio.3001239.ref016","first-page":"83","article-title":"Actions of caffeine in the brain with special reference to factors that contribute to its widespread use","volume":"51","author":"BB Fredholm","year":"1999","journal-title":"Pharmacol Rev"},{"issue":"4","key":"pbio.3001239.ref017","doi-asserted-by":"crossref","first-page":"676","DOI":"10.3390\/molecules22040676","article-title":"Adenosine A1 and A2A Receptors in the Brain: Current Research and Their Role in Neurodegeneration","volume":"22","author":"J Stockwell","year":"2017","journal-title":"Molecules (Basel, Switzerland)"},{"key":"pbio.3001239.ref018","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1146\/annurev.neuro.24.1.31","article-title":"The role and regulation of adenosine in the central nervous system","volume":"24","author":"TV Dunwiddie","year":"2001","journal-title":"Annu Rev Neurosci"},{"issue":"1\u20132","key":"pbio.3001239.ref019","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1002\/ddr.1125","article-title":"Adenosine and synaptic plasticity","volume":"52","author":"A de Mendon\u00e7a","year":"2001","journal-title":"Drug Dev Res"},{"issue":"2","key":"pbio.3001239.ref020","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1007\/s11302-005-0649-1","article-title":"Neuroprotection by adenosine in the brain: From A(1) receptor activation to A (2A) receptor blockade","volume":"1","author":"RA Cunha","year":"2005","journal-title":"Purinergic Signal"},{"issue":"2","key":"pbio.3001239.ref021","doi-asserted-by":"crossref","first-page":"509","DOI":"10.3233\/JAD-111982","article-title":"Caffeine consumption prevents memory impairment, neuronal damage, and adenosine A2A receptors upregulation in the hippocampus of a rat model of sporadic dementia.","volume":"34","author":"J Espinosa","year":"2013","journal-title":"Journal of Alzheimer\u2019s disease: JAD"},{"issue":"1\u20132","key":"pbio.3001239.ref022","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.lfs.2014.01.083","article-title":"Using caffeine and other adenosine receptor antagonists and agonists as therapeutic tools against neurodegenerative diseases: a review","volume":"101","author":"M Rivera-Oliver","year":"2014","journal-title":"Life Sci"},{"issue":"5","key":"pbio.3001239.ref023","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1161\/CIRCULATIONAHA.116.021311","article-title":"Beneficial Role of Erythrocyte Adenosine A2B Receptor-Mediated AMP-Activated Protein Kinase Activation in High-Altitude Hypoxia","volume":"134","author":"H Liu","year":"2016","journal-title":"Circulation"},{"issue":"6","key":"pbio.3001239.ref024","doi-asserted-by":"crossref","first-page":"544","DOI":"10.1111\/j.1365-2044.1977.tb10002.x","article-title":"Red cell 2,3-diphosphoglycerate and oxygen affinity","volume":"32","author":"R. MacDonald","year":"1977","journal-title":"Anaesthesia"},{"issue":"5","key":"pbio.3001239.ref025","doi-asserted-by":"crossref","first-page":"244","DOI":"10.14336\/AD.2013.0400244","article-title":"Age-related defects in erythrocyte 2,3-diphosphoglycerate metabolism in dementia","volume":"4","author":"YG Kaminsky","year":"2013","journal-title":"Aging and disease"},{"issue":"1","key":"pbio.3001239.ref026","doi-asserted-by":"crossref","first-page":"113","DOI":"10.2174\/1871527314666150821103444","article-title":"Relationship between chronic disturbance of 2,3-diphosphoglycerate metabolism in erythrocytes and Alzheimer disease","volume":"15","author":"EA Kosenko","year":"2016","journal-title":"CNS Neurol Disord Drug Targets"},{"key":"pbio.3001239.ref027","doi-asserted-by":"crossref","first-page":"728","DOI":"10.3389\/fnins.2017.00728","article-title":"Metabolic Abnormalities of Erythrocytes as a Risk Factor for Alzheimer\u2019s Disease","volume":"11","author":"EA Kosenko","year":"2018","journal-title":"Front Neurosci."},{"issue":"2","key":"pbio.3001239.ref028","first-page":"1726","article-title":"Association between age-related hearing loss and cognitive decline in C57BL\/6J mice","volume":"18","author":"Y Dong","year":"2018","journal-title":"Mol Med Rep"},{"issue":"4","key":"pbio.3001239.ref029","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1007\/s10162-007-0098-3","article-title":"Age-related hearing loss in C57BL\/6J mice has both frequency-specific and non-frequency-specific components that produce a hyperacusis-like exaggeration of the acoustic startle reflex.","volume":"8","author":"JR Ison","year":"2007","journal-title":"Journal of the Association for Research in Otolaryngology: JARO"},{"issue":"1","key":"pbio.3001239.ref030","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1186\/s12974-018-1059-y","article-title":"Age-related cognitive impairment is associated with long-term neuroinflammation and oxidative stress in a mouse model of episodic systemic inflammation","volume":"15","author":"JC d\u2019Avila","year":"2018","journal-title":"J Neuroinflammation"},{"issue":"10","key":"pbio.3001239.ref031","first-page":"136","article-title":"Role of pro-inflammatory cytokines released from microglia in Alzheimer\u2019s disease","volume":"3","author":"W-Y Wang","year":"2015","journal-title":"Ann Transl Med"},{"issue":"4","key":"pbio.3001239.ref032","doi-asserted-by":"crossref","first-page":"26","DOI":"10.3390\/cells7040026","article-title":"Microglia after Seizures and in Epilepsy","volume":"7","author":"T Hiragi","year":"2018","journal-title":"Cell"},{"issue":"4","key":"pbio.3001239.ref033","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1038\/nri.2017.125","article-title":"Microglia and macrophages in brain homeostasis and disease","volume":"18","author":"Q Li","year":"2018","journal-title":"Nat Rev Immunol"},{"key":"pbio.3001239.ref034","article-title":"Mechanisms of neuroimmune gene induction in alcoholism","volume":"233","author":"F Crews","year":"2015","journal-title":"Psychopharmacology"},{"issue":"1","key":"pbio.3001239.ref035","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1007\/s11920-009-0082-1","article-title":"Neuroinflammation and cognitive aging","volume":"12","author":"RL Ownby","year":"2010","journal-title":"Curr Psychiatry Rep"},{"issue":"4","key":"pbio.3001239.ref036","first-page":"503","article-title":"Oxygen sensing, HIF-1alpha stabilization and potential therapeutic strategies","volume":"443","author":"T Hofer","year":"2002"},{"issue":"2","key":"pbio.3001239.ref037","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1016\/j.cmet.2017.07.010","article-title":"Loss of Brain Aerobic Glycolysis in Normal Human Aging","volume":"26","author":"MS Goyal","year":"2017","journal-title":"Cell metabolism"},{"key":"pbio.3001239.ref038","article-title":"Aerobic glycolysis and tau deposition in preclinical Alzheimer disease","author":"AG Vlassenko","year":"2018"},{"issue":"5","key":"pbio.3001239.ref039","doi-asserted-by":"crossref","first-page":"4020","DOI":"10.1121\/1.5132545","article-title":"Inflammation associated with noise-induced hearing loss","volume":"146","author":"MD Frye","year":"2019","journal-title":"The Journal of the Acoustical Society of America"},{"issue":"8","key":"pbio.3001239.ref040","first-page":"1758","article-title":"Bone marrow-derived cells expressing Iba1 are constitutively present as resident tissue macrophages in the mouse cochlea","volume":"86","author":"T Okano","year":"2008"},{"issue":"6","key":"pbio.3001239.ref041","first-page":"930","article-title":"Repopulation of cochlear macrophages in murine hematopoietic progenitor cell chimeras: The role of CX3CR1.","volume":"506","author":"E Sato","year":"2008"},{"key":"pbio.3001239.ref042","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.neuroscience.2015.05.081","article-title":"Activation of the antigen presentation function of mononuclear phagocyte populations associated with the basilar membrane of the cochlea after acoustic overstimulation","volume":"303","author":"W Yang","year":"2015","journal-title":"Neuroscience"},{"key":"pbio.3001239.ref043","doi-asserted-by":"crossref","first-page":"407","DOI":"10.3389\/fnmol.2017.00407","article-title":"Macrophage-Mediated Glial Cell Elimination in the Postnatal Mouse Cochlea","volume":"10","author":"LN Brown","year":"2017","journal-title":"Front Mol Neurosci"},{"issue":"9","key":"pbio.3001239.ref044","doi-asserted-by":"crossref","first-page":"1211","DOI":"10.1038\/nn.3469","article-title":"M2 microglia and macrophages drive oligodendrocyte differentiation during CNS remyelination","volume":"16","author":"VE Miron","year":"2013","journal-title":"Nat Neurosci"},{"key":"pbio.3001239.ref045","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1016\/j.arr.2017.10.002","article-title":"Chronic inflammation\u2014inflammaging\u2014in the ageing cochlea: A novel target for future presbycusis therapy","volume":"40","author":"N Watson","year":"2017","journal-title":"Ageing Res Rev"},{"issue":"10","key":"pbio.3001239.ref046","doi-asserted-by":"crossref","first-page":"1549","DOI":"10.1023\/A:1025678510480","article-title":"A metabolic basis for Alzheimer disease","volume":"28","author":"G Perry","year":"2003","journal-title":"Neurochem Res"},{"issue":"2","key":"pbio.3001239.ref047","doi-asserted-by":"crossref","first-page":"250","DOI":"10.2174\/1871527315666160202121809","article-title":"A synopsis on the linkage between age-related dementias and vascular disorders.","volume":"15","author":"S Chibber","year":"2016","journal-title":"CNS Neurol Disord Drug Targets"},{"issue":"7","key":"pbio.3001239.ref048","doi-asserted-by":"crossref","first-page":"812","DOI":"10.2174\/1381612822666151209152013","article-title":"Alterations in Glucose Metabolism on Cognition: A Possible Link Between Diabetes and Dementia","volume":"22","author":"RE Gonz\u00e1lez-Reyes","year":"2016","journal-title":"Curr Pharm Des"},{"issue":"1","key":"pbio.3001239.ref049","doi-asserted-by":"crossref","first-page":"12086","DOI":"10.1038\/ncomms12086","article-title":"Sphingosine-1-phosphate promotes erythrocyte glycolysis and oxygen release for adaptation to high-altitude hypoxia","volume":"7","author":"K Sun","year":"2016","journal-title":"Nat Commun"},{"issue":"3","key":"pbio.3001239.ref050","first-page":"775","article-title":"AMPK activation ameliorates Alzheimer\u2019s disease-like pathology and spatial memory impairment in a streptozotocin-induced Alzheimer\u2019s disease model in rats","volume":"43","author":"L-L Du","year":"2015","journal-title":"Journal of Alzheimer\u2019s disease: JAD"},{"issue":"2","key":"pbio.3001239.ref051","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1101\/lm.033332.113","article-title":"AMPK agonist AICAR improves cognition and motor coordination in young and aged mice","volume":"21","author":"T Kobilo","year":"2014","journal-title":"Learning & memory (Cold Spring Harbor, NY)"},{"issue":"9","key":"pbio.3001239.ref052","doi-asserted-by":"crossref","first-page":"1577","DOI":"10.1007\/s00125-017-4342-z","article-title":"The mechanisms of action of metformin","volume":"60","author":"G Rena","year":"2017","journal-title":"Diabetologia"},{"issue":"3","key":"pbio.3001239.ref053","doi-asserted-by":"crossref","first-page":"a025932","DOI":"10.1101\/cshperspect.a025932","article-title":"Metformin: A Hopeful Promise in Aging Research","volume":"6","author":"MG Novelle","year":"2016","journal-title":"Cold Spring Harb Perspect Med."},{"key":"pbio.3001239.ref054","doi-asserted-by":"crossref","first-page":"19","DOI":"10.2741\/3229","article-title":"AMPK: Lessons from transgenic and knockout animals","volume":"14","author":"B Viollet","year":"2009","journal-title":"Front Biosci (Landmark Ed)"},{"issue":"4","key":"pbio.3001239.ref055","doi-asserted-by":"crossref","first-page":"709","DOI":"10.1016\/j.cell.2014.10.039","article-title":"Geroscience: linking aging to chronic disease","volume":"159","author":"BK Kennedy","year":"2014","journal-title":"Cell"},{"issue":"Suppl 1","key":"pbio.3001239.ref056","doi-asserted-by":"crossref","first-page":"S4","DOI":"10.1093\/gerona\/glu057","article-title":"Chronic inflammation (inflammaging) and its potential contribution to age-associated diseases","volume":"69","author":"C Franceschi","year":"2014","journal-title":"J Gerontol A Biol Sci Med Sci"},{"issue":"6","key":"pbio.3001239.ref057","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1093\/gerona\/61.6.575","article-title":"Interleukin-6 in aging and chronic disease: a magnificent pathway","volume":"61","author":"M Maggio","year":"2006","journal-title":"J Gerontol A Biol Sci Med Sci"},{"issue":"45","key":"pbio.3001239.ref058","doi-asserted-by":"crossref","first-page":"16241","DOI":"10.1523\/JNEUROSCI.3667-11.2011","article-title":"CX3CR1 deficiency leads to impairment of hippocampal cognitive function and synaptic plasticity","volume":"31","author":"JT Rogers","year":"2011","journal-title":"J Neurosci"},{"issue":"1","key":"pbio.3001239.ref059","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1523\/JNEUROSCI.0936-17.2017","article-title":"Abnormal Microglia and Enhanced Inflammation-Related Gene Transcription in Mice with Conditional Deletion of in -Expressing Neurons","volume":"38","author":"BE McGill","year":"2018","journal-title":"J Neurosci"},{"issue":"4","key":"pbio.3001239.ref060","doi-asserted-by":"crossref","first-page":"E197","DOI":"10.1073\/pnas.1111098109","article-title":"Microglia activation triggers astrocyte-mediated modulation of excitatory neurotransmission","volume":"109","author":"O Pascual","year":"2012","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"1","key":"pbio.3001239.ref061","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1038\/sj.npp.1301559","article-title":"Synaptic Plasticity: Multiple Forms, Functions, and Mechanisms","volume":"33","author":"A Citri","year":"2008","journal-title":"Neuropsychopharmacology"},{"issue":"2","key":"pbio.3001239.ref062","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1002\/dneu.22538","article-title":"Myelin development, plasticity, and pathology in the auditory system","volume":"78","author":"P Long","year":"2018","journal-title":"Dev Neurobiol"},{"key":"pbio.3001239.ref063","doi-asserted-by":"crossref","first-page":"895","DOI":"10.3389\/fneur.2019.00895","article-title":"Age-Related Changes in Immune Cells of the Human Cochlea","volume":"10","author":"KV Noble","year":"2019","journal-title":"Front Neurol"},{"issue":"10","key":"pbio.3001239.ref064","doi-asserted-by":"crossref","first-page":"2551","DOI":"10.1523\/JNEUROSCI.2487-17.2018","article-title":"Noise-Induced Dysregulation of RNA Binding Proteins Contributes to Auditory Nerve Demyelination and Hearing Loss","volume":"38","author":"CH Panganiban","year":"2018","journal-title":"J Neurosci"},{"issue":"11","key":"pbio.3001239.ref065","doi-asserted-by":"crossref","first-page":"855","DOI":"10.1080\/14789450.2018.1531710","article-title":"Red blood cells as an organ? How deep omics characterization of the most abundant cell in the human body highlights other systemic metabolic functions beyond oxygen transport.","volume":"15","author":"T Nemkov","year":"2018","journal-title":"Expert Rev Proteomics"},{"issue":"6500","key":"pbio.3001239.ref066","first-page":"167","article-title":"Blood factors transfer beneficial effects of exercise on neurogenesis and cognition to the aged brain.","volume":"369","author":"AM Horowitz","year":"2020"},{"issue":"4","key":"pbio.3001239.ref067","doi-asserted-by":"crossref","first-page":"624","DOI":"10.4103\/1673-5374.230277","article-title":"Young blood products: emerging treatment for Alzheimer\u2019s disease?","volume":"13","author":"R Khoury","year":"2018","journal-title":"Neural Regen Res"},{"issue":"6184","key":"pbio.3001239.ref068","doi-asserted-by":"crossref","first-page":"630","DOI":"10.1126\/science.1251141","article-title":"Vascular and neurogenic rejuvenation of the aging mouse brain by young systemic factors","volume":"344","author":"L Katsimpardi","year":"2014","journal-title":"Science (New York, NY)"},{"issue":"1","key":"pbio.3001239.ref069","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1016\/j.stem.2011.11.019","article-title":"Rejuvenation of regeneration in the aging central nervous system","volume":"10","author":"JM Ruckh","year":"2012","journal-title":"Cell stem cell"},{"key":"pbio.3001239.ref070","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1038\/s42003-019-0298-5","article-title":"Young bone marrow transplantation preserves learning and memory in old mice","volume":"2","author":"MM Das","year":"2019","journal-title":"Communications biology"},{"key":"pbio.3001239.ref071","doi-asserted-by":"crossref","DOI":"10.18632\/aging.202188","article-title":"Hyperbaric oxygen therapy increases telomere length and decreases immunosenescence in isolated blood cells: a prospective trial","author":"YJA Hachmo","year":"2020"},{"issue":"3","key":"pbio.3001239.ref072","doi-asserted-by":"crossref","first-page":"659","DOI":"10.1182\/blood-2003-05-1442","article-title":"A mouse model for visualization and conditional mutations in the erythroid lineage","volume":"104","author":"AC Heinrich","year":"2004","journal-title":"Blood"},{"issue":"1","key":"pbio.3001239.ref073","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1089\/neu.2018.6348","article-title":"Traumatic Brain Injury Induces Tau Aggregation and Spreading","volume":"37","author":"G Edwards","year":"2020","journal-title":"J Neurotrauma"},{"issue":"9","key":"pbio.3001239.ref074","doi-asserted-by":"crossref","first-page":"1327","DOI":"10.1038\/mp.2016.230","article-title":"Molecular interaction between type 2 diabetes and Alzheimer\u2019s disease through cross-seeding of protein misfolding","volume":"22","author":"I Moreno-Gonzalez","year":"2017","journal-title":"Mol Psychiatry"},{"issue":"24","key":"pbio.3001239.ref075","doi-asserted-by":"crossref","first-page":"10110","DOI":"10.1523\/JNEUROSCI.5606-12.2013","article-title":"Conditional deletion of Atoh1 reveals distinct critical periods for survival and function of hair cells in the organ of Corti","volume":"33","author":"T Cai","year":"2013","journal-title":"J Neurosci"},{"key":"pbio.3001239.ref076","doi-asserted-by":"crossref","first-page":"14338","DOI":"10.1038\/ncomms14338","article-title":"mTORC1-independent TFEB activation via Akt inhibition promotes cellular clearance in neurodegenerative storage diseases","volume":"8","author":"M Palmieri","year":"2017","journal-title":"Nat Commun"}],"container-title":["PLOS Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pbio.3001239","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,6,17]],"date-time":"2021-06-17T17:27:33Z","timestamp":1623950853000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pbio.3001239"}},"subtitle":[],"editor":[{"given":"Judith","family":"Campisi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2021,6,17]]},"references-count":76,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2021,6,17]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pbio.3001239","relation":{},"ISSN":["1545-7885"],"issn-type":[{"value":"1545-7885","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,6,17]]}}}