{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T09:03:09Z","timestamp":1792746189092,"version":"4.5.0"},"reference-count":29,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2022,12,14]],"date-time":"2022-12-14T00:00:00Z","timestamp":1670976000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000965","name":"American Federation for Aging Research","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000965","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000049","name":"National Institute on Aging","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["K01 AG054731"],"award-info":[{"award-number":["K01 AG054731"]}],"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":["T32 AG000279"],"award-info":[{"award-number":["T32 AG000279"]}],"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":["UL1 TR001082"],"award-info":[{"award-number":["UL1 TR001082"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Aging Cell"],"published-print":{"date-parts":[[2023,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Declining nicotinamide adenine dinucleotide (NAD<jats:sup>+<\/jats:sup>) concentration in the brain during aging contributes to metabolic and cellular dysfunction and is implicated in the pathogenesis of aging\u2010associated neurological disorders. Experimental therapies aimed at boosting brain NAD<jats:sup>+<\/jats:sup> levels normalize several neurodegenerative phenotypes in animal models, motivating their clinical translation. Dietary intake of NAD<jats:sup>+<\/jats:sup> precursors, such as nicotinamide riboside (NR), is a safe and effective avenue for augmenting NAD<jats:sup>+<\/jats:sup> levels in peripheral tissues in humans, yet evidence supporting their ability to raise NAD<jats:sup>+<\/jats:sup> levels in the brain or engage neurodegenerative disease pathways is lacking. Here, we studied biomarkers in plasma extracellular vesicles enriched for neuronal origin (NEVs) from 22 healthy older adults who participated in a randomized, placebo\u2010controlled crossover trial (NCT02921659) of oral NR supplementation (500\u2009mg, 2x \/day, 6\u2009weeks). We demonstrate that oral NR supplementation increases NAD<jats:sup>+<\/jats:sup> levels in NEVs and decreases NEV levels of A\u03b242, pJNK, and pERK1\/2 (kinases involved in insulin resistance and neuroinflammatory pathways). In addition, changes in NAD(H) correlated with changes in canonical insulin\u2013Akt signaling proteins and changes in pERK1\/2 and pJNK. These findings support the ability of orally administered NR to augment neuronal NAD<jats:sup>+<\/jats:sup> levels and modify biomarkers related to neurodegenerative pathology in humans. Furthermore, NEVs offer a new blood\u2010based window into monitoring the physiologic response of NR in the brain.<\/jats:p>","DOI":"10.1111\/acel.13754","type":"journal-article","created":{"date-parts":[[2022,12,14]],"date-time":"2022-12-14T12:03:30Z","timestamp":1671019410000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":73,"title":["Oral nicotinamide riboside raises <scp>NAD<\/scp>+ and lowers biomarkers of neurodegenerative pathology in plasma extracellular vesicles enriched for neuronal origin"],"prefix":"10.1111","volume":"22","author":[{"given":"Michael","family":"Vreones","sequence":"first","affiliation":[{"name":"Human Neuroscience Section National Institute on Aging  Baltimore Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maja","family":"Mustapic","sequence":"additional","affiliation":[{"name":"Human Neuroscience Section National Institute on Aging  Baltimore Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6812-0127","authenticated-orcid":false,"given":"Ruin","family":"Moaddel","sequence":"additional","affiliation":[{"name":"Human Neuroscience Section National Institute on Aging  Baltimore Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Krishna A.","family":"Pucha","sequence":"additional","affiliation":[{"name":"Human Neuroscience Section National Institute on Aging  Baltimore Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacqueline","family":"Lovett","sequence":"additional","affiliation":[{"name":"Human Neuroscience Section National Institute on Aging  Baltimore Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2391-9824","authenticated-orcid":false,"given":"Douglas R.","family":"Seals","sequence":"additional","affiliation":[{"name":"Department of Integrative Physiology University of Colorado Boulder  Boulder Colorado USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2181-3118","authenticated-orcid":false,"given":"Dimitrios","family":"Kapogiannis","sequence":"additional","affiliation":[{"name":"Human Neuroscience Section National Institute on Aging  Baltimore Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0578-2948","authenticated-orcid":false,"given":"Christopher R.","family":"Martens","sequence":"additional","affiliation":[{"name":"Department of Kinesiology &amp; Applied Physiology University of Delaware  Newark Delaware USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2022,12,14]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2022.02.001"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41580\u2010020\u201000313\u2010x"},{"key":"e_1_2_6_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ab.2019.02.019"},{"key":"e_1_2_6_5_1","doi-asserted-by":"publisher","DOI":"10.1111\/acel.12657"},{"key":"e_1_2_6_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/alz.12130"},{"key":"e_1_2_6_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41593\u2010018\u20100332\u20109"},{"key":"e_1_2_6_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2016.09.004"},{"key":"e_1_2_6_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2014.03.026"},{"key":"e_1_2_6_10_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1750\u20103639.2001.tb00387.x"},{"key":"e_1_2_6_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neurobiolaging.2012.12.005"},{"key":"e_1_2_6_12_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2011226118"},{"key":"e_1_2_6_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/s42255\u2010019\u20100161\u20105"},{"key":"e_1_2_6_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467\u2010018\u201003421\u20107"},{"key":"e_1_2_6_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.exger.2020.110888"},{"key":"e_1_2_6_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2013.06.016"},{"key":"e_1_2_6_17_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnagi.2017.00118"},{"key":"e_1_2_6_18_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnins.2017.00278"},{"key":"e_1_2_6_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0169\u2010328x(02)00488\u20106"},{"key":"e_1_2_6_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2018.05.009"},{"key":"e_1_2_6_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2016.07.027"},{"key":"e_1_2_6_22_1","doi-asserted-by":"publisher","DOI":"10.1080\/20013078.2018.1535750"},{"key":"e_1_2_6_23_1","doi-asserted-by":"publisher","DOI":"10.1038\/srep26933"},{"key":"e_1_2_6_24_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.aac4854"},{"key":"e_1_2_6_25_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11011\u2010018\u20100346\u20108"},{"key":"e_1_2_6_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neulet.2017.03.027"},{"key":"e_1_2_6_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2011.08.014"},{"key":"e_1_2_6_28_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.abe9985"},{"key":"e_1_2_6_29_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1471\u20104159.2001.00046.x"},{"key":"e_1_2_6_30_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1417921112"}],"container-title":["Aging Cell"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/acel.13754","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/acel.13754","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/acel.13754","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,21]],"date-time":"2023-08-21T00:30:41Z","timestamp":1692577841000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/acel.13754"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,12,14]]},"references-count":29,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2023,1]]}},"alternative-id":["10.1111\/acel.13754"],"URL":"https:\/\/doi.org\/10.1111\/acel.13754","archive":["Portico"],"relation":{},"ISSN":["1474-9718","1474-9726"],"issn-type":[{"value":"1474-9718","type":"print"},{"value":"1474-9726","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,12,14]]},"assertion":[{"value":"2022-08-23","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-11-28","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-12-14","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e13754"}}