{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T01:45:51Z","timestamp":1789436751973,"version":"build-2803163510"},"reference-count":82,"publisher":"National Academy of Sciences","issue":"49","license":[{"start":{"date-parts":[[2022,12,2]],"date-time":"2022-12-02T00:00:00Z","timestamp":1669939200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000049","name":"HHS | NIH | National Institute on Aging","doi-asserted-by":"publisher","award":["K23AG061253"],"award-info":[{"award-number":["K23AG061253"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000049","name":"HHS | NIH | National Institute on Aging","doi-asserted-by":"publisher","award":["R01AG032289"],"award-info":[{"award-number":["R01AG032289"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000049","name":"HHS | NIH | National Institute on Aging","doi-asserted-by":"publisher","award":["R01AG048234"],"award-info":[{"award-number":["R01AG048234"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000049","name":"HHS | NIH | National Institute on Aging","doi-asserted-by":"publisher","award":["ADRC P50 AG023501"],"award-info":[{"award-number":["ADRC P50 AG023501"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000049","name":"HHS | NIH | National Institute on Aging","doi-asserted-by":"publisher","award":["ADRC P30 AG062422"],"award-info":[{"award-number":["ADRC P30 AG062422"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100001167","name":"Larry L. Hillblom Foundation","doi-asserted-by":"publisher","award":["2014-A-004-NET"],"award-info":[{"award-number":["2014-A-004-NET"]}],"id":[{"id":"10.13039\/100001167","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000049","name":"HHS | NIH | National Institute on Aging","doi-asserted-by":"publisher","award":["1P01AG066591-01A1"],"award-info":[{"award-number":["1P01AG066591-01A1"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000049","name":"HHS | NIH | National Institute on Aging","doi-asserted-by":"publisher","award":["1P01AG066591-01A1"],"award-info":[{"award-number":["1P01AG066591-01A1"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2022,12,6]]},"abstract":"<jats:p>Aging is characterized by a progressive loss of brain volume at an estimated rate of 5%\u00a0per decade after age 40. While these morphometric changes, especially those affecting gray matter and atrophy of the temporal lobe, are predictors of cognitive performance, the strong association with aging obscures the potential parallel, but more specific role, of individual subject physiology. Here, we studied a cohort of 554 human subjects who were monitored using structural MRI scans and blood immune protein concentrations. Using machine learning, we derived a cytokine clock (CyClo), which predicted age with good accuracy (Mean Absolute Error = 6 y) based on the expression of a subset of immune proteins. These proteins included, among others, Placenta Growth Factor (PLGF) and Vascular Endothelial Growth Factor (VEGF), both involved in angiogenesis, the chemoattractant vascular cell adhesion molecule 1 (VCAM-1), the canonical inflammatory proteins interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF\u03b1), the chemoattractant IP-10 (CXCL10), and eotaxin-1 (CCL11), previously involved in brain disorders. Age, sex, and the CyClo were independently associated with different functionally defined cortical networks in the brain. While age was mostly correlated with changes in the somatomotor system, sex was associated with variability in the frontoparietal, ventral attention, and visual networks. Significant canonical correlation was observed for the CyClo and the default mode, limbic, and dorsal attention networks, indicating that immune circulating proteins preferentially affect brain processes such as focused attention, emotion, memory, response to social stress, internal evaluation, and access to consciousness. Thus, we identified immune biomarkers of brain aging which could be potential therapeutic targets for the prevention of age-related cognitive decline.<\/jats:p>","DOI":"10.1073\/pnas.2207181119","type":"journal-article","created":{"date-parts":[[2022,12,2]],"date-time":"2022-12-02T15:23:13Z","timestamp":1669994593000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":43,"title":["Age-related brain atrophy is not a homogenous process: Different functional brain networks associate differentially with aging and blood factors"],"prefix":"10.1073","volume":"119","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1417-1161","authenticated-orcid":false,"given":"Nikola T.","family":"Markov","sequence":"first","affiliation":[{"name":"Buck AI Platform, Buck Institute for Research on Aging, Novato, CA 94945"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cutter A.","family":"Lindbergh","sequence":"additional","affiliation":[{"name":"Department of Neurology, Memory and Aging Center, University of California San Francisco, Weill Institute for Neurosciences, San Francisco, CA 94158"},{"name":"Department of Psychiatry, University of Connecticut School of Medicine, Farmington, CT 06030"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adam M.","family":"Staffaroni","sequence":"additional","affiliation":[{"name":"Department of Neurology, Memory and Aging Center, University of California San Francisco, Weill Institute for Neurosciences, San Francisco, CA 94158"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin","family":"Perez","sequence":"additional","affiliation":[{"name":"Buck AI Platform, Buck Institute for Research on Aging, Novato, CA 94945"},{"name":"University of Lausanne, Lausanne CH-1015, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Stevens","sequence":"additional","affiliation":[{"name":"Buck AI Platform, Buck Institute for Research on Aging, Novato, CA 94945"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7306-588X","authenticated-orcid":false,"given":"Khiem","family":"Nguyen","sequence":"additional","affiliation":[{"name":"Buck AI Platform, Buck Institute for Research on Aging, Novato, CA 94945"},{"name":"Nguyen Tat Thanh Hi-Tech Institute, Nguyen Tat Thanh University, Ho Chi Minh City 70000, Vietnam"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalia F.","family":"Murad","sequence":"additional","affiliation":[{"name":"Buck AI Platform, Buck Institute for Research on Aging, Novato, CA 94945"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Corrina","family":"Fonseca","sequence":"additional","affiliation":[{"name":"Department of Neurology, Memory and Aging Center, University of California San Francisco, Weill Institute for Neurosciences, San Francisco, CA 94158"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Judith","family":"Campisi","sequence":"additional","affiliation":[{"name":"Buck AI Platform, Buck Institute for Research on Aging, Novato, CA 94945"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joel","family":"Kramer","sequence":"additional","affiliation":[{"name":"Department of Neurology, Memory and Aging Center, University of California San Francisco, Weill Institute for Neurosciences, San Francisco, CA 94158"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3654-9519","authenticated-orcid":false,"given":"David","family":"Furman","sequence":"additional","affiliation":[{"name":"Buck AI Platform, Buck Institute for Research on Aging, Novato, CA 94945"},{"name":"Instituto de Investigaciones en Medicina Traslacional, Universidad Austral, Consejo Nacional de Investigaciones Cient\u00edficas y T\u00e9cnicas, Pilar 1629, Argentina"},{"name":"Stanford 1000 Immunomes Project, Stanford University School of Medicine, Stanford, CA 94305"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2022,12,2]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cub.2012.07.024"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1186\/gb-2013-14-10-r115"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/s43587-021-00082-y"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-019-0675-0"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1037\/neu0000447"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1097\/JNN.0b013e3182527690"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1749-6632.2000.tb06651.x"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1093\/gerona\/glu057"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41569-018-0064-2"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2008.01.003"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2020.03.012"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41583-019-0255-9"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrn1886"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2018.05.011"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature20411"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.23-08-03295.2003"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.1001\/archneur.60.7.989"},{"key":"e_1_3_4_18_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0084093"},{"key":"e_1_3_4_19_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.3252-09.2009"},{"key":"e_1_3_4_20_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.pneurobio.2014.02.004"},{"key":"e_1_3_4_21_2","doi-asserted-by":"publisher","DOI":"10.1007\/s10548-018-0675-2"},{"key":"e_1_3_4_22_2","doi-asserted-by":"publisher","DOI":"10.1111\/acel.12271"},{"key":"e_1_3_4_23_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.278.5337.412"},{"key":"e_1_3_4_24_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.3067-17.2018"},{"key":"e_1_3_4_25_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2007.10.038"},{"key":"e_1_3_4_26_2","doi-asserted-by":"publisher","DOI":"10.1152\/jn.00338.2011"},{"key":"e_1_3_4_27_2","doi-asserted-by":"publisher","DOI":"10.1037\/neu0000696"},{"key":"e_1_3_4_28_2","doi-asserted-by":"publisher","DOI":"10.1093\/gerona\/glab162"},{"key":"e_1_3_4_29_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroimage.2007.07.007"},{"key":"e_1_3_4_30_2","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0b013e318248e50f"},{"key":"e_1_3_4_31_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neurobiolaging.2020.01.006"},{"key":"e_1_3_4_32_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neurobiolaging.2021.09.010"},{"key":"e_1_3_4_33_2","doi-asserted-by":"publisher","DOI":"10.3389\/fnagi.2020.603854"},{"key":"e_1_3_4_34_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM2003ra020003"},{"key":"e_1_3_4_35_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.arr.2014.01.004"},{"key":"e_1_3_4_36_2","doi-asserted-by":"publisher","DOI":"10.1136\/pgmj.2005.036665"},{"key":"e_1_3_4_37_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41380-018-0098-1"},{"key":"e_1_3_4_38_2","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00004.2002"},{"key":"e_1_3_4_39_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tins.2004.07.011"},{"key":"e_1_3_4_40_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1749-6632.2009.05118.x"},{"key":"e_1_3_4_41_2","doi-asserted-by":"publisher","DOI":"10.1016\/0197-4580(86)90086-2"},{"key":"e_1_3_4_42_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1749-6632.2009.04421.x"},{"key":"e_1_3_4_43_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pcbi.1000808"},{"key":"e_1_3_4_44_2","first-page":"201","article-title":"Minireview the magnificent compromise: Cortical field evolution in mammals minireview","volume":"56","author":"Krubitzer L.","year":"2007","unstructured":"L. Krubitzer, Minireview the magnificent compromise: Cortical field evolution in mammals minireview. Brain 56, 201\u2013208 (2007).","journal-title":"Brain"},{"key":"e_1_3_4_45_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tics.2013.09.017"},{"key":"e_1_3_4_46_2","doi-asserted-by":"publisher","DOI":"10.1177\/0891988708328216"},{"key":"e_1_3_4_47_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm1653"},{"key":"e_1_3_4_48_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0197-4580(01)00276-7"},{"key":"e_1_3_4_49_2","doi-asserted-by":"publisher","DOI":"10.1186\/1742-2094-2-9"},{"key":"e_1_3_4_50_2","doi-asserted-by":"publisher","DOI":"10.1007\/s12035-014-8657-1"},{"key":"e_1_3_4_51_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ynstr.2018.09.006"},{"key":"e_1_3_4_52_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroimage.2012.01.120"},{"key":"e_1_3_4_53_2","doi-asserted-by":"publisher","DOI":"10.1177\/1359105305055332"},{"key":"e_1_3_4_54_2","doi-asserted-by":"publisher","DOI":"10.1002\/hbm.25090"},{"key":"e_1_3_4_55_2","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btp491"},{"key":"e_1_3_4_56_2","doi-asserted-by":"publisher","DOI":"10.3389\/fgene.2021.706986"},{"key":"e_1_3_4_57_2","doi-asserted-by":"publisher","DOI":"10.4103\/1673-5374.238608"},{"key":"e_1_3_4_58_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-019-0440-4"},{"key":"e_1_3_4_59_2","doi-asserted-by":"publisher","DOI":"10.3727\/000000007783464731"},{"key":"e_1_3_4_60_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajpath.2011.10.024"},{"key":"e_1_3_4_61_2","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0b013e318266fa70"},{"key":"e_1_3_4_62_2","doi-asserted-by":"publisher","DOI":"10.1093\/gerona\/glu121"},{"key":"e_1_3_4_63_2","doi-asserted-by":"publisher","DOI":"10.1038\/mp.2015.131"},{"key":"e_1_3_4_64_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tins.2022.08.001"},{"key":"e_1_3_4_65_2","unstructured":"N. T. Markov J. Kramer D. Furman Brain Athrophy and Cytokines. Synapse. https:\/\/www.synapse.org\/#!Synapse:syn42844729\/files\/. Deposited 28 October 2022."},{"key":"e_1_3_4_66_2","unstructured":"The R Project for Statistical Computing Version 4.0.3. https:\/\/www.R-project.org\/. Accessed 10 October 2020."},{"key":"e_1_3_4_67_2","doi-asserted-by":"publisher","DOI":"10.1109\/42.668698"},{"key":"e_1_3_4_68_2","volume-title":"Statistical Parametric Mapping: The Analysis of Functional Brain Images","author":"Penny W.","year":"2007","unstructured":"W. Penny, K. Friston, J. Ashburner, S. Kiebel, T. Nichols, Statistical Parametric Mapping: The Analysis of Functional Brain Images (Elsevier Ltd., 2007), 10.1016\/B978-0-12-372560-8.X5000-1."},{"key":"e_1_3_4_69_2","doi-asserted-by":"publisher","DOI":"10.1006\/nimg.1995.1012"},{"key":"e_1_3_4_70_2","doi-asserted-by":"publisher","DOI":"10.1093\/gerona\/glz209"},{"key":"e_1_3_4_71_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jagp.2018.05.004"},{"key":"e_1_3_4_72_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbi.2020.05.014"},{"key":"e_1_3_4_73_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cyto.2018.05.032"},{"key":"e_1_3_4_74_2","doi-asserted-by":"publisher","DOI":"10.1093\/gerona\/gly028"},{"key":"e_1_3_4_75_2","doi-asserted-by":"publisher","DOI":"10.1111\/1440-1681.12758"},{"key":"e_1_3_4_76_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jamda.2013.05.009"},{"key":"e_1_3_4_77_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkv007"},{"key":"e_1_3_4_78_2","first-page":"1","article-title":"mice: Multivariate imputation by chained equations in R","volume":"45","author":"van Buuren S.","year":"2011","unstructured":"S. van Buuren, K. Groothuis-Oudshoorn, mice: Multivariate imputation by chained equations in R. J.\u00a0Stat. Softw. 45, 1\u201367 (2011).","journal-title":"J.\u00a0Stat. Softw."},{"key":"e_1_3_4_79_2","doi-asserted-by":"publisher","DOI":"10.18637\/jss.v033.i01"},{"key":"e_1_3_4_80_2","unstructured":"I. Gonzales S.R. Dejan CCA Canonical Correlation Analysis Package (Version 1.2.1. https:\/\/CRAN.R-project.org\/package=CCA 2021)."},{"key":"e_1_3_4_81_2","unstructured":"C. Butts YACCA Yet Another Canonical Correlation Analysis Package (Version 1.1.1 https:\/\/CRAN.R-project.org\/package=yacca 2018)."},{"key":"e_1_3_4_82_2","doi-asserted-by":"crossref","first-page":"71","DOI":"10.4135\/9781412983570","volume-title":"Canonical Correlation Analysis: Uses and Interpretation","author":"Thompson B.","year":"1984","unstructured":"B. Thompson, Canonical Correlation Analysis: Uses and Interpretation (Sage, 1984), vol. 1, p. 71."}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.2207181119","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,21]],"date-time":"2023-09-21T08:44:54Z","timestamp":1695285894000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/10.1073\/pnas.2207181119"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,12,2]]},"references-count":82,"journal-issue":{"issue":"49","published-print":{"date-parts":[[2022,12,6]]}},"alternative-id":["10.1073\/pnas.2207181119"],"URL":"https:\/\/doi.org\/10.1073\/pnas.2207181119","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,12,2]]},"assertion":[{"value":"2022-04-28","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-10-04","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-12-02","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e2207181119"}}