{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,7]],"date-time":"2026-11-07T04:30:07Z","timestamp":1794025807612,"version":"4.8.0"},"reference-count":58,"publisher":"Springer Science and Business Media LLC","issue":"6","license":[{"start":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T00:00:00Z","timestamp":1780272000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,6,15]],"date-time":"2026-06-15T00:00:00Z","timestamp":1781481600000},"content-version":"vor","delay-in-days":14,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Nat Med"],"published-print":{"date-parts":[[2026,6]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Aging is asynchronous across cells and organs. Here we tested whether plasma proteomics can be used to analyze cell type-specific aging. From analyses of over 7,000 plasma proteins measured in 60,542 individuals, we developed machine learning models to estimate the biological age of over 40 cell types spanning neuronal, immune, glial, endocrine, epithelial and musculoskeletal origins. We observed that 20\u201325% of individuals exhibited accelerated aging in a single cell type and 1\u20133% in 10 or more cell types. Cellular aging signatures were associated with disease status and predicted incident disease and mortality over 15 years of follow-up. Individuals with the\n                    <jats:italic>APOE4<\/jats:italic>\n                    genotype showed older astrocytes but younger macrophages compared to\n                    <jats:italic>APOE3<\/jats:italic>\n                    carriers, whereas the\n                    <jats:italic>APOE2<\/jats:italic>\n                    genotype had inverse associations. Moreover, extreme astrocyte aging tripled the risk of incident Alzheimer\u2019s Disease in individuals with two\n                    <jats:italic>APOE4<\/jats:italic>\n                    alleles, while youthful astrocytes reduced risk. Individuals with extremely aged compared to youthful skeletal myocytes exhibited a 12.7-fold higher risk of developing amyotrophic lateral sclerosis. In individuals who smoked, extreme respiratory epithelial cell aging was associated with a 58% higher lung cancer risk compared to smoking alone. Specific cellular vulnerabilities and cumulative cellular aging burden influenced survival, with youthful immune and neuronal cell types conferring protective effects. Finally, we developed a polycellular aging risk score that stratified mortality risk across cohorts and proteomics platforms. These findings establish a framework for quantifying human physiology at cellular resolution, revealing heterogeneous aging trajectories and their impact on disease susceptibility and resilience.\n                  <\/jats:p>","DOI":"10.1038\/s41591-026-04446-y","type":"journal-article","created":{"date-parts":[[2026,6,15]],"date-time":"2026-06-15T09:03:10Z","timestamp":1781514190000},"page":"2060-2072","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["Plasma proteomic signatures of cellular aging predict human disease"],"prefix":"10.1038","volume":"32","author":[{"given":"Daisy Yi","family":"Ding","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-5060-1142","authenticated-orcid":false,"given":"Veronica Augustina","family":"Bot","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenneth L.","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7803-8696","authenticated-orcid":false,"given":"James W.","family":"Groves","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R\u00f3bert","family":"P\u00e1lovics","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-1354-3245","authenticated-orcid":false,"given":"Daisuke","family":"Masuda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6697-8883","authenticated-orcid":false,"given":"Amelia","family":"Farinas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8192-7593","authenticated-orcid":false,"given":"Hamilton Se-Hwee","family":"Oh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1957-0658","authenticated-orcid":false,"given":"Viktoria","family":"Wagner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nannan","family":"Lu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"The Global Neurodegeneration Proteomics Consortium (GNPC)","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0276-2899","authenticated-orcid":false,"given":"Carlos","family":"Cruchaga","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1113-6889","authenticated-orcid":false,"given":"Alina","family":"Isakova","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2059-024X","authenticated-orcid":false,"given":"Jonathan M.","family":"Schott","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5893-0831","authenticated-orcid":false,"given":"Tony","family":"Wyss-Coray","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,6,15]]},"reference":[{"key":"4446_CR1","doi-asserted-by":"publisher","first-page":"e159","DOI":"10.1016\/S2468-2667(19)30019-2","volume":"4","author":"AY Chang","year":"2019","unstructured":"Chang, A. Y., Skirbekk, V. F., Tyrovolas, S., Kassebaum, N. J. & Dieleman, J. L. Measuring population ageing: an analysis of the Global Burden of Disease Study 2017. Lancet Public Health 4, e159\u2013e167 (2019).","journal-title":"Lancet Public Health"},{"key":"4446_CR2","doi-asserted-by":"publisher","first-page":"24","DOI":"10.1192\/apt.7.1.24","volume":"7","author":"CD McCullagh","year":"2001","unstructured":"McCullagh, C. D., Craig, D., McIlroy, S. P. & Passmore, A. P. Risk factors for dementia. Adv. Psychiatr. Treat. 7, 24\u201331 (2001).","journal-title":"Adv. Psychiatr. Treat."},{"key":"4446_CR3","doi-asserted-by":"publisher","DOI":"10.1186\/s12889-024-17686-9","volume":"24","author":"N Al Wachami","year":"2024","unstructured":"Al Wachami, N. et al. Estimating the global prevalence of chronic obstructive pulmonary disease (COPD): a systematic review and meta-analysis. BMC Public Health 24, 297 (2024).","journal-title":"BMC Public Health"},{"key":"4446_CR4","doi-asserted-by":"publisher","first-page":"1341","DOI":"10.2337\/dc11-1818","volume":"35","author":"QM Nguyen","year":"2012","unstructured":"Nguyen, Q. M., Xu, J.-H., Chen, W., Srinivasan, S. R. & Berenson, G. S. Correlates of age onset of type 2 diabetes among relatively young black and white adults in a community: the Bogalusa Heart Study. Diabetes Care 35, 1341\u20131346 (2012).","journal-title":"Diabetes Care"},{"key":"4446_CR5","doi-asserted-by":"publisher","unstructured":"Jacques, M. et al. DNA methylation ageing atlas across 17 human tissues. Preprint at bioRxiv https:\/\/doi.org\/10.1101\/2025.07.21.665830 (2025).","DOI":"10.1101\/2025.07.21.665830"},{"key":"4446_CR6","doi-asserted-by":"publisher","first-page":"2450","DOI":"10.1038\/s41591-024-03164-7","volume":"30","author":"MA Argentieri","year":"2024","unstructured":"Argentieri, M. A. et al. Proteomic aging clock predicts mortality and risk of common age-related diseases in diverse populations. Nat. Med. 30, 2450\u20132460 (2024).","journal-title":"Nat. Med."},{"key":"4446_CR7","doi-asserted-by":"publisher","first-page":"121","DOI":"10.1038\/s43587-022-00335-4","volume":"3","author":"MT Buckley","year":"2023","unstructured":"Buckley, M. T. et al. Cell-type-specific aging clocks to quantify aging and rejuvenation in neurogenic regions of the brain. Nat. Aging 3, 121\u2013137 (2023).","journal-title":"Nat. Aging"},{"key":"4446_CR8","doi-asserted-by":"publisher","unstructured":"Xiong, J. et al. Multi-omic underpinnings of heterogeneous aging across multiple organ systems. Cell Genom. https:\/\/doi.org\/10.1016\/j.xgen.2025.101032 (2025).","DOI":"10.1016\/j.xgen.2025.101032"},{"key":"4446_CR9","doi-asserted-by":"publisher","unstructured":"MULTI Consortium et al. MRI-based multi-organ clocks for healthy aging and disease assessment. Nat. Med. https:\/\/doi.org\/10.1038\/s41591-025-03999-8 (2025).","DOI":"10.1038\/s41591-025-03999-8"},{"key":"4446_CR10","doi-asserted-by":"publisher","first-page":"2703","DOI":"10.1038\/s41591-025-03798-1","volume":"31","author":"HS-H Oh","year":"2025","unstructured":"Oh, H. S.-H. et al. Plasma proteomics links brain and immune system aging with healthspan and longevity. Nat. Med. 31, 2703\u20132711 (2025).","journal-title":"Nat. Med."},{"key":"4446_CR11","doi-asserted-by":"publisher","first-page":"164","DOI":"10.1038\/s41586-023-06802-1","volume":"624","author":"HS-H Oh","year":"2023","unstructured":"Oh, H. S.-H. et al. Organ aging signatures in the plasma proteome track health and disease. Nature 624, 164\u2013172 (2023).","journal-title":"Nature"},{"key":"4446_CR12","doi-asserted-by":"publisher","first-page":"607","DOI":"10.1038\/s43587-025-00819-z","volume":"5","author":"W Li","year":"2025","unstructured":"Li, W. et al. Single-cell immune aging clocks reveal inter-individual heterogeneity during infection and vaccination. Nat. Aging 5, 607\u2013621 (2025).","journal-title":"Nat. Aging"},{"key":"4446_CR13","first-page":"e06109","volume":"12","author":"C Muralidharan","year":"2025","unstructured":"Muralidharan, C. et al. Human brain cell-type-specific aging clocks based on single-nuclei transcriptomics. Adv. Sci. Weinh. Baden-Wurtt. Ger. 12, e06109 (2025).","journal-title":"Adv. Sci. Weinh. Baden-Wurtt. Ger."},{"key":"4446_CR14","doi-asserted-by":"publisher","first-page":"13452","DOI":"10.18632\/aging.206184","volume":"16","author":"H Tong","year":"2024","unstructured":"Tong, H. et al. Cell-type specific epigenetic clocks to quantify biological age at cell-type resolution. Aging 16, 13452\u201313504 (2024).","journal-title":"Aging"},{"key":"4446_CR15","doi-asserted-by":"publisher","first-page":"4868","DOI":"10.1016\/j.cell.2023.09.012","volume":"186","author":"J Wolf","year":"2023","unstructured":"Wolf, J. et al. Liquid-biopsy proteomics combined with AI identifies cellular drivers of eye aging and disease in vivo. Cell 186, 4868\u20134884 (2023).","journal-title":"Cell"},{"key":"4446_CR16","doi-asserted-by":"publisher","first-page":"2556","DOI":"10.1038\/s41591-025-03834-0","volume":"31","author":"F Imam","year":"2025","unstructured":"Imam, F. et al. The Global Neurodegeneration Proteomics Consortium: biomarker and drug target discovery for common neurodegenerative diseases and aging. Nat. Med. 31, 2556\u20132566 (2025).","journal-title":"Nat. Med."},{"key":"4446_CR17","doi-asserted-by":"publisher","first-page":"590","DOI":"10.1038\/s41586-020-2496-1","volume":"583","author":"N Almanzar","year":"2020","unstructured":"Almanzar, N. et al. A single-cell transcriptomic atlas characterizes ageing tissues in the mouse. Nature 583, 590\u2013595 (2020).","journal-title":"Nature"},{"key":"4446_CR18","doi-asserted-by":"publisher","first-page":"16014","DOI":"10.1038\/npjamd.2016.14","volume":"2","author":"I Seim","year":"2016","unstructured":"Seim, I., Ma, S. & Gladyshev, V. N. Gene expression signatures of human cell and tissue longevity. NPJ Aging Mech. Dis. 2, 16014 (2016).","journal-title":"NPJ Aging Mech. Dis."},{"key":"4446_CR19","doi-asserted-by":"publisher","first-page":"565","DOI":"10.1038\/s41582-019-0244-7","volume":"15","author":"Y Hou","year":"2019","unstructured":"Hou, Y. et al. Ageing as a risk factor for neurodegenerative disease. Nat. Rev. Neurol. 15, 565\u2013581 (2019).","journal-title":"Nat. Rev. Neurol."},{"key":"4446_CR20","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1186\/s12866-021-02103-7","volume":"21","author":"J Chen","year":"2021","unstructured":"Chen, J. et al. Age-related changes of microbiota in midlife associated with reduced saccharolytic potential: an in vitro study. BMC Microbiol. 21, 47 (2021).","journal-title":"BMC Microbiol."},{"key":"4446_CR21","doi-asserted-by":"publisher","first-page":"2567","DOI":"10.1038\/s41380-019-0425-1","volume":"25","author":"M Boehme","year":"2020","unstructured":"Boehme, M. et al. Mid-life microbiota crises: middle age is associated with pervasive neuroimmune alterations that are reversed by targeting the gut microbiome. Mol. Psychiatry 25, 2567\u20132583 (2020).","journal-title":"Mol. Psychiatry"},{"key":"4446_CR22","doi-asserted-by":"publisher","first-page":"1718","DOI":"10.1073\/pnas.0909606106","volume":"107","author":"CE Finch","year":"2010","unstructured":"Finch, C. E. Evolution in health and medicine Sackler colloquium: evolution of the human lifespan and diseases of aging: roles of infection, inflammation, and nutrition. Proc. Natl Acad. Sci. USA 107, 1718\u20131724 (2010).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"4446_CR23","doi-asserted-by":"publisher","first-page":"e68231","DOI":"10.7554\/eLife.68231","volume":"10","author":"AR Garcia","year":"2021","unstructured":"Garcia, A. R. et al. APOE4 is associated with elevated blood lipids and lower levels of innate immune biomarkers in a tropical Amerindian subsistence population. Elife 10, e68231 (2021).","journal-title":"Elife"},{"key":"4446_CR24","doi-asserted-by":"publisher","unstructured":"Groves, J. W. et al. Eight decades of follow-up link life course exposures to proteomic organ ageing and longevity. Preprint at medRxiv https:\/\/doi.org\/10.1101\/2025.09.07.25335188 (2025).","DOI":"10.1101\/2025.09.07.25335188"},{"key":"4446_CR25","doi-asserted-by":"publisher","first-page":"634","DOI":"10.1016\/j.exger.2009.07.006","volume":"44","author":"R Hass","year":"2009","unstructured":"Hass, R. Rejuvenation in distinct cell populations\u2014what does it mean?. Exp. Gerontol. 44, 634\u2013638 (2009).","journal-title":"Exp. Gerontol."},{"key":"4446_CR26","doi-asserted-by":"publisher","first-page":"1363","DOI":"10.1016\/S0140-6736(22)01272-7","volume":"400","author":"EL Feldman","year":"2022","unstructured":"Feldman, E. L. et al. Amyotrophic lateral sclerosis. Lancet Lond. Engl. 400, 1363\u20131380 (2022).","journal-title":"Lancet Lond. Engl."},{"key":"4446_CR27","doi-asserted-by":"publisher","first-page":"227","DOI":"10.1111\/bpa.12350","volume":"26","author":"J-P Loeffler","year":"2016","unstructured":"Loeffler, J.-P., Picchiarelli, G., Dupuis, L. & Gonzalez De Aguilar, J.-L. The role of skeletal muscle in amyotrophic lateral sclerosis. Brain Pathol. 26, 227\u2013236 (2016).","journal-title":"Brain Pathol."},{"key":"4446_CR28","doi-asserted-by":"publisher","first-page":"272","DOI":"10.3109\/17482960903390855","volume":"11","author":"S Pavlovic","year":"2010","unstructured":"Pavlovic, S. et al. Impairment of cardiac autonomic control in patients with amyotrophic lateral sclerosis. Amyotroph. Lateral Scler. 11, 272\u2013276 (2010).","journal-title":"Amyotroph. Lateral Scler."},{"key":"4446_CR29","doi-asserted-by":"publisher","first-page":"e13129","DOI":"10.1111\/bpa.13129","volume":"33","author":"AB Ali","year":"2023","unstructured":"Ali, A. B., Islam, A. & Constanti, A. The fate of interneurons, GABAA receptor sub-types and perineuronal nets in Alzheimer\u2019s disease. Brain Pathol. 33, e13129 (2023).","journal-title":"Brain Pathol."},{"key":"4446_CR30","doi-asserted-by":"publisher","first-page":"777","DOI":"10.1038\/nrn.2016.141","volume":"17","author":"JJ Palop","year":"2016","unstructured":"Palop, J. J. & Mucke, L. Network abnormalities and interneuron dysfunction in Alzheimer disease. Nat. Rev. Neurosci. 17, 777\u2013792 (2016).","journal-title":"Nat. Rev. Neurosci."},{"key":"4446_CR31","doi-asserted-by":"publisher","first-page":"94","DOI":"10.1038\/s41583-018-0113-1","volume":"20","author":"CM Henstridge","year":"2019","unstructured":"Henstridge, C. M., Hyman, B. T. & Spires-Jones, T. L. Beyond the neuron-cellular interactions early in Alzheimer disease pathogenesis. Nat. Rev. Neurosci. 20, 94\u2013108 (2019).","journal-title":"Nat. Rev. Neurosci."},{"key":"4446_CR32","doi-asserted-by":"publisher","first-page":"148","DOI":"10.1038\/s41583-019-0132-6","volume":"20","author":"DA Butterfield","year":"2019","unstructured":"Butterfield, D. A. & Halliwell, B. Oxidative stress, dysfunctional glucose metabolism and Alzheimer disease. Nat. Rev. Neurosci. 20, 148\u2013160 (2019).","journal-title":"Nat. Rev. Neurosci."},{"key":"4446_CR33","doi-asserted-by":"publisher","first-page":"530219","DOI":"10.3389\/fnins.2020.530219","volume":"14","author":"X Yan","year":"2020","unstructured":"Yan, X., Hu, Y., Wang, B., Wang, S. & Zhang, X. Metabolic dysregulation contributes to the progression of Alzheimer\u2019s Disease. Front. Neurosci. 14, 530219 (2020).","journal-title":"Front. Neurosci."},{"key":"4446_CR34","doi-asserted-by":"publisher","first-page":"1279","DOI":"10.1111\/bph.15276","volume":"178","author":"R Manzano","year":"2021","unstructured":"Manzano, R. et al. What skeletal muscle has to say in amyotrophic lateral sclerosis: implications for therapy. Br. J. Pharmacol. 178, 1279\u20131297 (2021).","journal-title":"Br. J. Pharmacol."},{"key":"4446_CR35","doi-asserted-by":"publisher","first-page":"e73846","DOI":"10.1371\/journal.pone.0073846","volume":"8","author":"MC Rocha","year":"2013","unstructured":"Rocha, M. C., Pousinha, P. A., Correia, A. M., Sebasti\u00e3o, A. M. & Ribeiro, J. A. Early changes of neuromuscular transmission in the SOD1(G93A) mice model of ALS start long before motor symptoms onset. PLoS ONE 8, e73846 (2013).","journal-title":"PLoS ONE"},{"key":"4446_CR36","doi-asserted-by":"publisher","first-page":"fcac310","DOI":"10.1093\/braincomms\/fcac310","volume":"5","author":"H Zetterberg","year":"2023","unstructured":"Zetterberg, H. et al. The role of neurofilament light in genetic frontotemporal lobar degeneration. Brain Commun. 5, fcac310 (2023).","journal-title":"Brain Commun."},{"key":"4446_CR37","doi-asserted-by":"publisher","first-page":"752","DOI":"10.1016\/j.neuron.2016.04.001","volume":"90","author":"K Matsuda","year":"2016","unstructured":"Matsuda, K. et al. Transsynaptic modulation of kainate receptor functions by C1q-like proteins. Neuron 90, 752\u2013767 (2016).","journal-title":"Neuron"},{"key":"4446_CR38","doi-asserted-by":"publisher","first-page":"453","DOI":"10.3109\/21678421.2014.903974","volume":"15","author":"S Paganoni","year":"2014","unstructured":"Paganoni, S. et al. Diagnostic timelines and delays in diagnosing amyotrophic lateral sclerosis (ALS). Amyotroph. Lateral Scler. Frontotemporal Degener. 15, 453\u2013456 (2014).","journal-title":"Amyotroph. Lateral Scler. Frontotemporal Degener."},{"key":"4446_CR39","doi-asserted-by":"publisher","first-page":"388","DOI":"10.1016\/S1474-4422(15)70016-5","volume":"14","author":"MT Heneka","year":"2015","unstructured":"Heneka, M. T. et al. Neuroinflammation in Alzheimer\u2019s disease. Lancet Neurol. 14, 388\u2013405 (2015).","journal-title":"Lancet Neurol."},{"key":"4446_CR40","doi-asserted-by":"publisher","first-page":"1324522","DOI":"10.3389\/fgwh.2023.1324522","volume":"4","author":"MA O\u2019Neal","year":"2024","unstructured":"O\u2019Neal, M. A. Women and the risk of Alzheimer\u2019s disease. Front. Glob. Womens Health 4, 1324522 (2024).","journal-title":"Front. Glob. Womens Health"},{"key":"4446_CR41","doi-asserted-by":"crossref","unstructured":"Morris, J. C. Clinical dementia rating: a reliable and valid diagnostic and staging measure for dementia of the Alzheimer type. Int. Psychogeriatr. 9, 173\u2013176 discussion 177\u2013178 (1997).","DOI":"10.1017\/S1041610297004870"},{"key":"4446_CR42","doi-asserted-by":"publisher","DOI":"10.1186\/s12883-017-0846-x","volume":"17","author":"CA Lane","year":"2017","unstructured":"Lane, C. A. et al. Study protocol: Insight 46\u2014a neuroscience sub-study of the MRC National Survey of Health and Development. BMC Neurol. 17, 75 (2017).","journal-title":"BMC Neurol."},{"key":"4446_CR43","doi-asserted-by":"publisher","first-page":"1836","DOI":"10.3390\/biomedicines12081836","volume":"12","author":"R Lai","year":"2024","unstructured":"Lai, R., Li, B. & Bishnoi, R. P-tau217 as a reliable blood-based marker of Alzheimer\u2019s Disease. Biomedicines 12, 1836 (2024).","journal-title":"Biomedicines"},{"key":"4446_CR44","doi-asserted-by":"publisher","first-page":"961","DOI":"10.1001\/jamaneurol.2014.803","volume":"71","author":"MC Donohue","year":"2014","unstructured":"Donohue, M. C. et al. The preclinical Alzheimer cognitive composite: measuring amyloid-related decline. JAMA Neurol. 71, 961\u2013970 (2014).","journal-title":"JAMA Neurol."},{"key":"4446_CR45","doi-asserted-by":"publisher","first-page":"4910","DOI":"10.1073\/pnas.1112499109","volume":"109","author":"X Xu","year":"2012","unstructured":"Xu, X. et al. Evidence for type II cells as cells of origin of K-Ras-induced distal lung adenocarcinoma. Proc. Natl Acad. Sci. USA 109, 4910\u20134915 (2012).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"4446_CR46","doi-asserted-by":"publisher","first-page":"190","DOI":"10.1038\/nature12930","volume":"507","author":"TJ Desai","year":"2014","unstructured":"Desai, T. J., Brownfield, D. G. & Krasnow, M. A. Alveolar progenitor and stem cells in lung development, renewal and cancer. Nature 507, 190\u2013194 (2014).","journal-title":"Nature"},{"key":"4446_CR47","doi-asserted-by":"publisher","first-page":"36","DOI":"10.1038\/s41387-019-0103-z","volume":"9","author":"W He","year":"2019","unstructured":"He, W., Yuan, T. & Maedler, K. Macrophage-associated pro-inflammatory state in human islets from obese individuals. Nutr. Diabetes 9, 36 (2019).","journal-title":"Nutr. Diabetes"},{"key":"4446_CR48","doi-asserted-by":"publisher","first-page":"e039747","DOI":"10.1161\/JAHA.124.039747","volume":"14","author":"RM Biggs","year":"2025","unstructured":"Biggs, R. M. et al. Persistent fibrosis in heart failure with a reduced ejection fraction linked to phenotypic differences in human cardiac fibroblast populations. J. Am. Heart Assoc. 14, e039747 (2025).","journal-title":"J. Am. Heart Assoc."},{"key":"4446_CR49","doi-asserted-by":"publisher","first-page":"258","DOI":"10.3389\/fimmu.2015.00258","volume":"6","author":"M Nassef Kadry Naguib Roufaiel","year":"2015","unstructured":"Nassef Kadry Naguib Roufaiel, M., Wells, J. W. & Steptoe, R. J. Impaired T-cell function in B-cell lymphoma: a direct consequence of events at the immunological synapse?. Front. Immunol. 6, 258 (2015).","journal-title":"Front. Immunol."},{"key":"4446_CR50","doi-asserted-by":"publisher","unstructured":"Ferrant, J. et al. Myeloid landscape profiling identifies DLBCL-specific suppressive macrophages colocalized with blood endothelial cells. Blood Adv. https:\/\/doi.org\/10.1182\/bloodadvances.2024015689 (2025).","DOI":"10.1182\/bloodadvances.2024015689"},{"key":"4446_CR51","doi-asserted-by":"publisher","first-page":"1921","DOI":"10.1038\/s41591-021-01521-4","volume":"27","author":"A Niroula","year":"2021","unstructured":"Niroula, A. et al. Distinction of lymphoid and myeloid clonal hematopoiesis. Nat. Med. 27, 1921\u20131927 (2021).","journal-title":"Nat. Med."},{"key":"4446_CR52","doi-asserted-by":"publisher","first-page":"e650","DOI":"10.1016\/S2468-2667(20)30113-4","volume":"5","author":"J Fan","year":"2020","unstructured":"Fan, J. et al. Frailty index and all-cause and cause-specific mortality in Chinese adults: a prospective cohort study. Lancet Public Health 5, e650\u2013e660 (2020).","journal-title":"Lancet Public Health"},{"key":"4446_CR53","doi-asserted-by":"publisher","first-page":"62","DOI":"10.3389\/fnsys.2017.00062","volume":"11","author":"A Bayati","year":"2017","unstructured":"Bayati, A. & Berman, T. Localized vs. systematic neurodegeneration: a paradigm shift in understanding neurodegenerative diseases. Front. Syst. Neurosci. 11, 62 (2017).","journal-title":"Front. Syst. Neurosci."},{"key":"4446_CR54","doi-asserted-by":"publisher","first-page":"249","DOI":"10.1007\/s11357-022-00621-4","volume":"45","author":"C Dimovasili","year":"2022","unstructured":"Dimovasili, C. et al. Aging compromises oligodendrocyte precursor cell maturation and efficient remyelination in the monkey brain. GeroScience 45, 249\u2013264 (2022).","journal-title":"GeroScience"},{"key":"4446_CR55","doi-asserted-by":"publisher","first-page":"230","DOI":"10.1002\/1520-7560(2000)9999:9999<::AID-DMRR122>3.0.CO;2-W","volume":"16","author":"MI Harris","year":"2000","unstructured":"Harris, M. I. & Eastman, R. C. Early detection of undiagnosed diabetes mellitus: a US perspective. Diabetes Metab. Res. Rev. 16, 230\u2013236 (2000).","journal-title":"Diabetes Metab. Res. Rev."},{"key":"4446_CR56","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1021\/acschemneuro.3c00531","volume":"15","author":"R Tenchov","year":"2023","unstructured":"Tenchov, R., Sasso, J. M., Wang, X. & Zhou, Q. A. Aging hallmarks and progression and age-related diseases: a landscape view of research advancement. ACS Chem. Neurosci. 15, 1\u201330 (2023).","journal-title":"ACS Chem. Neurosci."},{"key":"4446_CR57","doi-asserted-by":"publisher","unstructured":"Uhl\u00e9n, M. et al. The human secretome. Sci. Signal. https:\/\/doi.org\/10.1126\/scisignal.aaz0274 (2019).","DOI":"10.1126\/scisignal.aaz0274"},{"key":"4446_CR58","doi-asserted-by":"publisher","first-page":"329","DOI":"10.1038\/s41586-023-06592-6","volume":"622","author":"BB Sun","year":"2023","unstructured":"Sun, B. B. et al. Plasma proteomic associations with genetics and health in the UK Biobank. Nature 622, 329\u2013338 (2023).","journal-title":"Nature"}],"container-title":["Nature Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41591-026-04446-y.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41591-026-04446-y","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41591-026-04446-y.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,19]],"date-time":"2026-06-19T07:03:38Z","timestamp":1781852618000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41591-026-04446-y"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6]]},"references-count":58,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2026,6]]}},"alternative-id":["4446"],"URL":"https:\/\/doi.org\/10.1038\/s41591-026-04446-y","relation":{},"ISSN":["1078-8956","1546-170X"],"issn-type":[{"value":"1078-8956","type":"print"},{"value":"1546-170X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6]]},"assertion":[{"value":"21 April 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"4 May 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"15 June 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"T.W.-C. and H.S.-H.O. are co-founders and scientific advisors of Teal Omics Inc. and have received equity stakes. T.W.-C. is a co-founder and scientific advisor of Alkahest Inc. and Qinotto Inc. and has received equity stakes in these companies. C.C. has received research support from GSK and EISAI. C.C. is a member of the scientific advisory board of Circular Genomics and owns stocks and is also a member of the scientific advisory board of ADmit. J.M.S. has received research funding and PET tracer from AVID Radiopharmaceuticals (a wholly owned subsidiary of Eli Lilly) and Alliance Medical, and has consulted for Roche, Eli Lilly, Biogen, MSD, GE Healthcare, Alamar Biosciences and Receptive Bio, and is Chief Medical Officer for Alzheimer\u2019s Research UK. The other authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}