{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,4]],"date-time":"2026-07-04T12:01:28Z","timestamp":1783166488718,"version":"3.54.6"},"posted":{"date-parts":[[2023,7,15]]},"group-title":"Systems Biology","reference-count":72,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2023,12,9]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>Loss of proteostasis is a highly conserved feature of aging across model organisms and typically results in the accumulation of insoluble protein aggregates. Protein insolubility is a central feature of major age-related neurodegenerative diseases, including Alzheimer\u2019s Disease (AD), where hundreds of insoluble proteins associate with aggregated amyloid beta (A\u03b2) in senile plaques. Moreover, proteins that become insoluble during aging in model organisms are capable of accelerating A\u03b2 aggregation in vitro. Despite the connection between aging and AD risk, therapeutic approaches to date have overlooked aging-driven protein insolubility as a contributory factor. Here, using an unbiased proteomics approach, we questioned the relationship between A\u03b2 and age-related protein insolubility. We demonstrate that A\u03b2 expression drives proteome-wide protein insolubility in C. elegans and this insoluble proteome closely resembles the insoluble proteome driven by normal aging, suggesting the possibility of a vicious feedforward cycle of aggregation in the context of AD. Importantly, using human genome-wide association studies (GWAS), we show that the CIP is replete with biological processes implicated not only in neurodegenerative diseases but also across a broad array of chronic, age-related diseases (CARDs). This provides suggestive evidence that age-related loss of proteostasis could play a role in general CARD risk. Finally, we show that the CIP is enriched with proteins that modulate the toxic effects of A\u03b2 and that the gut-derived metabolite, Urolithin A, relieves A\u03b2 toxicity, supporting its use in clinical trials for dementia and other age-related diseases.<\/jats:p>","DOI":"10.1101\/2023.07.13.548937","type":"posted-content","created":{"date-parts":[[2023,7,15]],"date-time":"2023-07-15T19:45:12Z","timestamp":1689450312000},"source":"Crossref","is-referenced-by-count":1,"title":["Amyloid \u03b2 accelerates age-related proteome-wide protein insolubility"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-6619-8899","authenticated-orcid":false,"given":"Edward","family":"Anderton","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0339-7894","authenticated-orcid":false,"given":"Manish","family":"Chamoli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dipa","family":"Bhaumik","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christina D.","family":"King","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xueshu","family":"Xie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Foulger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie K.","family":"Andersen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9907-2749","authenticated-orcid":false,"given":"Birgit","family":"Schilling","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gordon J.","family":"Lithgow","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2023121209050436000_2023.07.13.548937v3.1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2010.10.007"},{"key":"2023121209050436000_2023.07.13.548937v3.2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0804550105"},{"key":"2023121209050436000_2023.07.13.548937v3.3","doi-asserted-by":"crossref","unstructured":"Saarikangas, J. & Barral, Y. Protein aggregates are associated with replicative aging without compromising protein quality control. Elife 4, (2015).","DOI":"10.7554\/eLife.06197"},{"key":"2023121209050436000_2023.07.13.548937v3.4","doi-asserted-by":"publisher","DOI":"10.1111\/j.1474-9726.2011.00765.x"},{"key":"2023121209050436000_2023.07.13.548937v3.5","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pbio.1000450"},{"key":"2023121209050436000_2023.07.13.548937v3.6","doi-asserted-by":"crossref","first-page":"9596","DOI":"10.15252\/msb.20209596","article-title":"Reduced proteasome activity in the aging brain results in ribosome stoichiometry loss and aggregation","volume":"16","year":"2020","journal-title":"Mol Syst Biol"},{"key":"2023121209050436000_2023.07.13.548937v3.7","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-016-0001-8"},{"key":"2023121209050436000_2023.07.13.548937v3.8","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2020.03.009"},{"key":"2023121209050436000_2023.07.13.548937v3.9","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2015.03.032"},{"key":"2023121209050436000_2023.07.13.548937v3.10","first-page":"1227","article-title":"Vitamin D Promotes Protein Homeostasis and Longevity via the Stress Response Pathway Genes skn-1, ire-1, and xbp-1","volume":"17","year":"2016","journal-title":"CellReports"},{"key":"2023121209050436000_2023.07.13.548937v3.11","doi-asserted-by":"crossref","first-page":"975","DOI":"10.18632\/aging.100689","article-title":"Iron promotes protein insolubility and aging in C. elegans","volume":"6","year":"2014","journal-title":"Aging"},{"key":"2023121209050436000_2023.07.13.548937v3.12","doi-asserted-by":"publisher","DOI":"10.1038\/ng1718"},{"key":"2023121209050436000_2023.07.13.548937v3.13","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1619574114"},{"key":"2023121209050436000_2023.07.13.548937v3.14","doi-asserted-by":"publisher","DOI":"10.1126\/science.1072994"},{"key":"2023121209050436000_2023.07.13.548937v3.15","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9440(10)63388-3"},{"key":"2023121209050436000_2023.07.13.548937v3.16","doi-asserted-by":"publisher","DOI":"10.1038\/nrn2168"},{"key":"2023121209050436000_2023.07.13.548937v3.17","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2005.01.040"},{"key":"2023121209050436000_2023.07.13.548937v3.18","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2005.06.030"},{"key":"2023121209050436000_2023.07.13.548937v3.19","doi-asserted-by":"publisher","DOI":"10.1038\/nature06616"},{"key":"2023121209050436000_2023.07.13.548937v3.20","doi-asserted-by":"publisher","DOI":"10.1038\/nn1022"},{"key":"2023121209050436000_2023.07.13.548937v3.21","doi-asserted-by":"publisher","DOI":"10.1006\/exnr.1999.7085"},{"key":"2023121209050436000_2023.07.13.548937v3.22","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2010.11.050"},{"key":"2023121209050436000_2023.07.13.548937v3.23","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1910444117"},{"key":"2023121209050436000_2023.07.13.548937v3.24","doi-asserted-by":"publisher","DOI":"10.3389\/fnagi.2017.00138"},{"key":"2023121209050436000_2023.07.13.548937v3.25","doi-asserted-by":"publisher","DOI":"10.1016\/j.jalz.2007.04.381"},{"key":"2023121209050436000_2023.07.13.548937v3.26","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1016\/j.jalz.2010.11.007","article-title":"National estimates of the prevalence of Alzheimer\u2019s disease in the United States","volume":"7","year":"2011","journal-title":"Alzheimer\u2019s & Dementia"},{"key":"2023121209050436000_2023.07.13.548937v3.27","first-page":"481","article-title":"Clinical relevance of animal models in aging-related dementia research","volume":"3","year":"2023","journal-title":"Nature Aging 2023 3:5"},{"key":"2023121209050436000_2023.07.13.548937v3.28","first-page":"459","volume":"3","author":"The transforming landscape of dementia research","year":"2023","journal-title":"Nature Aging 2023 3:5"},{"key":"2023121209050436000_2023.07.13.548937v3.29","first-page":"1","article-title":"Quantification of insoluble protein aggregation in caenorhabditis elegans during aging with a novel data-independent acquisition workflow","volume":"2020","year":"2020","journal-title":"Journal of Visualized Experiments"},{"key":"2023121209050436000_2023.07.13.548937v3.30","doi-asserted-by":"publisher","DOI":"10.1186\/1750-1326-7-1"},{"key":"2023121209050436000_2023.07.13.548937v3.31","first-page":"1","article-title":"Multi-laboratory assessment of reproducibility, qualitative and quantitative performance of SWATH-mass spectrometry","volume":"8","year":"2017","journal-title":"Nature Communications 2017 8:1"},{"key":"2023121209050436000_2023.07.13.548937v3.32","doi-asserted-by":"crossref","unstructured":"Gillet, L. C. et al. Targeted Data Extraction of the MS\/MS Spectra Generated by Data-independent Acquisition: A New Concept for Consistent and Accurate Proteome Analysis. Molecular & Cellular Proteomics 11, O111.016717 (2012).","DOI":"10.1074\/mcp.O111.016717"},{"key":"2023121209050436000_2023.07.13.548937v3.33","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1007\/s12975-012-0161-1","article-title":"TOMM40 in Cerebral Amyloid Angiopathy Related Intracerebral Hemorrhage: Comparative Genetic Analysis with Alzheimer\u2019s Disease","volume":"3","year":"2012","journal-title":"Transl Stroke Res"},{"key":"2023121209050436000_2023.07.13.548937v3.34","doi-asserted-by":"publisher","DOI":"10.1086\/303003"},{"key":"2023121209050436000_2023.07.13.548937v3.35","first-page":"936","article-title":"Evaluation of late-onset Alzheimer disease genetic susceptibility risks in a Canadian population","volume":"35","year":"2014","journal-title":"Neurobiol Aging"},{"key":"2023121209050436000_2023.07.13.548937v3.36","doi-asserted-by":"publisher","DOI":"10.1534\/genetics.118.301307"},{"key":"2023121209050436000_2023.07.13.548937v3.37","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.06388-11"},{"key":"2023121209050436000_2023.07.13.548937v3.38","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-017-1691-0"},{"key":"2023121209050436000_2023.07.13.548937v3.39","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2010.11.050"},{"key":"2023121209050436000_2023.07.13.548937v3.40","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddl067"},{"key":"2023121209050436000_2023.07.13.548937v3.41","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0711018105"},{"key":"2023121209050436000_2023.07.13.548937v3.42","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1000027"},{"key":"2023121209050436000_2023.07.13.548937v3.43","doi-asserted-by":"crossref","first-page":"1002438","DOI":"10.1371\/journal.pgen.1002438","article-title":"A Genetic Screening Strategy Identifies Novel Regulators of the Proteostasis Network","volume":"7","year":"2011","journal-title":"PLoS Genet"},{"key":"2023121209050436000_2023.07.13.548937v3.44","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0307697101"},{"key":"2023121209050436000_2023.07.13.548937v3.45","doi-asserted-by":"publisher","DOI":"10.1111\/acel.12362"},{"key":"2023121209050436000_2023.07.13.548937v3.46","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0102985"},{"key":"2023121209050436000_2023.07.13.548937v3.47","doi-asserted-by":"publisher","DOI":"10.1021\/jf050384i"},{"key":"2023121209050436000_2023.07.13.548937v3.48","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmed.2021.04.009"},{"key":"2023121209050436000_2023.07.13.548937v3.49","doi-asserted-by":"crossref","unstructured":"D\u2019Amico, D. et al. Urolithin A improves mitochondrial health, reduces cartilage degeneration, and alleviates pain in osteoarthritis. Aging Cell 21, (2022).","DOI":"10.1111\/acel.13662"},{"key":"2023121209050436000_2023.07.13.548937v3.50","doi-asserted-by":"publisher","DOI":"10.1038\/s41593-018-0332-9"},{"key":"2023121209050436000_2023.07.13.548937v3.51","doi-asserted-by":"publisher","DOI":"10.1038\/nm.4132"},{"key":"2023121209050436000_2023.07.13.548937v3.52","doi-asserted-by":"crossref","first-page":"e2144279","DOI":"10.1001\/jamanetworkopen.2021.44279","article-title":"Effect of Urolithin A Supplementation on Muscle Endurance and Mitochondrial Health in Older Adults: A Randomized Clinical Trial","volume":"5","year":"2022","journal-title":"JAMA Netw Open"},{"key":"2023121209050436000_2023.07.13.548937v3.53","doi-asserted-by":"crossref","first-page":"595","DOI":"10.1038\/s42255-019-0073-4","article-title":"The mitophagy activator urolithin A is safe and induces a molecular signature of improved mitochondrial and cellular health in humans","volume":"1","year":"2019","journal-title":"Nat Metab"},{"key":"2023121209050436000_2023.07.13.548937v3.54","doi-asserted-by":"crossref","first-page":"1095","DOI":"10.1007\/s11357-022-00708-y","article-title":"Urolithin A reduces amyloid-beta load and improves cognitive deficits uncorrelated with plaque burden in a mouse model of Alzheimer\u2019s disease","volume":"45","year":"2023","journal-title":"Geroscience"},{"key":"2023121209050436000_2023.07.13.548937v3.55","unstructured":"What is Geroscience? - American Federation for Aging Research. https:\/\/www.afar.org\/what-is-geroscience."},{"key":"2023121209050436000_2023.07.13.548937v3.56","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2014.07.024"},{"key":"2023121209050436000_2023.07.13.548937v3.57","doi-asserted-by":"publisher","DOI":"10.1091\/mbc.E16-05-0313"},{"key":"2023121209050436000_2023.07.13.548937v3.58","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0806192105"},{"key":"2023121209050436000_2023.07.13.548937v3.59","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.RA118.002713"},{"key":"2023121209050436000_2023.07.13.548937v3.60","doi-asserted-by":"crossref","first-page":"e1010400.","DOI":"10.1371\/journal.pgen.1010400","article-title":"Oocyte mitophagy is critical for extended reproductive longevity","volume":"18","year":"2022","journal-title":"PLoS Genet"},{"key":"2023121209050436000_2023.07.13.548937v3.61","first-page":"1","article-title":"Genetic inhibition of an ATP synthase subunit extends lifespan in C. elegans","volume":"8","year":"2018","journal-title":"Scientific Reports 2018 8:1"},{"key":"2023121209050436000_2023.07.13.548937v3.62","doi-asserted-by":"publisher","DOI":"10.1038\/ng1056"},{"key":"2023121209050436000_2023.07.13.548937v3.63","doi-asserted-by":"publisher","DOI":"10.1111\/j.1474-9726.2007.00302.x"},{"key":"2023121209050436000_2023.07.13.548937v3.64","doi-asserted-by":"publisher","DOI":"10.1101\/gad.1308205"},{"key":"2023121209050436000_2023.07.13.548937v3.65","doi-asserted-by":"publisher","DOI":"10.1126\/science.1139952"},{"key":"2023121209050436000_2023.07.13.548937v3.66","doi-asserted-by":"crossref","unstructured":"Evans, D. S. et al. Longitudinal Functional Study of Murine Aging: A Resource for Future Study Designs. JBMR Plus 5, (2021).","DOI":"10.1002\/jbm4.10466"},{"key":"2023121209050436000_2023.07.13.548937v3.67","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.4096"},{"key":"2023121209050436000_2023.07.13.548937v3.68","doi-asserted-by":"crossref","unstructured":"Huang, D. W. et al. DAVID Bioinformatics Resources: Expanded annotation database and novel algorithms to better extract biology from large gene lists. Nucleic Acids Res 35, (2007).","DOI":"10.1093\/nar\/gkm415"},{"key":"2023121209050436000_2023.07.13.548937v3.69","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2008.211"},{"key":"2023121209050436000_2023.07.13.548937v3.70","doi-asserted-by":"publisher","DOI":"10.1093\/NAR\/GKAC1052"},{"key":"2023121209050436000_2023.07.13.548937v3.71","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0021800"},{"key":"2023121209050436000_2023.07.13.548937v3.72","doi-asserted-by":"publisher","DOI":"10.1101\/gr.1239303"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/2023.07.13.548937","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T04:55:02Z","timestamp":1768452902000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.1101\/2023.07.13.548937"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,7,15]]},"references-count":72,"URL":"https:\/\/doi.org\/10.1101\/2023.07.13.548937","relation":{"is-preprint-of":[{"id-type":"doi","id":"10.1007\/s11357-024-01169-1","asserted-by":"subject"}]},"subject":[],"published":{"date-parts":[[2023,7,15]]},"subtype":"preprint"}}