{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,27]],"date-time":"2026-02-27T06:18:27Z","timestamp":1772173107176,"version":"3.50.1"},"update-to":[{"DOI":"10.1371\/journal.pcbi.1010261","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2022,7,19]],"date-time":"2022-07-19T00:00:00Z","timestamp":1658188800000}}],"reference-count":95,"publisher":"Public Library of Science (PLoS)","issue":"7","license":[{"start":{"date-parts":[[2022,7,7]],"date-time":"2022-07-07T00:00:00Z","timestamp":1657152000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004359","name":"Vetenskapsr\u00e5det","doi-asserted-by":"publisher","award":["VR2016-03744"],"award-info":[{"award-number":["VR2016-03744"]}],"id":[{"id":"10.13039\/501100004359","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004359","name":"Vetenskapsr\u00e5det","doi-asserted-by":"publisher","award":["VR2017-05117"],"award-info":[{"award-number":["VR2017-05117"]}],"id":[{"id":"10.13039\/501100004359","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001729","name":"Stiftelsen f\u00f6r Strategisk Forskning","doi-asserted-by":"publisher","award":["FFL15-0238"],"award-info":[{"award-number":["FFL15-0238"]}],"id":[{"id":"10.13039\/501100001729","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.ploscompbiol.org"],"crossmark-restriction":false},"short-container-title":["PLoS Comput Biol"],"abstract":"<jats:p>The accumulation of protein damage is one of the major drivers of replicative ageing, describing a cell\u2019s reduced ability to reproduce over time even under optimal conditions. Reactive oxygen and nitrogen species are precursors of protein damage and therefore tightly linked to ageing. At the same time, they are an inevitable by-product of the cell\u2019s metabolism. Cells are able to sense high levels of reactive oxygen and nitrogen species and can subsequently adapt their metabolism through gene regulation to slow down damage accumulation. However, the older or damaged a cell is the less flexibility it has to allocate enzymes across the metabolic network, forcing further adaptions in the metabolism. To investigate changes in the metabolism during replicative ageing, we developed an multi-scale mathematical model using budding yeast as a model organism. The model consists of three interconnected modules: a Boolean model of the signalling network, an enzyme-constrained flux balance model of the central carbon metabolism and a dynamic model of growth and protein damage accumulation with discrete cell divisions. The model can explain known features of replicative ageing, like average lifespan and increase in generation time during successive division, in yeast wildtype cells by a decreasing pool of functional enzymes and an increasing energy demand for maintenance. We further used the model to identify three consecutive metabolic phases, that a cell can undergo during its life, and their influence on the replicative potential, and proposed an intervention span for lifespan control.<\/jats:p>","DOI":"10.1371\/journal.pcbi.1010261","type":"journal-article","created":{"date-parts":[[2022,7,7]],"date-time":"2022-07-07T13:43:25Z","timestamp":1657201405000},"page":"e1010261","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":5,"title":["Multi-scale model suggests the trade-off between protein and ATP demand as a driver of metabolic changes during yeast replicative ageing"],"prefix":"10.1371","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0962-0575","authenticated-orcid":true,"given":"Barbara","family":"Schnitzer","sequence":"first","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9816-6476","authenticated-orcid":true,"given":"Linnea","family":"\u00d6sterberg","sequence":"additional","affiliation":[]},{"given":"Iro","family":"Skopa","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5142-5100","authenticated-orcid":true,"given":"Marija","family":"Cvijovic","sequence":"additional","affiliation":[]}],"member":"340","published-online":{"date-parts":[[2022,7,7]]},"reference":[{"issue":"6","key":"pcbi.1010261.ref001","doi-asserted-by":"crossref","first-page":"1194","DOI":"10.1016\/j.cell.2013.05.039","article-title":"The Hallmarks of Aging","volume":"153","author":"C 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Rev"},{"issue":"5","key":"pcbi.1010261.ref072","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1016\/S1478-5382(03)02370-9","article-title":"CellDesigner: a process diagram editor for gene-regulatory and biochemical networks","volume":"1","author":"A Funahashi","year":"2003","journal-title":"BIOSILICO"},{"issue":"11","key":"pcbi.1010261.ref073","doi-asserted-by":"crossref","first-page":"4226","DOI":"10.1128\/AEM.64.11.4226-4233.1998","article-title":"Effect of Specific Growth Rate on Fermentative Capacity of Baker\u2019s Yeast","volume":"64","author":"P Van Hoek","year":"1998","journal-title":"Appl Environ Microbiol"},{"key":"pcbi.1010261.ref074","doi-asserted-by":"crossref","first-page":"1751","DOI":"10.1038\/1831751a0","article-title":"Life Span of Individual Yeast Cells","volume":"183","author":"RK Mortimer","year":"1959","journal-title":"Nature"},{"issue":"1","key":"pcbi.1010261.ref075","doi-asserted-by":"crossref","first-page":"eaao4666","DOI":"10.1126\/sciadv.aao4666","article-title":"The generational scalability of single-cell replicative aging","volume":"4","author":"P Liu","year":"2018","journal-title":"Sci Adv"},{"key":"pcbi.1010261.ref076","doi-asserted-by":"crossref","first-page":"e64860","DOI":"10.7554\/eLife.64860","article-title":"Evolution of natural lifespan variation and molecular strategies of extended lifespan in yeast","volume":"10","author":"A Kaya","year":"2021","journal-title":"eLife"},{"issue":"6","key":"pcbi.1010261.ref077","doi-asserted-by":"crossref","first-page":"723","DOI":"10.1016\/j.ceb.2008.09.004","article-title":"A mother\u2019s sacrifice: what is she keeping for herself?","volume":"20","author":"KA Henderson","year":"2008","journal-title":"Current Opinion in Cell 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Reports"},{"issue":"1-3","key":"pcbi.1010261.ref081","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1016\/S0014-5793(03)01462-5","article-title":"Chronological aging-independent replicative life span regulation by Msn2\/Msn4 and Sod2 in Saccharomyces cerevisiae","volume":"557","author":"P Fabrizio","year":"2004","journal-title":"FEBS Letters"},{"issue":"5751","key":"pcbi.1010261.ref082","doi-asserted-by":"crossref","first-page":"1193","DOI":"10.1126\/science.1115535","article-title":"Regulation of Yeast Replicative Life Span by TOR and Sch9 in Response to Nutrients","volume":"310","author":"M Kaeberlein","year":"2005","journal-title":"Science"},{"issue":"11","key":"pcbi.1010261.ref083","doi-asserted-by":"crossref","first-page":"482","DOI":"10.15698\/mic2018.11.655","article-title":"Conventional and emerging roles of the energy sensor Snf1\/AMPK in Saccharomyces cerevisiae","volume":"5","author":"P Coccetti","year":"2018","journal-title":"Microbial Cell"},{"issue":"23","key":"pcbi.1010261.ref084","doi-asserted-by":"crossref","first-page":"13134","DOI":"10.1073\/pnas.2235812100","article-title":"Saccharomyces cerevisiae phenotypes can be predicted by using constraint-based analysis of a genome-scale reconstructed metabolic network","volume":"100","author":"I Famili","year":"2003","journal-title":"Proceedings of the National Academy of Sciences"},{"issue":"4","key":"pcbi.1010261.ref085","doi-asserted-by":"crossref","first-page":"1802","DOI":"10.1091\/mbc.e05-04-0333","article-title":"Yeast AMID Homologue Ndi1p Displays Respiration-restricted Apoptotic Activity and Is Involved in Chronological Aging","volume":"17","author":"W Li","year":"2006","journal-title":"MBoC"},{"issue":"1","key":"pcbi.1010261.ref086","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1196\/annals.1395.055","article-title":"Effects of Deleting Mitochondrial Antioxidant Genes on Life Span","volume":"1100","author":"ES Unlu","year":"2007","journal-title":"Annals of the New York Academy of Sciences"},{"issue":"11-12","key":"pcbi.1010261.ref087","doi-asserted-by":"crossref","first-page":"692","DOI":"10.1016\/j.mad.2010.09.006","article-title":"The roles of thiol oxidoreductases in yeast replicative aging","volume":"131","author":"E Hacioglu","year":"2010","journal-title":"Mechanisms of Ageing and Development"},{"issue":"991","key":"pcbi.1010261.ref088","first-page":"224","article-title":"The maintenance energy of bacteria in growing cultures","volume":"163","author":"SJ Pirt","year":"1965","journal-title":"Proceedings of the Royal Society of London Series B, Biological Sciences"},{"issue":"4","key":"pcbi.1010261.ref089","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1007\/s00248-006-9049-5","article-title":"Microbial Maintenance: A Critical Review on Its Quantification","volume":"53","author":"P van Bodegom","year":"2007","journal-title":"Microbial Ecology"},{"key":"pcbi.1010261.ref090","unstructured":"Calabrese L, Grilli J, Osella M, Kempes CP, Lagomarsino MC, Ciandrini L. Role of protein degradation in growth laws; 2021. Available from: https:\/\/www.biorxiv.org\/content\/10.1101\/2021.03.25.436692v3."},{"key":"pcbi.1010261.ref091","doi-asserted-by":"crossref","DOI":"10.3389\/fmicb.2017.00031","article-title":"Drivers of Bacterial Maintenance and Minimal Energy Requirements","volume":"8","author":"CP Kempes","year":"2017","journal-title":"Frontiers in Microbiology"},{"issue":"2","key":"pcbi.1010261.ref092","doi-asserted-by":"crossref","first-page":"118","DOI":"10.1111\/j.1567-1364.2011.00767.x","article-title":"A flux-sensing mechanism could regulate the switch between respiration and fermentation","volume":"12","author":"DHEW Huberts","year":"2012","journal-title":"FEMS Yeast Research"},{"issue":"6","key":"pcbi.1010261.ref093","doi-asserted-by":"crossref","first-page":"514","DOI":"10.1016\/j.funbio.2017.12.003","article-title":"Oxidative stress and aging: Learning from yeast lessons","volume":"122","author":"E Eleutherio","year":"2018","journal-title":"Fungal Biology"},{"key":"pcbi.1010261.ref094","doi-asserted-by":"crossref","DOI":"10.3389\/ffunb.2021.665490","article-title":"Understanding the Impact of Industrial Stress Conditions on Replicative Aging in Saccharomyces cerevisiae","volume":"2","author":"M Eigenfeld","year":"2021","journal-title":"Frontiers in Fungal Biology"},{"issue":"41","key":"pcbi.1010261.ref095","doi-asserted-by":"crossref","first-page":"17845","DOI":"10.1073\/pnas.1005139107","article-title":"Probabilistic integrative modeling of genome-scale metabolic and regulatory networks in Escherichia coli and Mycobacterium tuberculosis","volume":"107","author":"S Chandrasekaran","year":"2010","journal-title":"Proc Natl Acad Sci USA"}],"updated-by":[{"DOI":"10.1371\/journal.pcbi.1010261","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2022,7,19]],"date-time":"2022-07-19T00:00:00Z","timestamp":1658188800000}}],"container-title":["PLOS Computational Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pcbi.1010261","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,7,19]],"date-time":"2022-07-19T13:39:08Z","timestamp":1658237948000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pcbi.1010261"}},"subtitle":[],"editor":[{"given":"Kiran Raosaheb","family":"Patil","sequence":"first","affiliation":[]}],"short-title":[],"issued":{"date-parts":[[2022,7,7]]},"references-count":95,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2022,7,7]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pcbi.1010261","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2022.03.07.483339","asserted-by":"object"}]},"ISSN":["1553-7358"],"issn-type":[{"value":"1553-7358","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,7,7]]}}}