{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T16:14:47Z","timestamp":1785428087191,"version":"3.56.0"},"reference-count":152,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,4,18]],"date-time":"2026-04-18T00:00:00Z","timestamp":1776470400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"crossref","award":["RS-2021NR060107"],"award-info":[{"award-number":["RS-2021NR060107"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"crossref"}]},{"award":["RS-2021NR060107"],"award-info":[{"award-number":["RS-2021NR060107"]}],"id":[{"id":"https:\/\/ror.org\/013aysd81","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Aging is one of the most complex biological processes, which leads to a gradual decline in the function of organs, tissues and cells, and significant increases in the risks of many age-associated diseases, including cancer, neurodegenerative disorders, and cardiovascular diseases. Protein biomarkers have attracted increasing attention in research on aging and age-related diseases. Considering the fact that proteins are large heterogenous biomolecules due to coding polymorphisms, alternative RNA splicing and post-translational modifications (PTMs), including glycosylation, phosphorylation, and methylation, mass spectrometry (MS)-based top-down proteomics (TDP) is a powerful technology that allows for measuring proteins without proteolysis, thus characterizing intact forms of proteins, which provides information on primary sequences, including their modifications. This review provides an overview of TDP technologies, with a particular focus on the separation, ionization, and fragmentation of intact proteins and introduces the most recent applications of TDP to the discovery of proteoform-resolved biomarkers associated with aging and age-related diseases.<\/jats:p>","DOI":"10.3390\/ijms27083610","type":"journal-article","created":{"date-parts":[[2026,4,20]],"date-time":"2026-04-20T08:24:23Z","timestamp":1776673463000},"page":"3610","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Top-Down Mass Spectrometry and Its Current Applications in Biomarker Discovery in Aging and Age-Related Diseases"],"prefix":"10.3390","volume":"27","author":[{"given":"Eun Ju","family":"Lee","sequence":"first","affiliation":[{"name":"Department of Chemical Engineering and Applied Chemistry, Chungnam National University, Daejeon 34134, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-2575-6600","authenticated-orcid":false,"given":"Haneul","family":"Choi","sequence":"additional","affiliation":[{"name":"Department of Chemical Engineering and Applied Chemistry, Chungnam National University, Daejeon 34134, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ki Ha","family":"Min","sequence":"additional","affiliation":[{"name":"Department of Biotechnology and Bioinformatics, Korea University, Sejong 30019, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hae-Min","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Chemical Engineering and Applied Chemistry, Chungnam National University, Daejeon 34134, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seung Pil","family":"Pack","sequence":"additional","affiliation":[{"name":"Department of Biotechnology and Bioinformatics, Korea University, Sejong 30019, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"806","DOI":"10.1021\/ja973655h","article-title":"Top Down versus Bottom Up Protein Characterization by Tandem High-Resolution Mass Spectrometry","volume":"121","author":"Kelleher","year":"1999","journal-title":"J. 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