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J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Autophagy\u2013lysosome dysfunction accompanies dermal fibroblast ageing, yet whether remodelling is transcriptional or post-transcriptional in primary human cells remains unresolved. We reanalysed the Genetic and Epigenetic Signatures of Translational Ageing Laboratory Testing(GESTALT) paired RNA sequencing (RNA-seq) and tandem mass tag (TMT) proteome from 82 donors (aged 22\u201389) using Data Integration Analysis for Biomarker discovery using Latent cOmponents (DIABLO) for supervised multi-omics integration, weighted gene co-expression network analysis (WGCNA), external Genotype-Tissue Expression(GTEx) transcriptomic comparison, network medicine proximity mapping and CDOCKER molecular docking. Three analyses converged on the autophagy\u2013lysosome axis: Kyoto Encyclopaedia of Genes and Genomes (KEGG) Lysosome ranked first in discordant-quadrant analysis; gene set enrichment analysis (GSEA) identified vacuole organisation and macroautophagy as the top age-upregulated Gene Ontology (GO) terms; and WGCNA recovered KEGG Lysosome in the brown module. Module regression localised most proteomic age signals to the lysosomal degradative-capacity module, whereas the proteasome was unaffected. McNemar testing and GTEx comparison supported a protein-side, post-transcriptional origin. TCIRG1, CTSA and ATP6V0D1 were recurrent hubs. Network proximity computationally prioritised hydroxytyrosol as a lysosomal-degradative-capacity-preferential candidate, and CDOCKER on cathepsin A linked its advantage over tyrosol to an ortho-hydroxyl group forming additional hydrogen bonds. These results support protein-layer-dominant autophagy\u2013lysosome remodelling as a feature of dermal fibroblast ageing and suggest a cell-type-resolved computational route from ageing proteomics to testable dietary candidates.<\/jats:p>","DOI":"10.3390\/ijms27156808","type":"journal-article","created":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T13:53:31Z","timestamp":1785333211000},"page":"6808","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Proteome-Level Autophagy\u2013Lysosome Remodelling Marks Ageing in Human Dermal Fibroblasts and Nominates Hydroxytyrosol as a Candidate Nutraceutical"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-8440-9645","authenticated-orcid":false,"given":"Meng","family":"Cai","sequence":"first","affiliation":[{"name":"Department of Nutrition and Food Hygiene, School of Public Health, Peking University, Beijing 100191, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7201-6982","authenticated-orcid":false,"given":"Meihong","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Nutrition and Food Hygiene, School of Public Health, Peking University, Beijing 100191, China"},{"name":"Beijing Key Laboratory of Toxicological Research and Risk Assessment for Food Safety, Peking University, Beijing 100191, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e14054","DOI":"10.1111\/acel.14054","article-title":"Aging in the dermis: Fibroblast senescence and its significance","volume":"23","author":"Zhang","year":"2024","journal-title":"Aging Cell"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"11776","DOI":"10.18632\/aging.206055","article-title":"Proteomic and secretomic comparison of young and aged dermal fibroblasts highlights cytoskeleton as a key component during aging","volume":"16","author":"Boismal","year":"2024","journal-title":"Aging"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"e13609","DOI":"10.1111\/acel.13609","article-title":"Proteomes of primary skin fibroblasts from healthy individuals reveal altered cell responses across the life span","volume":"21","author":"Tsitsipatis","year":"2022","journal-title":"Aging Cell"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"e13915","DOI":"10.1111\/acel.13915","article-title":"Transcriptomes of human primary skin fibroblasts of healthy individuals reveal age-associated mRNAs and long noncoding RNAs","volume":"22","author":"Tsitsipatis","year":"2023","journal-title":"Aging Cell"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1016\/j.cell.2022.11.001","article-title":"Hallmarks of aging: An expanding universe","volume":"186","author":"Blasco","year":"2023","journal-title":"Cell"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1429","DOI":"10.1126\/science.1204592","article-title":"TFEB links autophagy to lysosomal biogenesis","volume":"332","author":"Settembre","year":"2011","journal-title":"Science"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1095","DOI":"10.1038\/emboj.2012.32","article-title":"A lysosome-to-nucleus signalling mechanism senses and regulates the lysosome via mTOR and TFEB","volume":"31","author":"Settembre","year":"2012","journal-title":"EMBO J."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1949","DOI":"10.1083\/jcb.201610113","article-title":"Persistent mTORC1 signaling in cell senescence results from defects in amino acid and growth factor sensing","volume":"216","author":"Carroll","year":"2017","journal-title":"J. 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