{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T05:55:33Z","timestamp":1790574933299,"version":"4.1.0"},"reference-count":60,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T00:00:00Z","timestamp":1789084800000},"content-version":"vor","delay-in-days":10,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T00:00:00Z","timestamp":1788220800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100020595","name":"National Science and Technology Council","doi-asserted-by":"publisher","award":["114\u20102628\u2010B075\u2010B\u2010001\u2010MY3"],"award-info":[{"award-number":["114\u20102628\u2010B075\u2010B\u2010001\u2010MY3"]}],"id":[{"id":"10.13039\/100020595","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100011913","name":"Kaohsiung Veterans General Hospital","doi-asserted-by":"publisher","award":["KSVGH\u2010114\u2010056, 148"],"award-info":[{"award-number":["KSVGH\u2010114\u2010056, 148"]}],"id":[{"id":"10.13039\/501100011913","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Aging Cell"],"published-print":{"date-parts":[[2026,9]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>The accumulation of somatic mitochondrial DNA (mtDNA) mutations across life is among the oldest and most debated proposed drivers of aging. A defining, counter\u2010intuitive feature is that individual mutant molecules, although vanishingly rare when they arise, can come to dominate a cell's multi\u2010copy mtDNA population through intracellular clonal expansion, producing a mosaic of respiratory\u2010deficient cells across aging tissues. Here we synthesize current evidence to argue that clonal mosaicism of mtDNA heteroplasmy constitutes a quantifiable, tissue\u2010specific molecular clock of aging. We trace foundational single\u2010cell and multi\u2010tissue observations of somatic mtDNA mutation, examine the causal evidence from mtDNA mutator mice, and dissect the debate between neutral genetic drift and cellular selection that governs clonal expansion. We then integrate recent single\u2010cell and population\u2010scale studies that have transformed the field: deep multi\u2010tissue surveys revealing tissue\u2010specific accumulation and a biphasic signature, biobank analyses linking heteroplasmy burden to mortality and organ\u2010specific disease, and a two\u2010step mechanism in which cryptic replication\u2010error mutations become detectable through age\u2010related clonal mosaicism. We discuss technologies such as single\u2010cell mtDNA genotyping, duplex and long\u2010read sequencing, and droplet digital PCR that now read the clock at single\u2010molecule resolution, and we connect mutational accumulation to downstream aging phenotypes through mtDNA\u2010driven innate immune signaling, cellular senescence and inflammaging. Finally, we position the mitochondrial clock alongside epigenetic and other aging clocks, highlighting concordance, complementarity, and what must be resolved before heteroplasmy can serve as a blood\u2010based biomarker of biological age.<\/jats:p>","DOI":"10.1111\/acel.70718","type":"journal-article","created":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T04:12:13Z","timestamp":1789186333000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Clonal Mosaicism of Mitochondrial\n                    <scp>DNA<\/scp>\n                    Heteroplasmy as a Molecular Clock of Aging"],"prefix":"10.1111","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1016-2233","authenticated-orcid":false,"given":"Renin","family":"Chang","sequence":"first","affiliation":[{"name":"Department of Medical Education and Research Kaohsiung Veterans General Hospital  Kaohsiung Taiwan"},{"name":"Center of General Education Cheng Shiu University  Kaohsiung Taiwan"},{"name":"Center of General Education Shu\u2010Zen Junior College of Medicine and Management  Kaohsiung Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6400-544X","authenticated-orcid":false,"given":"Andy P.","family":"Tsai","sequence":"additional","affiliation":[{"name":"Department of Neurology and Neurological Sciences Stanford University School of Medicine  Stanford California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Boyang","family":"Wang","sequence":"additional","affiliation":[{"name":"Sundial Initiative  Palo Alto California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8090-8657","authenticated-orcid":false,"given":"Kuan\u2010Hao","family":"Tsui","sequence":"additional","affiliation":[{"name":"Center of General Education Cheng Shiu University  Kaohsiung Taiwan"},{"name":"Center of General Education Shu\u2010Zen Junior College of Medicine and Management  Kaohsiung Taiwan"},{"name":"Department of Obstetrics and Gynecology Kaohsiung Veterans General Hospital  Kaohsiung Taiwan"},{"name":"Institute of Biopharmaceutical Sciences National Sun Yat\u2010Sen University  Kaohsiung Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9063-2858","authenticated-orcid":false,"given":"Cheng\u2010Yoong","family":"Pang","sequence":"additional","affiliation":[{"name":"Department of Medical Research Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation  Hualien Taiwan"},{"name":"Center for Cell Therapy and Development Hualien Tzu Chi Hospital  Hualien Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3773-9015","authenticated-orcid":false,"given":"Chia\u2010Jung","family":"Li","sequence":"additional","affiliation":[{"name":"Center of General Education Cheng Shiu University  Kaohsiung Taiwan"},{"name":"Center of General Education Shu\u2010Zen Junior College of Medicine and Management  Kaohsiung Taiwan"},{"name":"Department of Obstetrics and Gynecology Kaohsiung Veterans General Hospital  Kaohsiung Taiwan"},{"name":"Institute of Biopharmaceutical Sciences National Sun Yat\u2010Sen University  Kaohsiung Taiwan"},{"name":"National Museum of Marine Biology &amp; Aquarium  Pingtung Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,9,11]]},"reference":[{"key":"e_1_2_15_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41588\u2010024\u201001838\u2010z"},{"key":"e_1_2_15_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mad.2014.06.003"},{"key":"e_1_2_15_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2019.05.035"},{"key":"e_1_2_15_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng1769"},{"key":"e_1_2_15_6_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkad208"},{"key":"e_1_2_15_7_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1523\u20101747.1998.00099.x"},{"key":"e_1_2_15_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2022.03.039"},{"key":"e_1_2_15_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/s43587\u2010025\u201000996\u2010x"},{"key":"e_1_2_15_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.jid.5700088"},{"key":"e_1_2_15_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41569\u2010018\u20100064\u20102"},{"key":"e_1_2_15_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41556\u2010017\u20100017\u20108"},{"key":"e_1_2_15_13_1","doi-asserted-by":"publisher","DOI":"10.1093\/g3journal\/jkad068"},{"key":"e_1_2_15_14_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1004620"},{"key":"e_1_2_15_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467\u2010025\u201057286\u20108"},{"key":"e_1_2_15_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467\u2010021\u201024956\u20102"},{"key":"e_1_2_15_17_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2201518120"},{"key":"e_1_2_15_18_1","doi-asserted-by":"crossref","unstructured":"Gupta R. 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