{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T16:11:34Z","timestamp":1791994294035,"version":"4.4.0"},"reference-count":153,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2025,12,15]],"date-time":"2025-12-15T00:00:00Z","timestamp":1765756800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004488","name":"Croatian Science Foundation","doi-asserted-by":"publisher","award":["IP-2022-10-4806"],"award-info":[{"award-number":["IP-2022-10-4806"]}],"id":[{"id":"10.13039\/501100004488","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Mitochondrial dysfunction is a defining hallmark of aging that connects redox imbalance, metabolic decline, and inflammatory signaling across organ systems. The mitochondrial deacetylase SIRT3 preserves oxidative metabolism and proteostasis, yet its age-related decline transforms metabolically demanding organs into sources of pro-senescent cues. This review synthesizes evidence showing how SIRT3 loss in select \u201cdriver tissues\u201d\u2014notably liver, adipose tissue, vascular endothelium, bone-marrow macrophages, and ovary\u2014initiates systemic aging through the release of cytokines, oxidized metabolites, and extracellular vesicles. We discuss molecular routes and mediators of senescence propagation, including the senescence-associated secretory phenotype (SASP), mitochondrial-derived vesicles, and circulating mitochondrial DNA, as well as sex-specific modulation of SIRT3 by hormonal and intrinsic factors. By integrating multi-tissue and sex-dependent data, we outline a framework in which SIRT3 activity defines the mitochondrial threshold separating local adaptation from systemic aging spread. Targeting SIRT3 and its NAD+-dependent network may offer a unified strategy to restore mitochondrial quality, dampen chronic inflammation, and therefore recalibrate the aging dynamics of an organism.<\/jats:p>","DOI":"10.3390\/genes16121497","type":"journal-article","created":{"date-parts":[[2025,12,15]],"date-time":"2025-12-15T13:32:37Z","timestamp":1765805557000},"page":"1497","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["SIRT3-Mediated Mitochondrial Regulation and Driver Tissues in Systemic Aging"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-4607-4002","authenticated-orcid":false,"given":"Kate","family":"\u0160e\u0161elja","sequence":"first","affiliation":[{"name":"Laboratory for Metabolism and Aging, Department of Molecular Medicine, Ru\u0111er Bo\u0161kovi\u0107 Institute, Bijeni\u010dka Cesta 54, 10000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0011-1985","authenticated-orcid":false,"given":"Ena","family":"\u0160imuni\u0107","sequence":"additional","affiliation":[{"name":"Laboratory for Metabolism and Aging, Department of Molecular Medicine, Ru\u0111er Bo\u0161kovi\u0107 Institute, Bijeni\u010dka Cesta 54, 10000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8915-6009","authenticated-orcid":false,"given":"Sandra","family":"Sobo\u010danec","sequence":"additional","affiliation":[{"name":"Laboratory for Metabolism and Aging, Department of Molecular Medicine, Ru\u0111er Bo\u0161kovi\u0107 Institute, Bijeni\u010dka Cesta 54, 10000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9423-9711","authenticated-orcid":false,"given":"Iva I.","family":"Podgorski","sequence":"additional","affiliation":[{"name":"Laboratory for Metabolism and Aging, Department of Molecular Medicine, Ru\u0111er Bo\u0161kovi\u0107 Institute, Bijeni\u010dka Cesta 54, 10000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1049-0237","authenticated-orcid":false,"given":"Marija","family":"Pinteri\u0107","sequence":"additional","affiliation":[{"name":"Laboratory for Metabolism and Aging, Department of Molecular Medicine, Ru\u0111er Bo\u0161kovi\u0107 Institute, Bijeni\u010dka Cesta 54, 10000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6522-3721","authenticated-orcid":false,"given":"Marijana Popovi\u0107","family":"Had\u017eija","sequence":"additional","affiliation":[{"name":"Laboratory for Metabolism and Aging, Department of Molecular Medicine, Ru\u0111er Bo\u0161kovi\u0107 Institute, Bijeni\u010dka Cesta 54, 10000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tihomir","family":"Balog","sequence":"additional","affiliation":[{"name":"Laboratory for Metabolism and Aging, Department of Molecular Medicine, Ru\u0111er Bo\u0161kovi\u0107 Institute, Bijeni\u010dka Cesta 54, 10000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Belu\u017ei\u0107","sequence":"additional","affiliation":[{"name":"Laboratory for Metabolism and Aging, Department of Molecular Medicine, Ru\u0111er Bo\u0161kovi\u0107 Institute, Bijeni\u010dka Cesta 54, 10000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,15]]},"reference":[{"key":"ref_1","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_2","doi-asserted-by":"crossref","first-page":"756","DOI":"10.1016\/j.tem.2024.11.013","article-title":"Inter-organ communication is a critical machinery to regulate metabolism and aging","volume":"36","author":"Tokizane","year":"2025","journal-title":"Trends Endocrinol. 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