SIRT3-Mediated Mitochondrial Regulation and Driver Tissues in Systemic Aging

Šešelja, Kate; Šimunić, Ena; Sobočanec, Sandra; Podgorski, Iva I.; Pinterić, Marija; Hadžija, Marijana Popović; Balog, Tihomir; Belužić, Robert (2025) SIRT3-Mediated Mitochondrial Regulation and Driver Tissues in Systemic Aging. Genes, 16 (12). ISSN 2073-4425

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Abstract

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 "driver tissues"-notably liver, adipose tissue, vascular endothelium, bone-marrow macrophages, and ovary-initiates 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.

Item Type:	Article
Uncontrolled Keywords:	SIRT3; mitochondrial acetylation; systemic aging; senescence; aging drivers; extracellular vesicles; NAD(+) metabolism; inflammaging; sex differences
Subjects:	BIOMEDICINE AND HEALTHCARE
Divisions:	Division of Molecular Medicine
Projects:	Project title Project leader Project code Project type Istraživanje spolno specifičnih metaboličkih učinaka Sirtuina 3 kod bolesti povezanih s pretilošću – Obese Sirt Sandra Sobočanec IP-2022-10-4806 UNSPECIFIED
Depositing User:	Ema Buhin Šaler
Date Deposited:	19 Jan 2026 15:44
URI:	http://fulir.irb.hr/id/eprint/10994
DOI:	10.3390/genes16121497

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