Mitochondrial homeostasis and aging: Mechanisms, disease associations, and targeted intervention strategies
Year: 2026
Type: article
Abstract: <?A3B2 tlsb=-.01w?>Mitochondria act as the central hub for cellular bioenergetics and inter/intracellular signal transduction, with dysregulation of their homeostasis emerging as a core driver of aging and age-related diseases (ARDs). Impaired mitochondrial function disrupts oxidative phosphorylation (OXPHOS) and the tricarboxylic acid (TCA) cycle, directly reducing ATP production while triggering cascading pathological events, including excessive reactive oxygen species (ROS) accumulation, mitochondrial DNA (mtDNA) lesions and mutations, activation of NF-κB/cGAS-STING inflammatory pathways, and dysregulated mitochondrial permeability transition pore (mPTP) gating. These perturbations collectively establish intimate etiological links with diverse ARDs, such as neurodegenerative disorders (Alzheimer’s, Parkinson’s), cardiovascular pathologies (atherosclerosis, heart failure), metabolic disorders (type 2 <?A3B2 pi129?>diabetes, non-alcoholic fatty liver disease), and multi-organ degenerative diseases (osteoporosis, age-related macular degeneration). In this review, we delineate four core mechanisms underlying mitochondrial dysfunction-driven aging: (1) the vicious cycle of ROS overproduction and inflammaging, mediated by the release of mitochondrial damage-associated molecular patterns (mtDAMPs); (2) mtDNA mutations (e.g., 4977 bp deletion) and heteroplasmy increase; (3) compromised mitochondrial quality control (encompassing mitophagy, fusion-fission dynamics, and biogenesis); (4) perturbed metabolic homeostasis involving NAD+-Sirtuin signaling, calcium buffering, and ketone oxidation. We then summarize multi-dimensional targeted interventions, including (1) lifestyle modifications (exercise, intermittent fasting, and calorie restriction) that activate the AMPK-Sirtuin-PGC-1α axis; (2) nutraceutical/pharmaceutical agents (NAD+ precursors: NMN, NR; mitochondria-targeted antioxidants: MitoQ, SS-31; AMPK agonists: metformin, AICAR; mTOR inhibitors: rapamycin) restoring bioenergetic and redox balance; (3) bioengineering technologies (extracellular vesicle-mediated mitochondrial transfer, mtDNA-editing tools, smart nanomedicines) overcoming delivery barriers. Notably, key challenges remain, including unelucidated tissue-specific mitochondrial heterogeneity, suboptimal targeting efficiency, and long-term safety of chronic interventions. By integrating cutting-edge advancements, this work provides a systematic scientific foundation for deepening the understanding of aging mechanisms and advancing precision prevention and treatment of ARDs.
Source: Shengming kexue
DOI: 10.3724/cbls.2026103
Authors: Bao-Sheng WANG, Ben ZHOU
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: bronze
OpenAlex ID: W7167793201