《生命科学》 2026, 38(6): 1042-1057
线粒体功能稳态与衰老：机制、疾病关联及靶向干预策略
摘 要：
线粒体作为细胞能量代谢与信号调控的核心枢纽，其功能稳态失衡是驱动衰老的关键因素，且与神经退行性疾病、心血管疾病、代谢综合征及多器官退行性病变等衰老相关疾病密切关联。在全球人口老龄化加剧的背景下，阐明线粒体调控衰老的分子机制、开发精准靶向干预策略已成为生物医学领域的研究热点。本文系统综述了线粒体功能紊乱驱动衰老的核心机制，涵盖活性氧（ROS）累积与炎性衰老的恶性循环、线粒体DNA（mtDNA）突变与异质性增加、线粒体质量控制失调，以及线粒体代谢稳态改变。在此基础上，进一步剖析了上述机制与多种衰老相关疾病的关联，并全面梳理了靶向线粒体的干预体系，为衰老机制的深入研究及相关疾病的防治提供了系统的科学依据。
通讯作者：周 犇 , Email:benzhou@sinh.ac.cn
Abstract:
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 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.
Communication Author：ZHOU Ben , Email:benzhou@sinh.ac.cn
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