Mitochondrial Dysfunction as a Central Hub of Aging: From Molecular Cascades to Inter-Organ Communication Networks

Abstract

: Background: Mitochondrial dysfunction serves as a fundamental driver of the aging process, precipitating progressive functional decline through complex molecular cascades. Summary: This review elucidates the core mechanisms underpinning this dysfunction, including reactive oxygen species (ROS)-induced redox imbalance, mitochondrial DNA (mtDNA) damage accumulation, impaired mitophagy, and metabolic reprogramming. Crucially, we examine how mitochondria act as signaling hubs for inter-organ crosstalk. Through the secretion of mitokines (e.g., FGF21, GDF15) and the release of damage-associated molecular patterns (DAMPs), dysfunctional mitochondria trigger chronic inflammation via the cyclic GMP–AMP synthase (cGAS)–stimulator of interferon genes (STING) and NLRP3 inflammasome (NLRP3) pathways, actively driving systemic aging within the skeletal muscle–brain and adipose/liver–cardiovascular axes. Additionally, this paper synthesizes current therapeutic interventions, ranging from lifestyle modifications and nicotinamide adenine dinucleotide (NAD+) precursors to frontier technologies like mitochondrial transplantation and gene editing. Key Messages: While promising in animal models, clinical translation of these interventions is currently hindered by limited long-term safety data and evidence gaps. Therefore, mitochondria-targeted studies incorporating integrated multi-organ phenotyping are urgently required to establish robust strategies for extending human healthspan.