The associations between brain aging and mitochondria dysfunction: Mechanism and intervention strategies

Brain aging, an exquisitely intricate biological phenomenon, is intertwined with cognitive deterioration and the pathogenesis of neurodegenerative maladies. Mitochondria, the cellular powerhouses responsible for energy homeostasis, assume a central and indispensable role in this process. This review delves deeply into the multifaceted associations between mitochondrial dysfunction and brain aging, encompassing perturbations in energy metabolism, exacerbation of oxidative stress, aberrations in mitochondrial dynamics, activation of the inflammatory response, and mitochondrial DNA mutations, all of which interact in a complex network to drive the progression of brain aging. Simultaneously, it undertakes a meticulous dissection of the functions of some key mitochondria-related molecules in brain aging. In terms of intervention strategies, emerging evidence suggests that inhibition of the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) signaling axis holds promise in alleviating the inflammatory phenotypes of senescent cells and tissues. Downregulating the levels of relevant transfer RNA-derived small RNAs (tsRNAs) represents a potential approach to safeguard crucial mitochondrial processes. Supplementation with spermidine and spermine has demonstrated efficacy in ameliorating mitochondrial function and cognitive performance. Moreover, comprehensive intervention paradigms targeting energy metabolism, antioxidative stress responses, and autophagy regulation offer potential avenues for retarding brain aging. Collectively, the existing body of research furnishes profound insights into the underlying mechanisms of brain aging and serves as a bedrock for the development of efficacious intervention modalities. Future research imperatives should center on elucidating the intricate molecular mechanisms, formulating highly precise intervention strategies, and expediting the translation of basic research findings into clinical applications. This is of utmost significance for enhancing the quality of life of the elderly and forestalling the onset and progression of neurodegenerative diseases.