Aging-Driven Mitochondrial Dysfunction And Enhanced Risk Of Cerebral Ischemia: Mechanisms And Therapeutic Perspectives

Aging is an inevitable biological process that disrupts cellular function. Mitochondria play a key role in aging and age-related diseases. A vicious cycle exists between aging and mitochondrial dysfunction: aging weakens mitochondrial quality control (MQC), leading to the accumulation of damaged mitochondria, while mitochondrial dysfunction accelerates aging. This interaction, however, remains insufficiently explored. With age, mitochondrial efficiency declines, impairing the electron transport chain (ETC), increasing electron leakage and reactive oxygen species (ROS) production. Elevated oxidative stress damages mitochondrial DNA (mtDNA), proteins, and membranes. Because mtDNA is located near the ETC and functions independently of nuclear DNA, it is especially vulnerable to oxidative damage. mtDNA mutations can trigger inflammatory responses via pathways such as NF-κB and receptors like CD۳۸, which further exacerbate mitochondrial dysfunction by depleting NAD+ levels. The MQC system—comprising mitophagy, mitochondrial fission/fusion, and the mitochondrial unfolded protein response (UPRmt)—normally prevents the accumulation of defective mitochondria. However, during aging, increased oxidative stress and diminished antioxidant defenses impair MQC, leading to the aggregation of dysfunctional mitochondria. This contributes to neuronal damage, exacerbates oxidative stress, and plays a central role in the pathogenesis and progression of cerebral ischemia. Therefore, understanding the central role of mitochondrial dysfunction in age-related diseases is crucial. This article aims to explore the interplay between aging, mitochondrial dysfunction, and age-related diseases, and to discuss potential therapeutic strategies targeting key regulators of mitochondrial health.

کلیدواژه ها:

Aging ، Mitochondrial dysfunction ، Cerebral ischemia ، Oxidative stress ، neuroprotection