Ferroptosis is a form of programmed cell death associated with iron metabolism. A body of evidence supports a role for excessive ferroptosis in the progression of Alzheimer's disease and other age-related conditions, a maladaptive reaction to forms of age-related damage present in the brain, such as mitochondrial dysfunction, an increased burden of senescent cells, chronic inflammatory signaling, and so forth. Researchers are starting to consider suppression of ferropotosis as an approach to treating neurodegenerative conditions, which leads to papers such as this one, a discussion of the mechanisms by which exercise acts to reduce ferroptosis. That is a step along the road to identifying potential targets for drug development. Attempting to mimic specific outcomes of exercise, calorie restriction, or other environmental effects on metabolism is a widely employed strategy, though it seems unlikely to be capable of more than modestly slowing disease progression or modestly reducing severity.
Ferroptosis, a regulated form of cell death driven by iron-dependent lipid peroxidation, has emerged as a critical link between cellular senescence and Alzheimer's disease (AD). Senescent cells disrupt iron metabolism, promote peroxidation-prone lipid remodeling, and suppress antioxidant defenses, creating a pro-ferroptotic environment that accelerates neuronal degeneration. This review integrates recent mechanistic evidence demonstrating that these senescence-induced changes heighten ferroptotic susceptibility and drive AD pathology through pathways involving protein aggregation, autophagic failure, and inflammatory synaptic loss.
Importantly, physical exercise has emerged as a pleiotropic intervention that counteracts these ferroptotic mechanisms at multiple levels. Exercise restores iron homeostasis, reprograms lipid metabolism to reduce peroxidation risk, reactivates antioxidant systems such as GPX4, enhances mitochondrial and autophagic function, and suppresses chronic neuroinflammation. Moreover, systemic adaptations through muscle, liver, and gut axes coordinate peripheral support for brain health. By targeting ferroptosis driven by cellular senescence, exercise not only halts downstream neurodegenerative cascades but also interrupts key upstream drivers of AD progression.
These findings position ferroptosis as a therapeutic checkpoint linking aging biology to neurodegeneration and establish exercise as a mechanistically grounded strategy for AD prevention and intervention.
Link: https://doi.org/10.3389/fcell.2025.1742209
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