# Exercise mitigates Alzheimer’s disease by targeting ferroptosis driven by cellular senescence

## TL;DR

Exercise helps prevent Alzheimer's disease by reducing a type of cell death called ferroptosis, which is linked to aging cells in the brain.

## Contribution

This paper highlights exercise as a novel, multi-level intervention that counteracts ferroptosis driven by cellular senescence in Alzheimer’s disease.

## Key findings

- Exercise restores iron balance and reduces lipid peroxidation in senescent cells.
- Exercise reactivates antioxidant systems like GPX4 and improves mitochondrial and autophagic function.
- Exercise suppresses neuroinflammation and coordinates peripheral organs to support brain health.

## Abstract

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.