# Is Ferroptosis the Mechanistic Bridge Connecting Iron Dysregulation to Muscle Wasting and Functional Decline in Aging?

## TL;DR

The paper explores how ferroptosis, a type of cell death involving iron and lipid damage, may explain muscle loss and weakness in aging.

## Contribution

It proposes a novel framework linking iron imbalance, antioxidant failure, and ferroptosis to age-related muscle dysfunction.

## Key findings

- Ferroptosis signatures are observed in aged muscle across multiple study types.
- Iron dyshomeostasis and impaired antioxidant defenses create a pro-ferroptotic environment in aging muscle.
- Targeting iron handling and lipid peroxidation pathways may offer therapeutic opportunities for age-related muscle decline.

## Abstract

Age‐related decline in physical function is a hallmark of aging and a major driver of morbidity, disability, and loss of independence in older adults, yet the molecular processes linking muscle aging to functional deterioration remain incompletely defined. Emerging evidence implicates ferroptosis, defined as iron‐dependent, lipid peroxidation‐driven cell death, as a compelling but underexplored contributor to age‐related muscle wasting and weakness. Although ferroptosis signatures appear in aged muscle across cellular, animal, and human studies, their causal role in functional decline has not been clearly established. Here, we synthesize current evidence to propose a framework in which iron dyshomeostasis, impaired antioxidant defenses, and dysregulated ferritinophagy converge to create a pro‐ferroptotic milieu that compromises muscle energetics, structural integrity, and regenerative capacity. We delineate key knowledge gaps, including the absence of ferroptosis‐specific biomarkers in human muscle and limited longitudinal data linking ferroptotic stress to mobility outcomes. Finally, we highlight potential therapeutic opportunities targeting iron handling and lipid peroxidation pathways. A better understanding of the contribution of ferroptosis to muscle aging may enable development of mechanistically informed biomarkers and interventions to preserve strength and mobility in older adults.

This work proposes ferroptosis as a mechanistic driver of age‐related muscle dysfunction, whereby iron dyshomeostasis and impaired antioxidant capacity promote lipid peroxidation, and eventually trigger ferroptosis, leading to muscle wasting, and ultimately contributing to weakness and functional decline with aging.