Abstract: Iron accumulation and neuroinflammation are cardinal features of many neurodegenerative diseases (Urrutia et al., 2021). However, the hierarchy in the pathogenic mechanisms and the molecular connections between these processes are still obscure. In this perspective, we will discuss current evidence showing that aging, the main risk factor for neurodegenerative diseases, negatively impacts lysosomal function by triggering a paradoxical condition of iron accumulation accompanied by functional iron deficiency. This condition is self-sustaining in the neuroinflammatory process.