Unveiling Ferroptosis Resistance Mechanisms in Aged T Cells

Aging significantly impairs T cell immunity, reducing vaccine efficacy, increasing susceptibility to infections, and weakening immunosurveillance. Recent studies have shown that introducing defective T cells into young hosts accelerates aging phenotypes across multiple organs. Our lab uncovered a bidirectional relationship between T cells and their aged host, revealing how age-related changes in the spleen drive T cell aging.

Specifically, we found that hemolytic conditions accumulating in the aged spleen, due to inefficient recycling of red blood cells, expose T cells to toxic concentrations of heme and iron deposits. Aged T cells adapt to this hostile microenvironment by developing resistance to ferroptosis—a form of iron- and ROS-induced cell death. This study investigates the mechanisms underlying ferroptosis resistance in aged T cells.

We discovered that exposure to hemolytic conditions impairs lysosomal function, leading to downregulation of lipophagy and the accumulation of lipid droplets. Lipid droplets act as protective reservoirs, sequestering excess fatty acids and preventing lipid peroxidation, which would otherwise trigger ferroptosis. These findings suggest that T cells ‘intentionally’ inhibit lysosomal activity as a survival strategy, challenging the current paradigm that enhancing lysosomal function could counteract aging.

Our results provide new insights into the adaptive responses of aged T cells and highlight potential pathways to improve immune function in aging populations.