Figure 7. Model of RPM dysfunction and collapse during aging.

Iron-dependent functional defects of RPMs are initiated early during aging. Intracellular iron loading of RPMs, in concert with proteostasis defects, precedes the deposition of iron in a form of extracellular protein-rich aggregates, likely emerging from damaged RPMs. The build-up of un-degradable iron-rich deposits, in concert with increased hepcidin levels, and reduced erythrophagocytic and lysosomal activity of the remaining RPMs limit plasma iron availability during aging. A drop in RBC clearance capacity leads to enhanced splenic hemolysis.