Rag2(−/−) accelerates lipofuscin accumulation in the brain: Implications for human stem cell brain transplantation studies

Immunodeficient mice are widely used in human stem cell transplantation research. Recombination activating gene 1 (Rag1) deletion results in immunodeficiency and leads to accelerated aging in zebrafish with increased cytosolic accumulation of lipofuscin (LF). Unlike zebrafish, mammals have two homologs, Rag1 and Rag2, that regulate adaptive immunity. Currently, little is known if and how Rag1(−/−) and Rag2(−/−) may impact aging and LF accumulation in immunodeficient mouse brains and how this may confound results in human neural cell transplantation studies. Here, we demonstrate that in Rag2(−/−) mouse brains, LF appears early, spreads broadly, emits strong autofluorescence, and accumulates with age. LF is found in various types of glial cells, including xenografted human microglia. Surprisingly, in Rag1(−/−) mouse brains, LF autofluorescence is seen at much older ages compared with Rag2(−/−) brains. This study provides direct evidence that Rag2(−/−) expedites LF occurrence and sets a context for studies using aged immunodeficient mice.