Researchers from The University of Tokyo and St. Jude Children's Research Hospital announced on Apr. 16 that they have discovered how certain stress signals contribute to the decline of the immune system as people age. Their findings focus on hematopoietic stem cells (HSCs), which are responsible for producing all types of blood cells but lose effectiveness over time.
The study is important because it sheds light on why older individuals experience weakened immune responses and a higher risk of disease. The research identifies a specific signaling pathway, involving receptor-interacting protein kinase 3 (RIPK3) and mixed lineage kinase like (MLKL), that contributes to this decline by damaging cell mitochondria rather than causing cell death.
Dr. Masayuki Yamashita, who led the study, said, "We discovered an unexpected phenotype in HSCs of MLKL-knockout mice repeatedly treated with 5-fluorouracil, where aging-associated functional changes were markedly attenuated despite no detectable difference in HSC death, prompting us to investigate whether this pathway might induce functional changes beyond cell death." This observation led researchers to examine non-lethal roles for MLKL.
Using genetic mouse models and various laboratory techniques such as bone marrow transplantation assays and mitochondrial analyses, the team found that activation of MLKL in response to stress did not kill stem cells but instead damaged their mitochondria. This resulted in hallmark features of aging: reduced self-renewal capacity, less production of lymphoid cells needed for immunity, and a shift toward myeloid-biased output.
When MLKL was deleted or deactivated in these models, many signs of aging were reduced even under stressful conditions or advanced age. Stem cells maintained their ability to regenerate blood components and showed healthier mitochondrial function without major changes at the gene expression level.
The authors conclude that MLKL acts as a stress-responsive factor driving functional decline through direct effects on mitochondria rather than through its traditional role in programmed cell death or inflammation. They suggest these findings could lead to new approaches for preserving immune health during aging.
