In Search of Immune System Differences in Long-Lived Mammals

What are the mechanisms that allow long-lived mammals to be long-lived? It remains to be seen as to whether it will be cost-effective and of sizable benefit to isolate specific genetic differences that can be used as a basis for therapies in humans, but it isn't a terrible idea to conduct the search. Clearly cancer suppression is an interesting topic, and one it might well be possible to build novel therapies based on the study of whales and elephants. Another good place to start is the operation of the immune system. The age-related decline of immune function is clearly important to the onset and progression of age-related disease. We might well ask how long-lived mammals maintain functional immune systems for a much longer period of time than shorter-lived but otherwise quite similar species.

Although immunosenescence may result in increased morbidity and mortality, many mammals have evolved effective immune coping strategies to extend their lifespans. Thus, the immune systems of long-lived mammals present unique models to study healthy longevity. To identify the molecular clues of anti-immunosenescence, we first built high-quality reference genome for a long-lived myotis bat, and then compared three long-lived mammals (i.e., bat, naked mole rat, and human) versus the short-lived mammal, mouse, in splenic immune cells at single-cell resolution.

A close relationship between B-cell:T-cell ratio and immunosenescence was detected, as B-cell:T-cell ratio was much higher in mouse than long-lived mammals and significantly increased during aging. Importantly, we identified several iron-related genes that could resist immunosenescence changes, especially the iron chaperon, PCBP1, which was upregulated in long-lived mammals but dramatically downregulated during aging in all splenic immune cell types. Supportively, immune cells of mouse spleens contained more free iron than those of bat spleens, suggesting higher level of reactive oxygen species (ROS)-induced damage in mouse.

PCBP1 downregulation during aging was also detected in hepatic but not pulmonary immune cells, which is consistent with the crucial roles of spleen and liver in organismal iron recycling. Furthermore, PCBP1 perturbation in immune cell lines would result in cellular iron dyshomeostasis and senescence. Finally, we identified two transcription factors that could regulate PCBP1 during aging. Together, our findings highlight the importance of iron homeostasis in splenic anti-immunosenescence, and provide unique insight for improving human healthspan.