Longevity through immunity: the unusual naked mole-rat immune system

Naked mole-rats (NMR, Heterocephalus glaber) defy Gompertzian rules of mortality and age-dependent senescence(definition) to lead healthy lives well into their fourth decade. The NMR immune system likely contributes to this phenotype by protecting against infections, regulating tissue repair, and eradicating neoplastic cells. In keeping with their many other paedomorphic traits, adult NMRs retain functional thymic tissue in the submandibular triangle. Despite this additional thymic tissue, perinatal NMR thymi are half the size of mouse thymi, yet both species show similar thymic involution trajectories. Smaller thymi may indicate less diverse thymocyte clonotypes that need to complete selection before being released as functional, self-tolerant T cells. Transcriptomic studies revealed that when compared with mice, NMRs have a larger myeloid to lymphoid ratio, lack natural killer (NK) cells, and that the αβ clonotypic diversity of NMR CD8 T cells is limited and smaller than that of their CD4 T cells. NMRs, strikingly, have a large circulating population of γδ T cells with two distinct subsets; one with a large diversity of γ and δ TCR loci and the other, a cytotoxic T cell subset with a dominant clonotype. Collectively, these data suggest that NMRs, living in a sealed milieu, rely more upon the innate immune response and have evolved under relaxed viral selective pressure. Rather, they have selected for an atypical myeloid-biased mode of innate immune surveillance and circulating populations of cytotoxic γδ T cells. In summary, the NMR appears to have been optimized to provide better immunosurveillance, tissue homeostasis, and protection against cancer rather than protection against unlikely environmental exposure to viral pathogens. These features likely contribute to their prolonged healthspan(definition) and exceptional longevity.