Naked mole-rats show little decline of function until late life, are highly resistant to cancer, and live nine times longer than similarly sized rodent species. An important aspect of immune system aging in mammals is the atrophy of the thymus. Thymocytes created in the bone marrow migrate to the thymus where they mature into T cells of the adaptive immune system. As active thymic tissue is replaced with fat, in the process of thymic involution, this supply of T cells declines. Absent reinforcements, the T cell population of the body becomes ever more damaged, malfunctioning, exhausted, and senescent. Researchers here show that not only do naked mole-rats have much delayed thymic involution, but they also exhibit the presence of multiple thymi.
Here, we provide the first characterization of the naked mole rat (NMR) thymus. We discovered that naked mole rats have an additional pair of cervical thymi. This is an unexpected finding as mammals, including humans and mice, as a rule, have only one bilateral thymus. Cervical thymi can occasionally be detected in mice, but their frequency is rare and they have unilateral appearance. Similarly, rare ectopic cervical human thymi had been reported in children. In contrast, cervical thymi are a principal component of NMR ontogenesis. Interestingly, among vertebrates, chickens have seven, sharks five, and amphibians three thymi. It is tempting to speculate that the presence of additional thymi in the naked mole rat may contribute to prolonged maintenance of immune function during their lifespan.
We provide evidence for a delay of thymic involution in naked mole rats beyond the 1st decade of their lifespan. Age-associated marker expression and thymic cell composition remained at the level of neonates. The absence of thymic involution up to midlife is unprecedented in mammals. This would translate into similar or even slightly heightened thymic weights and cell counts for humans in their 30s.
Thymic involution decreases output of naive T cells and reduces the ability to mount protective responses against new antigens. In naked mole rats, we did not see thymic involution in animals older than 10 years old, while markers for thymic function and development, AIRE and FOXN1, were maintained at neonatal levels. Furthermore, the reduction of early T-cell progenitors accompanying age-related lymphoid decline did not manifest in naked mole rats, arguing that their intrinsic myeloid bias in the marrow does not predispose hematopoiesis toward less lymphoid commitment. However, naked mole rats are not immortal and do show frailty in old age. Therefore, an eventual decline in thymic cellularity and immune function is to be anticipated, albeit delayed as opposed to the lifelong steady decline in humans and mice.