The primary function of the thymus is to produce mature T-cells and to implement controls to prevent auto-immunity. Lymphocyte precursors migrate from the bone-marrow to the thymus, where they become thymocytes and subsequently mature into T-cells. Since the T-cell repertoire is generated relatively early in life, the thymus is most active during childhood, begins to atrophy around puberty, and is barely detectable in the elderly.
A team led by researchers at the Children’s Hospital of Pittsburgh have now reported knock-out mice that live 30% longer than their wild-type counterparts and in which the thymus remains intact throughout life. The scientists knocked out the gene encoding pregnancy-associated plasma protein A (PAPPA), a recently identified zinc metalloprotease that degrades insulin-like growth factor binding proteins (IGFBP). The knockout mice exhibit proportional dwarfism, similar to IGF1, IGF2 and IGF-receptor (IGFR) knockouts (although IGF1 and IGFR knockout mice are not viable).
The team suggests that the PAPPA-knockout mice benefit from reduced IGF signalling in tissues as a consequence of increased levels of IGFBPs. Indeed, maintenance of thymic structure with ageing correlated with lower steady-state levels of IGF1 in the thymus. Elderly knockout mice continued to generate new T-cells and maintained a robust immune system. Whilst the subtleties of the model require further elucidation, the work so far suggests that manipulation of PAPPA may be a route to modulation of immune competence and healthy ageing.
The study is published in full in the Proceedings of the National Academy of Sciences.