Borghesi, Lisa

Abstract Thymus organogenesis is dependent on insulin-like growth factor (IGF), but involuted thymi of old mice cannot be reconstituted with infusion of IGF. In adult humans, tumor growth is associated with local upregulation of IGF, but increased incidence of cancer with aging is associated with decreasing levels of serum IGF. We hypothesized that suppression of tissue availability of IGF prevents/delays thymic atrophy and maintains a pool of functionally competent T cells throughout life. Hence, we examined mice with homozygous deletion of PAPPA, a gene encoding for a protease that degrades inhibitory IGF-binding proteins (IGFBP) that limit IGF levels in tissues. PAPPA-/- mice have normal serum IGF levels, indicating maintenance of the endocrine IGF reservoir. They have 40% extension of lifespan; and have reduced burden of spontaneous tumors, the major cause of early mortality of wildtype mice. Strikingly, PAPPA-/- mice aged =18 months have histologically organized thymi densely populated by CD4+CD8+ thymocytes with high TREC levels. Bone marrows of old mutants are enriched with thymus-seeding progenitors. Old mutant mice have a diverse repertoire of T cells that are functionally indistinguishable from young wildtype mice. These data indicate an IGF-immune axis of longevity. We suggest that PAPPA-mediated proteolysis is a potential target for intervention to maintain thymic function and promote healthy aging.

Pregnancy-associated plasma protein A (PAPPA) is a metalloproteinase that controls the tissue availability of insulin-like growth factor (IGF). Homozygous deletion of PAPPA in mice leads to lifespan extension. Since immune function is an important determinant of individual fitness, we examined the natural immune ecology of PAPPA −/− mice and their wild-type littermates reared under specific pathogen-free condition with aging. Whereas wild-type mice exhibit classic age-dependent thymic atrophy, 18-month-old PAPPA −/− mice maintain discrete thymic cortex and medulla densely populated by CD4 + CD8 + thymocytes that are capable of differentiating into single-positive CD4 and CD8 T cells. Old PAPPA −/− mice have high levels of T cell receptor excision circles, and have bone marrows enriched for subsets of thymus-seeding progenitors. PAPPA −/− mice have an overall larger pool of naive T cells, and also exhibit an age-dependent accumulation of CD44 + CD43 + memory T cells similar to wild-type mice. However, CD43 + T cell subsets of old PAPPA −/− mice have significantly lower prevalence of 1B11 and S7, glycosylation isoforms known to inhibit T cell activation with normal aging. In bioassays of cell activation, splenic T cells of old PAPPA −/− mice have high levels of activation antigens and cytokine production, and also elicit Ig production by autologous B cells at levels equivalent to young wild-type mice. These data suggest an IGF-immune axis of healthy longevity. Controlling the availability of IGF in the thymus by targeted manipulation of PAPPA could be a way to maintain immune homeostasis during postnatal development and aging.