Citations

AbstractCurrent knowledge of the metabolic role, biosynthesis, cellular uptake, excretion and turnover of carnitine is reviewed. The clinical spectrum and possible aetiology of the primary muscle and primary systemic carnitine deficiency syndromes are considered and the various genetic defects of intermediary metabolism which can give rise to secondary carnitine deficiency are indicated.

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.