Lifespan Extension, Nutrient Sensing and Immune Competence

Abstract

Immune protection wanes during aging. This is evidenced by increased morbidity and mortality from infectious disease in aged individuals. As the aging population continues to increase worldwide, it will become increasingly important to determine both causes and therapeutic strategies for defects in the aged immune response. In particular, CD8 T cells have been shown to be highly susceptible to age-related defects. Recently, metabolic pathways have been implicated as critical factors in T cell fate decisions during immune responses. Of note, metabolic pathways are also considered primary determinants of lifespan in mammals. Therefore, we hypothesized that metabolic manipulations to extend lifespan would have significant effects on the aging immune system and protection during infection. In particular, we investigated the impact of rapamycin (rapa), both acute and chronic treatment regimens, on adult and old mice. Specifically, we tested how T cell development, peripheral homeostasis, and effector immunity became altered during treatment. We made side-by-side comparisons in calorically restricted (CR) old mice as a gold standard model of longevity extension. Importantly, both of these interventions have been reported to benefit immune function and extend lifespan in mice. However, our data strongly indicate that both rapa and CR induce distinct but deleterious consequences to overall immunity in mice. We conclude that neither rapa nor CR may be ideal candidates for extending lifespan in humans.