The immune system undergoes numerous age-associated changes. Immunosenescence is defined as the age-dependent deterioration of the immune system which can result in its reduced ability to respond to infections. Degradation of proteins in the lysosomes by autophagy plays a key role in maintaining proper cell homeostasis, by reducing the accumulation of damaged proteins and recycling amino acids for new protein synthesis. In addition, it may also play crucial roles in modifying protein levels in response to extracellular signals. Evidence suggests that decreased macroautophagic activity in an old organism may be responsible for the deterioration of cell function with age which would result in alterations of proper function of many organs and systems. Recent evidence supports the implication of autophagy in the regulation of T cell function. My working hypothesis is that macroautophagy plays a key role in regulation of T cell function, and that the age-dependent dysregulation of autophagy may account, at least in part, for the defective T cell function that defines immunosenescence. The purpose of this project is: 1. To charecterize the role and regulation of macroatuophagy in T cells and 2. To determine if the age dependent dysregulation of macroatophagy contributes to immunosenescence. For this purpose I will employ biochemical and cellular approaches to study macroautophagy in young and aged T cells, defining how age-dependent changes in this process affect the molecular mechanism that are regulated by macroautophagy. I also intend to develop methods to restore these defects, and analyze the impact of these restorative methods on T cell function and immunosenescence. Relevance to Public Health: Inadequate upregulation of protein turnover could contribute to defects in T cell function with age. Decreased responses to pathogens and low vaccine efficacy in the aging population results in increased morbidity and mortality. Consequently, a better understanding of the molecular mechanisms that contribute to decreased T cell response with age could lead to novel approaches to modulate this response in aging populations to improve immune system responses.
| Hubbard, Vanessa M; Valdor, Rut; Macian, Fernando et al. (2012) Selective autophagy in the maintenance of cellular homeostasis in aging organisms. Biogerontology 13:21-35 |
| Hubbard, Vanessa M; Valdor, Rut; Patel, Bindi et al. (2010) Macroautophagy regulates energy metabolism during effector T cell activation. J Immunol 185:7349-57 |
