Proteostasis and Autophagy in Immune Senescence (360G-Wellcome-220784_A_20_Z)

Lymphocyte function underpins effective immunity to infection and cancer, and is adversely affected by age in a process called immune senescence, a major obstacle to having a healthy lifespan. The cellular basis of T cell senescence is largely unknown. Maintaining proteostasis, regulated by protein synthesis and degradation, in the face of intrinsic and environmental insults is a key determinant of cellular and organismal lifespan. We will address the hypothesis that modulating the conserved degradation and recycling process known as autophagy, can restore immune responses in lymphocytes in the elderly. We have shown that autophagy prevents immune aging, and demonstrated a decline in autophagic flux in lymphocytes with age, and a global age-related decline of protein translation. But it is uncertain which of the synthesized and degraded proteins are most important. It is clear, however, that the induction of specific repair pathways, including autophagy, extends life and health span. We have uncovered a novel pathway that rejuvenates lymphocyte function by regulating autophagy translationally, which we intend now to fully characterize. Our goal is to identify potential therapeutic strategies for restoring health span in the elderly. This work will also address fundamental gaps in our understanding of the aging process.