Selective Autophagy in the Fight Against Aging

A.M. Cuervo
Albert Einstein College of Medicine, Bronx, NY

Accumulation of altered proteins and damaged organelles is a characteristic common to most types of cells and tissues in old organisms. Although often at a very slow peace, this progressive accumulation often compromises important cellular functions and eventually becomes detrimental and leads to cell death. Cells count on two surveillance systems to handle protein alterations: chaperones and proteolytic systems. Malfunctioning of these systems contribute in large extend to the abnormal accumulation of those altered proteins in cells and tissues in numerous diseases and in aging. Our studies have focused primarily in one of these removal systems, chaperone-mediated autophagy (CMA), which mediates selective targeting of cytosolic proteins to lysosomes for their degradation. Maximal activation of CMA is attained during stresses such as nutritional stress, mild-oxidative stress or toxin exposure. CMA activity declines with age due to a decrease in the levels of the lysosomal receptor that mediates substrate translocation.

As part of our ongoing studies, we have developed a transgenic mouse model in which we can preserve normal CMA activity until advanced ages in liver by correcting the age-related defect in this pathway in this organ. Old mice with preserved CMA activity display overall improved cellular homeostasis (lower content of oxidized proteins, reduced number of protein aggregates, decreased amount of lipofuscin and proper organelle turnover), better resistance to stress (lower levels of cellular death in response to hepatotoxic compounds) and a general improvement in basic liver functions (drug metabolism and clearance). We intend to use similar approaches to evaluate the importance of maintaining proper protein removal until advanced ages in different organs.

Keywords: Autophagy, Aging, Proteases, Lysosomes, Chaperones