New Scholar Award in Aging
Ana Maria Cuervo, M.D., Ph.D.
Albert Einstein College of Medicine of Yeshiva University

Restoration of chaperone-mediated autophagy activity in old rodents

A common feature of aging is the accumulation of abnormal or damaged proteins inside cells with a consequent negative effect in cell function. Any attempt to remove these abnormal proteins may help in the functional recovery of different organs affected in aged organisms. Damaged or abnormal proteins are continuously removed from inside cells through degradation by the different intracellular proteolytic systems. Activity of lysosomes, one of the major systems of degradation of intracellular proteins, seems to be particularly reduced in many tissues of aged animals. 

We have recently identified, in rodent tissues and cultured aged fibroblasts, a defect in one of the lysosomal pathways of protein degradation known as chaperone-mediated autophagy. Degradation of cytosolic proteins by this pathway requires their binding to a receptor protein at the lysosomal membrane, and we have found a dramatic decrease in the levels of that receptor with age. We intend now to prevent the age-related decline in this lysosomal pathway in the liver of old mice by restoring normal levels of the receptor protein. 

To restore normal receptor levels in old rodents, we have generated a bitrasgenic mice in which we can turn on expression of the receptor at advanced ages. In addition, since reduction of food intake (caloric restriction) has been shown to prevent the age-related decline in other proteolytic systems, we will also evaluate the effect of caloric restriction on chaperone-mediated autophagy. 

If, as we expect, the decline in chaperone-mediated autophagy is prevented, we could further test if preservation of normal CMA activity precludes the intracellular accumulation of abnormal proteins, and whether or not that results in improved function in old organisms.

Contact Dr. Cuervo.