On the Decline of Chaperone-Mediated Autophagy in the Liver
More than six years ago a research group demonstrated that autophagy can be boosted in the liver to reverse some of the age-related decline in function of that organ. Old mice were shown to have some measures of liver function little different from young mice. Science is a slow business, however. These researchers are still working their way around this area of study, and at this time there is no significant movement in the direction of translating this and other potential autophagy enhancing treatments into human therapies. This is very much the standard story when it comes to potential treatments for aging, sad to say:
Chaperone-mediated autophagy (CMA), a cellular process that contributes to protein quality control through targeting of a subset of cytosolic proteins to lysosomes for degradation, undergoes a functional decline with age. We have used a mouse model with liver-specific defective CMA to identify changes in proteostasis attributable to reduced CMA activity in this organ with age. We have found that other proteolytic systems compensate for CMA loss in young mice which helps to preserve proteostasis. However, these compensatory responses are not sufficient for protection against proteotoxicity induced by stress (oxidative stress, lipid challenges) or associated with aging.Livers from old mice with CMA blockage exhibit altered protein homeostasis, enhanced susceptibility to oxidative stress and hepatic dysfunction manifested by a diminished ability to metabolize drugs, and a worsening of the metabolic dysregulation identified in young mice. Our study reveals that while the regulatory function of CMA cannot be compensated for in young organisms, its contribution to protein homeostasis can be handled by other proteolytic systems. However, the decline in the compensatory ability identified with age explains the more severe consequences of CMA impairment in older organisms and the contribution of CMA malfunction to the gradual decline in proteostasis and stress resistance observed during aging.