Reference SummarySchneider JL, Aging Cell 2015 Apr;14(2):249-64


Loss of hepatic chaperone-mediated autophagy accelerates proteostasis failure in aging.


Schneider JL; Villarroya J; Diaz-Carretero A; Patel B; Urbanska AM; Thi MM; Villarroya F; Santambrogio L; Cuervo AM


Aging Cell










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.


J:223649 – MGI References
25620427 – National Library of Medicine/PubMed

Strain Notes

Strain Note
C57BL/6J These mice were purchased from the Jackson Laboratory.
[not specified]-Lamp2tm1Amcu Speer6-ps1Tg(Alb-cre)21Mgn/? These mice were generated by crossing male B6.Cg-Tg(Alb-cre)21Mgn/J mice from the Jackson Laboratory (Stock No. 003574) to female mice homozygous for the floxed Lamp2tm1Amcu allele.


Strain Model Name Treatment Agent(s) Organ Affected Frequency Model Details
[not specified]-Lamp2tm1Amcu Speer6-ps1Tg(Alb-cre)21Mgn/? Liver hepatocellular adenoma Liver


[not specified]-Lamp2tm1Amcu Speer6-ps1Tg(Alb-cre)21Mgn/? Liver tumor Liver

0 - 26.9

C57BL/6J Liver tumor Liver