Is Aging and its Associated Co-morbidities Due to Diminished Autophagy?

Conrad Weihl, M.D., Ph.D.


Project Overview:
Cells and tissues have developed many adaptive responses that mediate longevity and healthspans. One of these is autophagy, or “self-eating.” Autophagy is a mechanism by which cells and tissues recycle damaged protein and organelles. Autophagy may protect against aging and aging-related diseases. Loss of autophagy leads to many diseases associated with aging, including neurodegeneration and muscle atrophy in model organisms.

Little is known about autophagy in human tissues. This is because no reliable assay has been developed to selectively measure autophagic degradation in vivo in human patients. This proposal will develop and validate a novel in vivo autophagic degradation assay that uses stable isotope labeling and tandem mass spectrometry of the autophagic substrate p62. Upon completion of this study, we will be ready to move directly into human patients and evaluate rates of autophagic degradation in select tissues beginning with skeletal muscle.

Final Report Abstract:
Autophagy, or “self-eating”, is a mechanism by which cells and tissues recycle damaged protein and organelles. Recent studies suggest that autophagy is protective against aging and aging-related diseases. In addition, loss of autophagy leads to many diseases associated with aging, including neurodegeneration and muscle atrophy in model organisms. However, little is known about the rates of autophagic degradation in human tissues. This is because no reliable assay has been developed to selectively measure autophagic degradation in vivo in human patients. This research sought to develop and validate a novel in vivo autophagic degradation assay using stable isotope labeling and tandem mass spectrometry of the autophagic substrate p62. Upon completion of this study, we hope to be able to move directly into human patients and evaluate rates of autophagic degradation in select tissues, beginning with skeletal muscle. Read the full Final Report.