Advanced glycation endproducts (AGEs) have been implicated in age-related disease and aging itself, convincingly enough that significant effort has gone into finding compounds that can “break” or reverse them.
Among many unresolved questions: Are specific proteins AGEylated, and if so, which proteins are being modified within cells? Unterluggauer et al. report that in both senescent fibroblasts and senescent endothelial cells, the chaperone Hsc70 is modified by AGE:
Identification of Hsc70 as target for AGE modification in senescent human fibroblasts
Cellular senescence is known as a potent mechanism of tumor suppression, and cellular senescence in vitro also reflects at least some features of aging in vivo. The Free Radical Theory of aging suggests that reactive oxygen species are important causative agents of aging and cellular senescence. Besides damage of nucleic acids and lipids, also oxidative modifications of proteins have been described as potential causative events in the senescence response. However, the identity of protein targets for post-translational modifications in senescent cells has remained unclear. In the present communication, we analyzed the occurrence of oxidative posttranslational modifications in senescent human endothelial cells and dermal fibroblasts. We found a significant increase in the level of protein carbonyls and AGE modification with senescence in both cell types. Using 2D-Gel electrophoresis and Western Blot we found that heat shock cognate protein 70 is a bona fide target for AGE modification in human fibroblasts.
If a major chaperone is modified by AGEs, and the modification is deleterious to its function, this could dramatically decrease the efficiency of protein folding, which (given that chaperones are proteins too) could dramatically decrease the number of chaperones, which…
Garbage catastrophe, anyone? (Then again: senescent cells persist in culture for a long time, implying that they have some way to deal with the admittedly hypothetical protein-folding death spiral implied in the previous paragraph.)