?-Guanidinopropionic acid extends the lifespan of Drosophila melanogaster via an AMP-activated protein kinase-dependent increase in autophagy.

ABSTRACT: Previous studies have demonstrated that AMP-activated protein kinase (AMPK) controls autophagy through the mammalian target of rapamycin (mTOR) and Unc-51 like kinase 1 (ULK1/Atg1) signaling, which augments the quality of cellular housekeeping, and that ?-guanidinopropionic acid (?-GPA), a creatine analog, leads to a chronic activation of AMPK. However, the relationship between ?-GPA and aging remains elusive. In this study, we hypothesized that feeding ?-GPA to adult Drosophila produces the lifespan extension via activation of AMPK-dependent autophagy. It was found that dietary administration of ?-GPA at a concentration higher than 900 mm induced a significant extension of the lifespan of Drosophila melanogaster in repeated experiments. Furthermore, we found that Atg8 protein, the homolog of microtubule-associated protein 1A/1B-light chain 3 (LC3) and a biomarker of autophagy in Drosophila, was significantly upregulated by ?-GPA treatment, indicating that autophagic activity plays a role in the effect of ?-GPA. On the other hand, when the expression of Atg5 protein, an essential protein for autophagy, was reduced by RNA interference (RNAi), the effect of ?-GPA on lifespan extension was abolished. Moreover, we found that AMPK was also involved in this process. ?-GPA treatment significantly elevated the expression of phospho-T172-AMPK levels, while inhibition of AMPK by either AMPK-RNAi or compound C significantly attenuated the expression of autophagy-related proteins and lifespan extension in Drosophila. Taken together, our results suggest that ?-GPA can induce an extension of the lifespan of Drosophila via AMPK-Atg1-autophagy signaling pathway.

SUBMITTER: Yang S 

PROVIDER: S-EPMC4693457 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature