PMID- 26120775 OWN - NLM STAT- MEDLINE DCOM- 20161025 LR - 20211203 IS - 1474-9726 (Electronic) IS - 1474-9718 (Print) IS - 1474-9718 (Linking) VI - 14 IP - 6 DP - 2015 Dec TI - beta-Guanidinopropionic acid extends the lifespan of Drosophila melanogaster via an AMP-activated protein kinase-dependent increase in autophagy. PG - 1024-33 LID - 10.1111/acel.12371 [doi] AB - 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 beta-guanidinopropionic acid (beta-GPA), a creatine analog, leads to a chronic activation of AMPK. However, the relationship between beta-GPA and aging remains elusive. In this study, we hypothesized that feeding beta-GPA to adult Drosophila produces the lifespan extension via activation of AMPK-dependent autophagy. It was found that dietary administration of beta-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 beta-GPA treatment, indicating that autophagic activity plays a role in the effect of beta-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 beta-GPA on lifespan extension was abolished. Moreover, we found that AMPK was also involved in this process. beta-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 beta-GPA can induce an extension of the lifespan of Drosophila via AMPK-Atg1-autophagy signaling pathway. CI - (c) 2015 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd. FAU - Yang, Si AU - Yang S AD - Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China. FAU - Long, Li-Hong AU - Long LH AD - Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China. AD - The Key Laboratory of Neurological Diseases (HUST), Ministry of Education of China, Wuhan, 430030, China. AD - Hubei Key Laboratory of Drug Target Researches and Pharmacodynamic Evaluation (HUST), Wuhan, 430030, China. AD - The Laboratory of Neuropsychiatric Diseases, The Institute of Brain Research, Huazhong University of Science and Technology, Wuhan, 430030, China. FAU - Li, Di AU - Li D AD - Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China. FAU - Zhang, Jian-Kang AU - Zhang JK AD - Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China. FAU - Jin, Shan AU - Jin S AD - College of Life Science, Hubei University, Wuhan, 430062, China. FAU - Wang, Fang AU - Wang F AD - Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China. AD - The Key Laboratory of Neurological Diseases (HUST), Ministry of Education of China, Wuhan, 430030, China. AD - Hubei Key Laboratory of Drug Target Researches and Pharmacodynamic Evaluation (HUST), Wuhan, 430030, China. AD - The Laboratory of Neuropsychiatric Diseases, The Institute of Brain Research, Huazhong University of Science and Technology, Wuhan, 430030, China. FAU - Chen, Jian-Guo AU - Chen JG AD - Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China. AD - The Key Laboratory of Neurological Diseases (HUST), Ministry of Education of China, Wuhan, 430030, China. AD - Hubei Key Laboratory of Drug Target Researches and Pharmacodynamic Evaluation (HUST), Wuhan, 430030, China. AD - The Laboratory of Neuropsychiatric Diseases, The Institute of Brain Research, Huazhong University of Science and Technology, Wuhan, 430030, China. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20150629 PL - England TA - Aging Cell JT - Aging cell JID - 101130839 RN - 0 (Atg5 protein, Drosophila) RN - 0 (Atg8a protein, Drosophila) RN - 0 (Drosophila Proteins) RN - 0 (Guanidines) RN - 0 (Propionates) RN - 0 (RNA, Small Interfering) RN - BBX060AN9V (Hydrogen Peroxide) RN - EC 2.7.11.1 (Atg1 protein, Drosophila) RN - EC 2.7.11.1 (Autophagy-Related Protein-1 Homolog) RN - EC 2.7.11.1 (Protein Serine-Threonine Kinases) RN - EC 2.7.11.31 (AMP-Activated Protein Kinases) RN - UL1984YRKA (guanidinopropionic acid) SB - IM MH - AMP-Activated Protein Kinases/genetics/*metabolism MH - Aging/*drug effects MH - Animals MH - Autophagy/*drug effects MH - Autophagy-Related Protein-1 Homolog MH - Caloric Restriction MH - Drosophila Proteins/biosynthesis/genetics/metabolism MH - Drosophila melanogaster/*physiology MH - Enzyme Activation/drug effects MH - Female MH - Guanidines/*pharmacology MH - Hydrogen Peroxide/pharmacology MH - Longevity/*drug effects MH - Male MH - Oxidative Stress/drug effects MH - Phosphorylation/drug effects MH - Propionates/*pharmacology MH - Protein Serine-Threonine Kinases/metabolism MH - RNA Interference MH - RNA, Small Interfering/genetics MH - Signal Transduction/drug effects MH - Up-Regulation PMC - PMC4693457 OTO - NOTNLM OT - AMP-activated protein kinase OT - Drosophila OT - autophagy OT - autophagy-related protein 1 OT - lifespan OT - beta-guanidinopropionic acid EDAT- 2015/06/30 06:00 MHDA- 2016/10/26 06:00 PMCR- 2015/12/01 CRDT- 2015/06/30 06:00 PHST- 2015/06/09 00:00 [accepted] PHST- 2015/06/30 06:00 [entrez] PHST- 2015/06/30 06:00 [pubmed] PHST- 2016/10/26 06:00 [medline] PHST- 2015/12/01 00:00 [pmc-release] AID - ACEL12371 [pii] AID - 10.1111/acel.12371 [doi] PST - ppublish SO - Aging Cell. 2015 Dec;14(6):1024-33. doi: 10.1111/acel.12371. Epub 2015 Jun 29.