title: β-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 β-guanidinopropionic acid (β-GPA), a creatine analog, leads to a chronic activation of AMPK. However, the relationship between β-GPA and aging remains elusive. In this study, we hypothesized that feeding β-GPA to adult Drosophila produces the lifespan extension via activation of AMPK-dependent autophagy. It was found that dietary administration of β-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 β-GPA treatment, indicating that autophagic activity plays a role in the effect of β-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 β-GPA on lifespan extension was abolished. Moreover, we found that AMPK was also involved in this process. β-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 β-GPA can induce an extension of the lifespan of Drosophila via AMPK-Atg1-autophagy signaling pathway.
authors.affiliation: Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
authors.forename: Si
authors.initials: S
authors.lastname: Yang
authors.affiliation: Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.|The Key Laboratory of Neurological Diseases (HUST), Ministry of Education of China, Wuhan, 430030, China.|Hubei Key Laboratory of Drug Target Researches and Pharmacodynamic Evaluation (HUST), Wuhan, 430030, China.|The Laboratory of Neuropsychiatric Diseases, The Institute of Brain Research, Huazhong University of Science and Technology, Wuhan, 430030, China.
authors.forename: Li-Hong
authors.initials: LH
authors.lastname: Long
authors.affiliation: Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
authors.forename: Di
authors.initials: D
authors.lastname: Li
authors.affiliation: Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
authors.forename: Jian-Kang
authors.initials: JK
authors.lastname: Zhang
authors.affiliation: College of Life Science, Hubei University, Wuhan, 430062, China.
authors.forename: Shan
authors.initials: S
authors.lastname: Jin
authors.affiliation: Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.|The Key Laboratory of Neurological Diseases (HUST), Ministry of Education of China, Wuhan, 430030, China.|Hubei Key Laboratory of Drug Target Researches and Pharmacodynamic Evaluation (HUST), Wuhan, 430030, China.|The Laboratory of Neuropsychiatric Diseases, The Institute of Brain Research, Huazhong University of Science and Technology, Wuhan, 430030, China.
authors.forename: Fang
authors.initials: F
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.|The Key Laboratory of Neurological Diseases (HUST), Ministry of Education of China, Wuhan, 430030, China.|Hubei Key Laboratory of Drug Target Researches and Pharmacodynamic Evaluation (HUST), Wuhan, 430030, China.|The Laboratory of Neuropsychiatric Diseases, The Institute of Brain Research, Huazhong University of Science and Technology, Wuhan, 430030, China.
authors.forename: Jian-Guo
authors.initials: JG
authors.lastname: Chen
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D000375:Aging / Q000187:drug effects*; D000818:Animals; D001343:Autophagy / Q000187:drug effects*; D000071189:Autophagy-Related Protein-1 Homolog; D031204:Caloric Restriction; D029721:Drosophila Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D004331:Drosophila melanogaster / Q000502:physiology*; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D006146:Guanidines / Q000494:pharmacology*; D006861:Hydrogen Peroxide / Q000494:pharmacology; D008136:Longevity / Q000187:drug effects*; D008297:Male; D018384:Oxidative Stress / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D011422:Propionates / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D015854:Up-Regulation
chemical_list: C000611761:Atg5 protein, Drosophila; C527373:Atg8a protein, Drosophila; D029721:Drosophila Proteins; D006146:Guanidines; D011422:Propionates; D034741:RNA, Small Interfering; D006861:Hydrogen Peroxide; C518074:Atg1 protein, Drosophila; D000071189:Autophagy-Related Protein-1 Homolog; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; C005775:guanidinopropionic acid
keywords: AMP-activated protein kinase; Drosophila; autophagy; autophagy-related protein 1; lifespan; β-guanidinopropionic acid