β‐Guanidinopropionic acid extends the lifespan of Drosophila melanogaster via an AMP‐activated protein kinase‐dependent increase in autophagy

Abstract

SummaryPrevious 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.

Drug repurposing for aging research using model organisms

“…Yang et al . () evaluated the effect of β‐guanidinopropionic acid and dorsomorphin (TAK) on wild‐type D. melanogaster lifespan. While the effect of dorsomorphin on wild‐type flies was not discussed, the survival curves showed, probably significant, lifespan shortening, which is in line with what would be expected by inhibiting AMPK and confirms the lifespan changing effects of one of our top ranked compounds.…”

Latent mitochondrial DNA deletion mutations drive muscle fiber loss at old age

“…The increased incidence of respiratory‐deficient muscle fibers by expansion of latent mtDNA deletion mutations demonstrates the existence of specific pathways that control mitochondrial DNA mutation accumulation and, more importantly, that these pathways can be modulated in vivo . While the activation of mitochondrial biogenesis is suspected to have beneficial effects on aging (Martin‐Montalvo et al ., ; Yang et al ., ), if that process lacks selectivity for competent mitochondrial genomes, adverse effects may accrue due to the expansion of mtDNA deletion mutations in mammals (Lin et al ., ). Similarly, treatments designed to affect aging phenotypes by manipulating mitochondrial quality control require examination of those interventions on both normal and mutant mtDNA populations.…”

“…GPA, by inhibiting the creatine transporter, decreases intracellular creatine, high energy phosphocreatine, and ATP in skeletal muscle (Oudman et al ., ), increasing the AMP/ATP ratio (Bergeron et al ., ). The resulting energy deficit, likely through chronic AMPK activation, initiates mitochondrial biogenesis (Zong et al ., ; Chaturvedi et al ., ; Yang et al ., ). Similarly, creatine deficiency increased mitochondrial mass and respiratory enzyme activity in knockout mice (Schmidt et al ., ).…”

Targeting AMPK Signaling as a Neuroprotective Strategy in Parkinson’s Disease

“…GPA appears to have similar neuroprotective effects. It extends lifespan in Drosophila via activation of AMPK [167], and it is neuroprotective in MPTP treated mice [168]. A diet of 1% GPA for 4 weeks robustly increased AMPK activity and mitochondrial respiratory capacity in the striatum, and fully prevented MPTP-induced loss of DA neurons in the SNc and ameliorated DA depletion in the striatum.…”