An AMPK-FOXO Pathway Mediates Longevity Induced by a Novel Method of Dietary Restriction in C. elegans

Greer, Eric Lieberman; Dowlatshahi, Dara P.; Banko, Max R.; Villén, Judit; Hoang, Kimmi L.; Blanchard, Daniel; Gygi, Steven P.; Brunet, Anne

doi:10.1016/j.cub.2007.08.047

Cited by 701 publications

(785 citation statements)

References 56 publications

(98 reference statements)

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“…In the first instance, we diluted the amount of bacteria (provided as a nutritional source for the nematodes) to which the nematodes were exposed. This intervention was already shown to extend lifespan (Greer et al, 2007). We also subjected worms to a complete bacterial deprivation as of their first day of adulthood.…”

Section: Resultsmentioning

confidence: 89%

A salicylic acid derivative extends the lifespan of Caenorhabditis elegans by activating autophagy and the mitochondrial unfolded protein response

et al. 2018

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Plant extracts containing salicylates are probably the most ancient remedies to reduce fever and ease aches of all kind. Recently, it has been shown that salicylates activate adenosine monophosphate‐activated kinase (AMPK), which is now considered as a promising target to slow down aging and prevent age‐related diseases in humans. Beneficial effects of AMPK activation on lifespan have been discovered in the model organism Caenorhabditis elegans (C. elegans). Indeed, salicylic acid and acetylsalicylic acid extend lifespan in worms by activating AMPK and the forkhead transcription factor DAF‐16/FOXO. Here, we investigated whether another salicylic acid derivative 5‐octanoyl salicylic acid (C8‐SA), developed as a controlled skin exfoliating ingredient, had similar properties using C. elegans as a model. We show that C8‐SA increases lifespan of C. elegans and that a variety of pathways and genes are required for C8‐SA‐mediated lifespan extension. C8‐SA activates AMPK and inhibits TOR both in nematodes and in primary human keratinocytes. We also show that C8‐SA can induce both autophagy and the mitochondrial unfolded protein response (UPRmit) in nematodes. This induction of both processes is fully required for lifespan extension in the worm. In addition, we found that the activation of autophagy by C8‐SA fails to occur in worms with compromised UPRmit, suggesting a mechanistic link between these two processes. Mutants that are defective in the mitochondrial unfolded protein response exhibit constitutive high autophagy levels. Taken together, these data therefore suggest that C8‐SA positively impacts longevity in worms through induction of autophagy and the UPRmit.

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Section: Resultsmentioning

confidence: 89%

A salicylic acid derivative extends the lifespan of Caenorhabditis elegans by activating autophagy and the mitochondrial unfolded protein response

et al. 2018

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“…Chronic food limitation increases lifespan by downregulating TOR activity, which increases autophagy and diminishes translation, probably through PHA‐4/FOXA transcription factor and S6 kinase, respectively, in a DAF‐16/FoxO‐independent manner (Kaeberlein et al ., 2005; Hansen et al ., 2007; Pan et al ., 2007; Sheaffer et al ., 2008). AMPK (AMP kinase), an energy sensor for cellular AMP/ATP ratio that enables catabolic reactions for energy gain, has been shown to respond to dietary restriction by increasing stress resistance and extending longevity in C. elegans in a DAF‐16/FOXO‐dependent manner (Apfeld et al ., 2004; Greer et al ., 2007a). AMPK directly phosphorylates and activates DAF‐16/FoxO (Greer et al ., 2007a).…”

Section: Animal Modelsmentioning

confidence: 99%

“…AMPK (AMP kinase), an energy sensor for cellular AMP/ATP ratio that enables catabolic reactions for energy gain, has been shown to respond to dietary restriction by increasing stress resistance and extending longevity in C. elegans in a DAF‐16/FOXO‐dependent manner (Apfeld et al ., 2004; Greer et al ., 2007a). AMPK directly phosphorylates and activates DAF‐16/FoxO (Greer et al ., 2007a). Dietary restriction with every‐other‐day feeding is likely to promote C. elegans longevity via downregulation of the IIS pathway (Honjoh et al ., 2009).…”

Section: Animal Modelsmentioning

confidence: 99%

Long live FOXO: unraveling the role of FOXO proteins in aging and longevity

2015

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SummaryAging constitutes the key risk factor for age‐related diseases such as cancer and cardiovascular and neurodegenerative disorders. Human longevity and healthy aging are complex phenotypes influenced by both environmental and genetic factors. The fact that genetic contribution to lifespan strongly increases with greater age provides basis for research on which “protective genes” are carried by long‐lived individuals. Studies have consistently revealed FOXO (Forkhead box O) transcription factors as important determinants in aging and longevity. FOXO proteins represent a subfamily of transcription factors conserved from Caenorhabditis elegans to mammals that act as key regulators of longevity downstream of insulin and insulin‐like growth factor signaling. Invertebrate genomes have one FOXO gene, while mammals have four FOXO genes: FOXO1, FOXO3, FOXO4, and FOXO6. In mammals, this subfamily is involved in a wide range of crucial cellular processes regulating stress resistance, metabolism, cell cycle arrest, and apoptosis. Their role in longevity determination is complex and remains to be fully elucidated. Throughout this review, the mechanisms by which FOXO factors contribute to longevity will be discussed in diverse animal models, from Hydra to mammals. Moreover, compelling evidence of FOXOs as contributors for extreme longevity and health span in humans will be addressed.

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“…For example, in anoxic myocardial cells, upregulation of AMPK can decrease the phosphorylation level of FOXO1 and FOXO3, and exclusion of them from the nucleus, leading to sequential activation of target genes, such as catalase (62). It has been demonstrated that AMPK phosphorylates the FOXO homologue, DAF-16, at multiple sites and activates DAF-16-dependent transcription (63). Notably, DAF-16 can induce the expression of genes encoded by AMPK, which slows aging in Caenorhabiditis elegans.…”

Section: Adenosine Monophosphate-activated Protein Kinase (Ampk)mentioning

confidence: 99%

Post-translational modifications of FOXO family proteins

Wang

Huang

2016

Molecular Medicine Reports

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Abstract. The Forkhead box O (FOXO) protein family is predominantly involved in apoptosis, oxidative stress, DNA damage/repair, tumor angiogenesis, glycometabolism, regulating life span and other important biological processes. Its activity is affected by a variety of posttranslational modifications (PTMs), including phosphorylation, acetylation, ubiquitination, methylation and glycosylation. When cells are subjected to different environments, the corresponding PTMs act on the FOXO protein family, to change transcriptional activity or subcellular localization, and the expression of downstream target genes, will ultimately affect the biological behavior of the cells. In this review, we will discuss the biological characteristics of FOXO protein PTMs.

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An AMPK-FOXO Pathway Mediates Longevity Induced by a Novel Method of Dietary Restriction in C. elegans

Abstract: Our study shows that an energy-sensing AMPK-FOXO pathway mediates the lifespan extension induced by a novel method of dietary restriction in C. elegans.

Cited by 701 publications

References 56 publications

A salicylic acid derivative extends the lifespan of Caenorhabditis elegans by activating autophagy and the mitochondrial unfolded protein response

A salicylic acid derivative extends the lifespan of Caenorhabditis elegans by activating autophagy and the mitochondrial unfolded protein response

Long live FOXO: unraveling the role of FOXO proteins in aging and longevity

Post-translational modifications of FOXO family proteins

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