JNK Extends Life Span and Limits Growth by Antagonizing Cellular and Organism-Wide Responses to Insulin Signaling

Wang, Meng C.; Bohmann, Dirk; Jasper, Heinrich

doi:10.1016/j.cell.2005.02.030

Cited by 502 publications

(546 citation statements)

References 58 publications

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“…The stress‐responsive JNK pathway also requires dFoxO to extend lifespan in Drosophila (Wang et al ., 2005). JNK has been shown to antagonize IIS, promoting dFoxO nuclear localization, therefore inducing expression of growth control and stress defense genes.…”

Section: Animal Modelsmentioning

confidence: 99%

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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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Section: Animal Modelsmentioning

confidence: 99%

“…JNK has been shown to antagonize IIS, promoting dFoxO nuclear localization, therefore inducing expression of growth control and stress defense genes. Moreover, the repression of IIS ligands by JNK and dFoxO in neuroendocrine cells systemically downregulates the IIS pathway (Wang et al ., 2005). …”

Section: Animal Modelsmentioning

confidence: 99%

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

2015

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“…Among them are Drosophila insulin-like peptide 3 and 5 (dIlp3 and dIlp5) involved in insulin-like signaling, which is a major pathway known to modulate lifespan in worms, flies, and rodents (Broughton et al 2005;Fontana et al 2010). Supplementation of resveratrol also downregulated glutathione S transferase D1 (GstD1) and heat shock protein 68, two downstream targets of Jun kinase (JNK) signaling pathway, which is a major oxidative stress response pathway and is known to modulate lifespan in several model organisms (Wang et al 2005;Karpac and Jasper 2009). In addition, two peroxiredoxin (Prx) genes, Prx2540-1 and Prx6005, were downregulated by supplementation of resveratrol.…”

Section: Influence Of Dietary Composition On the Effect Of Resveratromentioning

confidence: 99%

The effect of resveratrol on lifespan depends on both gender and dietary nutrient composition in Drosophila melanogaster

Wang

Wheeler

Alberico

et al. 2011

AGE

101

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Resveratrol, a polyphenolic compound, has been shown to extend lifespan in different organisms. Emerging evidence suggests that the prolongevity effect of resveratrol depends on dietary composition. However, the mechanisms underlying the interaction of resveratrol and dietary nutrients in modulating lifespan remain elusive. Here, we investigated the effect of resveratrol on lifespan of Drosophila melanogaster fed diets differing in the concentrations of sugar, yeast extract, and palmitic acid representing carbohydrate, protein, and fat, respectively. Resveratrol at up to 200 μM in diets did not affect lifespan of wild-type female flies fed a standard, restricted or high sugar-low protein diet, but extended lifespan of females fed a low sugar-high protein diet. Resveratrol at 400 μM extended lifespan of females fed a high-fat diet. Lifespan extension by resveratrol was associated with downregulation of genes in aging-related pathways, including antioxidant peroxiredoxins, insulin-like peptides involved in insulin-like signaling and several downstream genes in Jun-kinase signaling involved in oxidative stress response. Furthermore, resveratrol increased lifespan of superoxide dismutase 1 (sod1) knockdown mutant females fed a standard or high-fat diet. No lifespan extension by resveratrol was observed in wild-type and sod1 knockdown males under the culture conditions in this study. Our results suggest that the gender-specific prolongevity effect of resveratrol is influenced by dietary composition and resveratrol promotes the survival of flies by modulating genetic pathways that can reduce cellular damage. This study reveals the context-dependent effect of resveratrol on lifespan and suggests the importance of dietary nutrients in implementation of effective aging interventions using dietary supplements.

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“…In contrast, higher ROS levels can induce an oxidative stress response that involves JNK activation and Tor inhibition (Reiling & Sabatini, 2006; Takimoto and Kass, 2007). Activated JNK, in turn, activates Foxo by phosphorylation, which overcomes the Foxo nuclear import barrier induced by IIS (Oh et al ., 2005; Tzivion et al ., 2011) and enables Foxo activity despite Akt‐dependent phosphorylation (Wang et al ., 2005). This Foxo activation is necessary for activated JNK to increase lifespan (Wang et al ., 2005).…”

Section: Greatly Elevated Cytoplasmic Oxidation Late In Life: Implicamentioning

confidence: 99%

“…Activated JNK, in turn, activates Foxo by phosphorylation, which overcomes the Foxo nuclear import barrier induced by IIS (Oh et al ., 2005; Tzivion et al ., 2011) and enables Foxo activity despite Akt‐dependent phosphorylation (Wang et al ., 2005). This Foxo activation is necessary for activated JNK to increase lifespan (Wang et al ., 2005). Although the mechanism underlying the Tor inhibition that occurs under high ROS is not completely clear, it is possible that a role is played by the ROS‐dependent activation of AMPK (Cardaci et al ., 2012), which inhibits Tor both by phosphorylating and activating the Tor inhibitor Tsc1/Tsc2 (Fig.…”

Section: Greatly Elevated Cytoplasmic Oxidation Late In Life: Implicamentioning

confidence: 99%

Evidence that a mitochondrial death spiral underlies antagonistic pleiotropy

Stern

2017

Aging Cell

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SummaryThe antagonistic pleiotropy (AP) theory posits that aging occurs because alleles that are detrimental in older organisms are beneficial to growth early in life and thus are maintained in populations. Although genes of the insulin signaling pathway likely participate in AP, the insulin‐regulated cellular correlates of AP have not been identified. The mitochondrial quality control process called mitochondrial autophagy (mitophagy), which is inhibited by insulin signaling, might represent a cellular correlate of AP. In this view, rapidly growing cells are limited by ATP production; these cells thus actively inhibit mitophagy to maximize mitochondrial ATP production and compete successfully for scarce nutrients. This process maximizes early growth and reproduction, but by permitting the persistence of damaged mitochondria with mitochondrial DNA mutations, becomes detrimental in the longer term. I suggest that as mitochondrial ATP output drops, cells respond by further inhibiting mitophagy, leading to a further decrease in ATP output in a classic death spiral. I suggest that this increasing ATP deficit is communicated by progressive increases in mitochondrial ROS generation, which signals inhibition of mitophagy via ROS‐dependent activation of insulin signaling. This hypothesis clarifies a role for ROS in aging, explains why insulin signaling inhibits autophagy, and why cells become progressively more oxidized during aging with increased levels of insulin signaling and decreased levels of autophagy. I suggest that the mitochondrial death spiral is not an error in cell physiology but rather a rational approach to the problem of enabling successful growth and reproduction in a competitive world of scarce nutrients.

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JNK Extends Life Span and Limits Growth by Antagonizing Cellular and Organism-Wide Responses to Insulin Signaling

Cited by 502 publications

References 58 publications

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

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

The effect of resveratrol on lifespan depends on both gender and dietary nutrient composition in Drosophila melanogaster

Evidence that a mitochondrial death spiral underlies antagonistic pleiotropy

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