Glucose Shortens the Life Span of C. elegans by Downregulating DAF-16/FOXO Activity and Aquaporin Gene Expression

Lee, Seung-Jae; Murphy, Coleen T.; Kenyon, Cynthia

doi:10.1016/j.cmet.2009.10.003

Cited by 301 publications

(390 citation statements)

References 63 publications

(112 reference statements)

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“…This effect involves the downregulation of an aquaporin glycerol channel, aqp‐1 , which is also inhibited by glucose in mammals. Moreover, when 2% glucose was provided to C. elegans insulin/IGF‐1 receptor mutants, their lifespan extension was nearly completed repressed (Lee et al ., 2009). The expression of components of the insulin/IGF‐1 longevity pathway in subsets of cells can affect the rate of aging of the entire organism, implying an active coordination of the aging rates between the different tissues to establish homeostasis.…”

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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Section: Animal Modelsmentioning

confidence: 99%

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

2015

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“…Oxygen consumption rates were measured as in previously published protocols using a Oxytherm (Hansatech) oxygen electrode (42)(43)(44). Briefly, two crowded but not starved 60-mm diameter plates containing L4 larvae were washed three times with M9 buffer and resuspended in 1 mL of M9 buffer and then transferred into the chamber, and respiration was measured at 20°C for at least 10 min.…”

Section: Methodsmentioning

confidence: 99%

The mitochondrial unfolded protein response activator ATFS-1 protects cells from inhibition of the mevalonate pathway

Rauthan

Ranji

Pradenas

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

111

134

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Statins are cholesterol-lowering drugs that inhibit 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase, the rate-limiting enzyme in the synthesis of cholesterol via the mevalonate pathway. This pathway also produces coenzyme Q (a component of the respiratory chain), dolichols (important for protein glycosylation), and isoprenoids (lipid moieties responsible for the membrane association of small GTPases). We previously showed that the nematode Caenorhabditis elegans is useful to study the noncholesterol effects of statins because its mevalonate pathway lacks the sterol synthesis branch but retains all other branches. Here, from a screen of 150,000 mutagenized genomes, we isolated four C. elegans mutants resistant to statins by virtue of gain-of-function mutations within the first six amino acids of the protein ATFS-1, the key regulator of the mitochondrial unfolded protein response that includes activation of the chaperones HSP-6 and HSP-60. The atfs-1 gain-of-function mutants are also resistant to ibandronate, an inhibitor of an enzyme downstream of HMG-CoA reductase, and to gliotoxin, an inhibitor acting on a subbranch of the pathway important for protein prenylation, and showed improved mitochondrial function and protein prenylation in the presence of statins. Additionally, preinduction of the mitochondrial unfolded protein response in wild-type worms using ethidium bromide or paraquat triggered statin resistance, and similar observations were made in Schizosaccharomyces pombe and in a mammalian cell line. We conclude that statin resistance through maintenance of mitochondrial homeostasis is conserved across species, and that the cell-lethal effects of statins are caused primarily through impaired protein prenylation that results in mitochondria dysfunction.

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“…Aquaporin genes 7 (AQP7) and 9 (AQP9) in mammals have features common to C. elegans aqp-1, and have been suggested to be its homolog. 32 The mRNA of AQP7 and AQP9 in mammals decreases with insulin secretion, and AQP7-knockout mice show insulin resistance and obesity. 33 Expression of the AQP7 gene is reduced in obese women, and polymorphisms of this gene are associated with obesity and diabetes.…”

Section: Introductionmentioning

confidence: 99%

“…31 C. elegans responds to a 2% glucose diet with a shortened lifespan, and the authors postulate a connection with insulin resistance. 32 Mutations of daf-2 increase lifespan by removing the inhibition of the FOXO transcription factor, DAF-16, and the heat-shock transcription factor (HSF-1). Thus, it would be expected that inhibitors of DAF-16 and HSF-1 would decrease lifespan.…”

Section: Introductionmentioning

confidence: 99%

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Caenorhabditis elegans as a model for obesity research

Zheng

Greenway

2011

Int J Obes

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Caenorhabditis elegans (C. elegans) is a small nematode that conserves 65% of the genes associated with human disease, has a 21-day lifespan, reproductive cycles of 3 days, large brood sizes, lives in an agar dish and does not require committee approvals for experimentation. Research using C. elegans is encouraged and a Caenorhabditis Genetics Center (CGC, Minnesota) is funded by the National Institutes of Health-National Center for Research Resources. Many genetically manipulated strains of C. elegans are available at nominal cost from the CGC. Studies using the C. elegans model have explored insulin signaling, response to dietary glucose, the influence of serotonin on obesity, satiety, feeding and hypoxia-associated illnesses. C. elegans has also been used as a model to evaluate potential obesity therapeutics, explore the mechanisms behind single gene mutations related to obesity and to define the mechanistic details of fat metabolism. Obesity now affects a third of the US population and is becoming a progressively more expensive public health problem. Faster and less expensive methods to reach more effective treatments are clearly needed. We present this review hoping to stimulate interest in using the C. elegans model as a vehicle to advance the understanding and future treatment of obesity.

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Glucose Shortens the Life Span of C. elegans by Downregulating DAF-16/FOXO Activity and Aquaporin Gene Expression

Cited by 301 publications

References 63 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 mitochondrial unfolded protein response activator ATFS-1 protects cells from inhibition of the mevalonate pathway

Caenorhabditis elegans as a model for obesity research

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