LC–MS Proteomics Analysis of the Insulin/IGF-1-Deficient<i>Caenorhabditis elegans daf-2(e1370)</i>Mutant Reveals Extensive Restructuring of Intermediary Metabolism

Depuydt, Geert; Xie, Fang; Petyuk, Vladislav; Smolders, Arne; Brewer, Heather M.; Camp, David G.; Smith, Richard; Braeckman, Bart P.

doi:10.1021/pr401081b

Cited by 62 publications

(91 citation statements)

References 161 publications

(421 reference statements)

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“…With the dawn of the omics era, transcriptomic (McElwee et al, 2003;Murphy et al, 2003;McElwee et al, 2004;Halaschek-Wiener et al, 2005), proteomic (Dong et al, 2007;Jones et al, 2010;Depuydt et al, 2013Depuydt et al, , 2014Stout et al, 2013;Walther et al, 2015) and metabolomic (Fuchs et al, 2010) studies showed that IIS mutants undergo massive changes in gene expression and shifts in metabolic networks. DAF-16 targets were also determined by analysing DNA binding sites of this transcription factor with DamID and ChIP (Oh et al, 2006;Schuster et al, 2010).…”

Section: The Foxo/daf-16 Lifespan Programmentioning

confidence: 99%

“…The morphology of IIS mutants may provide a first clue: daf-2 mutants tend to accumulate large amounts of fat (Ogg et al, 1997;Depuydt et al, 2014) and glycogen (Frazier & Roth, 2009;Depuydt et al, 2014) in the intestine, hypodermis and to some extent in the body wall muscles, thereby phenocopying dauers (Fig. 2).…”

Section: Investment In Fat and Glycogen Synthesismentioning

confidence: 99%

“…The fat and glycogen storage phenotype is supported in proteomic studies. Many enzymes involved in fatty acid β-oxidation are upregulated in adult daf-2(e1370) mutants, while food uptake is drastically lowered, hinting at the use of stored fat as an energy source during adulthood in IIS mutants (Depuydt et al, 2014). In these mutants, most enzymes involved in carbohydrate metabolism are also strongly upregulated with glycogen synthase (GSY-1) belonging to the top most upregulated proteins.…”

Section: Investment In Fat and Glycogen Synthesismentioning

confidence: 99%

“…In short, fat can be converted into glycogen by glyoxylate cycle activity. It comes as no surprise that icl-1 is drastically upregulated in dauers (Holt & Riddle, 2003;Wang & Kim, 2003;Erkut et al, 2016) and IIS mutants (Murphy et al, 2003;Depuydt et al, 2014;Shen et al, 2014). Moreover, icl-1 activity is responsible for up to 45% of the lifespan extension observed in daf-2 mutants (Murphy et al, 2003;Shen et al, 2014).…”

Section: Investment In Fat and Glycogen Synthesismentioning

confidence: 99%

“…3). Also the glutamate synthase homologue W07E11.1, which, like ICL-1, only occurs in bacteria, plants and nematodes, is highly upregulated in daf-2 mutants hinting at an important function in the IIS longevity phenotype (Depuydt et al, 2014). These metabolic patterns seem all part of an ancient genetic program that allows small organisms with limited mobility to undergo anhydrobiosis and survive repetitive drought/rehydration cycles (Alpert, 2006;Erkut et al, 2016).…”

Section: Relevance To Human Biologymentioning

confidence: 99%

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Lifespan extension in Caenorhabditis elegans insulin/IGF-1 signalling mutants is supported by non-vertebrate physiological traits

Braeckman

Dhondt

2017

Nematol

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Summary -The insulin/IGF-1 signalling (IIS) pathway connects nutrient levels to metabolism, growth and lifespan in eukaryotes ranging from yeasts to humans, including nematodes such as the genetic model organism Caenorhabditis elegans. The link between ageing and the IIS pathway has been thoroughly studied in C. elegans; upon reduced IIS signalling, a genetic survival program is activated resulting in a drastic lifespan extension. One of the components of this program is the upregulation of antioxidant activity but experiments failed to show a clear causal relation to longevity. However, oxidative damage, such as protein carbonyls, accumulates at a slower pace in long-lived C. elegans mutants with reduced IIS. This is probably not achieved by increased macroautophagy, a process that sequesters cellular components to be eliminated as protein turnover rates are slowed down in IIS mutants. The IIS mutant daf-2, bearing a mutation in the insulin/IGF-1 receptor, recapitulates the dauer survival program, including accumulation of fat and glycogen. Fat can be converted into glucose and glycogen via the glyoxylate shunt, a pathway absent in vertebrates. These carbohydrates can be used as substrates for trehalose synthesis, also absent in mammals. Trehalose, a non-reducing homodimer of glucose, stabilises intracellular components and is responsible for almost half of the lifespan extension in IIS mutants. Hence, the molecular mechanisms by which lifespan is extended under reduced IIS may differ substantially between phyla that have an active glyoxylate cycle and trehalose synthesis, such as ecdysozoans and fungi, and vertebrate species such as mammals.

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Section: The Foxo/daf-16 Lifespan Programmentioning

confidence: 99%

Section: Investment In Fat and Glycogen Synthesismentioning

confidence: 99%

Section: Investment In Fat and Glycogen Synthesismentioning

confidence: 99%

Section: Investment In Fat and Glycogen Synthesismentioning

confidence: 99%

Section: Relevance To Human Biologymentioning

confidence: 99%

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Lifespan extension in Caenorhabditis elegans insulin/IGF-1 signalling mutants is supported by non-vertebrate physiological traits

Braeckman

Dhondt

2017

Nematol

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Small Molecule from Natural Phytochemical Mimics Dietary Restriction by Modulating FoxO3a and Metabolic Reprogramming

et al. 2020

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Many studies utilizing animal models have revealed the genetic and pharmacogenetic modulators of the rate of organismal aging. However, finding routes for healthy aging during extended life remains one of the largest questions. With regards to an antiaging reagent, it has been shown that natural phytochemical syringaresinol (SYR) delays cellular senescence by activating sirtuin1 (SIRT1). Here, it is found that SYR treatment results in metabolic changes similar to those observed during dietary restriction (DR). The DR mimetic effects are mediated by FoxO3a‐dependent SIRT1 activation and insulin/insuline growth factor‐1 signaling modulation. The direct binding of SYR‐FoxO3a is identified and this could partially explain the DR‐like phenotype. The report gives a clue as to how the longevity gene involves the DR pathway and suggests that natural phytochemicals applied as a geroprotector mimics DR effects.

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Glycogen at the Crossroad of Stress Resistance, Energy Maintenance, and Pathophysiology of Aging

Gusarov

Nudler

2018

BioEssays

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Glycogen is synthesized and stored to maintain postprandial blood glucose homeostasis and to ensure an uninterrupted energy supply between meals. Although the regulation of glycogen turnover has been well studied, the effects of glycogen on aging and disease development have been largely unexplored. In Caenorhabditis elegans fed a high sugar diet, glycogen potentiates resistance to oxidants, but paradoxically, shortens lifespan. Depletion of glycogen by oxidants or inhibition of glycogen synthesis extends the lifespan of worms by an AMPK-dependent mechanism. Thus, glycogen is not merely an inert storage molecule, but also an active regulator of energy balance and aging. Its depletion by oxidants may be beneficial in the treatment of hyperglycemia and glycogen-related diseases.

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LC–MS Proteomics Analysis of the Insulin/IGF-1-DeficientCaenorhabditis elegans daf-2(e1370)Mutant Reveals Extensive Restructuring of Intermediary Metabolism

Cited by 62 publications

References 161 publications

Lifespan extension in Caenorhabditis elegans insulin/IGF-1 signalling mutants is supported by non-vertebrate physiological traits

Lifespan extension in Caenorhabditis elegans insulin/IGF-1 signalling mutants is supported by non-vertebrate physiological traits

Small Molecule from Natural Phytochemical Mimics Dietary Restriction by Modulating FoxO3a and Metabolic Reprogramming

Glycogen at the Crossroad of Stress Resistance, Energy Maintenance, and Pathophysiology of Aging

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