Reduced Insulin/Insulin-like Growth Factor-1 Signaling and Dietary Restriction Inhibit Translation but Preserve Muscle Mass in Caenorhabditis elegans

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

doi:10.1074/mcp.m113.027383

Cited by 85 publications

(145 citation statements)

References 160 publications

(218 reference statements)

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“…Although some evidence points toward BCAAs as a metabolic signature of long life in C. elegans insulin receptor mutants (31,32), other studies have causally linked BCAAs to the development of insulin resistance, diabetes (33), and neuropathologies (34). Interestingly, BCAAs, leucine in particular, are potent activators of the target of rapamycin (TOR) kinase.…”

Section: Discussionmentioning

confidence: 99%

Metformin promotes lifespan through mitohormesis via the peroxiredoxin PRDX-2

Haes

Frooninckx

Assche

et al. 2014

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

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The antiglycemic drug metformin, widely prescribed as first-line treatment of type II diabetes mellitus, has lifespan-extending properties. Precisely how this is achieved remains unclear. Via a quantitative proteomics approach using the model organism Caenorhabditis elegans, we gained molecular understanding of the physiological changes elicited by metformin exposure, including changes in branched-chain amino acid catabolism and cuticle maintenance. We show that metformin extends lifespan through the process of mitohormesis and propose a signaling cascade in which metformin-induced production of reactive oxygen species increases overall life expectancy. We further address an important issue in aging research, wherein so far, the key molecular link that translates the reactive oxygen species signal into a prolongevity cue remained elusive. We show that this beneficial signal of the mitohormetic pathway is propagated by the peroxiredoxin PRDX-2. Because of its evolutionary conservation, peroxiredoxin signaling might underlie a general principle of prolongevity signaling.

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Section: Discussionmentioning

confidence: 99%

Metformin promotes lifespan through mitohormesis via the peroxiredoxin PRDX-2

Haes

Frooninckx

Assche

et al. 2014

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

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“…For example, DR can be achieved by diluting the bacteria in a liquid medium. This intervention, which extends the lifespan and decreases animal size, is partially dependent on both daf-16, a key transcription factor of the insulin-like signaling pathway, and aak-2, the catalytic subunit of AMP-activated protein kinase (AMPK) (7,8). In a different DR model, a mutation in the eat-2 gene decreases the rate of pharyngeal contractions, limiting the animals' feeding rate.…”

mentioning

confidence: 99%

Cell size and fat content of dietary-restricted Caenorhabditis elegans are regulated by ATX-2, an mTOR repressor

Bar

Charar

Dorfman

et al. 2016

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

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Dietary restriction (DR) is a metabolic intervention that extends the lifespan of multiple species, including yeast, flies, nematodes, rodents, and, arguably, rhesus monkeys and humans. Hallmarks of lifelong DR are reductions in body size, fecundity, and fat accumulation, as well as slower development. We have identified atx-2, the Caenorhabditis elegans homolog of the human ATXN2L and ATXN2 genes, as the regulator of these multiple DR phenotypes. Down-regulation of atx-2 increases the body size, cell size, and fat content of dietary-restricted animals and speeds animal development, whereas overexpression of atx-2 is sufficient to reduce the body size and brood size of wild-type animals. atx-2 regulates the mechanistic target of rapamycin (mTOR) pathway, downstream of AMP-activated protein kinase (AMPK) and upstream of ribosomal protein S6 kinase and mTOR complex 1 (TORC1), by its direct association with Rab GDP dissociation inhibitor β, which likely regulates RHEB shuttling between GDP-bound and GTP-bound forms. Taken together, this work identifies a previously unknown mechanism regulating multiple aspects of DR, as well as unknown regulators of the mTOR pathway. They also extend our understanding of diet-dependent growth retardation, and offers a potential mechanism to treat obesity.Caenorhabditis elegans | metabolism | mTOR pathway | TORC1 D ietary restriction (DR), limiting food consumption below ad libitum to levels that do not cause malnutrition, is a highly conserved metabolic intervention. Different DR regimes extend the lifespan of most tested animal species (1). Moreover, DR regimens have been found to reduce the risk of diabetes in monkeys and to positively change metabolic health biomarkers in humans (2). Lifelong DR causes reduced body size, lower fat levels, and a smaller brood size (3-6). Although the pathways by which DR extends lifespan have been thoroughly investigated, less is known about the causes of reduced body size and fat content.Multiple DR regimens have been developed for Caenorhabditis elegans (7). Surprisingly, the different DR regimens vary in the genes essential for lifespan extension (7). For example, DR can be achieved by diluting the bacteria in a liquid medium. This intervention, which extends the lifespan and decreases animal size, is partially dependent on both daf-16, a key transcription factor of the insulin-like signaling pathway, and aak-2, the catalytic subunit of AMP-activated protein kinase (AMPK) (7,8). In a different DR model, a mutation in the eat-2 gene decreases the rate of pharyngeal contractions, limiting the animals' feeding rate. Unlike bacterial dilution, this model was shown to be independent of both daf-16 and aak-2, at least with respect to lifespan (7).The mechanistic target of rapamycin (mTOR) pathway is a key regulator of multiple processes, including transcription and translation, protein and lipid synthesis, cell growth and size, and cellular metabolism (9). It contains two main protein complexes, mTOR complex 1 (TORC1) and complex 2 (TORC2) (10). TOR...

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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%

“…Quantitative proteomics data showed a clear decrease in ribosomal subunits and translation factors in daf-2 mutants suggesting a decrease in protein synthesis rates in these worms (Depuydt et al, 2013;Stout et al, 2013). Active insulin and IGF pathways are known to support anabolic growth.…”

Section: Damage Clearance and Protein Turnovermentioning

confidence: 99%

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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Reduced Insulin/Insulin-like Growth Factor-1 Signaling and Dietary Restriction Inhibit Translation but Preserve Muscle Mass in Caenorhabditis elegans

Cited by 85 publications

References 160 publications

Metformin promotes lifespan through mitohormesis via the peroxiredoxin PRDX-2

Metformin promotes lifespan through mitohormesis via the peroxiredoxin PRDX-2

Cell size and fat content of dietary-restricted Caenorhabditis elegans are regulated by ATX-2, an mTOR repressor

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

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