Insulin/IGF‐1‐mediated longevity is marked by reduced protein metabolism

Stout, Gerdine J.; Stigter, E.C.A.; Essers, Paul; Mulder, Klaas W.; Kolkman, Annemieke; Snijders, Dorien S; Broek, Niels J. F. van den; Betist, Marco C.; Korswagen, Hendrik C.; MacInnes, Alyson W.; Brenkman, Arjan B.

doi:10.1038/msb.2013.35

Cited by 70 publications

(98 citation statements)

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“…The loss of protein homeostasis is one of the hallmarks of aging (Balch et al, 2008;Ló pez-Otín et al, 2013), and protein aggregation is implicated in the pathology of age-related diseases like Parkinson's disease, Huntington's disease, cancer, and Alzheimer's disease (Powers et al, 2009). The idea that loss of protein homeostasis is implicated in aging comes mostly from studies that measure global protein synthesis and translation rates (by 35 S-methionine [ 35 S-Met] incorporation and polysome profiling, respectively) during normal aging and in models of age-related disease (Depuydt et al, 2013Hansen et al, 2007;Kirstein-Miles et al, 2013;Pan et al, 2007;Stout et al, 2013). Other studies used quantitative mass spectrometry or SDS-PAGE and western blotting to measure changes in the relative abundance of proteins in the proteome of aging model systems (Depuydt et al, 2013Kirstein-Miles et al, 2013;Walther et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

“…The relatively short lifespan of C. elegans makes it a convenient aging model system, and many of the preceding observations regarding changes in protein synthesis with aging come from work using this model organism (Depuydt et al, 2013Hansen et al, 2007;Kirstein-Miles et al, 2013;Pan et al, 2007;Stout et al, 2013;Walther et al, 2015). One of the best-characterized strains is the long-lived insulin receptor daf-2 mutant, which is generally found to have decreased protein synthesis or translation activity (Depuydt et al, 2013Hansen et al, 2007;Pan et al, 2007;Stout et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

“…One of the best-characterized strains is the long-lived insulin receptor daf-2 mutant, which is generally found to have decreased protein synthesis or translation activity (Depuydt et al, 2013Hansen et al, 2007;Pan et al, 2007;Stout et al, 2013). Loss of daf-2 is known to extend the lifespan of C. elegans more than 2-fold, which is, by epistasis analysis, attributed to DAF-16 function (Kenyon et al, 1993).…”

Section: Introductionmentioning

confidence: 99%

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Proteome-wide Changes in Protein Turnover Rates in C. elegans Models of Longevity and Age-Related Disease

et al. 2016

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The balance between protein synthesis and protein breakdown is a major determinant of protein homeostasis, and loss of protein homeostasis is one of the hallmarks of aging. Here we describe pulsed SILAC-based experiments to estimate proteome-wide turnover rates of individual proteins. We applied this method to determine protein turnover rates in Caenorhabditis elegans models of longevity and Parkinson's disease, using both developing and adult animals. Whereas protein turnover in developing, long-lived daf-2(e1370) worms is about 30% slower than in controls, the opposite was observed in day 5 adult worms, in which protein turnover in the daf-2(e1370) mutant is twice as fast as in controls. In the Parkinson's model, protein turnover is reduced proportionally over the entire proteome, suggesting that the protein homeostasis network has a strong ability to adapt. The findings shed light on the relationship between protein turnover and healthy aging.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Proteome-wide Changes in Protein Turnover Rates in C. elegans Models of Longevity and Age-Related Disease

et al. 2016

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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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In search of antiaging modalities: Evaluation of mTOR‐ and ROS/DNA damage‐signaling by cytometry

et al. 2014

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This review presents the evidence in support of the IGF-1/mTOR/S6K1 signaling as the primary factor contributing to aging and cellular senescence. Reviewed are also specific interactions between mTOR/S6K1 and ROS-DNA damage signaling pathways. Outlined are critical sites along these pathways, including autophagy, as targets for potential antiaging (gero-suppressive) and/or chemopreventive agents. Presented are applications of flow- and laser scanning- cytometry utilizing phospho-specific Abs, to monitor activation along these pathways in response to the reported antiaging drugs rapamycin, metformin, berberine, resveratrol, vitamin D3, 2-deoxyglucose, and acetylsalicylic acid. Specifically, effectiveness of these agents to attenuate the level of constitutive mTOR signaling was tested by cytometry and confirmed by Western blotting through measuring phosphorylation of the mTOR-downstream targets including ribosomal protein S6. The ratiometric analysis of phosphorylated to total protein along the mTOR pathway offers a useful parameter reporting the effects of gero-suppressive agents. In parallel, their ability to suppress the level of constitutive DNA damage signaling induced by endogenous ROS was measured. While the primary target of each of these agents may be different the data obtained on several human cancer cell lines, WI-38 fibroblasts and normal lymphocytes suggest common downstream mechanism in which the decline in mTOR/S6K1 signaling and translation rate is coupled with a reduction of oxidative phosphorylation and ROS that leads to decreased oxidative DNA damage. The combined assessment of constitutive γH2AX expression, mitochondrial activity (ROS, ΔΨPm), and mTOR signaling provides an adequate gamut of cell responses to test effectiveness of gero-suppressive agents. Described is also an in vitro model of induction of cellular senescence by persistent replication stress, its quantitative analysis by laser scanning cytometry, and application to detect the property of the studied agents to attenuate the induction of senescence. Discussed is cytometric analysis of cell size and heterogeneity of size as a potential biomarker used to asses gero-suppressive agents and longevity.

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Insulin/IGF‐1‐mediated longevity is marked by reduced protein metabolism

Abstract: Quantitative proteomics, lifespan analysis, and biochemical assays were utilized to show that Insulin/IGF-1-mediated longevity in C. elegans is strongly associated with a daf-16 dependent global reduction in protein metabolism.

Cited by 70 publications

References 59 publications

Proteome-wide Changes in Protein Turnover Rates in C. elegans Models of Longevity and Age-Related Disease

Proteome-wide Changes in Protein Turnover Rates in C. elegans Models of Longevity and Age-Related Disease

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

In search of antiaging modalities: Evaluation of mTOR‐ and ROS/DNA damage‐signaling by cytometry

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