Forward and reverse genetics approaches to uncover metabolic aging pathways in Caenorhabditis elegans

Gao, Arwen W.; Bos, Jelmi uit de; Sterken, M.G.; Kammenga, J.E.; Smith, Reuben L.; Houtkooper, Riekelt H.

doi:10.1016/j.bbadis.2017.09.006

Cited by 24 publications

(24 citation statements)

References 124 publications

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“…Accumulating lines of evidence have uncovered that glucose metabolism was closely associated with aging process [31][32][33]. PCK1 was the first rate-limiting enzyme in the gluconeogenesis pathway and was probably involved in the aging process in C. elegans.…”

Section: Discussionmentioning

confidence: 99%

PCK1Deficiency Shortens the Replicative Lifespan ofSaccharomyces cerevisiaethrough Upregulation ofPFK1

Yuan

Lin

Cui

et al. 2020

BioMed Research International

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The cytosolic isozyme of phosphoenolpyruvate carboxykinase (PCK1) was the first rate-limiting enzyme in the gluconeogenesis pathway, which exerted a critical role in maintaining the blood glucose levels. PCK1 has been established to be involved in various physiological and pathological processes, including glucose metabolism, lipid metabolism, diabetes, and tumorigenesis. Nonetheless, the association of PCK1 with aging process and the detailed underlying mechanisms of PCK1 on aging are still far to be elucidated. Hence, we herein constructed the PCK1-deficient (pck1Δ) and PCK1 overexpression (PCK1 OE) Saccharomyces cerevisiae. The results unveiled that PCK1 deficiency significantly shortened the replicative lifespan (RLS) in the S. cerevisiae, while overexpression of PCK1 prolonged the RLS. Additionally, we noted that the ROS level was significantly enhanced in PCK1-deficient strain and decreased in PCK1 OE strain. Then, a high throughput analysis by deep sequencing was performed in the pck1Δ and wild-type strains, in an attempt to shed light on the effect of PCK1 on the lifespan of aging process. The data showed that the most downregulated mRNAs were enriched in the regulatory pathways of glucose metabolism. Fascinatingly, among the differentially expressed mRNAs, PFK1 was one of the most upregulated genes, which was involved in the glycolysis process and ROS generation. Thus, we further constructed the pfk1Δpck1Δ strain by deletion of PFK1 in the PCK1-deficient strain. The results unraveled that pfk1Δpck1Δ strain significantly suppressed the ROS level and restored the RLS of pck1Δ strain. Taken together, our data suggested that PCK1 deficiency enhanced the ROS level and shortened the RLS of S. cerevisiae via PFK1.

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Section: Discussionmentioning

confidence: 99%

PCK1Deficiency Shortens the Replicative Lifespan ofSaccharomyces cerevisiaethrough Upregulation ofPFK1

Yuan

Lin

Cui

et al. 2020

BioMed Research International

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“…C. elegans is one of the most popular model organisms for aging studies due to its relatively short lifespan, fully annotated genome and its ease of manipulation 5 . The first aging gene to be discovered was daf-2, which encodes a homolog of mammalian insulin/insulin-like growth factor (IGF), and its regulatory mechanisms involved in longevity are highly conserved across a wide range of species, including yeast, flies, mice and human beings 6 .…”

Section: Introductionmentioning

confidence: 99%

“…diluting bacterial food) 9,10 . eat-2 mutant animals have a dysfunctional pharynx, which slows down food intake, and results in a lifespan increase of approximately 50% 5 . Previous studies on daf-2 and eat-2 mutants have outlined the essential biological processes involved in the regulatory networks of aging, and have opened up novel avenues for treatments and biomarkers for agingrelated diseases 7 .…”

Section: Introductionmentioning

confidence: 99%

Identification of key pathways and metabolic fingerprints of longevity in C. elegans

Gao

Smith

Weeghel

et al. 2017

Preprint

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Impaired insulin/IGF-1 signaling (IIS) pathway and caloric restriction (CR) are two wellestablished interventions to prolong lifespan in worm C. elegans. However, a cross comparison of these longevity pathways using a multi-omics integration approach is lacking.In this study, we aimed to identify key pathways and metabolite fingerprints of longevity that are shared between IIS and CR worm models using a multi-omics integration approach. We generated transcriptomics and metabolomics data from two long-lived mutant worm strains, i.e. daf-2 (impaired IIS pathway) and eat-2 (CR model) and compared them with the N2 strain. Transcriptional profiling identified shared longevity signatures between the two strains, such as an upregulation of lipid storage and defense responses and downregulation of macromolecule synthesis and developmental processes. The shared longevity signatures revealed by metabolomics profiling included an increase in the levels of glycerol-3P, ademine, xanthine, and AMP, and a decrease in the levels of the amino acid pool, the C18:0 and C17:1 fatty acids. After we integrated transcriptomics and metabolomics data based on the annotations in KEGG, our results highlighted a downregulation of pyrimidine metabolism and upregulation of purine metabolism as a commonality between the two longevity mechanisms. Overall, our findings point towards the existence of shared metabolic pathways that are likely important for lifespan extension and provide novel insights into potential regulators and metabolic fingerprints for longevity.

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“…C. elegans is a versatile model organism for understanding complex genetic pathways underlying distinct phenotypes such as stress response, lifespan, host-pathogen interaction, and behavior (Gao et al 2017b). The Kammenga group generated a segregating population of C. elegans derived from the genetically and ecologically divergent strains N2 (Bristol) and CB4856 (Hawaii), which is suitable for studying genome-to-phenome relations (Li et al 2006;Andersen et al 2012;Sterken et al 2015).…”

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confidence: 99%

Natural genetic variation inC. elegansidentified genomic loci controlling metabolite levels

et al. 2018

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Metabolic homeostasis is sustained by complex biological networks that respond to nutrient availability. Genetic and environmental factors may disrupt this equilibrium, leading to metabolic disorders, including obesity and type 2 diabetes. To identify the genetic factors controlling metabolism, we performed quantitative genetic analysis using a population of 199 recombinant inbred lines (RILs) in the nematode We focused on the genomic regions that control metabolite levels by measuring fatty acid (FA) and amino acid (AA) composition in the RILs using targeted metabolomics. The genetically diverse RILs showed a large variation in their FA and AA levels with a heritability ranging from 32% to 82%. We detected strongly co-correlated metabolite clusters and 36 significant metabolite quantitative trait loci (mQTL). We focused on mQTL displaying highly significant linkage and heritability, including an mQTL for the FA C14:1 on Chromosome I, and another mQTL for the FA C18:2 on Chromosome IV. Using introgression lines (ILs), we were able to narrow down both mQTL to a 1.4-Mbp and a 3.6-Mbp region, respectively. RNAi-based screening focusing on the Chromosome I mQTL identified several candidate genes for the C14:1 mQTL, including, Y87G2A.2, ,, and Overall, this systems approach provides us with a powerful platform to study the genetic basis of metabolism. Furthermore, it allows us to investigate interventions such as nutrients and stresses that maintain or disturb the regulatory network controlling metabolic homeostasis, and identify gene-by-environment interactions.

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Forward and reverse genetics approaches to uncover metabolic aging pathways in Caenorhabditis elegans

Cited by 24 publications

References 124 publications

PCK1Deficiency Shortens the Replicative Lifespan ofSaccharomyces cerevisiaethrough Upregulation ofPFK1

PCK1Deficiency Shortens the Replicative Lifespan ofSaccharomyces cerevisiaethrough Upregulation ofPFK1

Identification of key pathways and metabolic fingerprints of longevity in C. elegans

Natural genetic variation inC. elegansidentified genomic loci controlling metabolite levels

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