Translational Regulation of Non-autonomous Mitochondrial Stress Response Promotes Longevity

Lan, Jianfeng; Rollins, Jarod; Zang, Xiao Ping; Wu, Di; Zou, Lina; Wang, Zi; Ye, Chang; Wu, Zixing; Kapahi, Pankaj; Rogers, Aric N.; Chen, Di

doi:10.1016/j.celrep.2019.06.078

Cited by 60 publications

(51 citation statements)

References 71 publications

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“…Using genome-wide translational state analysis and genetic screening, Lan et al identified ribosomal protein genes and cyc-2.1 , which encodes one of the worm cytochrome orthologs, as negative regulators of longevity ( 80 ). Cyc-2.1 knockdown significantly extended lifespan by activating the intestinal mitochondrial unfolded protein response (UPR mt ), mitochondrial fission, and AMPK ( 80 ). The influence of mitophagy is to extend the lifespan, thus, the role of mTOR mediated mitophagy in longevity needs further study.…”

Section: Transcriptional Regulators and Epigenetic Regulation In mentioning

confidence: 99%

Caenorhabditis elegans as a Useful Model for Studying Aging Mutations

et al. 2020

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The Caenorhabditis elegans genome possesses homologs of about two-thirds of all human disease genes. Based on its physiological aging characteristics and superiority, the use of C. elegans as a model system for studies on aging, age-related diseases, mechanisms of longevity, and drug screening has been widely acknowledged in recent decades. Lifespan increasing mutations in C. elegans were found to delay aging by impinging several signaling pathways and related epigenetic modifications, including the insulin/IGF-1 signaling (IIS), AMP-activated protein kinase (AMPK), and mechanistic target of rapamycin (mTOR) pathways. Interestingly, dietary restriction (DR) has been shown to increase the lifespan of numerous metazoans and protect them from multiple age-related pathologies. However, the underlying molecular mechanisms are unclear. In recent decades, C. elegans has been used as a unique model system for high-throughput drug screening. Here, we review C. elegans mutants exhibiting increased in lifespan and age-dependent changes under DR, as well as the utility of C. elegans for drug screening. Thus, we provide evidence for the use of this model organism in research on the prevention of aging.

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Section: Transcriptional Regulators and Epigenetic Regulation In mentioning

confidence: 99%

Caenorhabditis elegans as a Useful Model for Studying Aging Mutations

et al. 2020

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“…(B) Dietary restriction (DR) and the long-lived double mutant daf-2(e1370); rsks-1(ok1255) are predicted to be significantly younger than WT samples of the same chronological age (4 days). Data from GSE119485 103,170 .…”

Section: Resultsmentioning

confidence: 99%

A transcriptome based aging clock near the theoretical limit of accuracy

Meyer

Schumacher

2020

Preprint

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Aging clocks dissociate biological from chronological age. The estimation of biological age is important for identifying gerontogenes and assessing environmental, nutritional or therapeutic impacts on the aging process. Recently, methylation markers were shown to allow estimation of biological age based on age-dependent somatic epigenetic alterations. However, DNA methylation is absent in some species such as Caenorhabditis elegans and it remains unclear whether and how the epigenetic clocks affect gene expression. Aging clocks based on transcriptomes have suffered from considerable variation in the data and relatively low accuracy. Here, we devised an approach that uses temporal scaling and binarization of C. elegans transcriptomes to define a gene set that predicts biological age with an accuracy that is close to the theoretical limit. Our model accurately predicts the longevity effects of diverse strains, treatments and conditions. The involved genes support a role of specific transcription factors as well as innate immunity and neuronal signaling in the regulation of the aging process. We show that this transcriptome clock can also be applied to human age prediction with high accuracy. This transcriptome aging clock could therefore find wide application in genetic, environmental and therapeutic interventions in the aging process.

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“…Long-lived daf-2 /insulin receptor mutants show changes in their translatome 28 and the extended lifespan of daf-2;rsks-1 /S6K double mutants is mediated by the selective translational repression of the cytochrome cyc-2 . 1 18 . Our study shows that Gcn(-) mutations change translational efficiency of specific mRNAs that are required for the observed lifespan extension.…”

Section: Discussionmentioning

confidence: 99%

eIF2B extends lifespan through inhibition of the integrated stress response

Derisbourg

Wester

Baddi

et al. 2020

Preprint

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Protein homeostasis is modulated by stress response pathways and its deficiency is a hallmark of aging. The integrated stress response (ISR) is a conserved stress-signaling pathway that tunes mRNA translation via phosphorylation of the translation initiation factor eIF2. ISR activation and translation initiation are finely balanced by eIF2 kinases and by the eIF2 guanine nucleotide exchange factor eIF2B. However, the role of the ISR during aging remains unexplored. Using a genomic screen in Caenorhabditis elegans, we discovered a role of eIF2B and the eIF2 kinases in longevity. By limiting the ISR, these mutations enhanced protein homeostasis and increased lifespan. Consistently, full ISR inhibition using phosphorylation-defective eIF2α or pharmacological ISR inhibition prolonged lifespan. Lifespan extension through ISR inhibition occurred without changes in overall protein synthesis, and depended on enhanced translational efficiency of the kinase KIN-35. Evidently, lifespan is limited by the ISR and its inhibition may provide an intervention in aging.

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Translational Regulation of Non-autonomous Mitochondrial Stress Response Promotes Longevity

Cited by 60 publications

References 71 publications

Caenorhabditis elegans as a Useful Model for Studying Aging Mutations

Caenorhabditis elegans as a Useful Model for Studying Aging Mutations

A transcriptome based aging clock near the theoretical limit of accuracy

eIF2B extends lifespan through inhibition of the integrated stress response

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