Lifespan extension in <i>C. elegans</i> by a molecular chaperone dependent upon insulin‐like signals

Walker, Glenda A.; Lithgow, Gordon J.

doi:10.1046/j.1474-9728.2003.00045.x

Cited by 284 publications

(216 citation statements)

References 50 publications

(56 reference statements)

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“…C. elegans have been shown to live longer when fed NO‐producing bacteria in a process that results in hsp16 activation (Gusarov et al ., 2013). Increases in the heat shock protein hsp16 have been shown to increase lifespan in C. elegans in a DAF‐16‐dependent manner (Walker & Lithgow, 2003). However, DAF‐16 is not required for the lifespan increase induced by TSA.…”

Section: Discussionmentioning

confidence: 99%

A network pharmacology approach reveals new candidate caloric restriction mimetics in C. elegans

et al. 2015

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SummaryCaloric restriction (CR), a reduction in calorie intake without malnutrition, retards aging in several animal models from worms to mammals. Developing CR mimetics, compounds that reproduce the longevity benefits of CR without its side effects, is of widespread interest. Here, we employed the Connectivity Map to identify drugs with overlapping gene expression profiles with CR. Eleven statistically significant compounds were predicted as CR mimetics using this bioinformatics approach. We then tested rapamycin, allantoin, trichostatin A, LY‐294002 and geldanamycin in Caenorhabditis elegans. An increase in lifespan and healthspan was observed for all drugs except geldanamycin when fed to wild‐type worms, but no lifespan effects were observed in eat‐2 mutant worms, a genetic model of CR, suggesting that life‐extending effects may be acting via CR‐related mechanisms. We also treated daf‐16 worms with rapamycin, allantoin or trichostatin A, and a lifespan extension was observed, suggesting that these drugs act via DAF‐16‐independent mechanisms, as would be expected from CR mimetics. Supporting this idea, an analysis of predictive targets of the drugs extending lifespan indicates various genes within CR and longevity networks. We also assessed the transcriptional profile of worms treated with either rapamycin or allantoin and found that both drugs use several specific pathways that do not overlap, indicating different modes of action for each compound. The current work validates the capabilities of this bioinformatic drug repositioning method in the context of longevity and reveals new putative CR mimetics that warrant further studies.

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Section: Discussionmentioning

confidence: 99%

A network pharmacology approach reveals new candidate caloric restriction mimetics in C. elegans

et al. 2015

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“…HSF‐1, the C. elegans heat‐shock transcription factor, is also required in DAF‐2 mutants to extend lifespan. HSF‐1, along with DAF‐16, promotes longevity by activating specific longevity genes, including genes that encode small heat‐shock proteins (Garigan et al ., 2002; Hsu et al ., 2003; Walker & Lithgow, 2003; Morley & Morimoto, 2004). The importance of DAF‐18/PTEN tumor suppressor in longevity and dauer larva formation, through the regulation of the IIS pathway, has been established in the late 1990s by several research groups (Ogg & Ruvkun, 1998; Gil et al ., 1999; Mihaylova et al ., 1999; Rouault et al ., 1999).…”

Section: Animal Modelsmentioning

confidence: 99%

Long live FOXO: unraveling the role of FOXO proteins in aging and longevity

2015

Self Cite

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SummaryAging constitutes the key risk factor for age‐related diseases such as cancer and cardiovascular and neurodegenerative disorders. Human longevity and healthy aging are complex phenotypes influenced by both environmental and genetic factors. The fact that genetic contribution to lifespan strongly increases with greater age provides basis for research on which “protective genes” are carried by long‐lived individuals. Studies have consistently revealed FOXO (Forkhead box O) transcription factors as important determinants in aging and longevity. FOXO proteins represent a subfamily of transcription factors conserved from Caenorhabditis elegans to mammals that act as key regulators of longevity downstream of insulin and insulin‐like growth factor signaling. Invertebrate genomes have one FOXO gene, while mammals have four FOXO genes: FOXO1, FOXO3, FOXO4, and FOXO6. In mammals, this subfamily is involved in a wide range of crucial cellular processes regulating stress resistance, metabolism, cell cycle arrest, and apoptosis. Their role in longevity determination is complex and remains to be fully elucidated. Throughout this review, the mechanisms by which FOXO factors contribute to longevity will be discussed in diverse animal models, from Hydra to mammals. Moreover, compelling evidence of FOXOs as contributors for extreme longevity and health span in humans will be addressed.

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“…Among the most abundant transcripts (100 -800 tags in at least one of the libraries), we found the daf-21/hsp-90 (C47E8.5), hsp-16.2 and hsp-16.41 (Y46H3A.3 and Y46H3A.2). These three genes encode highly conserved molecular chaperones previously implicated in longevity (Murphy et al, 2003;Walker and Lithgow, 2003).…”

Section: Analysis Of Sage Data For Genes Related To Energy Generationmentioning

confidence: 99%

Genes that may modulate longevity in C. elegans in both dauer larvae and long-lived daf-2 adults

Ruzanov

Riddle

Marra

et al. 2007

Experimental Gerontology

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SummaryWe used Serial Analysis of Gene Expression (SAGE) to compare the global transcription profiles of long-lived mutant daf-2 adults and dauer larvae, aiming to identify aging-related genes based on similarity of expression patterns. Genes that are expressed similarly in both long-lived types potentially define a common life-extending program. Comparison of eight SAGE libraries yielded a set of 120 genes, the expression of which was significantly different in long-lived worms versus normal adults. The gene annotations indicate a strong link between oxidative stress and life span, further supporting the hypothesis that metabolic activity is a major determinant in longevity. The SAGE data show changes in mRNA levels for electron transport chain components, elevated expression of glyoxylate shunt enzymes and significantly reduced expression for components of the TCA cycle in longer-lived nematodes. We propose a model for enhanced longevity through a cytochrome c oxidase-mediated reduction in reactive oxygen species commonly held to be a major contributor to aging.

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Lifespan extension in C. elegans by a molecular chaperone dependent upon insulin‐like signals

Cited by 284 publications

References 50 publications

A network pharmacology approach reveals new candidate caloric restriction mimetics in C. elegans

A network pharmacology approach reveals new candidate caloric restriction mimetics in C. elegans

Long live FOXO: unraveling the role of FOXO proteins in aging and longevity

Genes that may modulate longevity in C. elegans in both dauer larvae and long-lived daf-2 adults

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