Pharmacogenetic Analysis of Lithium-induced Delayed Aging in Caenorhabditis elegans

McColl, Gawain; Killilea, David W.; Hubbard, Alan; Vantipalli, Maithili C.; Melov, Simon; Lithgow, Gordon J.

doi:10.1074/jbc.m705028200

Cited by 182 publications

(151 citation statements)

References 59 publications

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“…Although histone methyltransferases have not been previously implicated in modulating organismal longevity, several other highly conserved chromatinmodifying enzymes have been. In addition to SIR2 and RPD3, the histone H3K4 demethylase LSD-1 has also recently been implicated in modulating longevity in C. elegans (50). Given the roles of these enzymes in the epigenetic maintenance of transcriptional states, it seems likely that additional chromatin modifying enzymes will be found to modulate longevity.…”

Section: Discussionmentioning

confidence: 99%

Polycomb Repressive Complex 2 and Trithorax modulate Drosophila longevity and stress resistance

Siebold¹,

Banerjee²,

Tie³

et al. 2009

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

177

149

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Polycomb Group (PcG) and Trithorax Group (TrxG) proteins are key epigenetic regulators of global transcription programs. Their antagonistic chromatin-modifying activities modulate the expression of many genes and affect many biological processes. Here we report that heterozygous mutations in two core subunits of Polycomb Repressive Complex 2 (PRC2), the histone H3 lysine 27 (H3K27)-specific methyltransferase E(Z) and its partner, the H3 binding protein ESC, increase longevity and reduce adult levels of trimethylated H3K27 (H3K27me3). Mutations in trithorax (trx), a well known antagonist of Polycomb silencing, elevate the H3K27me3 level of E(z) mutants and suppress their increased longevity. Like many long-lived mutants, E(z) and esc mutants exhibit increased resistance to oxidative stress and starvation, and these phenotypes are also suppressed by trx mutations. This suppression strongly suggests that both the longevity and stress resistance phenotypes of PRC2 mutants are specifically due to their reduced levels of H3K27me3 and the consequent perturbation of Polycomb silencing. Consistent with this, long-lived E(z) mutants exhibit derepression of Abd-B, a well-characterized direct target of Polycomb silencing, and Odc1, a putative direct target implicated in stress resistance. These findings establish a role for PRC2 and TRX in the modulation of organismal longevity and stress resistance and indicate that moderate perturbation of Polycomb silencing can increase longevity.aging | epigenetics | histone methyltransferase | Polycomb silencing

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Section: Discussionmentioning

confidence: 99%

Polycomb Repressive Complex 2 and Trithorax modulate Drosophila longevity and stress resistance

Siebold¹,

Banerjee²,

Tie³

et al. 2009

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

177

149

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“…The freeliving soil nematode Caenorhabditis elegans has been a leading system for studying genetic and pharmacologic influences on lifespan. Four categories of compounds have been reported to extend C. elegans lifespan: a variety of antioxidant compounds (Harrington & Harley, 1988;Adachi & Ishii, 2000;Melov et al ., 2000;Ishii et al ., 2004;Keaney et al ., 2004); complex mixtures derived from plants (Wu et al ., 2002;Wilson et al ., 2006); resveratrol, a potential modulator of Sir2 activity (Wood et al ., 2004;Bass et al ., 2007); and medications such as heterocyclic anticonvulsant medications that are likely to act by affecting neural activity (Evason et al ., 2005;Petrascheck et al ., 2007;McColl et al ., 2008). Drosophila melanogaster has also been an important system for the discovery of drugs that extend lifespan, and several histone deacetylase (HDAC) inhibitors delay Drosophila aging (Kang et al ., 2002;Zhao et al ., 2005).…”

Section: Introductionmentioning

confidence: 99%

Valproic acid extends Caenorhabditis elegans lifespan

et al. 2008

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SummaryAging is an important biological phenomenon and a major contributor to human disease and disability, but no drugs have been demonstrated to delay human aging. Caenorhabditis elegans is a valuable model for studies of animal aging, and the analysis of drugs that extend the lifespan of this animal can elucidate mechanisms of aging and might lead to treatments for age-related disease. By testing drugs that are Food and Drug Administration approved for human use, we discovered that the mood stabilizer and anticonvulsant valproic acid (VA) extended C. elegans lifespan. VA also delayed age-related declines of body movement, indicating that VA delays aging. Valproic acid is a small carboxylic acid that is the most frequently prescribed anticonvulsant drug in humans. A structure-activity analysis demonstrated that the related compound valpromide also extends lifespan. Valproic acid treatment may modulate the insulin/IGF-1 growth factor signaling pathway, because VA promoted dauer larvae formation and DAF-16 nuclear localization. To investigate the mechanism of action of VA in delaying aging, we analyzed the effects of combining VA with other compounds that extend the lifespan of C. elegans . Combined treatment of animals with VA and the heterocyclic anticonvulsant trimethadione caused a lifespan extension that was significantly greater than treatment with either of these drugs alone. These data suggest that the mechanism of action of VA is distinct from that of trimethadione, and demonstrate that lifespan-extending drugs can be combined to produce additive effects.

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“…However, lithium seems to have many other functions including enhanced phosphorylation of Akt by inhibiting protein phosphatase 2A (PP2A) [20,21]. A recent study showing the effects of lithium on histone methylation and chromatin structure in C. elegans [22] suggests a wide range of effects of lithium. Lithium also protects ethanol-induced apoptosis in P7 mice and cultured neurons [23].…”

Section: Introductionmentioning

confidence: 99%

Lithium blocks ethanol-induced modulation of protein kinases in the developing brain

Chakraborty

Shimada

Mao

et al. 2008

Biochemical and Biophysical Research Communications

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Lithium has been shown to be neuroprotective against various insults including ethanol exposure. We previously reported that ethanol-induced apoptotic neurodegeneration in the postnatal day 7 (P7) mice is associated with decreases in phosphorylation levels of Akt, glycogen synthase kinase-3β (GSK-3β), and AMP-activated protein kinase (AMPK), and alteration in lipid profiles in the brain. Here, P7 mice were injected with ethanol and lithium, and the effects of lithium on ethanol-induced alterations in phosphorylation levels of protein kinases and lipid profiles in the brain were examined. Immunoblot and immunohistochemical analyses showed that lithium significantly blocked ethanolinduced caspase-3 activation and reduction in phosphorylation levels of Akt, GSK-3β and AMPK. Further, lithium inhibited accumulation of cholesterol ester (ChE) and Nacylphosphatidylethanolamine (NAPE) triggered by ethanol in the brain. These results suggest that Akt, GSK-3β, and AMPK are involved in ethanol-induced neurodegeneration and the neuroprotective effects of lithium by modulating both apoptotic and survival pathways.

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Pharmacogenetic Analysis of Lithium-induced Delayed Aging in Caenorhabditis elegans

Cited by 182 publications

References 59 publications

Polycomb Repressive Complex 2 and Trithorax modulate Drosophila longevity and stress resistance

Polycomb Repressive Complex 2 and Trithorax modulate Drosophila longevity and stress resistance

Valproic acid extends Caenorhabditis elegans lifespan

Lithium blocks ethanol-induced modulation of protein kinases in the developing brain

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