Article

Valproic acid extends Caenorhabditis elegans lifespan

Department of Developmental Biology, Washington University School of Medicine, 660 South Euclid Ave., Campus Box 8103, St. Louis, MO 63110, USA.
Aging cell (Impact Factor: 6.34). 07/2008; 7(3):305-17. DOI: 10.1111/j.1474-9726.2008.00375.x
Source: PubMed

ABSTRACT

Aging 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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Available from: Kerry Kornfeld, Feb 18, 2015
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    • "Several genetic and pharmacological strategies have been shown to prolong the lifespan of various organisms, including C. elegans (Kenyon et al., 1993; Kaeberlein et al., 1999; Curran and Ruvkun, 2007; Evason et al., 2008; Onken and Driscoll, 2010; Alavez et al., 2011; Chin et al., 2014; Ye et al., 2014; Tatum et al., 2015). Mutations in age-1 or daf-2, for example, slow degenerative processes occurring throughout life, thereby constantly lowering mortality rates (Johnson, 1990; Kenyon et al., 1993; Taylor et al., 2014). "
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    ABSTRACT: Longevity mechanisms increase lifespan by counteracting the effects of aging. However, whether longevity mechanisms counteract the effects of aging continually throughout life, or whether they act during specific periods of life, preventing changes that precede mortality is unclear. Here, we uncover transcriptional drift , a phenomenon that describes how aging causes genes within functional groups to change expression in opposing directions. These changes cause a transcriptome-wide loss in mRNA stoichiometry and loss of co-expression patterns in aging animals, as compared to young adults. Using Caenorhabditis elegans as a model, we show that extending lifespan by inhibiting serotonergic signals by the antidepressant mianserin attenuates transcriptional drift, allowing the preservation of a younger transcriptome into an older age. Our data are consistent with a model in which inhibition of serotonergic signals slows age-dependent physiological decline and the associated rise in mortality levels exclusively in young adults, thereby postponing the onset of major mortality.
    Full-text · Article · Dec 2015 · eLife Sciences
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    • "For the tiny nature of the worms, the drug delivery methods were indirect and often varied from one study to another. The drugs were either applied to the LB medium growing the bacteria, the food of worms (LB medium method), or directly spotted onto the surface of NGM plates (spot dead method), or to the NGM with live (NGM live method) [21] or dead bacteria (NGM dead method) spread on the surface of the plates [22]–[24]. Another method was to keep the worms in liquid medium (liquid growing method) [15], [25], [26]. These different delivery methods might result in different drug absorption efficiency, causing confusing results between different studies [25]–[28]. "
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    ABSTRACT: Background Caenorhbditis elegans has being vigorously used as a model organism in many research fields and often accompanied by administrating with various drugs. The methods of delivering drugs to worms are varied from one study to another, which make difficult in comparing results between studies. Methodology/Principal Findings We evaluated the drug absorption efficiency in C. elegans using five frequently used methods with resveratrol with low aqueous solubility and water-soluble 5-Fluoro-2′-deoxyuridine (FUDR) as positive compounds. The drugs were either applied to the LB medium with bacteria OP50, before spreading onto Nematode Growth Medium (NGM) plates (LB medium method), or to the NGM with live (NGM live method) or dead bacteria (NGM dead method), or spotting the drug solution to the surface of plates directly (spot dead method), or growing the worms in liquid medium (liquid growing method). The concentration of resveratrol and FUDR increased gradually within C. elegans and reached the highest during 12 hours to one day and then decreased slowly. At the same time point, the higher the drug concentration, the higher the metabolism rate. The drug concentrations in worms fed with dead bacteria were higher than with live bacteria at the same time point. Consistently, the drug concentration in medium with live bacteria decreased much faster than in medium with dead bacteria, reach to about half of the original concentration within 12 hours. Conclusion Resveratrol with low aqueous solubility and water-soluble FUDR have the same absorption and metabolism pattern. The drug metabolism rate in worms was both dosage and time dependent. NGM dead method and liquid growing method achieved the best absorption efficiency in worms. The drug concentration within worms was comparable with that in mice, providing a bridge for dose translation from worms to mammals.
    Full-text · Article · Feb 2013 · PLoS ONE
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    • "mianserin) as well as anticonvulsant medicines (e.g. ethosuximide) that affect neuronal activity (Evason et al. 2005; Petrascheck et al. 2007; Evason et al. 2008). Here, we report that the anti-inflammatory drug celecoxib and its derivatives significantly extend C. elegans lifespan and delay the onset of age-associated proteotoxicity and tumor growth. "
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    ABSTRACT: One goal of aging research is to develop interventions that combat age-related illnesses and slow aging. Although numerous mutations have been shown to achieve this in various model organisms, only a handful of chemicals have been identified to slow aging. Here, we report that celecoxib, a nonsteroidal anti-inflammatory drug widely used to treat pain and inflammation, extends Caenorhabditis elegans lifespan and delays the age-associated physiological changes, such as motor activity decline. Celecoxib also delays the progression of age-related proteotoxicity as well as tumor growth in C. elegans. Celecoxib was originally developed as a potent cyclooxygenase-2 (COX-2) inhibitor. However, the result from a structural-activity analysis demonstrated that the antiaging effect of celecoxib might be independent of its COX-2 inhibitory activity, as analogs of celecoxib that lack COX-2 inhibitory activity produce a similar effect on lifespan. Furthermore, we found that celecoxib acts directly on 3'-phosphoinositide-dependent kinase-1, a component of the insulin/IGF-1 signaling cascade to increase lifespan.
    Full-text · Article · Feb 2011 · Aging cell
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