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: 5.94). 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.

Download full-text

Full-text

Available from: Kerry Kornfeld, Feb 18, 2015
1 Follower
 · 
162 Views
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    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.
    Aging cell 02/2011; 10(3):506-19. DOI:10.1111/j.1474-9726.2011.00688.x · 5.94 Impact Factor
  • Source
    • "In addition, metabolic functions such as mitochondrial electron transport (Anson and Hansford, 2004) and protein translation (Hansen et al., 2007; Pan et al., 2007) are also likely drug targets based on the lifespan enhancing effect of lowering the rates of these processes in some circumstances. A range of chemical interventions have been shown to enhance C. elegans lifespan, such as superoxide dismutase and catalase mimetics (Melov et al., 2000), resveratrol (Wood et al., 2004), and a range of compounds that are commonly used in the treatment of neurological disease including the anticonvulsants drugs ethosuximide (Evason et al., 2005) and valproic acid (Evason et al., 2008), the mood-stabilizing lithium (McColl et al., 2008) and a series of antidepressants (mianserin, mirtazapine, methiothepin and cyproheptadine) (Petrascheck et al., 2007). In addition, some complex plant extracts extend lifespan including Ginkgo biloba extract EGb 761 (Strayer et al., 2003; Wu et al., 2002) and a proanthocyanid-rich fraction of blueberry extract (Wilson et al., 2006). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The observation that long-lived and relatively healthy animals can be obtained by simple genetic manipulation prompts the search for chemical compounds that have similar effects. Since aging is the most important risk factor for many socially and economically important diseases, the discovery of a wide range of chemical modulators of aging in model organisms could prompt new strategies for attacking age-related disease such as diabetes, cancer and neurodegenerative disorders [Collins, J.J., Evason, K., Kornfeld, K., 2006. Pharmacology of delayed aging and extended lifespan of Caenorhabditis elegans. Exp. Gerontol.; Floyd, R.A., 2006. Nitrones as therapeutics in age-related diseases. Aging Cell 5, 51-57; Gill, M.S., 2006. Endocrine targets for pharmacological intervention in aging in Caenorhabditis elegans. Aging Cell 5, 23-30; Hefti, F.F., Bales, R., 2006. Regulatory issues in aging pharmacology. Aging Cell 5, 3-8]. Resistance to multiple types of stress is a common trait in long-lived genetic variants of a number of species; therefore, we have tested compounds that act as stress response mimetics. We have focused on compounds with antioxidant properties and identified those that confer thermal stress resistance in the nematode Caenorhabditis elegans. Some of these compounds (lipoic acid, propyl gallate, trolox and taxifolin) also extend the normal lifespan of this simple invertebrate, consistent with the general model that enhanced stress resistance slows aging.
    Experimental gerontology 09/2008; 43(10):882-91. DOI:10.1016/j.exger.2008.08.049 · 3.53 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: It was recently suggested that specific antidepressants of the serotonin-antagonist type, namely mianserin and methiothepin, may exert anti-aging properties and specifically extend lifespan of the nematode C.elegans by causing a state of perceived calorie restriction (Petrascheck M, Ye X, Buck LB: An antidepressant that extends lifespan in adult Caenorhabditis elegans; Nature, Nov 22, 2007;450(7169):553-6, PMID 18033297). Using the same model organism, we instead observe a reduction of life expectancy when employing the commonly used, standardized agar-based solid-phase assay while applying the same or lower concentrations of the same antidepressants. Consistent with a well-known side-effect of these compounds in humans, antidepressants not only reduced lifespan but also increased body fat accumulation in C. elegans reflecting the mammalian phenotype. Taken together and in conflict with previously published findings, we find that antidepressants of the serotonin-antagonist type not only promote obesity, but also decrease nematode lifespan.
    PLoS ONE 02/2008; 3(12):e4062. DOI:10.1371/journal.pone.0004062 · 3.53 Impact Factor
Show more