Anticonvulsant Medications Extend Worm Life-Span

Abstract

Genetic studies have elucidated mechanisms that regulate aging, but there has been little progress in identifying drugs that delay aging. Here, we report that ethosuximide, trimethadione, and 3,3-diethyl-2-pyrrolidinone increase mean and maximum life-span of Caenorhabditis elegans and delay age-related declines of physiological processes, indicating that these compounds retard the aging process. These compounds, two of which are approved for human use, are anticonvulsants that modulate neural activity. These compounds also regulated neuromuscular activity in nematodes. These findings suggest that the life-span-extending activity of these compounds is related to the anticonvulsant activity and implicate neural activity in the regulation of aging.

A Predictable Worm: Application of Caenorhabditis elegans for Mechanistic Investigation of Movement Disorders

“…In this regard, we examined the data gathered from a few researchers who have calculated external versus internal chemical concentrations in worms following chemical exposures. Their data revealed vastly differing results for the fold difference of chemical concentration between the external environment and uptake in animals, whereby the external concentration of different molecules ranged from 8× to 66× more concentrated (Table 2) [50][51][52]. A more in-depth analysis was performed following MeHgCl exposure in C. elegans, where it was demonstrated that the internal accumulation of this chemical was dose-, developmental stage-, and timedependent [47].…”

“…Additional problems related to translational dose response analyses include differences in cell permeability, the experimental time course (important for diseases of aging), and sensitivity to solvents. A survey of a few worm-to-cell culture translational studies reveals wide ranging fold Ethosuximide 2 mg/ml 30 μg/ml 66X [52] differences between these experimental systems, wherein 0.5× to 160× chemical was used in the C. elegans studies (Table 3). It should be noted, however, that in most of these studies, only a single concentration of chemical was examined in either the worm or cell culture experiments [26,45,54].…”

Nutrition, Histone Epigenetic Marks, and Disease

“…The efficacy of SIRT1 in enhancing the life span in mammals appears to depend on salvaging NAD in the nicotinamide phosphoribosyl transferase pathway (Ho et al 2009a). The phenolic compound resveratrol activates sirtuins and increases the life span in Saccharomyces cerevisiae, Caenorhabditis elegans, Drosophila melanogaster, and the fish Nothobranchius furzeri, but its efficacy in mammals is uncertain (Evason et al 2005;Howitz et al 2003;Kang et al 2002;Valenzano et al 2006). Resveratrol is present in grapes and red wine at relatively high concentration (Celotti et al 1996).…”

Rules for the use of model organisms in antiaging pharmacology

“…Many of these pathways are already considered candidates for pharmaceutical modulation (Melov et al ., 2000(Melov et al ., , 2001Lonn et al ., 2002;Evason et al ., 2005). However, the treatment of aging is highly likely to involve secondary and nonadditive effects, given the multifold pathways that affect aging (Fleming et al ., 1993;Pletcher et al ., 2002;Rose & Long, 2002).…”

“…Unfortunately, the pharmacology of candidate antiaging compounds, even in Caenorhabditis and Drosophila , is not yet well defined. There are a few studies in the literature where these organisms were fed such compounds and the pharmacological properties of these compounds were assessed by the phenotypic response elicited (Kang et al ., 2002;Wood et al ., 2004;Evason et al ., 2005). However, doseresponse relationships have not been established for antiaging compounds in these animal models.…”