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. 2008 Jun;7(3):305-17.
doi: 10.1111/j.1474-9726.2008.00375.x. Epub 2008 Jan 29.

Valproic acid extends Caenorhabditis elegans lifespan

Kimberley Evason  1 , James J Collins, Cheng Huang, Stacie Hughes, Kerry Kornfeld
Affiliations

Valproic acid extends Caenorhabditis elegans lifespan

Kimberley Evason et al. Aging Cell. 2008 Jun.

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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Figures

Figure 1
Figure 1
Dose–response analysis of valproic acid (VA). (A) Wild‐type (WT) hermaphrodites were cultured with no drug or VA from conception until death, and monitored for survival. Doses are in mm. The mean lifespans for 0 mm, 3 mm, 6 mm, 12 mm, 18 mm, and 24 mm VA were days [SD (n)]: 16.4 ± 4.3 (66), 20.9 ± 6.7 (56), 23.2 ± 7.3 (52), 14.7 ± 6.4 (37), 7.4 ± 3.9 (48), and 9.8 ± 2.5 (4), respectively. Treatment with 3 mm and 6 mm VA extended the mean lifespan significantly (P < 0.0001), whereas treatment with 18 mm and 24 mm VA shortened the mean lifespan significantly (P < 0.0001 and P < 0.05, respectively). Most animals cultured in the presence of 24 mm VA died or arrested development before reaching the fourth larval stage, and we analyzed the adult lifespan of the rare animals that survived to adulthood. (B) Valproic acid extends the lifespan of animals treated with kanamycin. Wild‐type hermaphrodites were cultured with no drug (WT, n = 80), with 3 mm VA alone ( + VA 3, n = 51), with kanamycin alone ( + KAN, n = 56), or with both kanamycin and VA ( + KAN + VA 3, n = 70) from conception until death. Treatment with 3 mm VA alone or with kanamycin alone significantly extended lifespan compared to animals with no drug treatment (P < 0.0002 and P < 0.0001, respectively). Treatment with kanamycin and 3 mm VA significantly extended lifespan compared to treatment with kanamycin alone (P < 0.0007). These data represent the results of a single trial; combined data for two trials are presented in Table 1.
Figure 2
Figure 2
Valproic acid (VA) extends worm lifespan and delays the age‐related decline in body movement. (A) Structures of VA, valpromide, and trimethadione. (B) Wild‐type (WT) hermaphrodites were cultured without drug (WT, n = 113) or with 6 mm VA from conception until death ( + VA 6, n = 102), from fourth larval (L4) until death ( + VA 0/6, n = 100), or from conception until L4 ( + VA 6/0, n = 107). (C) Wild‐type hermaphrodites were cultured with no drug (WT, n = 180) or with 6 mm VA ( + VA 6, n = 80). Animals were classified as fast moving if they displayed continuous and well‐coordinated sinusoidal movements, and not fast moving if they displayed discontinuous or sluggish movements (Huang et al., 2004). Survival and fast body movement were monitored beginning at the L4 stage (day 0).
Figure 3
Figure 3
Valproic acid (VA) does not decrease reproduction of mated hermaphrodites. We mated wild‐type (WT) hermaphrodites to WT males and counted progeny of hermaphrodites cultured without drug (WT) or with 6 mm VA ( + VA 6). Hermaphrodites cultured with and without drug produced 413 ± 125 (n = 28) and 434 ± 102 (n = 65) progeny, respectively (not significantly different). Hermaphrodites cultured with and without drug produced 2.3 ± 6.9 (n = 68) and 2.7 ± 9.4 (n = 86) progeny after day 9, respectively (not significantly different).
Figure 4
Figure 4
Valpromide (VPD) extends Caenorhabditis elegans lifespan. Wild‐type (WT) hermaphrodites were cultured with ethanol alone (WT, n = 168) or with 6 mm VPD dissolved in ethanol ( + VPD 6, n = 152) from conception until death.
Figure 5
Figure 5
Lifespan‐extending effects of ethosuximide and trimethadione (TRI) can be additive at suboptimal dosages, but are not additive at optimal individual dosages. (A) Wild‐type worms were cultured with only 14 mm TRI ( + TRI 14, mean lifespan 21.1 ± 5.3, n = 65), only 28 mm TRI ( + TRI 28, mean lifespan 24.2 ± 7.8, n = 70), only 14 mm ethosuximide ( + ETH 14, mean lifespan 19.6 ± 5.1, n = 67), or with a combination of 14 mm ethosuximide and 14 mm TRI ( + ETH 14 + TRI 14, mean lifespan 23.3 ± 6.4, n = 59). Treatment with a combination of ethosuximide and TRI caused a greater lifespan extension than treatment with 14 mm ethosuximide alone (P = 0.0005) or 14 mm TRI alone (P < 0.05), but treatment with the combination did not cause a greater lifespan extension than treatment with the optimal dose of 28 mm TRI alone (P = 0.51). (B) Worms cultured with a combination of 28 mm ethosuximide and 28 mm TRI ( + ETH 28 + TRI 28, mean lifespan 11.4 ± 2.9, n = 49) displayed a significantly shorter lifespan than worms cultured with only 28 mm ethosuximide ( + ETH 28, mean lifespan 20.0 ± 5.0, n = 57) (P < 0.0001) or only 28 mm TRI ( + TRI 28, mean lifespan 21.9 ± 6.6, n = 58) (P < 0.0001).
Figure 6
Figure 6
Lifespan‐extending effects of valproic acid (VA) and trimethadione (TRI) are additive. Worms were cultured with only VA ( + VA 6), only TRI ( + TRI 28), or a combination of VA and TRI ( + VA 6 + TRI 28).
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