Oxaloacetate supplementation increases lifespan in Caenorhabditis elegans through an AMPK/FOXO-dependent pathway

Abstract

Reduced dietary intake increases lifespan in a wide variety of organisms. It also retards disease progression. We tested whether dietary supplementation of citric acid cycle metabolites could mimic this lifespan effect. We report that oxaloacetate supplementation increased lifespan in Caenorhabditis elegans. The increase was dependent on the transcription factor, FOXO/DAF-16, and the energy sensor, AMP-activated protein kinase, indicating involvement of a pathway that is also required for lifespan extension through dietary restriction. These results demonstrate that supplementation of the citric acid cycle metabolite, oxaloacetate, influences a longevity pathway, and suggest a tractable means of introducing the health-related benefits of dietary restriction.

Fig. 1

Survival of Caenorhabditis elegans on agar cultures with and without oxaloacetate supplementation. (A–D) Survival curves of control (N2) and mutant [sir-2.1 (ok434), daf-16 (mgDf50), aak-2 (ok524)] worms. The curves represent the means of the survival curves from the individual experiments. (A) Increased lifespan due to 8 mm oxaloacetate in control worms. (B) Increased lifespan due to 8 mm oxaloacetate in sir-2.1 mutant worms (data from N2 worms tested in the same experiments are also shown). (C) Increased lifespan due to 8 mm oxaloacetate is blocked in FOXO mutant daf-16 worms (data from N2 worms tested in the same experiments are also shown). (D) Increased lifespan due to 8 mm oxaloacetate is blocked in AMP-activated protein kinase mutant aak-2 worms (data from N2 worms tested in the same experiments are also shown). (E) Bar graph showing the change in median lifespan in response to 8 mm oxaloacetate (relative to the same strain grown without oxaloacetate). The change shown by each bar is the mean of the medians measured from all repeats of each experiment ± SEM (shown as error bars), where n = number of repeats for a given experiment. This graph illustrates some of the data shown in Table 1, where data on maximal lifespan and the results of statistical analyses are also given. **P < 0.001, *P < 0.01, by log rank test.