title: The effect of dichloroacetate on health- and lifespan in C. elegans.
abstract: Aging is associated with increased vulnerability to chronic, degenerative diseases and death. Strategies for promoting healthspan without necessarily affecting lifespan or aging rate have gained much interest. The mitochondrial free radical theory of aging suggests that mitochondria and, in particular, age-dependent mitochondrial decline play a central role in aging, making compounds that affect mitochondrial function a possible strategy for the modulation of healthspan and possibly the aging rate. Here we tested such a "metabolic tuning" approach in nematodes using the mitochondrial modulator dichloroacetate (DCA). We explored DCA as a proof-of-principle compound to alter mitochondrial parameters in wild-type animals and tested whether this approach is suitable for reducing reactive oxygen species (ROS) production and for improving organismal health- and lifespan. In parallel, we addressed the potential problem of operator bias by running both unblinded and blinded lifespan studies. We found that DCA treatment (1) increased ATP levels without elevating oxidative protein damage and (2) reduced ROS production in adult C. elegans. DCA treatment also significantly prolonged nematode health- and lifespan, but did not strongly impact mortality doubling time. Operator blinding resulted in considerably smaller lifespan-extending effects of DCA. Our data illustrate the promise of a "metabolic tuning" intervention strategy, emphasize the importance of mitochondria in nematode aging and highlight operator bias as a potential confounder in lifespan studies.
authors.affiliation: Department of Biochemistry, Centre for Life Sciences, National University of Singapore, Singapore. bchsebas@nus.edu.sg
authors.forename: S
authors.initials: S
authors.lastname: Schaffer
authors.forename: J
authors.initials: J
authors.lastname: Gruber
authors.forename: L F
authors.initials: LF
authors.lastname: Ng
authors.forename: S
authors.initials: S
authors.lastname: Fong
authors.forename: Y T
authors.initials: YT
authors.lastname: Wong
authors.forename: S Y
authors.initials: SY
authors.lastname: Tang
authors.forename: B
authors.initials: B
authors.lastname: Halliwell
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000375:Aging / Q000502:physiology*; D000818:Animals; D017173:Caenorhabditis elegans / Q000378:metabolism / Q000502:physiology*; D004272:DNA, Mitochondrial / Q000378:metabolism; D003999:Dichloroacetic Acid / Q000494:pharmacology*; D050356:Lipid Metabolism; D008124:Locomotion; D008136:Longevity / Q000187:drug effects*; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D004272:DNA, Mitochondrial; D017382:Reactive Oxygen Species; D000255:Adenosine Triphosphate; D003999:Dichloroacetic Acid