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.

Long-term dietary exposure to low concentration of dichloroacetic acid promoted longevity and attenuated cellular and functional declines in aged Drosophila melanogaster

“…When we examined the level of ROS generation in DCA-exposed flies at different days of their life, we observed that prolonged exposure of DCA to Drosophila reduced the level of ROS generation with an advancement of their age. This is in agreement with a previous study wherein reduced ROS level was evident in DCA-exposed C. elegans (Schaffer et al 2011). Concurrent with reduced ROS level, a significantly higher GSH content was observed in DCA-exposed aged flies as evident by a negative correlation drawn between ROS and GSH content (Y ROS = −0.848 GSH +1.881, r=−0.966, P=0.0017) with respect to age.…”

“…In addition, modulated expression of hsps (hsp70, hsp27, and hsp22) has been reported to alter life span in flies (Kim et al 2010;Liao et al 2008;Tatar et al 1997) and higher level of HSPs is reported in longerlived mammals and birds (Salway et al 2011). In the same context, improved health-and life span were observed in DCA-exposed Caenorhabditis elegans (Schaffer et al 2011). However, studies regarding expression of hsps in DCA-exposed organisms are inadequate.…”

Clonal expansion of mitochondrial DNA deletions is a private mechanism of aging in long‐lived animals

“…Mitochondrial copy number was quantified according to (Schaffer et al, 2011). Briefly, individual worms were picked into PCR tubes, lysed, and mtDNA copy number of individual nematodes was determined by quantitative real‐time PCR (qRT‐PCR) as previously described (quantified by serial dilution) (Gruber et al, 2011; Schaffer et al, 2011).…”

Biogerontology: from here to where? The Lord Cohen Medal Lecture-2011

“…Furthermore, it has been realized that the nutritional components, specially the sugars and metal-based micronutrients, can induce, enhance and amplify the molecular damage either independently or in combination with other inducers of damage (Schaffer et al 2011). Additionally, interest in the role of epigenetics as the molecular basis for age-related changes has resurged (Kahn and Fraga 2009).…”