Research Article: The ω‐3 fatty acid α‐linolenic acid extends Caenorhabditis elegans lifespan via NHR‐49/PPARα and oxidation to oxylipins

Date Published: August 03, 2017

Publisher: John Wiley and Sons Inc.

Author(s): Wenbo Qi, Gloria E. Gutierrez, Xiaoli Gao, Hong Dixon, Joe A. McDonough, Ann M. Marini, Alfred L. Fisher.


The dietary intake of ω‐3 polyunsaturated fatty acids has been linked to a reduction in the incidence of aging‐associated disease including cardiovascular disease and stroke. Additionally, long‐lived Caenorhabditis elegans glp‐1 germ line‐less mutant animals show a number of changes in lipid metabolism including the increased production of the ω‐3 fatty acid, α‐linolenic acid (ALA). Here, we show that the treatment of C. elegans with ALA produces a dose‐dependent increase in lifespan. The increased longevity of the glp‐1 mutant animals is known to be dependent on both the NHR‐49/PPARα and SKN‐1/Nrf2 transcription factors, although the mechanisms involved are incompletely understood. We find that ALA treatment increased the lifespan of wild‐type worms and that these effects required both of these transcription factors. Specifically, NHR‐49 was activated by ALA to promote the expression of genes involved in the β‐oxidation of lipids, whereas SKN‐1 is not directly activated by ALA, but instead, the exposure of ALA to air results in the oxidation of ALA to a group of compounds termed oxylipins. At least one of the oxylipins activates SKN‐1 and enhances the increased longevity resulting from ALA treatment. The results show that ω‐3 fatty acids inhibit aging and that these effects could reflect the combined effects of the ω‐3 fatty acid and the oxylipin metabolites. The benefits of ω‐3 fatty acid consumption on human health may similarly involve the production of oxylipins, and differences in oxylipin conversion could account for at least part of the variability found between observational vs. interventional clinical trials.

Partial Text

The ω‐3 fatty acids are characterized by desaturation at the third carbon from the methyl, or ω‐carbon, end of the molecule, and the most biologically relevant ω‐3 fatty acids include α‐linolenic acid (ALA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) (reviewed in von Schacky, 1987). In people, the ω‐3 fatty acids are essential, and common dietary sources include plants for ALA and fish or fish oils for EPA and DHA. Interest in these polyunsaturated fatty acids increased greatly after epidemiologic studies linked greater fish intake to a greatly reduced rate of hypertension and atherosclerotic cardiovascular disease (von Schacky, 1987). Subsequent basic and translational science studies suggested that these benefits could be due to changes in eicosanoid production favoring reductions in vascular reactivity and blood clotting along with favorable changes in serum cholesterol levels. However, these benefits have been difficult to reproduce in clinical trials using dietary ω‐3 fatty acid supplements, and more recent analyses of the dietary studies have suggested that the benefits of dietary ω‐3 fatty acid intake may be more modest than previously reported (Chowdhury et al., 2014). Nevertheless, it is possible that the augmentation of ω‐3 fatty acid intake could produce multiple health benefits, particularly if the optimal dose and dosing regimen can be rigorously established and if those individuals that are most likely to benefit could be more readily be identified (Weylandt et al., 2015).

This work was supported by funds from the South Texas VA Healthcare System, National Institute of Aging grants AG013319 and AG044768, and National Institute of Environmental Health Sciences grant ES017761 to ALF.

WQ, GEG, HD, JAM, AMM, and ALF conceived and designed the experiments. WQ, XG, and ALF performed the experiments. GEG, HD, JAM contributed reagents/materials/analysis tools. WQ, XG, JAM, AMM, and ALF analyzed the data. WQ and ALF wrote the paper.

None declared.




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