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

Abstract

SummaryThe 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.

Nuclear hormone receptor NHR-49 shapes immuno-metabolic response ofCaenorhabditis elegans to Enterococcus faecalisinfection

“…It has been reported that NHR-49 activity positively regulates expression of detoxification genes such as glutathione-S-transferase (gst-4). While we were writing the manuscript another study indicated that flavin mono-oxygenase (fmo-2) upregulation during oxidative stress was dependent on NHR-49 (Qi et al, 2017;Goh et al, 2018;Hu et al, 2018). Our study shows that NHR-49 regulates detoxification enzymes in the context of infection as well.…”

NHR‐49/HNF4 integrates regulation of fatty acid metabolism with a protective transcriptional response to oxidative stress and fasting

“…Alternatively, lipid‐derived ligand(s), including oxidized molecules, may increase NHR‐49 activity, with exposure to organic peroxide or fasting both increasing the levels of such a lipid. A recent paper showed that linolenic acid, and an oxidized derivative thereof, regulate lifespan and gene expression in an nhr‐49 ‐dependent fashion (Qi et al., 2017). Although we note that fmo‐2 was not among the responsive genes (Qi et al., 2017), this nevertheless raises the possibility that similar molecules may be involved in the nhr‐49 ‐dependent stress adaptation mechanisms identified here.…”

Targeting Mitochondria to Counteract Age-Related Cellular Dysfunction

“…However, this enhanced mitochondrial activity might harm the cell long-term, for instance, by increased ROS production, and might even further promote age-related cellular dysfunction ( Figure 1 ). Interventions, like CR [ 117 ], exercise [ 128 ], and drugs, such as polyphenols [ 139 ], antioxidants [ 160 ], metformin [ 171 ], ω-3 fatty acids [ 168 ], aspirin [ 6 ], and senolytics [ 12 ], specifically target mitochondria and thereby successfully counteract these age-related damages. Nevertheless, it seems critical when intervention is brought to bear and at which time.…”

“…Omega-3 fatty acids : Treatment with ω-3 fatty acid α-linolenic acid (ALA) increased lifespan of C. elegans via the activation of the transcription factors NHR-49, the worm orthologue of human PPARα, and SKN1, the worm orthologue of human NRF2. NHR-49-activated genes are involved in the β-oxidation of free fatty acids, promoting the generation of energy via mitochondrial respiration and NRF2-induced mitochondrial biogenesis [ 168 ]. In the brains of aged mice, exhibiting reduced ATP levels and decreased activity of complexes I, II and IV of the mitochondrial respiration system, ω-3 polyunsaturated fatty acids from fish oil induced neuroprotective actions and improved mitochondrial ATP production and function [ 169 ].…”