Polyunsaturated fatty acids and p38-MAPK link metabolic reprogramming to cytoprotective gene expression during dietary restriction

Abstract

The metabolic state of an organism instructs gene expression modalities, leading to changes in complex life history traits, such as longevity. Dietary restriction (DR), which positively affects health and life span across species, leads to metabolic reprogramming that enhances utilisation of fatty acids for energy generation. One direct consequence of this metabolic shift is the upregulation of cytoprotective (CyTP) genes categorized in the Gene Ontology (GO) term of “Xenobiotic Detoxification Program” (XDP). How an organism senses metabolic changes during nutritional stress to alter gene expression programs is less known. Here, using a genetic model of DR, we show that the levels of polyunsaturated fatty acids (PUFAs), especially linoleic acid (LA) and eicosapentaenoic acid (EPA), are increased following DR and these PUFAs are able to activate the CyTP genes. This activation of CyTP genes is mediated by the conserved p38 mitogen-activated protein kinase (p38-MAPK) pathway. Consequently, genes of the PUFA biosynthesis and p38-MAPK pathway are required for multiple paradigms of DR-mediated longevity, suggesting conservation of mechanism. Thus, our study shows that PUFAs and p38-MAPK pathway function downstream of DR to help communicate the metabolic state of an organism to regulate expression of CyTP genes, ensuring extended life span.

Mitochondria-originated redox signalling regulates KLF-1 to promote longevity in Caenorhabditis elegans

“…It is therefore likely that increased levels of oxidation as observed in isp-1;ctb-1 mutant worms lead to the NSY-1/ASK1 activation, which subsequently drives p38 MAPK signalling cascade. In further agreement with our findings, SEK-1 induces a cytoprotective machinery in dietary restriction-mediated longevity, by increasing the nematode's xenobiotic detoxification program [ 84 ], while both SEK-1 and SEK-3 were identified in a screen for factors regulating extended the lifespan of C. elegans mitochondrial mutants [ 85 ]. In the later study, PMK-3 was shown to be a key regulator of longevity in isp-1(qm150) and nuo-6(qm200) mutant worms, and upon nuo-2 and cco-1 RNAi, although no further mechanistic insight was provided [ 85 ].…”

PI(18:1/18:1) is a SCD1-derived lipokine that limits stress signaling

“…Together, the altered gene expression profile of starved planarians implies that silencing of cct3A is associated with an enhanced sensitivity towards p38 MAPK signaling, autophagy and potentially apoptosis, as expected from the depletion of PI(18:1/18:1). It is tempting to speculate that consequent p38 MAPK activation links dietary restriction to cytoprotective gene expression 79 .…”

Dietary regulation in health and disease

“… 81 In terms of types of fatty acids, the elevated abundance of the mono- and poly-unsaturated fatty acids in response to CR is a key component of cell membrane structures and has been revealed to upregulate pro-survival mechanisms such as cellular detoxification. 82 Taken together, these results indicate that reinforced rates of both fatty acid synthesis and breakdown are vital controllers of CR-mediated longevity. In addition, special attention should be given when assessing the influence of CR on fatty acid metabolism.…”