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

Manish Chamoli, Anita Goyala, Syed Shamsh Tabrez, Atif Ahmed Siddiqui, Anupama Singh, Adam Antebi, Gordon J. Lithgow, Jennifer L. Watts and Arnab Mukhopadhyay ()
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Manish Chamoli: National Institute of Immunology
Anita Goyala: National Institute of Immunology
Syed Shamsh Tabrez: National Institute of Immunology
Atif Ahmed Siddiqui: National Institute of Immunology
Anupama Singh: National Institute of Immunology
Adam Antebi: Max Planck Institute for Biology of Ageing
Gordon J. Lithgow: Buck Institute for Research on Aging
Jennifer L. Watts: Washington State University
Arnab Mukhopadhyay: National Institute of Immunology

Nature Communications, 2020, vol. 11, issue 1, 1-13

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-18690-4

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