key: cord-103343-k4v5ksvq
authors: Naim, Nikki; Amrit, Francis RG; Ratnappan, Ramesh; DelBuono, Nicholas; Loose, Julia A; Ghazi, Arjumand
title: NHR-49 Acts in Distinct Tissues to Promote Longevity versus Innate Immunity
date: 2020-09-11
journal: bioRxiv
DOI: 10.1101/2020.09.11.290452
sha: 
doc_id: 103343
cord_uid: k4v5ksvq

Aging and immunity are inextricably linked and many genes that extend lifespan also enhance immunoresistance. However, it remains unclear if longevity-enhancing factors modulate immunity and longevity by distinct or shared mechanisms. Here, we demonstrate that the Caenorhabditis elegans pro-longevity factor, NHR-49, also promotes resistance against Pseudomonas aeruginosa, but modulates immunity and longevity by spatially and mechanistically distinct mechanisms. Fenofibrate, an agonist of NHR-49’s mammalian functional homolog, PPARα, enhanced worm immunoresistance in an NHR-49-dependent manner. NHR-49 expression is increased by germline ablation, an intervention that extends lifespan, but lowered by pathogen exposure. NHR-49 acted in multiple somatic tissues to promote longevity, whereas, it’s pro-immunity function was mediated by neuronal expression. The canonical NHR-49 target genes, acs-2 and fmo-2, were upregulated by germline loss, but infection triggered fmo-2 downregulation and acs-2 upregulation. Interestingly, neither gene conferred resistance against Gram-negative Pseudomonas, unlike their reported roles in immunity against Gram-positive pathogens. Thus, NHR-49 is differentially regulated by interventions that bring about long-term changes (lifespan extension) vs. short-term stress (pathogen exposure) and in response it orchestrates distinct outputs, including pathogen-specific transcriptional programs. Overall, our study demonstrates the independent control of immunity and longevity by a conserved regulatory protein.

INTRODUCTION 46 9 down-regulated by DAF-16 and TCER-1 too, the shared group (JOINT DOWN) 179 showed a much higher overlap with the NHR-49 DOWN class (~36%, 26/73, R 5.5, 180 P <2.094e-13) as compared to genes specifically down-regulated by either factor 181 alone (Fig. S1B) . Thus, NHR-49 targets share the largest overlap with genes whose 182 In this study, we demonstrate that NHR-49 is a pro-longevity factor that modulates 368 lifespan and immunity through distinct mechanisms. NHR-49 is influenced differently 369 by, and orchestrates distinct responses to, the acute stress of pathogen attack vs. a We found that NHR-49 expression in neurons alone could rescue the immunity 391 deficits of germline-less, nhr-49;glp-1 mutants, whereas, their lifespan was 392 substantially restored by expression in any somatic tissue. In fertile, nhr-49 single 393 mutants, immunity was restored by presence in neurons or intestine, but lifespan 394 could be rescued from other tissues as well. This suggests that pathogen response 395 may be more sensitive to NHR-49's location as compared to longevity. Interestingly, 396 NHR-49 expression in muscles provided little or no immunity benefit in any of the 397 genetic backgrounds we tested, irrespective of the presence or absence of the 398 germline in the animal. In fact, expression in muscles mostly diminished immunity. 399

This is in noticeable contrast to the broad immunity advantages conferred by tissues including the liver, brain, heart, muscles and immune cells (e.g., 488 macrophages, monocytes, and lymphocytes). Importantly, PPARα performs distinct 489 functions in these tissues and its activity is governed by tissue-specific mechanisms. 490

For instance, it mediates fatty acid oxidation in liver and heart, but its endogenous 491 ligands and their sources are different in the two organs. In liver, a lipid species, 492 16:0/18:1-GPC, derived by Fatty Acid Synthase (FAS)-mediated de novo 493 lipogenesis, serves as its endogenous ligand (Chakravarthy et al., 2009) generated. Transgene-carrying strains were maintained and selected for lifespan 599 and pathogen stress assays using a Leica M165C microscope with a fluorescence 600 attachment. A complete listing of all strains created for this study is provided in Table  601 S7. 602 603 Fenofibrate supplementation assay: 100 µL of 10 µM Fenofibrate (Sigma F6020) 604 in 0.1% DMSO were placed onto both NGM and slow-killing plates before seeding 605 with OP50 or PA14, respectively, as described above (Brandstädt et al., 2013; 606 Leiteritz et al., 2020). Upon the drying and growth of the bacterial lawn, eggs were 607 grown to L4 on either the Fenofibrate or 0.1% DMSO control plates, then transferred 608 to PA14 plates (similarly supplemented with Fibrate or DMSO) at L4 larval stage and 609 survival monitored. Worms were transferred to fresh plates as described above. Fig. 3 Trial 3

Trial 2 

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