The Caenorhabditis elegans Germ Line Regulates Distinct Signaling Pathways to Control Lifespan and Innate Immunity

Abstract

The relationship between the mechanisms that control an organism's lifespan and its ability to respond to environmental challenges are poorly understood. In Caenorhabditis elegans, an insulin-like signaling pathway modulates lifespan and the innate immune response to bacterial pathogens via a common mechanism involving transcriptional regulation by the DAF-16/ FOXO transcription factor. The C. elegans germ line also modulates lifespan in a daf-16-dependent manner. Here, we show that the germ line controls the innate immune response of C. elegans somatic cells to two different Gram-negative bacteria. In contrast to the insulin-like signaling pathway, the germ line acts via distinct signaling pathways to control lifespan and innate immunity. Under standard nematode culture conditions, the germ line regulates innate immunity in parallel to a known p38 MAPK signaling pathway, via a daf-16-independent pathway. Our findings indicate that a complex regulatory network integrates inputs from insulin-like signaling, p38 MAPK signaling, and germ line stem cells to control innate immunity in C. elegans. We also confirm that innate immunity and lifespan in C. elegans are distinct processes, as nonoverlapping regulatory networks control survival in the presence of pathogenic and nonpathogenic bacteria. Finally, we demonstrate that the p38 MAPK pathway in C. elegans is activated to a similar extent by both pathogenic and nonpathogenic bacteria, suggesting that both can induce the nematode innate immune response.In Caenorhabditis elegans, inhibition of either daf-2 insulin/ IGF-1-like signaling or germ line proliferation increases nematode lifespan (1-4), increases resistance to environmental stress (1, 5-11), and increases nematode survival in the presence of pathogen (12)(13)(14). Insulin-like signaling also affects lifespan and stress resistance in Drosophila and rodents (15)(16)(17)(18)(19), and possibly in humans (20 -23), indicating that this pathway is evolutionarily conserved. The germ line, under some conditions, can also modulate lifespan in Drosophila (24). The germ line may also affect lifespan and stress resistance in mammals, as transplantation of young ovarian tissue into older mice can lengthen mouse lifespan (25), and postponement of menopause in mice delays some age-related health complications (26). Thus, the role of the germ line in the regulation of lifespan may also be evolutionarily conserved.Here, we show that the C. elegans germ line controls nematode resistance to two different Gram-negative bacterial pathogens, Pseudomonas aeruginosa and Serratia marcescens. However, unlike the case with daf-2, the effects of the germ line on lifespan and pathogen resistance are mediated by separate signaling pathways. While the FOXO family transcription factor DAF-16 is necessary for germ line-induced changes in lifespan (1, 2), daf-16 does not affect germ line-induced changes in innate immunity under standard nematode culture conditions. Our findings also indicate that the germ line acts in parallel to a p38 MAPK 2 ...

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“…DAF-16 plays an important role in the control of longevity and immunity (40 -44). In addition, it is known to control the extended life span of glp-1 animals and the enhanced resistance to pathogens of glp-4 animals (37,45,46). Our results strengthen the notion that DAF-16 functions at the intersection of pathways that control immunity, longevity, and stress responses.…”

Proteostasis and longevity: when does aging really begin?

“…glp-1 mutants also show increased autophagy, enhanced resistance to oxidative stress, and reduced susceptibility to pathogenic bacteria, suggesting that GSCs can modulate a range of protective pathways [58][59][60]. While these observations support a link between somatic proteostasis, aging, and reproduction, the signaling pathways involved are likely to be complex as the removal of the entire gonad does not result in the lifespan extension or maintenance of proteostasis [48,61].…”

Roles for ROS and hydrogen sulfide in the longevity response to germline loss in Caenorhabditis elegans

“…Oxidative damage (39), impaired-insulin/IGF-1 signaling (34), and pathogen infection (40) all activate SKN-1 via the p38 MAP kinase PMK-1 and its upstream regulator SEK-1 kinase. However, pmk-1 makes only a small contribution to the longevity of germline-deficient animals (41). Similarly, the pmk-1(km25) deletion mutation only partially reduced Pgst-4::GFP expression in germline-deficient animals, and the sek-1(km4) mutation did not reduce it at all (SI Appendix, Fig.…”