Functional conservation in genes and pathways linking ageing and immunity

Abstract

At first glance, longevity and immunity appear to be different traits that have not much in common except the fact that the immune system promotes survival upon pathogenic infection. Substantial evidence however points to a molecularly intertwined relationship between the immune system and ageing. Although this link is well-known throughout the animal kingdom, its genetic basis is complex and still poorly understood. To address this question, we here provide a compilation of all genes concomitantly known to be involved in immunity and ageing in humans and three well-studied model organisms, the nematode worm Caenorhabditis elegans, the fruit fly Drosophila melanogaster, and the house mouse Mus musculus. By analysing human orthologs among these species, we identified 7 evolutionarily conserved signalling cascades, the insulin/TOR network, three MAPK (ERK, p38, JNK), JAK/STAT, TGF-β, and Nf-κB pathways that act pleiotropically on ageing and immunity. We review current evidence for these pathways linking immunity and lifespan, and their role in the detrimental dysregulation of the immune system with age, known as immunosenescence. We argue that the phenotypic effects of these pathways are often context-dependent and vary, for example, between tissues, sexes, and types of pathogenic infection. Future research therefore needs to explore a higher temporal, spatial and environmental resolution to fully comprehend the connection between ageing and immunity.

Keywords: Ageing; Conservation; Immunity; Immunosenescence; Lifespan; Longevity.

Fig. 1

Major differences in immunity of C. elegans, D. melanogaster and mammals. Invertebrates, such as nematodes and insects, represented by C. elegans and D. melanogaster respectively, completely rely on innate immunity upon infection, while vertebrates (represented by mammals) have also evolved an adaptive immune system. Cellular immunity occurs in fruit flies as hemocytes (immune cells in the hemolymph), and as different types of leukocytes in mammals, but is absent in worms. In contrast to this, the germ-line encoded complement system is unique to mammals. Moreover, pattern recognition receptors (PRRs) of the innate immune system – most prominently the Toll- and Toll-like receptors, are incremental for pathogen-recognition in fruit flies and mammals, but whether the single Toll-like receptor homolog in C. elegans fulfils the same function is still under debate. Finally, Nf-κB transcription factors, which regulate the expression of immune-related genes, are central to D. melanogaster and mammalian immunity, but have not been identified in C. elegans. The well-known cross-talk between immune and JNK MAPK signalling is indicated, but notably several other pathway interactions do also exist. Immunity genes and protein complexes also associated with lifespan and ageing are marked in green and bold

Fig. 2

Overlap in 437 Human immuno-ageing orthologs between C. elegans (blue), D. melanogaster (green), M. musculus (orange), and H. sapiens (red). Orthologs were obtained using DIOPT. Details on shared orthologs, original gene names and methods are given in Table S2

Fig. 3

Simplified overview of the insulin-insulin-like growth factor and TOR signalling (IIS/TOR) network. Activation of IIS/TOR network signalling is induced by insulin and insulin-like peptides, environmental cues and nutrients, and leads to a signalling cascade promoting growth and reducing lifespan. In absence of IIS/TOR signalling, such as under dietary restriction, Foxo transcription factors and the 4E-BP inhibitor of translation inhibit growth and promote longevity. Factors stimulating IIS/TOR signalling and thought to reduce lifespan are shown in red, those generally beneficial for lifespan in blue. Gene names are given in the white boxes in the order of C. elegans, D. melanogaster and H. sapiens (overall, equal to M. musculus). Genes with pleiotropic effects on immunity are marked in green and bold

Fig. 4

MAPK, JAK/STAT and TGF-β pathways regulate ageing and immunity. Multiple signalling cascades in addition to the IIS and TOR pathways contribute to ageing, longevity and immunity. Three MAPK pathways are conserved in worms, flies and mammals. The ERK-MAPK pathway is activated by growth and other factors through binding to receptors, including EGFR, and can further be triggered by the IIS pathway. Activity leads to transcription factors mainly promoting growth, cell division and differentiation of cells. In contrast, p38 and JNK MAPK pathways are classically considered to respond to stress including infections, while the JNK cascade is also mediated by Nf-κB signalling (Fig. 1). The multiple transcription factors downstream of p38 and JNK stimulate inflammation, immunity, longevity and other functions. JAK/STAT signalling is triggered by upd cytokines in D. melanogaster, and interferons, multiple cytokines and other factors in mammals. Upon receptor binding, the JAK/STAT signalling cascade leads to activation of STAT transcription factors, which are best known for fostering inflammation and immunity, particularly against viral infections. Notably, JAK/STAT in C. elegans only includes the two STAT transcription factors, sta-1 and sta-2, but does not share the same upstream factors as fruit flies and mammals. Finally, the branches of TGF-β pathways are activated by BMPs, activins and other factors. The signalling cascade regulates multiple transcription factors, leading to immunosuppression, anti-inflammatory responses and several other physiological effects. Notably, the pathways show various amounts of cross-regulation among each other but also with the IIS/TOR network and the Nf-κB cascade, and for simplicity, only well-known cross-talk is indicated. Gene names are given in the white boxes in the order of C. elegans, D. melanogaster and H. sapiens (overall, equal to M. musculus). Genes and factors concomitantly involved in lifespan, ageing, and immunity are marked in green and bold

Fig. 5

Antiviral RNAi pathway. The antiviral RNA interference (RNAi) pathway shows genetic and functional conservation across D. melanogaster, C. elegans and mammals. In both, C. elegans and D. melanogaster, antiviral RNAi is thought to be a major innate defence against viruses. However, even though antiviral RNAi exists in mammals, its importance is currently under debate as they contain other potent mechanisms of virus defence, such as the interferon response and adaptive immunity. Components also involved in lifespan in at least one of the represented species are marked in green and bold