| dc.description.abstract | The global demographic is shifting towards an aged population. As the eldest members of society are more vulnerable to both infectious and aged-related diseases, improving healthy ageing and limiting age-related pathologies is imperative. Immune decline over ageing, or immunosenescence, is implicated in age-related vulnerability via increased inflammation that is deleterious to health and heightened infectious disease susceptibility, and thus represents a promising target in limiting age-related pathologies. Yet, immunosenescence remains a relatively elusive phenomenon with little understanding of interindividual variation therein, which arises from genotype, including sex, and environmental factors. Furthermore, such population diversity will influence responses to therapies targeting immunosenescence, rendering an understanding of variation in the trait crucial. In this thesis, I explore the relationship between immunity and ageing through the lens of interindividual variation. My chapters consider how such variation can be harnessed to gain broad insight into the nature of immunosenescence. Specifically, I have outlined the power of leveraging natural variation in immunosenescence and how Drosophila melanogaster are particularly well-poised for such an approach, provided proof-of-principle for this method, and assessed the contribution of transposable elements to variation in ageing and immunity.
First, we wrote an opinion piece (Chapter 2) outlining the value of considering natural variation in immunosenescence, and championed D. melanogaster as a particularly well-suited model for an approach that aims to do so. Most research in immunosenescence focuses on defining its molecular and physiological underpinnings in the context of a single genotype, sex and environment. We argue that leveraging variation in immunosenescence would not only grant mechanistic insight, but also guide the development of therapies that target it. We further outline how the rich history of D. melanogaster in the fields of evolutionary biology of ageing, biogerontology and innate immunity and that their conceptual and technical convergence on the model render it ideal in such a pursuit.
In Chapters 3 and 4 I provide some proof-of-principle for such an approach using D. melanogaster. First, I sought to examine the relationship between immunity and ageing with a particular focus on how this varies between the sexes. Sex differences in both the physiologies of ageing and in immune responses are prevalent. Evidence suggests that males may be experiencing greater immunosenescence than females, but how this relates to dimorphic physiologies of ageing is unknown. As a proxy for the relationship between immunosenescence and ageing, I began by assessing the lifespan effects of removing environmental microbes, and thus opportunistic infections, from mid- and late-life with antibiotics in outbred flies of both sexes. Further, I examined immunosenescence in an acute context by challenging young and aged outbred flies to Providencia rettgeri. I then focused on directly assessing the relationship between immunity and ageing, using Drosophila genetic reference panel (DGRP) lines to leverage and relate variation in lifespan to that of P. rettgeri susceptibility at young and old age. I observed a male-specific motif trend in the relationship of immunity and ageing, whereby removal of environmental microbes selectively enhanced male lifespan, males displayed greater immunosenescence in acute infection and that late-life susceptibility was predictive of lifespan in males only. These findings are consistent with previous observations of comparatively greater immunosenescence in males, but further suggest that such may be contributing to sex-specific physiologies of ageing.
Next, in Chapter 4, I further harnessed the power of the DGRP in capturing variation in immunosenescence to both gain broad insight into the mechanisms underpinning age-related susceptibility to P. rettgeri, and to examine the potential of rapamycin, an established therapy with positive effects on ageing, in improving immunosenescence. Host defence is the composite of two strategies: resistance and disease tolerance. Whether age-related susceptibility is generally associated with impairments to one, or both, of these strategies remains relatively unexplored. I leveraged covariation in age- related changes in susceptibility and that in the corresponding pathogen load upon death (PLUD) in DGRP lines to gain broad mechanistic insight into age-related susceptibility. I applied the findings of recent theoretical modelling to their observed relationship to determine the underpinning strategy, whereby positive and negative relationships between susceptibility and PLUD implicate resistance and disease tolerance as most associated with vulnerability, respectively. I found that, generally, age-related susceptibility to P. rettgeri is linked to reductions in disease tolerance. I also found that short-term treatment with rapamycin resulted in male-specific improvements to age-related susceptibility to P. rettgeri. My findings cement the potential of leveraging variation in immunosenescence, awarding broad, initial mechanistic insight and further underscore the importance of considering variation from a therapeutic perspective.
In my final chapter (Chapter 5), I narrowed my scope of natural variation down to that arising from transposable elements (TE). Specifically, I built upon a previous genome-wide TE association study with longevity in the DGRP that identified a putative longevity-associated TE inserted into the Dorsal-related immune (Dif) locus. While TEs are typically regarded as harmful to their hosts, and indeed their age-dependent activity can have pathological outcomes, they have been recognised as adaptive sources of variation in host fitness. Yet, the contribution of TEs to life-history traits like lifespan remain unexplored. I first sought to validate the association of this TE with longevity and then, given its insertion into an immune gene, to examine its effect on immunity to Enterococcus faecalis. To do this, I took an adapted Mendelian recombination approach to produce an F1 panel of genotypes that were either homozygous for the TE in an otherwise heterozygous background, or lacking the TE entirely. I found that the TE had no effect on lifespan in either sex, but that it exerted sex-specific effects on E. faecalis infection outcome. I suggest some possible explanations for why I was unable to confirm the relationship between this TE and lifespan. The implication of the insertion in sex-specific immunity underscores the contribution of TEs to natural variation and suggests that genome-wide TE association studies with immunity and lifespan may grant insight into other hitherto sources of variation in these traits. While interindividual variation can complicate conclusions about the physiologies of immunosenescence, there are also gains to be made by leveraging such variation in the phenomenon. This thesis provides proof for such an approach in D. melanogaster through revealing general trends in the relationship between immunosenescence and ageing, the mechanisms associated with age-related susceptibility and thus potentially revealing therapeutic targets, and the sex-specific responses of therapies like rapamycin in targeting it. This thesis further highlights TEs as sources of natural variation in traits like immunity and likely sources of such in ageing. | en |
