Why leveraging sex differences in immune trade-offs may illuminate the evolution of senescence

Abstract

The immune system affects senescence (declines in probabilities of survival or reproduction with age), by shaping late age vulnerability to chronic inflammatory diseases and infections. It is also a dynamic interactive system that must balance competing demands across the life course. Thus, immune system function remains an important frontier in understanding the evolution of senescence.Here, we review our expanding mechanistic understanding of immune function over the life course, in the context of theoretical predictions from life-history evolution. We are especially interested in stage- and sex-dependent costs and benefits of investment in the immune system, given differential life-history priorities of the life stages and sexes.We introduce the costs likely to govern immune allocation across the life course. We then discuss theoretical expectations for differences between the sexes and their likely consequences in terms of how the immune system is both modulated by and may modulate senescence, building on information from life-history theory, experimental immunology and demography.We argue that sex differences in immune function provide a potentially powerful probe of selection pressures on the immune system across the life course. In particular, differences in 'competing' and 'caring' between the sexes have evolved across the tree of life, providing repeated instances of divergent selection pressures on immune function occurring within the same overall bauplan.We conclude by detailing an agenda for future research, including development of theoretical predictions of the differences between the sexes under an array of existing models for sex differences in immunity, and empirical tests of such predictions across the tree of life. A free http://onlinelibrary.wiley.com/doi/10.1111/1365-2435.13458/suppinfo can be found within the Supporting Information of this article.

Keywords: immunity; life history theory; senescence; sex differences.

Figure 1

Mortality and immunity across the life course. (a) Mortality rates (y‐axis) tend to decline during the first years of life (x‐axis is age) as individuals grow out of small vulnerable life stages and then increase later in life, a manifestation of senescence or ageing (noting that a wide range of mortality trajectories are possible). Mortality rates are often higher in one sex across all ages (e.g. red vs. blue). On top of this, sex differences in senescence and thus longevity might manifest via an increase in the rate of ageing (blue dashed line) or an earlier age of onset of ageing (blue dotted line) in one or other sex. One sex might also have higher mortality associated with reproductive years (shown as the horizontal red line above the baseline). (b) Differences in age trajectories of mortality will translate into different age profiles (red vs. blue bars, here assuming equal sex ratios at birth), but older individuals are consistently rare, an important driver of the evolution of senescence (noting, however, that late age individuals might have high reproductive value that could counterweight this effect). (c) The immune system is involved in both protection (infectious diseases and cancers) and harmful outcomes (immunopathologies, such as cardiovascular disease, strokes or autoimmunity) across this same time course (x‐axis indicates age, with for example cancers predominantly arising at late ages)

Figure 2

Dynamics of immunity. Many immune defences are inducible, triggered once growing parasite populations (red hexagons) are detected by the pattern recognition receptors of innate immunity identifying either pathogen‐ or damage‐associated molecular patterns (x‐axis is time following parasite arrival). Innate immune effectors are then launched (purple lightning bars). For species that have adaptive immunity, lymphocytes can subsequently be recruited (coloured circles), potentially leading to amplification of specific B‐ or T‐cell clones that recognize the pathogen (blue circles). These early processes generally correspond to a phase of positive feedback. Immune defences are also associated with active downregulation, by production of repressive cytokines, such as IL10, or (for species with adaptive immunity) engagement of T‐regs promoting a tolerizing environment, that is a phase of negative feedback. Infection and the broad return to homeostasis may nevertheless harbour changes that can result in longer term effects (far right) that may negatively (purple) or positively (green) affect survival rates. Background damage shaped by immune effectors could potentially driving earlier or faster senescence; ‘learning’ by immunity will both enhance protection to previously observed pathogens, but deplete memory, reducing ability to ‘remember’ new pathogens. Finally, early infection may enable immunity to develop a broadly tolerizing environment, protecting the organism from late life immunopathology. Each of these phases of induction and return to homeostasis map onto different trade‐offs relevant for balancing costs associated with immunity (alphabetically labelled boxes correspond to labels on Figure 3). The whole process can potentially occur multiple times over the course of an individual's life span, with potential consequences for rates of senescence (see text)

Figure 3

Immune trade‐offs. (a) A discrimination trade‐off: distinguishing between overlapping molecular signatures of the host (grey histogram) and pathogens (black histogram), or deciding where to draw the dashed vertical line, results in a trade‐off between false positive and false negatives (this is framed as a sensitivity/specificity trade‐off by epidemiologists, lower panel). (b) A trade‐off around the magnitude of the immune response: large responses (x‐axis, response magnitude increases left to right) reduce parasite burden (top panel, black line) and thus reduce the impact of parasites on mortality (lower panel, the black bars reflecting how parasites reduce host survival diminish in size) but increase negative effects associated with immunopathology (lower panel, purple bars reflecting how immunopathology reduces host survival increase in size). The optimal response is where the combined burden of parasite‐associated mortality and immunopathology‐related mortality is the smallest (vertical dashed black line). Relative to this baseline, hosts might be (c) more tolerant, where the trajectory of parasite burden (top panel) is unchanged but the impact of parasites on survival is reduced (black bars are smaller, noting that impacts might manifest via fertility instead), or (d) more resistant, where the parasite burden is lower for equivalent magnitude immune responses. The base case (b) represents the trade‐off directly emerging from danger associated with immunity, but both tolerance and resistance will require additional resource allocation, and are thus often found to trade‐off. Tracing these four trade‐offs across the life span is an important direction for future work