key: cord-0917565-43ts09zl authors: Tidière, Morgane; Badruna, Adèle; Fouchet, David; Gaillard, Jean-Michel; Lemaître, Jean-François; Pontier, Dominique title: Pathogens shape sex differences in mammalian aging date: 2020-05-07 journal: Trends Parasitol DOI: 10.1016/j.pt.2020.05.004 sha: 4e5269fc97d900c370cbc332b8f947661a69d333 doc_id: 917565 cord_uid: 43ts09zl ABSTRACT Understanding the origin of sex differences in lifespan and aging patterns remains a salient challenge in both biogerontology and evolutionary biology. Different factors have been studied but the potential influence of pathogens has never been investigated. Sex differences especially in hormones and resource allocation generate a differential response to pathogens and thereby shape sex differences in lifespan or aging. We provide an integrative framework linking host pathogenic environment with both sex-specific selections on immune performance and mortality trajectories. We propose future directions to fill existing knowledge gaps about mechanisms that link sex differences, not only to exposition and sensitivity to pathogens, but also to mortality patterns, whilst emphasizing the urgent need to consider the role of sex in medicine. It has become increasingly clear that males and females differ in immune responses [15] . As a general rule, females exhibit greater capability of producing antibodies than males [16] . They are less susceptible to infectious diseases [15] but can develop a stronger predisposition to autoimmune or inflammatory diseases than males [15] . However, the consequences in terms of sex differences in lifespan and aging are yet to be accurately quantified [17] . Differences in disease prevalence and expression between males and females are mainly attributed to sex steroids (e.g. estrogens, testosterone, progesterone), which, by binding to hormone receptors on the surface of immune cells, modulate the phenotype of immunological cells [7, 15] . Most of them express multiple sex hormone receptors that drive sex-specific immune responses following antigen stimulation [7] . Males and females differ in steroid concentrations: males have a higher concentration of testosterone and females a greater concentration of estrogen and progesterone. Estrogen receptors are detected in immune cell populations, including lymphocytes, monocytes and macrophages [18] , and have an immunoenhancing effect as well as diverse protective effects [19] . On the contrary, progesterone and testosterone have mainly immunosuppressive effects [20] . Folstad and Karter [21] proposed that testosterone has, in fact, a double-sword effect that increases the probability of mating for a male while decreasing its ability to fight over pathogens. For instance, territorial male chamois (Rupicapra rupicapra) have almost six times more fecal androgen metabolites and are three times more parasitized during the rut period than non-territorial males [22] . Hence, we may expect that males will develop stronger disease symptoms resulting in a lower probability to survive and thereby increased between-sex differences of lifespan in pathogenrich environments. However, inconsistencies among studies of vertebrate species (e.g. Cape ground squirrels, Xerus inauris [23] ) suggest that testosterone is not all story. J o u r n a l P r e -p r o o f Major physiological changes occur during reproductive seasons or cycles. Typically, testosterone production is increased in males when competing for fecund females, while pregnancy induces a decrease in estrogen and an increase in progesterone concentration to avoid the immunologic aggression of the fetus [24] . However, infectious diseases that are acquired during pregnancy or lactation are often associated with lower birth mass and reduced breast-milk in humans, suggesting that females reactivate the formally quiescent immune system [25] to combat infection at the expense of reproduction. For example, women who contract malaria during pregnancy have higher circulating levels of pro-inflammatory cytokines, which in turn are associated with lower birth mass [26] . This suggests that females should show a lower lifetime reproductive success in an environment with high pathogenetic load, but their lifespan should be much less affected than that of males. From an evolutionary viewpoint, the immune response is a key fitness-related trait, but the energy it requires should inevitably be traded for allocation to life-history traits governing other biological functions [27] . For instance, the growth and maintenance of secondary sexual traits impair male immune performance through a resource-based allocation trade-off [28], making them more sensitive to pathogens [29] (Figure 1 ). Many observations in rodents, birds, and insects document substantial energetic, reproductive, and survival costs of immune activation [30] . Hence, organismal responses to pathogens should involve sex differences given that the optimal solution to the trade-off between reproduction and survival differs between sexes, with females allocating more than males to their immune responses to not jeopardize their survival and increase thereby their lifetime reproductive success [27] . We can even expect that iteroparous females should rapidly redirect their energy to immune functions J o u r n a l P r e -p r o o f 6 at the expense of fetus/offspring survival when exposed to a pathogen during pregnancy. The optimal strategy should be radically different in semelparous females who only have one opportunity to reproduce. For example, parasite removal reduces reproducing female survival in the Taiwan field mouse (Apodemus semotus), possibly by allowing breeding females to increase maternal investment (i.e. allocation at the cost of their future survival [31]). By contrast, in males, immune performance is impaired by the growth and maintenance of secondary sexual traits, which makes them more sensitive to pathogens [28] . In mice, increased aggression is costly and is associated with reduced resistance to disease [32] . As a consequence, sex differences of lifespan should increase in favor of females when pathogen load increases (Box 3). Finally, males and females correspond to markedly different environments for pathogens, which may shape their evolution. Hence, the observed sex-biased disease prevalence and/or severity might be the result of the parasite having adapted to grow in specific host sex [33] . Úbeda and Jansen [34] formalized this idea and suggested that natural selection can act differently on pathogens in males and females depending on the transmission route of the pathogen. In Japan, where the transmission of HTLV-1 (Human T-cell Lymphotropic Virus Type 1) occurs through breast-feeding rather than through sexual transmission, the progression to Adult T-cell Leukemia is slower in women than men. Sex-specific adaptation of HTLV-1 to preserve women as a viral route could be a potential explanation for this puzzling observation [34] . Challenges within species J o u r n a l P r e -p r o o f 7 The immune system includes many different immune cell types, each having its unique function, and collectively protecting the host against pathogens. The reliable measurement of multiple markers of both immunity (e.g. cellular components, T cell repertoire) and aging (e.g. epigenetic markers of biological age [35]) remains challenging. However, such metrics are required to allow a better understanding of the ecological (pathogen exposure) and evolutionary forces that shape the sex-specific decline of immune responses and between-sex differences in lifespan. Ideally, these measures should be made in wild populations, which display a large variation in the magnitude of sex differences in lifespan (see [2]) because of differential risk-taking behavior, food requirements, mortality due to direct sexual competition, or exposition to commensal and pathogenic organisms. Longitudinal studies are thus required to assess how immunosenescence patterns are shaped according to sex (see for example [36] , and references in [8] ) and also to identify mortality causes, which allows deciphering the different ways through which pathogens reduce individuals' lifespan (through early deaths from lethal diseases or through advanced immunosenescence due to immune exhaustion). This has yet rarely been investigated in wild populations (but see [37] ). Even though studies of rodents (reviewed in [38]) show that reaching this aim is possible in wild populations, it remains a complex task. Populations living in protected conditions (e.g. wild species in zoos, domestic animals and companion animals living with humans, laboratory animals) would offer excellent simplified systems to explore more deeply the deterioration of immune functions with increasing age and its role in between-sex mortality patterns (see [39] for an example in mice). This would allow an investigation into how the level of pathogen exposure as well as the virulence of pathogens to which hosts are exposed shape the immunosenescence profile and thus the mortality rate and lifespan of males and females. J o u r n a l P r e -p r o o f 8 Captive mammalian populations could also provide insightful information on the potential effect of chronic and putatively asymptomatic infections on the differential rates of immunosenescence between sexes, which is currently totally underestimated. Research on human health has provided important and somewhat unexpected results in this field. Notably, the chronic infection by the common CMV (cytomegalovirus) is involved in the remodeling of the immune system. Hence chronic exposition to any microbial agent (i.e. not only known pathogens) could be both implied in shaping sex-specific immunosenescence [40] . Only longterm monitoring of individuals from birth to death, in which molecular and cellular markers of adaptive and innate functions can be recorded repeatedly throughout their lifetime, and a reliable estimate of the infection date becomes available at the individual level, will allow a deeper understanding of immunosenescence according to age and sex concerning microbial agent exposure. Additionally, the comparative analysis of populations within a single species occupying multiple habitat types can offer important insights into the intraspecific variation in immunosenescence and its consequences on life history traits such as lifespan in both sexes. Selection is expected to produce the immune response that maximizes individual fitness, in interaction with other selection pressures imposed by the environmental context (i.e. resource availability, weather conditions), the social and mating systems, and the pathogen exposure. Thus, the immune system of rodents from different populations and environments in the wild differs from that of laboratory rodents, the former being continuously exposed to commensal and pathogenic organisms (reviewed in [38] ). It would be thus interesting to evaluate how such excessive energetic demands to activate the immune system compromise other fitness components of laboratory rodents according to their pathogenic environment, notably the differential actuarial senescence rates between males and females. Inter-specific comparisons J o u r n a l P r e -p r o o f 9 Taking into account the evolutionary history of mammals, their pathogen species richness, which varies largely across species [41] , may help explain between-sex differences in lifespan. In presence of numerous pathogens, males from species subjected to strong sexual selection should be more exposed to pathogens compared to females than males from species with a low sexual selection [42] . This could partly explain sex differences in immunosenescence (see for example [8] ) and highlight how these differences are likely determined by fine scale interactions between sex-specific physiological pathways and the local environment in pathogens [2]. Variation in pathogen richness, infection rate, and pathogen load correlates with numerous morphological and ecological traits, mostly driven by sexual selection, which are also related to the lifespan variation in mammals [43] . Among these traits, variation in host body size [44] , mating system and sexual size dimorphism [42] , MHC allelic diversity [45] , geographical range [46] , social group size [47], population density [48] , and phylogeny [6, 41] have been identified as playing a role. However, most cross-species studies that investigate the interaction between pathogens and host ecological and life-history traits performed to date did not include between-sex differences in pathogens nor their consequences in terms of sexspecific lifespan (e.g. [49] ). Although male-biased parasitism is positively correlated with the level of polygyny in mammals [42] , the level of polygyny also correlates with a shorter lifespan and a more pronounced aging in males compared to females, at least across captive populations of large herbivores [6]. All these challenges will be made possible thanks to databases gathering longitudinal data that measure accurately sex differences in lifespan, which are becoming increasingly available information should inform on how pathogens shape sex differences rather than how sex differences shape responses to pathogens because the magnitude of sex differences seems to be context-specific (see [2] for a study of mortality patterns). It might be thus difficult to envision mammals evolving differential responses to parasites mediated by sex differences if the magnitude of sex differences is so labile. Understanding the determinants of differences in male and female outcomes is becoming a Progressive deterioration of the organism results from concomitant retention (or exacerbation) of innate immunity coupled with a dysregulation (or dysfunction) of adaptive immunity [53] . For now, in all studies conducted so far in humans, a universal age-associated immune alteration is consistently observed. The numbers and proportions of naive peripheral blood CD8+ T cells are reduced as a consequence of the developmentally-programmed thymic involution [53] . Moreover, as the establishment of the innate immune response causes inflammation and ROS production that induce collateral tissue damage, we can hypothesize that the more an organism is subject to a repeated innate immune response (e.g. due to high exposure to pathogens), the more permanent the damage will be. This potentially accelerates an organism's deterioration, ultimately leading to its death. Similarly, the adaptive immune system is particularly affected by the effect of long-term exposure to a variety of antigenic stimuli. Accordingly, an adaptive immune system highly exposed to pathogens will quickly lose efficiency, leading it to exhaustion with dramatic consequences such as high mortality. As increased solicitation of the immune system leads to an acceleration of its dysregulation and efficiency, we suggest that in presence of pathogens, males undergo stronger immunosenescence than females, because of their higher exposure and tolerance to infectious agents. This results in the observed higher mortality rate and shorter lifespan of males compared to females. For example, Zeng et al. [54] highlighted that two immune pathways, the cytokine IL-6 and TLR3 proinflammatory signaling pathways, are positively associated with the lifespan of centenarian men but not women. This suggests that dysregulation of these proinflammatory pathways with age makes elderly men more susceptible to infectious pathogens than elderly women. However, while numerous researchers asked for more longitudinal studies to define more accurately immunosenescence profiles and identify the underlining mechanisms [53] , sex remains overlooked in biological research despite its critical consequences in the veterinarian and human medicine. Investigating the role of pathogens on sex differences in aging highlighted how much males and females differ regarding their immune system and their response to infectious diseases. In spite of this, physicians still tend to prescribe the same treatment to both male and female patients for a given diagnostic. One reason for this is that sex differences in immune functions are not well understood yet. During the last thirty years, most biomedical research has routinely used only males in both cohort and animal model studies because the cyclic hormonal fluctuations of females introduce additional experimental variation [55] . This could explain the higher number of secondary effects observed in women than in men following the commercialization of a given drug [56] . Upon vaccination, women develop a higher antibody immune response, but also more frequent and severe adverse side effects than men [57] . The application of sex-specific medicine is thus urgently required [56] . The American National Institute of Health recently declared that clinical trials not taking sex-specific responses into account will no longer be funded [58] . A great deal of knowledge about sex differences in immune functions comes from laboratory animals, notably the mouse model, which have been used extensively to develop research and test therapies before they are used in humans. However, very little is known about how much information from inbred and laboratory-adapted mice can be extrapolated to mammalian immune responses in the wild [59] . First, the selection of laboratory mice has resulted in the alteration of life-history traits (such as reproduction or lifespan, see [60] ) and immunological animals is thus crucially needed to reveal both the relevance and limitations of laboratory animals as immunological models. Linking wild and laboratory animal immunology by using tools and concepts of immunology, but also of ecology and evolutionary biology, is badly needed. In that respect, companion animals, which live in the same environment as their owners and are exposed to similar pathogens [61] , may potentially serve as bridges between laboratory and wild species. The affordability of new 'omic' approaches and the availability of new trusted biomarkers (e.g. antibodies, cytokines, cellular responses) and immunological reagents (e.g. monoclonal antibodies) will help to quantify male and female exposition to microbes and the dysregulation of immune parameters with increasing age in a wider range of mammalian species, aiding immunologists, ecologists and evolutionary biologists to work altogether. Using between-sex differences of mean adult lifespan in 13 mammalian species (8 carnivores and 5 primates, see more details in supplemental Table S1 ), a preliminary analysis ( Figure Years of research in biomedical sciences have revealed that sex-specific immune responses to pathogens can be associated with sex-specific consequences on health. These effects partly account for the observed sex gap in lifespan leading women to be longerlived than males in human populations. Sexual selection exerted on males and the environment in terms of pathogens may explain at least partly the sex-difference of lifespan generally observed across mammalian populations. Impact of CMV upon immune aging: facts and fiction Phylogeny matters: revisiting 'a comparison of bats and rodents as reservoirs of zoonotic viruses Parasites as a viability cost of sexual selection in natural populations of mammals Mammalian metabolism, longevity and parasite species richness Latitudinal gradients of parasite richness: a review and new insights from helminths of cricetid rodents Major histocompatibility complex alleles associated with parasite susceptibility in wild giant pandas Parasite and viral species richness of Southeast Asian bats: Fragmentation of area distribution matters Infectious disease and group size: more than just a numbers game Comparative tests of parasite species richness in primates Host longevity and parasite species richness in mammals PHI-base: a new interface and further additions for the multispecies pathogen-host interactions database DBatVir: the database of bat-associated viruses Age and immunity: What is "immunosenescence Sex differences in genetic associations with longevity Of mice and women: the bias in animal models Personalized vaccinology: one size and dose might not fit both sexes Sex-based differences in immune function and responses to vaccination NIH to balance sex in cell and animal studies The comparative immunology of wild and laboratory mice, Mus musculus domesticus Mouse models of human disease: an evolutionary perspective Susceptibility of ferrets, cats, dogs, and other domesticated animals to SARS-coronavirus 2. Science DOI: 10.1126/science.abb7015 OUTSTANDING QUESTIONS What is the true contribution of pathogens to overall mammalian mortality? Do between-sex differences of immunosenescence really occur in mammals? Is there a differential effect of resistance and tolerance on between-sex differences of lifespan across mammalian species in relation to variation in generation time? Do immunosenescence patterns vary with the intensity of pathogen exposure? Are sex-specific immunosenescence patterns associated with between-sex differences in lifespan and aging across mammals?