Introduction
The immune system is of primary importance to control diseases throughout an individual’s life, and therefore crucial to its fitness. In vertebrates, the immune system involves different immune functions which are classically divided into innate and adaptive components (Hoebe et al., 2004); in close interaction with each other (Iwasaki & Medzhitov, 2010, 2015). The innate immune functions are the first defence against pathogens, involving phagocytic cells (e.g. neutrophils, macrophages and dendritic cells) and molecules such as cytokines, also able to activate other components of the immune system (Akira et al., 2006; Mantovani et al., 2011; Nathan, 2006; Vivier et al., 2011). The adaptive immune functions comprise a cell-mediated immune response, with the stimulation of T lymphocytes, and a humoral immune response, controlled by activated B lymphocytes that can produce immunoglobulins against specific antigens (Iwasaki & Medzhitov, 2010; Mantovani et al., 2011; Vivier et al., 2011).
Mounting an immune response carries costs (Graham et al., 2005; Lochmiller & Deerenberg, 2000; Maizels & Nussey, 2013) and trade-offs with other life-history traits are likely to emerge (Eraud et al., 2009; Graham et al., 2010; Hanssen et al., 2004; Lemaitre et al., 2015; Viney et al., 2005). Therefore, immunity is likely to change during an individual’s life. Changes of immunity with age has been mainly studied in humans and laboratory animals (Bektas et al., 2017; Frasca et al., 2005; Gayoso et al., 2011; Larbi et al., 2008; Noreen et al., 2011; Solana et al., 2012), with the general pattern being a decline in adaptive immunity with age, while innate immunity remains unchanged and inflammatory markers increase (Bauer & De la Fuente, 2016; Franceschi, Bonafe, et al., 2000a; Franceschi, Bonafe, et al., 2000b; Franceschi et al., 2007; Frasca et al., 2011; Panda et al., 2009; Shaw et al., 2013; Simon et al., 2015). In non-model organisms, a recent review found similar trends (Peters et al., 2019).
Some studies indicate that the decrease in the immune functions with age could impaired survival (e.g. Froy et al., 2019; Hanssen et al., 2004; Schneeberger et al., 2014). However, others suggest that variations in immune functions, characterised by changes in the proportion of the different cells involved in the immune response, could be adaptive (i.e. immune remodelling ) and could fit with the different immune challenges faced throughout life (Fulop et al., 2018, p. 2018; Mueller et al., 2013; Nikolich-Zugich, 2018). It could even be a combination of both (Fulop et al., 2020).
Because the immune system is complex, involving many cell types and pathways, its characterization in non-model organisms is challenging, thus limiting the study of age-related variation of immunity in free-ranging animals (Boughton et al., 2011; Demas et al., 2011). Nevertheless, cross-sectional studies investigated the variations in the immune function with age (mammals: Abolins et al., 2018; Cheynel et al., 2017; Nussey et al., 2012; birds: Hill et al., 2016; Lecomte et al., 2010; Palacios et al., 2007; Saino et al., 2003; Vermeulen et al., 2017; reptiles: Massot et al., 2011; Ujvari & Madsen, 2011; Zimmerman et al., 2013; see Peters et al. 2019 for a review), and seem to confirm the pattern observed in humans and laboratory animals (see above). However, these studies cannot disentangle whether the observed variations arise from within-individual changes or from processes like selective disappearance, which supposedly eliminate individuals with poor (or unappropriate) immune defences from the population (van de Pol & Verhulst, 2006; van de Pol & Wright, 2009). Longitudinal studies investigating variations in immune functions with age exist, but are still very limited (to the best of our knowledge, seven studies: Beirne et al., 2016; Bichet et al., 2022; Froy et al., 2019; Graham et al., 2010; Roast et al., 2022; Schneeberger et al., 2014; Vermeulen et al., 2017). Therefore, we are far to understand the evolutionary consequences of such variations, and, more broadly how proximate mechanisms, like immunity, could explain (even partly) processes such as ageing (Bouwhuis & Vedder, 2017; Lemaitre et al., 2013; Peters et al., 2019).
In the present study, we recorded the age-specific leukocyte concentration and profile in 52 dominant individuals (i.e. fully grown and reproductive individuals) repeatedly sampled between 2011 and 2015 (for a total of 169 measurements) from a wild and long-term studied (1992-2018) population of Alpine marmots. We first tested whether leukocyte concentration and profile changed within individuals’ ages (i.e. within-individual level). We then investigated if changes in these immune parameters could also be explained by selective (dis)appearance of individuals (i.e. among-individual level) with particular immune parameters, influencing their risk of death (survival analysis). Based on the previous studies, we expected the relative number of lymphocytes (mainly involved in acquired immunity) to decrease with age, while the others relative numbers of leukocytes (neutrophils, monocytes, eosinophils; mainly involved in innate immunity) to increase with age, at the within-individual level. We further expect both leukocyte concentration and leukocyte profile to compromise individual age-specific survival.
Material and methods