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 can be divided into innate and adaptive components (Hoebe et al.,
2004). 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 parts 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,
Allen, & Read, 2005; Lochmiller & Deerenberg, 2000; Maizels & Nussey,
2013) and trade-offs with other life-history traits are likely to emerge
(Eraud,
Jacquet, & Faivre, 2009; Graham et al., 2010; Hanssen, Hasselquist,
Folstad, & Erikstad, 2004; Lemaitre et al., 2015; Viney, Riley, &
Buchanan, 2005). Therefore, according to the theory of senescence
(Medawar, 1952), and more particularly the disposable soma theory
(Kirkwood & Rose 1991), a decrease in immune performance with age is
expected (reviewed in Lavoie, 2006; Shanley, Aw, Manley, & Palmer,
2009; Simon, Hollander, & McMichael, 2015).
Immunosenescence was mainly studied in humans and laboratory animals
(Bektas,
Schurman, Sen, & Ferrucci, 2017; Frasca, Riley, & Blomberg, 2005;
Gayoso et al., 2011; Larbi et al., 2008; Noreen, Bourgeon, & Bech,
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 et al., 2007; Frasca, Diaz, Romero,
Landin, & Blomberg, 2011; Panda et al., 2009; Shaw, Goldstein, &
Montgomery, 2013; Simon et al., 2015). In non-model organisms, a recent
review found similar trends
(Peters
et al., 2019). These findings
suggest that the decrease in the immune functions with age could occur
and impaired survival (e.g.
Froy
et al., 2019; Schneeberger, Courtiol, Czirjak, & Voigt, 2014), but that
a remodelling of the immune functions and ‘inflammaging’ (accumulation
of pro-inflammatory factors, (Franceschi et al., 2018; Goto, 2008)
characterized by changes in the proportion of the different cells
involved in the immune response could also take place. Such changes
could lead immune changes with age to be adaptive
(Fulop
et al., 2018; Mueller et al., 2013; Nikolich-Zugich, 2018).
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
immunosenescence in free-ranging animals
(Boughton
et al., 2011; Demas et al., 2011). Only few cross-sectional studies
investigated the variations in the immune function with age (mammals:
Abolins
et al., 2018; Cheynel et al., 2017; Nussey, Watt, Pilkington, Zamoyska,
& McNeilly, 2012; birds:
Hill
et al., 2016; Lecomte et al., 2010; Palacios, Cunnick, Winkler, &
Vleck, 2007; Saino, Ferrari, Romano, Rubolini, & Moller, 2003;
Vermeulen, Eens, Van Dongen, & Muller, 2017; reptiles:
Massot
et al., 2011; Ujvari & Madsen, 2011; Zimmerman et al., 2013), and even
less with survival (Froy et al., 2019; Hanssen et al., 2004;
Schneeberger et al., 2014). However, cross-sectional studies cannot
disentangle whether the observed variations arise from within-individual
changes or from processes like selective disappearance
(van
de Pol & Verhulst, 2006; van de Pol & Wright, 2009). Due to this
shortcoming, immunosenescence can be either hidden when it occurs or
observed when it does not
(Nussey,
Coulson, Festa-Bianchet, & Gaillard, 2008) leading to inappropriate
conclusions regarding its evolutionary consequences.
The current lack of longitudinal
studies investigating variations in immune functions with age (to the
best of our knowledge, four studies:
Beirne
et al., 2016; Andrea L. Graham et al., 2010; Schneeberger et al., 2014;
van Lieshout et al., 2020) is one of the biggest limitations to our
understanding of immunosenescence in wild populations
(Peters
et al., 2019). In the present study, we recorded the age-specific
leukocyte concentration and counts in 52 dominant 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, once controlled for a potential selective
disappearance, individuals’ leukocyte concentration and counts only
decrease as they age as expected from the disposable soma theory or
whether more complex patterns involving changes in leukocyte counts do
occur. We further tested whether
age variations in leukocyte concentration and counts correlated with
survival probabilities using a longitudinal approach.
Material and methods