Abstract
BackgroundPhysiological homeostasis decline, immunosenescence, and increased risk for multiple diseases, including neurodegeneration, are all hallmarks of ageing. Importantly, it is known that the ageing process is sex-biased. For example, there are sex differences in predisposition for multiple age-related diseases, including neurodegenerative and autoimmune diseases. However, sex differences in age-associated immune phenotypes are not clearly understood.ResultsHere, we examined the effects of age on immune cell phenotypes in both sexes of C57BL/6J mice with a particular focus on NK cells. We found female-specific spleen weight increases with age and concordant reduction in the number of splenocytes per gram of spleen weight compared to young females. To evaluate sex- and age-associated changes in splenic immune cell composition, we performed flow cytometry analysis. In male mice, we observed an age-associated reduction in the frequencies of monocytes and NK cells; female mice displayed a reduction in B cells, NK cells, and CD8 + T cells and increased frequency of monocytes and neutrophils with age. We then performed a whole blood stimulation assay and multiplex analyses of plasma cytokines and observed age- and sex-specific differences in immune cell reactivity and basal circulating cytokine concentrations. As we have previously illustrated a potential role of NK cells in Parkinson’s disease, an age-related neurodegenerative disease, we further analyzed age-associated changes in NK cell phenotypes and function. There were distinct differences between the sexes in age-associated changes in the expression of NK cell receptors, IFN-γ production, and impairment of α-synuclein endocytosis.ConclusionsThis study demonstrates sex- and age-specific alterations in splenic lymphocyte composition, circulating cytokine/chemokine profiles, and NK cell phenotype and effector functions. Our data provide evidence that age-related physiological perturbations differ between the sexes which may help elucidate sex differences in age-related diseases, including neurodegenerative diseases, particularly Parkinson’s disease, where immune dysfunction is implicated in their etiology.
Highlights
Physiological homeostasis decline, immunosenescence, and increased risk for multiple diseases, including neurodegeneration, are all hallmarks of ageing
When spleen weights were normalized to body weight, females displayed a significant age-dependent increase in spleen/body weight ratio, but there was no age-related difference in males (Fig. 1c)
When the number of splenocytes was normalized to spleen weight, an age-dependent decrease in the number of splenocytes per g of spleen was observed in females (Fig. 1e) but no differences were observed in males (Fig. 1e)
Summary
Physiological homeostasis decline, immunosenescence, and increased risk for multiple diseases, including neurodegeneration, are all hallmarks of ageing. Within the ageing immune system, it is reported that while similar changes may take place in both sexes, overall rates of these immune system changes differ between the sexes (reviewed in [4]). Despite these differences, most studies have overwhelmingly favored the use of males, without consideration of sexually dimorphic effects on disease prevalence, intervention efficacy, and outcomes. Several age-related neurodegenerative diseases have sex-associated differences in prevalence including Parkinson’s disease (PD) (higher prevalence in males) [5], multiple sclerosis (higher prevalence in females) [6], and Alzheimer’s disease (higher prevalence in females) [7]. Inflammageing, or the reshaping of cytokine expression patterns with a progressive tendency toward a proinflammatory phenotype, is a characteristic feature of both ageing and age-related diseases [9]
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