Physiological 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. Here, 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. This 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.

中文翻译：

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C57BL/6J 小鼠脾脏免疫细胞谱和 NK 细胞表型和功能的性别和年龄依赖性改变

生理稳态下降、免疫衰老和多种疾病的风险增加，包括神经退行性变，都是衰老的标志。重要的是，众所周知，衰老过程是有性别偏见的。例如，多种年龄相关疾病的易感性存在性别差异，包括神经退行性疾病和自身免疫性疾病。然而，与年龄相关的免疫表型的性别差异尚不清楚。在这里，我们检查了年龄对两性 C57BL/6J 小鼠免疫细胞表型的影响，特别关注 NK 细胞。我们发现女性特异性脾脏重量随着年龄的增长而增加，并且与年轻女性相比，每克脾脏重量的脾细胞数量一致减少。为了评估脾脏免疫细胞组成中与性别和年龄相关的变化，我们进行了流式细胞术分析。在雄性小鼠中，我们观察到与年龄相关的单核细胞和 NK 细胞频率降低。随着年龄的增长，雌性小鼠的 B 细胞、NK 细胞和 CD8 + T 细胞减少，单核细胞和中性粒细胞的频率增加。然后，我们对血浆细胞因子进行了全血刺激测定和多重分析，并观察了免疫细胞反应性和基础循环细胞因子浓度的年龄和性别特异性差异。正如我们之前阐明的 NK 细胞在帕金森病（一种与年龄相关的神经退行性疾病）中的潜在作用一样，我们进一步分析了 NK 细胞表型和功能中与年龄相关的变化。与年龄相关的 NK 细胞受体表达变化、IFN-γ 产生、和 α-突触核蛋白内吞作用受损。这项研究证明了脾淋巴细胞组成、循环细胞因子/趋化因子谱以及 NK 细胞表型和效应器功能的性别和年龄特异性改变。我们的数据提供的证据表明，与年龄相关的生理扰动在两性之间存在差异，这可能有助于阐明与年龄相关的疾病的性别差异，包括神经退行性疾病，特别是帕金森病，其中免疫功能障碍与其病因有关。