Dema María, Eixarch Herena, Hervera Arnau, Castillo Mireia, Villar Luisa M, Montalban Xavier, Espejo Carmen
Servei de Neurologia, Centre d'Esclerosi Múltiple de Catalunya (Cemcat), Vall d'Hebron Institut de Recerca (VHIR), Hospital Universitari Vall d'Hebron, Barcelona, Spain.
Universitat Autònoma de Barcelona, Bellaterra, Spain.
Aging Cell. 2025 May;24(5):e14491. doi: 10.1111/acel.14491. Epub 2025 Feb 2.
The onset of multiple sclerosis (MS) in older individuals correlates with a higher risk of developing primary progressive MS, faster progression to secondary progressive MS, and increased disability accumulation. This phenomenon can be related to age-related changes in the immune system: with age, the immune system undergoes a process called immunosenescence, characterized by a decline in the function of both the innate and adaptive immune responses. This decline can lead to a decreased ability to control inflammation and repair damaged tissue. Additionally, older individuals often experience a shift toward a more pro-inflammatory state, known as inflammaging, which can exacerbate the progression of neurodegenerative diseases like MS. Therefore, age-related alterations in the immune system could be responsible for the difference in the phenotype of MS observed in older and younger patients. In this study, we investigated the effects of age on the immunopathogenesis of experimental autoimmune encephalomyelitis (EAE). Our findings indicate that EAE is more severe in aged mice due to a more inflammatory and neurodegenerative environment in the central nervous system. Age-related changes predominantly affect adaptive immunity, characterized by altered T cell ratios, a pro-inflammatory Th1 response, increased regulatory T cells, exhaustion of T cells, altered B cell antigen presentation, and reduced NK cell maturation and cytotoxicity. Transcriptomic analysis reveals that fewer pathways and transcription factors are activated with age in EAE. These findings allow us to identify potential therapeutic targets specific to elderly MS patients and work on their development in the future.
老年个体中多发性硬化症（MS）的发病与发展为原发性进行性MS的较高风险、更快进展为继发性进行性MS以及残疾累积增加相关。这种现象可能与免疫系统的年龄相关变化有关：随着年龄增长，免疫系统会经历一个称为免疫衰老的过程，其特征是先天性和适应性免疫反应的功能均下降。这种下降会导致控制炎症和修复受损组织的能力降低。此外，老年个体常出现向更促炎状态的转变，即炎症衰老，这会加剧像MS这样的神经退行性疾病的进展。因此，免疫系统的年龄相关改变可能是导致老年和年轻MS患者中观察到的MS表型差异的原因。在本研究中，我们调查了年龄对实验性自身免疫性脑脊髓炎（EAE）免疫发病机制的影响。我们的研究结果表明，由于中枢神经系统中更具炎症性和神经退行性的环境，EAE在老年小鼠中更为严重。年龄相关变化主要影响适应性免疫，其特征为T细胞比例改变、促炎性Th1反应、调节性T细胞增加、T细胞耗竭、B细胞抗原呈递改变以及自然杀伤细胞成熟和细胞毒性降低。转录组分析显示，随着年龄增长，EAE中被激活的信号通路和转录因子减少。这些发现使我们能够确定老年MS患者特有的潜在治疗靶点，并在未来致力于其开发。
