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Deciphering the role of aging in Multiple Sclerosis: focusing on frailty index, neuroinflammation and microbiome
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Age has a negative impact on Multiple Sclerosis (MS), namely influencing disease worsening and the poor response to treatments. With age, the ability to initiate an effective immune response is lost due to a strong accumulation of health deficits leading to MS progression. Although studies highlighted associated pathological mechanisms, influence of frailty and microbiota are now emerging and the impact of age is not yet understood. Further, we previously demonstrated that S100B may be considered a biomarker and an effective therapeutic target in MS. However, how S100B ablation may impact MS along age have not been addressed yet.
Female C57BL/6 mice were EAE induced at three different ages: 3-, 6-, and 12-month-old. Disease course was evaluated using both 5-point Clinical Score and a newly developed EAE Clinical Frailty Index (FI). Interestingly, 12-month-old mice showed atypical disease course, better characterized with the EAE-Clinical FI. Indeed, they developed highest FI scores with no signs of recovery, suggesting a worse disease outcome. Additionally, 12-month-old EAE mice displayed increased glial reactivity in demyelinated spinal cord lesions, with enhanced inflammatory milieu and impaired phagocytosis of microglia. Older mice also displayed increased T cell infiltration in lesions with increased percentage of exhaustive Treg cells at the periphery. Interestingly, the ablation of S100B reduced neuroinflammatory responses with increased regulatory T cells in the periphery, especially in older mice. Microbiome results revealed distinct bacterial composition between the different groups culminating in alterations of gut epithelial tissue in an age dependent manner.
Overall, we demonstrated that age favors a more progressive disease and peripheral changes, namely at microbiome, may contribute for exacerbated pathogenesis, clearly stating the need for more specific therapeutic strategies to better treat MS at advanced ages. In sum, these results are a first step towards the comprehension of how age impact the EAE course and MS-like pathology.
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Modelo animal de Esclerose Múltipla envelhecimento silenciamento do gene S100B índice de fragilidade patogénese do sistema nervoso central resposta imunitária periférica Multiple Sclerosis animal model age of onset S100B knockout Frailty Index central nervous system pathogenesis peripheral immune response