Review of evidence linking exposure to environmental stressors and associated alterations in the dynamics of immunosenescence (ISC) with the global increase in multiple sclerosis (MS).

Historical survey confirms that, over the latter part of the 20^th century, autoimmune-based diseases, including multiple sclerosis (MS), have shown a worldwide increase in incidence and prevalence. Analytical population studies have established that the exponential rise in MS is not solely due to improvements in diagnosis and healthcare but relates to an increase in autoimmune risk factors. Harmful environmental exposures, including non-communicable social determinants of health, anthropogens and indigenous or transmissible microbes, constitute a group of causal determinants that have been closely linked with the global rise in MS cases. Exposure to environmental stressors has profound effects on the adaptive arm of the immune system and, in particular, the associated intrinsic process of immune ageing or immunosenescence (ISC). Stressor-related disturbances to the dynamics of ISC include immune cell-linked untimely or premature (p) alterations and an accelerated replicative (ar) change. A recognised immune-associated feature of MS is pISC and current evidence supports the presence of an arISC during the disease. Moreover, collated data illustrates the immune-associated alterations that characterise pISC and arISC are inducible by environmental stressors strongly implicated in causing duplicate changes in adaptive immune cells during MS. The close relationship between exposure to environmental risk factors and the induction of pISC and arISC during MS offers a valid mechanism through which pro-immunosenescent stressors may act and contribute to the recorded increase in the global rate and number of new cases of the disease. Confirmation of alterations to the dynamics of ISC during MS provides a rational and valuable therapeutic target for the use of senolytic drugs to either prevent accumulation and enhance ablation of less efficient untimely senescent adaptive immune cells or decelerate the dysregulated process of replicative proliferation. A range of senotherapeutics are available including kinase and transcriptase inhibitors, rapalogs, flavanols and genetically-engineered T cells and the use of selective treatments to control emerging and unspecified aspects of pISC and arISC are discussed.