Genetic, Environmental and Lifestyle Determinants of Accelerated Telomere Attrition as Contributors to Risk and Severity of Multiple Sclerosis

Abstract

Telomeres are protective structures at the ends of linear chromosomes. Shortened telomere lengths (TL) are an indicator of premature biological aging and have been associated with a wide spectrum of disorders, including multiple sclerosis (MS). MS is a chronic inflammatory, demyelinating and neurodegenerative disease of the central nervous system. The exact cause of MS is still unclear. Here, we provide an overview of genetic, environmental and lifestyle factors that have been described to influence TL and to contribute to susceptibility to MS and possibly disease severity. We show that several early-life factors are linked to both reduced TL and higher risk of MS, e.g., adolescent obesity, lack of physical activity, smoking and vitamin D deficiency. This suggests that the mechanisms underlying the disease are connected to cellular aging and senescence promoted by increased inflammation and oxidative stress. Additional prospective research is needed to clearly define the extent to which lifestyle changes can slow down disease progression and prevent accelerated telomere loss in individual patients. It is also important to further elucidate the interactions between shared determinants of TL and MS. In future, cell type-specific studies and advanced TL measurement methods could help to better understand how telomeres may be causally involved in disease processes and to uncover novel opportunities for improved biomarkers and therapeutic interventions in MS.

Keywords: aging; disease modifiers; environment; genetics; lifestyle; multiple sclerosis; risk factors; telomere length; telomere shortening.

Figure 1

Common factors known to influence telomere length as well as susceptibility and course of multiple sclerosis (MS). A combination of genetic, environmental and lifestyle/behavioral factors contributes to risk and severity of MS. Shown in the outer ring are MS risk factors that have also been described to influence the shortening of telomere lengths (TL) with age. Accelerated loss of telomeric repeats, mediated by increased oxidative stress and chronic inflammation, can lead to genomic instability and altered immune cell functions. In MS, this may contribute to an abnormal response of the immune system that is directed against the central nervous system (CNS). Moreover, senescence mechanisms in CNS-specific cells may also play a role in the pathogenesis and progression of MS. It remains to be elucidated in more detail how exactly interactions between genetic and nongenetic factors may decisively shape the risk of MS in childhood/adolescence and the course of the disease in later life.