Life is short, may your telomeres not get shorter

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As cells divide, chromosomes replicate so that each cell contains the full complement of genetic material required for it to work. Telomeres are stretches of genetic material that are found at the ends of chromosomes protecting it from damage.

There are a few interesting facts related to telomere length: 1) telomere length shortening is believed to be a major contributor to ageing; 2) telomere length is longer in women compared to men; 3) European children have a shorter telomere than Pacific children as the latter from an evolutionary perspective are less genetically diverse.

MS also seems to also have a role to play in this story. Viruses, such as the Human Herpesvirus (HHV)-6A long linked to MS also integrates into telomeres of chromosomes. The length of telomeres in the immune cell genes (called leukocyte telomere length, LTL) may also vary between MS subtypes. In this study by Michael Hecker and colleagues in Germany, leukocyte telomere length was significantly shorter in RRMS than controls (irrespective of sex), and those with shorter leukocyte telomere length were more likely to convert to SPMS within 10 years (see Figure 1c,d below).

Fig. 2
Figure 1: Telomere dynamics and long-term clinical course stratified by telomere length. a For 10 MS patients, relative LTL was measured at baseline and after >10 years. The connected scatterplot shows similar LTL decrease over time (paired t-test p=2.0e-04), independent of disease subtype at baseline. bd The group of RRMS patients was split into two groups with low (n=24) and high (n=16) LTL, respectively. They were followed up for 10 years after the blood sampling. b Kaplan-Meier curves for relapse-free survival. Overall, the curves of both groups were similar. The Cox proportional hazard ratio (HR) and the logrank test p value are given in the figure, and right-censored observations are indicated by vertical dashes. c Kaplan-Meier plot showing that RRMS patients with low LTL have a much higher risk for conversion to SPMS. d Comparison of disability progression for RRMS patients with low and high LTL at baseline. There was a tendency of elevated average EDSS scores in the group of patients with relatively short telomeres. 

So your genes have it, in this case your leukocyte genes. If you add in the other known knowns about telomere length, being male and European may also be risk factors. One thing this work doesn’t touch upon is the influence of the inflammatory milieu and oxidative stress found in MS on telomere length, which is an important facet to understand.

Abstract

Mol Neurobiol. 2021 Feb 5. doi: 10.1007/s12035-021-02315-y. Online ahead of print.

Leukocyte Telomere Length in Patients with Multiple Sclerosis and Its Association with Clinical Phenotypes

Aging is a significant factor influencing the course of multiple sclerosis (MS). Accelerated telomere attrition is an indicator of premature biological aging and a potential contributor to various chronic diseases, including neurological disorders. However, there is currently a lack of studies focusing on telomere lengths in patients with MS. We measured the average leukocyte telomere length (LTL) in biobanked DNA samples of 40 relapsing-remitting MS patients (RRMS), 20 primary progressive MS patients (PPMS), and 60 healthy controls using a multiplex quantitative polymerase chain reaction method. Changes in LTL over a period of >10 years were evaluated in a subset of 10 patients. Association analyses of baseline LTL with the long-term clinical profiles of the patients were performed using inferential statistical tests and regression models adjusted for age and sex. The cross-sectional analysis revealed that the RRMS group was characterized by a significantly shorter relative LTL, on average, as compared to the PPMS group and controls. Shorter telomeres at baseline were also associated with a higher conversion rate from RRMS to secondary progressive MS (SPMS) in the 10-year follow-up. The LTL decrease over time was similar in RRMS patients and PPMS patients in the longitudinal analysis. Our data suggest a possible contributory role of accelerated telomere shortening in the pathobiology of MS. The interplay between disease-related immune system alterations, immunosenescence, and telomere dynamics deserves further investigation. New insights into the mechanisms of disease might be obtained, e.g., by exploring the distribution of telomere lengths in specific blood cell populations.

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Neuro Doc Gnanapavan

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