Shorter Telomeres Increase Risk for MS Disability Progression
Researchers found an association between telomere length and disability progression in multiple sclerosis.
Biological age, as reflected in telomere length, is a risk factor for disability progression in multiple sclerosis (MS) beyond chronological age, according to a study published September 4 online in Annals of Neurology. The study indicates that those patients with shorter leukocyte telomeres are more likely to have higher disability scores and lower brain volume.
“We found an association between telomere shortening and disability accumulation,” said lead study author Jennifer S. Graves, MD, PhD, MAS, assistant clinical professor of neurology at the University of California, San Francisco (UCSF) and the Weill Institute for Neurosciences. “We found this association with clinical disability in cross-section, and in a longitudinal assessment. It supports the concept that biological aging may be a key driver for development of a progressive phenotype in MS.”
Telomeres are repeating DNA sequences at the tips of chromosomes, which shorten during each cell division. Oxidative stress promotes shortening, as does DNA damage, making telomere length a marker of “biological,” rather than just chronological, aging.
“There is heterogeneity in aging across different individuals with the same birth date,” Dr. Graves said, which is reflected in telomere length, as well as several other indices of biological age. In a study of a large cohort of 38-year-olds, for instance, biological age ranged from 25 to 60 years; chemotherapy causes accelerated aging in the survivors of childhood cancers.
Age clearly influences phenotype in MS, she added; in pediatric disease, the inflammatory component is severe, but recovery is often almost complete, whereas older patients, complete remission is rarer.
“At some point in many patients, we don't see those relapses, and instead the patient develops a smoldering inflammation that never remits.”
But not every patient develops progressive disease, and it is this heterogeneity that Dr. Graves hopes to understand better.
“We have known for some time that chronological age is associated with accumulation of disability,” Dr. Graves said, with greater age at onset predictive of faster progression. “But we wanted to understand what is happening biologically as well.” Telomeres have been described as “the ultimate biological clock for aging,” she said, making them the obvious target for understanding the role of biological age in MS.
Study Design, Findings
To do so, Dr. Graves and colleagues studied 516 individuals who were seen at the UCSF MS Center from 2004 to 2005 and who were followed for up to 10 years. Patients received standard MS assessments, and baseline telomere length was determined in blood leukocytes, which are a common reference cell type for telomere studies. Telomere length was also determined longitudinally in a subgroup of 46 patients.
Patients had a mean age of 42.6 years, with a median disease duration of six years, encompassing a wide range, from 0 to 45 years. At baseline, the average leukocyte telomere length was 5,615 base pairs, similar to measures of the healthy population at large. Shorter telomere length was associated with both higher age and longer disease duration. For each year of chronological age, telomere length was 24 base pairs shorter. The choice of disease-modifying therapy used by the patient was not correlated with telomere length, suggesting that differences between agents do not include any ability to slow the shortening of telomeres.
Dr. Graves and her team next looked at the relationship between telomere length and disability score, as measured by the Expanded Disability Status Scale (EDSS). They found that after adjusting for age, disease duration, and sex, for every reduction in telomere length of 0.2 base pairs, EDSS score was 0.27 higher (worse), and brain volume as measured by MRI was 7.4 cubic millimeters less. Both associations were statistically significant.
They then conducted a mediation analysis to determine to what degree the effects of age and telomere length were linked, and in which direction. They found that 15 percent of the effect of increasing age on worsening EDSS was mediated by (or explained by) the decrease in telomere length, indicating that the observed effect of telomere length was not simply a reflection of increased age.
Baseline telomere length was only a weak predictor of the rate of disability progression over time, although those with shorter telomeres at baseline did have smaller brain volumes after 10 years of follow-up. In the small group of patients with longitudinal assessment of telomere length, shortening of telomeres was associated with worsening disability.
“We have been searching for some time for the drivers of accumulating disability in MS, for those factors that switch patients into a progressive form of the disease,” Dr. Graves said. “The key feature may be the host's changing immune system as it ages. As the immune cells becoming senescent, they secrete different cytokines that may drive a chronic inflammatory state.”
Whether telomere shortening is just a marker for the underlying causes of biological aging, or is itself a contributor to that process, is not yet clear, Dr. Graves said. “Shortening of telomeres is one part of the DNA damage response, and when they are shortened, there are downstream effects” that may tip cells toward senescence. “That is a plausible mechanism, but we don't yet have the evidence that this is operating in MS.”
Whether telomeres themselves will be an appropriate target for therapy is unclear, Dr. Graves said. While there is a naturally occurring enzyme called telomerase that adds base pairs to telomeres, telomere lengthening is a risk factor for malignancy. But other contributors to aging may be appropriate targets, she said.
“I think that the researchers have discovered yet another fascinating biomarker for disability progression,” commented Lawrence Steinman, MD, PhD, FAAN, professor of pediatrics, neurology and neurological Sciences at Stanford University. “Such a biomarker may be a valuable way to stratify patients for clinical trials based on their biological age and therefore their progression risk,” he said.
“This puts to rest a lot of speculation on how length of telomeres affects disability in MS,” said Arthur A. Vandenbark, PhD, professor of neurology at Oregon Health and Science University in Portland Portland and senior research career scientist at the Portland Veterans Administration Medical Center, where he researches pathogenic mechanisms in MS.
“This is a very well-done study, and I am well persuaded that their conclusions are really on target,” Dr. Vandenbark said. “The fact they were able to assign a percent contribution of telomere shortening to disability, above what the age-related change would be, is really important, because it gives us a metric to say how much of an impact it is having on progression, an important factor to consider in trial enrollment and analysis.
“But there are clearly other factors contributing as well,” he said, “and we need to understand those better. My hope is that, as a collective group of scientists, we can come up with enough of those modifiers that we can control, so that we will have better ways to slow progression.”