Telomere Length in Aging Cells May Influence Disability Progression in Multiple Sclerosis

Jennifer Graves, MD, PhD, addresses the room about her findings at the CMSC Annual Meeting.
Image courtesy: Shmulik Almany

Secondary progressive multiple sclerosis (SPMS) is actually an age-related disease. Jennifer Graves, MD, PhD, presented this argument in her Presidential Lecture at the 2023 Annual Meeting of the Consortium of Multiple Sclerosis Centers (CMSC) on Thursday, June 1, 2023. According to this theory, MS phenotype is closely dependent on characteristics of the host, and of these characteristics, the most important is age.

“People living with MS experience normal aging, but they also likely experience accelerated aging related to the disease process itself,” Graves, an associate professor of neurosciences and the director of neuroimmunology research at the University of California San Diego (UCSD), said. “Biological aging has been shown to contribute to neurodegeneration in people with MS, with a decline in remyelination capacity and altered immunologic responses with age.”

In people with MS, being older at the time of diagnosis is associated with shorter time to disability milestones independent of disease duration. "But the number of birthdays isn't everything," Graves added. Biological age often differs significantly from chronological age. An algorithm developed by the National Health and Nutrition Examination Survey lists 10 biomarkers that collectively measure biological age, including such as C-reactive protein, serum creatinine, cholesterol levels, forced expiratory volume in 1 second, and systolic blood pressure. In a large study of 1000 individuals aged 38 years based on this algorithm, the subjects' biological ages ranged from 25 years to as high as 60 years.

Telomeres are another way to gauge biological age, Graves said. As quantifiable measures of the body's response to the passage of time, telomeres represent "the ultimate biological clock," she said. Telomeres consist of proteins and nucleotide sequences at the end of each chromosome, protecting the end of the chromosome from deterioration. They also shorten with each cell division, thus serving as a hallmark of the aging process. Telomere length is highly susceptible to oxidative stress and can be affected by genetic, biologic, and external factors.

People with MS have shorter telomere lengths relative to matched controls without MS, Graves reported. Shortened telomere length has also been observed in people with atherosclerotic cardiovascular disease, dementia, and autoimmune diseases such as lupus and rheumatoid arthritis. In people with MS, oxidative stress and damage to DNA, along with a genetic predisposition, may shorten telomere length on the leukocytes, potentially hastening MS disability. "Leukocyte telomere length triggers the DNA damage response and drives biological aging processes, including the generation of senescent cells," Graves said. Senescent cells cannot replicate, but because they accumulate in the body, these cells continue to produce cytokines that drive chronic inflammation.

Image courtesy: Shmulik Almany

Research by Graves and colleagues showed that biological aging, as measured by leukocyte telomere length, is associated with clinical disability and brain volume in MS, independent of a person’s chronological age or duration of disease. The study used the EPIC cohort of 516 patients (mean age at baseline, 43 years; 71% relapsing MS; 15% clinically isolated syndrome; 9% SPMS; 4% primary progressive MS). At baseline, leukocyte telomere length was consistent with that of control populations in this age range, Graves explained, and over a 10-year follow-up period:

• Telomere length, independent of disease duration and chronological age, was significantly associated with higher disability scores on the EDSS (P <.001);
• Shorter telomere length was associated with reduced brain volume (total brain and white matter volumes) with clinically relevant effects sizes;
• Telomere attrition explained 15% of the variance of the effect of chronological age on disability.

In a subset of 46 patients whose telomere lengths were measured over time, the researchers matched pairs based on baseline age, disability, and disease duration. One half went on to develop secondary progressive MS and the other half did not. "We found an association with disability," she said. For every 0.2 telomere to single copy gene ratio shortening of leukocyte telomere length was a 0.3 higher EDSS score, which was statistically significant. The group is currently working on analysis for a larger dataset to replicate these results.

As somatic aging becomes better understood, many branches of science and medicine want to harness anti-aging strategies in search of the fountain of youth, Graves suggested. Treating comorbidities and improving diet and exercise will come into focus as important ways to modify the disease over a lifetime. Experimental pathways include using pharmacologic approaches, such as chimeric antigen receptor–T cell inhibition, to aid the body in ridding itself of senescent cells while preserving nonsenescent cells, she said. Ultimately, “targeting aging-related processes may be a therapeutic strategy for addressing disability in progressive MS.”

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