Telomere Length Linked to Age-Related Brain Diseases

Longer leukocyte telomeres are linked to a lower risk for stroke, dementia, and late-life depression (LLD), early research suggests. The findings also indicated that adopting a healthy lifestyle may help reduce risks associated with shorter telomere lengths.

“Measuring leukocyte telomere length may offer insights into a patient’s risk for stroke, dementia, and late-life depression”, study investigator, Tamara N. Kimball, MD, a postdoctoral research fellow at the Henry and Allison McCance Center for Brain Health, Massachusetts General Hospital, Boston, told Medscape Medical News.

However, while the findings are encouraging, Kimball cautioned they are preliminary and need further validation before they could be integrated into clinical practice.

The findings were presented on February 5 at the International Stroke Conference (ISC) 2025.

A Biomarker for Cellular Aging

Telomeres, the protective caps on the end of chromosomes, “act as a biomarker that reflects cellular aging” and increase susceptibility to age-related disease, said Kimball. “If we don’t have telomeres of a certain length, our DNA is more prone to damage,” she explained.

Leukocyte telomere length (LTL) is influenced by a complex interplay of lifestyle and heritable factors. The heritability of LTL is estimated to be up to 83%, although this varies significantly and depends on family history, said Kimball.

It’s unclear to what extent healthy lifestyles can modify the relationship between LTL and age-related diseases.

Using data from the UK Biobank (UKB), the study included 356,173 participants, mean age, 57 years without stroke, dementia, or depression. Researchers analyzed blood samples provided by subjects to determine LTL measurements.

They stratified LTL into tertiles — shortest [T1], intermediate [T2], and longest [T3].

To assess the risks associated with different risk factor profiles, researchers used the Brain Care Score (BCS), a validated metric in the UKB for age-related brain diseases. The BCS includes factors such as blood pressure, blood sugar, cholesterol, body mass index, nutrition, alcohol consumption, smoking, sleep, stress, and social relationships.

In this case, the BCS score goes up to 19 points, with more points reflecting a more favorable risk factor profile. Researchers stratified study subjects into those with a high BCS (≥ 15 points) and low BCS (≤ 10 points).

Participants were followed for a median of 12 years to monitor for the onset of stroke, dementia, or LLD.

After adjusting for age, sex, and a 5-point higher baseline BCS, telomere length was associated with a significantly increased risk for age-related brain diseases as a composite outcome (hazard ratio [HR], 1.11; 95% CI, 1.08-1.15 for T1 compared with T3).

Researchers also found significant associations between LTL for the individual diseases under study. The HRs for the shortest vs longest leukocyte telomere groups were: 1.08 (95% CI, 1.02-1.15) for stroke; 1.19 (95% CI, 1.12-1.26) for dementia; and 1.14 (95% CI, 1.09-1.18) for LLD.

Role of Depression 

The researchers included depression alongside stroke and dementia due to their frequent comorbidity. “These conditions compound the overall impact, creating a significant burden on the aging population,” said Kimball, noting that they also share a common pathophysiology through cerebral small vessel disease.

Using the Mendelian Randomization statistical method, researchers did not find a direct causal relationship between telomere length and age-related brain diseases. However, they did uncover a role for healthy lifestyles.

Individuals with a favorable risk factor profile within the shortest leukocyte telomere group did not show a significant increase in the risk for age-related brain diseases.

In contrast, thosein the shortest LTL tertile with the low BCS had a significantly increased risk for the composite outcome of stroke, dementia, and LLD.

“Improved modifiable risk factor profiles, as reflected by higher BCS, appears to mitigate the impact of leucocyte telomere length on these diseases”, said Kimball. “By adopting and maintaining healthier behaviors, individuals may counteract some of the detrimental effects associated with leukocyte telomere length.”

Holistic Approach

Telomere length has recently become a prominent focus of research. The goal is to develop therapeutic interventions that directly influence telomere length, though potential risks remain.

“We’re proposing that a more holistic approach centered on modifiable lifestyle factors might offer a promising strategy to promote healthier aging and also reduce the risk of these age-related brain diseases,” said Kimball.

The study was conducted only in people of European ancestry. As LTL is strongly related to ancestry as well as to sex and age, Kimball and colleagues would like the findings replicated in other populations to determine whether they are generalizable.

Another potential approach is to conduct a longitudinal study that assesses both lifestyle factors and LTL at multiple time points.

“This could allow a more comprehensive understanding of the dynamics of these leukocyte telomere lengths over time, and also to see how these lifestyle factors interact with leukocyte telomere length,” said Kimball.

Kimball suggested another future direction: Utilizing aging biomarkers to develop a risk prediction tool may offer another future direction.

“The ideal would be to develop personalized interventions and identify individuals who are at the highest risk of developing these outcomes based on their cellular aging biomarkers.”

However, she said, it’s too early to recommend measuring LTL as a standard clinical practice. “Even though it’s promising, we still wouldn’t recommend it as a standard practice at this moment, but maybe the future will take us over there.”

A Significant and Measurable Risk Factor

Commenting on the research, Costantino Iadecola, MD, director and chair, Feil Family Brain and Mind Research Institute, New York City, and Anne Parrish Titzell, professor of neurology, Weill Cornell Medicine, New York City, noted the important role of telomeres in aging.

“As we get older, telomeres get shorter and shorter, exposing more of the genetic material to the deleterious effects” of, for example, environmental exposures like radiation and chemicals that may lead to mutations and promote disease processes associated with aging, said Iadecola in an AHA statement.

The finding that leukocyte telomeres essentially correlate with stroke, dementia, and depression in old age “is very, very significant because it provides an insight into a kind of measurable factor that we can use to assess risk,” he said.

Up for discussion, though, is what steps physicians could take in the presence of telomere shortening, he added.

Kimball and Iadecola reported no relevant financial relationships.