Shorter telomeres linked to higher risk of age-related brain diseases

People with shorter protective caps at the end of their chromosomes (called telomeres) may be more likely to develop age-related brain diseases such as stroke, dementia and late-life depression (usually diagnosed at age 60 or older), according to a preliminary study to be presented at the American Stroke Association's International Stroke Conference 2025. The meeting is in Los Angeles, Feb. 5-7, 2025 and is a world premier meeting for researchers and clinicians dedicated to the science of stroke and brain health.

Leukocyte telomere length, which reflects the length of the telomeres within white blood cells (leukocytes), is a known marker of biological aging. Telomeres gradually shorten with age, reducing their ability to protect the chromosomes' genetic material, leading to cellular aging and increased susceptibility to age-related diseases. The length of telomeres is affected by unchangeable factors such as genetics, ancestry and gender, as well as modifiable factors such as lifestyle choices and environmental stressors, including pollution.

No studies have examined the impact of leukocyte telomere length on a composite outcome of age-related brain diseases that include stroke, dementia and late-life depression. All three conditions are linked to cerebral small vessel disease, a condition associated with aging and accumulation of vascular risk factors."

Tamara N. Kimball, M.D., postdoctoral research fellow at the Henry and Allison McCance Center for Brain Health, Massachusetts General Hospital, Boston

The current study uses data from more than 356,000 participants in the large UK Biobank to address three questions. When participants were recruited for the study between 2006 and 2010, they provided blood samples to analyze leukocyte telomere length. Additionally, they underwent a Brain Care Score assessment, a tool designed to quantify modifiable factors such as physical factors, lifestyle choices and social interactions. Participants were followed for a median duration of 12 years to monitor the onset of stroke, dementia or late-life depression.

After analyzing whether shorter leukocyte telomeres were associated with stroke, dementia, and late-life depression individually and as a combined outcome, the analysis found:

• Compared to participants with longer leukocyte telomeres, people with the shortest leukocyte telomere length had an 8% higher risk of stroke, a 19% higher risk of dementia and a 14% higher risk of late-life depression.
• Overall, compared to participants with longer leukocyte telomeres, people with the shortest leukocyte telomere length had an 11% higher risk of developing at least one of the age-related brain diseases studied.

"In a clinical setting, leukocyte telomere length could help identify people who may need more intensive monitoring or preventive measures. It could also guide personalized interventions, including lifestyle adjustments and therapeutic approaches, to enhance overall health. However, given that the evidence linking leukocyte telomere length to stroke risk is still exploratory, we currently do not suggest leukocyte telomere length measurement be used as a standard practice," Kimball said.

Using a statistical method that identifies potential causality in the relationship between exposure and health outcomes, researchers can more accurately determine how certain risk factors may lead to health conditions. This study found no evidence that leukocyte telomere length may cause stroke, dementia or late-life depression.

"Our findings suggest that, while leukocyte telomere length may be a well-known indicator of biological aging, it does not directly cause these age-related diseases. Instead, leukocyte telomere length may act more as a reflective marker of underlying biological processes and cellular stress that precede these age-related diseases," Kimball said.

After exploring whether healthy behaviors can influence the association between leukocyte telomere length and age-related brain diseases, the analysis also found:

• In people with a low Brain Care Score/less favorable modifiable risk factor profile, shorter leukocyte telomeres significantly increased (by 11%) the risk for stroke, dementia and late-life depression as a combined outcome.
• Conversely, among people with a high Brain Care Score, indicating healthier lifestyle choices, shorter leukocyte telomeres were not associated with an increased risk of age-related brain diseases.

"This suggests that adopting healthier lifestyles and improving modifiable risk factor profile may lower the negative effects of shorter leukocyte telomeres. In short, it is never too late to start taking better care of your brain," said Kimball.

More research and longer studies are needed to understand the dynamics of leukocyte telomere length over time, how it interacts with various risk factors, and how it might be used in personalized health care strategies.

"Rather than focusing on developing therapeutic drugs to directly alter telomere length – which may carry potential risks – a holistic approach centered on modifiable lifestyle factors might offer a promising strategy for promoting healthier aging and reducing the risks of these diseases," Kimball said.

The study has several limitations. It focused solely on people of European ancestry, so the results may not be generalizable to other populations. The leukocyte telomere length and the Brain Care Score were measured at baseline, so the researchers could not analyze changes over time. While leukocyte telomere length is a proxy for overall telomere length and is increasingly accepted as a marker of adverse cellular aging, it may not represent telomere length in cell types other than white blood cells.

"This study suggests that the aging process directly impacts the risk of major age-related brain diseases, relatively independent of other risk factors. While the link between aging and stroke, dementia and late-life depression is well established, the finding that telomere shortening in white blood cells can be a sign of aging holds significant clinical implications for assessing risks and predicting health outcomes," said Costantino Iadecola, M.D., FAHA, director and chair of the Feil Family Brain and Mind Research Institute and Anne Parrish Titzell Professor of Neurology at Weill Cornell Medicine, New York. "Recent research shows that different parts of the body age at different rates, each with its own "aging clock." Evidence suggests that longer telomeres in white blood cells are connected to a lower risk of major brain diseases related to aging. This indicates a strong link between the aging clock of the immune system and the brain." Iadecola was not involved in this study.

Study details, background or design:

• The analysis included more than 356,000 participants (average age 56 at the start of the study, 46% men) in the UK Biobank (a large-scale population-based prospective study that has enrolled over half a million volunteer participants from 22 centers in the United Kingdom).
• Leukocyte telomere length (a proposed marker of biological age) was measured at enrollment. Because leukocyte telomere length is associated with genetics and ancestry, people were excluded if their ancestry was other than European and if they were blood relatives of anyone else in the study.
• Participants were enrolled in the Biobank between 2006 and 2010, during which detailed baseline questionnaires, physical measurements and biomedical assessments were obtained. These were used to assess the leukocyte telomere length and calculate the Brain Care Score. This 19-point scale includes potentially modifiable factors (such as blood pressure), lifestyle factors (such as diet and exercise), and social/emotional factors (such as stress and the strength of social relationships) related to brain health. None of the participants had been diagnosed with stroke, dementia or late-life depression at the beginning of the study.
• Using national health databases and periodic medical assessments, participants were tracked for a median of 12 years for the diagnosis of stroke, dementia, or late-life depression.
• To assess the association of leukocyte telomere length with the diagnoses, leukocyte telomere length measurements were divided into the shortest, intermediate and longest thirds for analysis.
• Researchers used a statistical method called Mendelian Randomization to explore whether there is a causal association between leukocyte telomere length and these age-related brain diseases.