Clinical Context

Telomeres consist of thousands of repeated TTAGGG hexanucleotide sequences located at the ends of each chromosome. By preventing DNA damage response and repair mechanisms from acting on the chromosomal ends, telomeres protect genetic material.

Shortening of telomeres results from cell division. Shorter telomere length (TL) is a biological marker associated with cellular aging and potentially with faster biological aging of the organism as a whole. The study goal was to examine whether shorter TL measured in human blood samples was associated with the development of Alzheimer's disease and mortality among persons 65 years or older.

Study Synopsis and Perspective

Shortening of leukocyte telomeres, the extreme ends of chromosomal DNA, is associated with risks for dementia and mortality, and may be a marker of biological aging, according to a new study.

The results suggest that if TL is a determinant of aging, it might be possible to develop agents that prevent telomere shortening, and this might decrease the incidence of age-related dementia, said lead author Lawrence S. Honig, MD, PhD, from the Taub Institute for Research on Alzheimer's Disease and the Aging Brain, and professor of clinical neurology, at Columbia University, New York City.

"If telomere shortening is truly an important part of the pathogenetic process of aging and not simply some sort of marker of aging, then we might imagine that intervening in that shortening process might somehow cause people to be biologically younger at a given age."

The study, which is published online July 23 in the Archives of Neurology, also confirms that men have shorter telomeres than women, suggesting that men are biologically older than women of the same chronological age.

DNA Samples

Located at the ends of each chromosome, telomeres are responsible for maintaining chromosome stability. They become shorter with each round of DNA replication, which correlates with cellular aging. TL is likely influenced by genetic factors, as well as by factors such as smoking, diet, and physical activity, the researchers write.

Cancer researchers are studying the impact of telomere loss on cancer risk. It appears that telomere shortening may be a necessary biological process in cancer prevention.

The current study used DNA samples from 1978 participants 66 to 101 years of age (mean age, 78.3 years), from the Washington Heights-Inwood Community Aging Project, a population-based study of aging and dementia. The group of study participants was ethnically diverse — 39.9% Hispanic, 30.3% African American, and 28.5% white — and was mostly (68.3%) female. The mean follow-up for mortality was 7.8 years, with a range of 1 to 16 years.

Experts performed apolipoprotein E genotyping and used polymerase chain reaction, a "robust" method of measuring TL now being pursued in the fields of both cancer and aging, said Dr. Honig. "It allows one to come up with mostly reproducible and more informative numbers as to the average telomere repeat length."

Telomeres are measured in base pairs (bp). In this study, the mean TL was 6371 bp for all participants.

The study showed that those who were older at the time of the blood draw had shorter TL. A mean decline of 31.1 bp per year of age was noted (95% confidence interval [CI], 25.7 - 36.5; P < .001).

Men Versus Women

The analysis also showed that telomeres were shorter in men than in women by a mean of 128 bp (95% CI, 48 - 208; P = .002). This, said Dr. Honig, roughly translates into men being 4 years older biologically than women of the same chronological age.

This finding makes sense in that men die earlier than women, although it's difficult to determine if they develop more dementia, said Dr. Honig. "There are more demented women around, but that's because there are more older women than older men. Whether it's truly a sex predilection for dementia is somewhat controversial, but for mortality, there's no question that men do have earlier mortality than women."

The TL also varied by ethnicity, being shortest in the Hispanic population. The relationship of TL to ethnicity persisted for those who remained free of dementia during follow-up.

The study showed that TL varies widely between individuals even within the same age stratum. This, said Dr. Honig, could be because of variations at birth, differences in the rate of telomere attrition during life, environmental influences affecting aging such as diet and exercise, and the presence of other diseases.

"We all know how old somebody is in years, be that 60, or 70, or 40, but the telomere length somehow informs us beyond this chronological age," said Dr. Honig. Patients who develop signs of aging such as skin damage or cataracts might be considered older biologically than someone else of the same chronological age without these conditions.

Because TL varies so much between individuals, it cannot be used by itself as a measure of biological or chronological age, the authors write. However, they say that the combination of TL and chronological age is likely to be more informative than either one alone.

Dementia Link

As for cognition status, 15.9% of participants had prevalent dementia (present at the time the blood sample was drawn), and 9.6% developed dementia during follow-up. Of those with dementia, 79.6% were classified as having probable Alzheimer's disease and 13.9% as having possible Alzheimer's disease.

The study showed a modest association between shorter TL and risk for dementia, taking into account age differences. Shorter TL as a continuous variable was a risk for dementia (hazard ratio, 1.21; 95% CI, 1.00 - 1.46; P = .05).

However, after stratification, the association of TL with dementia was significant only in women, perhaps because there were so few men with incident dementia (n = 56) compared with women (n = 134).

After controlling for age, sex, ethnicity, education, and apolipoprotein E status, the risk of mortality for those with the shortest TL compared with the longest was 1.72 (95% CI, 1.40 - 2.11; P < .001). This association might indicate that shortened TL causes processes that lead to earlier mortality, that other biological processes or preclinical disorders cause TL shortening, or that some environmental or genetic influences cause shortening of TL and increase mortality.

Although at least 1 company has already reportedly jumped on the bandwagon to market a test that determines TL, there is still no way of changing the telomere shortening process, noted Dr. Honig. "What's the point of finding out something about yourself which at the present time you can't intervene to change?" he said.

But that could change in the future. And when researchers do work on developing an agent that curbs telomere shortening, they should consider the effects on cancer, Dr. Honig stressed.

Wide Variation in Telomere Length

Pim van der Harst, MD, PhD, from the Departments of Cardiology and Genetics at the University Medical Center, University of Groningen, The Netherlands, an expert in the field of telomeres, agreed to comment on these findings for Medscape Medical News.

Dr. van der Harst noted that because the study was cross-sectional, it does not show cause and effect. Although the authors also acknowledge this, it's a very important point to stress, said Dr. van der Harst. "It's an association from which we do not learn anything about causality; it might mark some process but does not determine it," he said.

As with his own studies, this research shows very wide variation in TL between individuals of the same age. "On a group level, there are differences, but at an individual level, telomere length will be minimally informative — which isn’t to say totally uninformative — in predicting whether a subject will develop dementia."

Because of this wide intraindividual variation, the observed link between TL and dementia or mortality may not be of much clinical use, said Dr. van der Harst. "It does not accurately inform us as to whether an individual is going to develop dementia or die early."

However, he added that the study should spark further research into the biology of telomeres and dementia that may refine potential clinical use.

The authors have disclosed no relevant financial relationships.

Arch Neurol. Published online July 23, 2012. Abstract

Clinical Implications

• Findings of a prospective study showed an association between shortened TL and mortality risk among persons 65 years or older. TL may be a factor indicative of biological age.
• This prospective study also showed an association of shortened TL with Alzheimer's disease. If TL is a determinant rather than a marker of aging, treatments aimed at modifying TL shortening might theoretically be helpful in reducing the incidence of age-related dementia.

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