Telomeres, Dementia, and Mortality

Abstracts & Commentary

By Gregg L. Caporaso, MD, PhD, Assistant Professor of Neurology and Neuroscience, Weill Cornell Medical College. Dr. Caporaso reports no financial relationship relevant to this field of study.

Synopsis: Short telomeres in peripheral white blood cells might be a prognostic marker for dementia and death following stroke, and for Alzheimer's disease and death in the elderly.

Sources: Martin-Ruiz C, et al. Telomere Length Predicts Poststroke Mortality, Dementia, and Cognitive Decline. Ann Neurol. 2006;60:174-180; Honig LS, et al. Shorter Telomeres are Associated with Mortality in Those with APOE Epsilon4 and Dementia. Ann Neurol. 2006;60:181-187.

The ends of eukaryotic chromosomes are capped by protective structures called telomeres. These are composed of long, tandem TTAGGG DNA repeats (10- to 15-kilobase pairs in humans) and associated binding proteins. Evidence suggests that telomeres prevent chromosomal ends from being recognized as broken or damaged DNA and subsequently triggering cellular DNA repair mechanisms. Since conventional DNA polymerases require an RNA primer to initiate DNA synthesis, a portion of 3'-end telomeric DNA of the template strand is not copied, thus resulting in progressive telomere shortening with repeated rounds of cell division. Germ cells, stem cells, and most cancers circumvent this end-replication problem by expressing the enzyme telomerase, a specialized DNA polymerase that can synthesize TTAGGG repeats at 3'-ends. In most somatic cells, which lack telomerase, critical telomere shortening eventually triggers apoptotic cell death or replicative senescence, a permanent exit from the cell cycle. Further, telomere shortening correlates both with cellular aging—which places a limit on proliferative capacity—and with aging of the organism as a whole. Thus, telomeres might serve as a biomarker for aging. Indeed, telomeres in readily accessible peripheral white blood cells have been studied, and telomere length was found to correlate inversely with the prevalence for a variety of age-related diseases, such as atherosclerosis, myocardial infarction, and dementia, as well as death.

Two new studies now examine further the possible relationship between telomere length and dementia or mortality. Martin-Ruiz and colleagues prospectively followed a cohort of 195 nondemented survivors of stroke ages 75 years and older. Telomere length in peripheral white blood cells was measured 3 months after the stroke. Subjects were assessed cognitively for the development of dementia for up to 2 years and for survival up to 5 years. Baseline telomere lengths ranged from 4892-7785 base pairs (average 6166 bp). Surprisingly, telomere lengths did not correlate with age. However, there was a significant association between telomere length at baseline and risk of death (a decrease by a factor of 0.49 for every 1000-bp increase in telomere length) or of the development of dementia (odds ratio of 0.19 for every 1000-bp increase). In addition, among subjects with telomere lengths in the shortest quartile, a statistically significant reduction of 1.3 points on the Mini-Mental Status Examination (scale 0-30 points) was seen over 2 years. Martin-Ruiz et al note, though, that most of the risk of death was likewise attributable to the shortest quartile, and that this relationship was weaker and less significant after allowing for MMSE scores.

Using clinical data and stored blood samples from the large Washington Heights-Inwood Columbia Aging Project, Honig and colleagues analyzed relative telomere length, prevalence of Alzheimer's disease (AD), and survival in a case-control study of 257 subjects (mean age 81 years). Subjects were selected from the larger group to provide a study population in which 50% had AD and 50% had died during a 10-year follow-up period. Telomere analysis was performed on blood samples that had been collected upon entrance in the study. Telomere lengths were shorter in those with AD and in those who had died. Subjects who had AD and subsequently died, had the shortest telomeres on average. There was no significant effect of telomere length on mortality in the absence of dementia or in subjects lacking an APOE4 allele but, in subjects with at least one APOE4 allele who fell into the shortest telomere tertile, the odds ratio for mortality was 9 times that of those in the longest tertile after adjustment for dementia status.

Commentary

These 2 studies provide additional evidence supporting a relationship between telomere shortening and age-related diseases or survival. It is difficult to make direct comparisons of their results, though, due to marked differences in their study populations and since the 2 groups used different methods to determine telomere length (Martin-Ruiz et al directly measured telomere length, whereas Honig et al determined the amount of telomeric DNA relative to a marker gene). Nonetheless, this new work complements previous studies that have shown a correlation between short telomeres and either vascular dementia or AD. Further, they add to the existing literature by providing a prospective analysis of telomere length and neurological outcomes and also by showing a relationship between telomere length and mortality in demented, but not nondemented, elderly individuals.

At this time, we may only conjecture about the biological underpinnings of the association between telomere length and dementia or death. Does AD or stroke stimulate an immune response that results in white blood cell proliferation and subsequent telomere shortening? Do neurological diseases evoke other biological responses that actively shorten telomeres independently of cell proliferation, or is telomere loss merely a surrogate measure of telomerase down-regulation? Indeed, a variety of new evidence suggests that telomerase might play a role in cell survival unrelated to telomere extension. Does aging of the immune system, reflected in white blood cell telomere loss, predispose to dementia? The most straightforward explanation, provided by both sets of authors, is that telomere shortening occurs as a result of metabolic stress over an individual's lifespan, which also predisposes to a variety of age-related illnesses. Oxidative stress, in particular, has been linked to atherosclerosis, stroke, and dementia and, more recently, to telomere shortening.1 One intriguing study found that average telomere length in the peripheral mononuclear blood cells of premenopausal women who perceived psychological stress in their lives was shorter by the equivalent of one decade of aging.2

The wide variability seen in telomere lengths within each clinical outcome group, as well as the considerable overlap of telomere lengths between these groups, makes it unlikely that absolute telomere lengths could be used as a prognostic marker for disease outcome or mortality. Both studies used blood samples collected at study entry to determine telomere length. It would be interesting to follow telomere lengths prospectively to see if absolute telomere lengths or rates of telomere shortening have greater prognostic significance. Future studies might also test family members to determine whether short telomeres reflect a genetic predisposition to age-related illnesses that increase susceptibility to death or disease.

References

1. von Zglinicki T. Oxidative Stress Shortens Telomeres. Trends Biochem Sci. 2002;27:339-344.

2. Epel ES, et al. Accelerated Telomere Shortening in Response to Life Stress. Proc Natl Acad Sci USA. 2004;101:17312-17315.