Association Between Leukocyte Telomere Length and Vascular Dementia and Cancer Mortality in an Elderly Population

To the Editor: Telomeres are regions of repeating TTAGGG hexanucleotide sequences located at the ends of each chromosome.1 Telomeres prevent loss of genetic material during cell replication as enzymes that duplicate deoxyribonucleic acid (DNA) are unable to duplicate to the end of a strand of DNA. Consequently, telomeres shorten with each cell cycle, ultimately leading to permanent growth arrest, thus limiting the number of divisions a cell is capable of.1 Previous studies have identified correlations between leukocyte telomere lengths and various lifestyle factors that are frequently associated with cancer and cardiovascular diseases, which represent major causes of mortality in the developed world.2 As a biomarker for cellular stress and aging, particularly of the immune cells and cells of the vascular tree,3 telomere length may be associated with age-related diseases such as cancer and vascular dementia. Participants aged 75 and older were recruited from the Bankstown-Lidcombe Hospital memory clinic and geriatric wards and the War Memorial Hospital, Sydney, Australia. Individuals with a diagnosis of dementia of predominantly vascular etiology were included. Individuals with dementia of predominantly other causes were excluded. Individuals with vascular dementia with an Alzheimer's component were included if it was not the dominant cause clinically for dementia. Control participants were determined to be cognitively normal (Mini-Mental State Examination score ≥28). Control participants with evidence of cerebrovascular events through history or on imaging were excluded. Upon recruitment, participants were guided through a comprehensive questionnaire including medical history and lifestyle factors. Participants were examined, and a blood sample was obtained. Relative telomere length in peripheral white blood cells was measured using a previously described real-time quantitative polymerase chain reaction (RT-qPCR) technique.4 Participants were followed up 2 years after initial examination. Nonparametric Mann–Whitney U-tests were used to compare the differences between the groups. P < .05 was considered statistically significant. Participants with vascular dementia patients had a MMSE score of 19.4 ± 7.1 (n = 39), which was significantly lower (P < .001) than that of controls (29.0 ± 2.1, n = 14). Participants with vascular dementia had a shorter mean leukocyte telomere length (1.07 ± 0.18) than controls (1.21 ± 0.43), although this result was not statistically significant (P = .25). No significant difference (P = .35) was found in the telomere lengths of participants with a cancer diagnosis (alive or dead) (1.23 ± 0.45) and those who never had cancer (1.15 ± 0.35) at the time of recruitment. At follow-up after a mean period of 2 years on 53 participants, 14 participants had died, of which seven deaths were cancer related (nonhematologic) and seven of other causes. Participants who died of cancer had significantly shorter leukocyte telomere lengths than those who died without a cancer diagnosis (P = .002) and those still alive (P < .001) (Figure 1). Two meta-analyses found a significant association between shorter leukocyte telomeres and overall cancer risk,5, 6 although another large population study found a significant correlation between shorter survival after diagnosis of cancer and shorter telomere lengths but no correlation with overall cancer risk.7 The current study focused on older subjects and is in agreement with the latter study. The findings in the current study's older cohort that shorter leukocyte telomere length at the time of cancer diagnosis may be a predictor of future death from cancer is novel, but further studies are needed because the current study was limited mainly by a small sample size. Few studies have examined the association between telomere length and vascular dementia, with contradicting results. One cross-sectional study found that the odds ratio for vascular dementia was significantly higher in those with the shortest telomeres than in those with the longest.8 Another retrospective cohort study found no significant difference in telomere length between individuals with Alzheimer's disease, mixed dementia, and vascular dementia and controls.9 The current study results are in agreement with the latter study. Telomere shortening in leukocytes may result in a reduction in the potency of immune cells, reflecting a decline in their ability to respond to an insult such as cancer. This provides a possible explanation for the trends observed in the curret study. Studies in colorectal cancer have demonstrated a significant association between tumor-infiltrating T-cell density and better prognosis. A similar role has been observed for macrophage infiltration. A significant negative correlation was found between leukocyte telomere length and cancer survival in older adults, and this is novel. Telomere length may be a prognostic indicator in older adults with cancer. Larger studies are required for confirmation. The authors would like to thank the War Memorial Hospital for participation in this study. Conflict of Interest: The editor in chief has reviewed the conflict of interest checklist provided by the authors and has determined that the authors have no financial or any other kind of personal conflicts with this paper. Author Contributions: Daniel Chan conceived the idea of this investigation. Cecil Chen and Ying-Hua Xu drafted the analysis plan, were responsible for the overall analysis, and drafted the manuscript. Zhi-Ming Fang was responsible for blood sample storage and DNA extraction. Nady Braidy was responsible for the molecular analysis. Jihan Khalil and Ciaran Upton were responsible for participant recruitment and collection of medical history. The coauthors reviewed the text, and all approved the final version of the manuscript. Sponsor's Role: None.