In this nested case-control study, we found that men with relative shorter telomeres had a lower risk for PD. This runs contrary to what we had expected, because shorter telomeres are considered a marker of oxidative stress 10
, and oxidative stress has been proposed as an important contributor to PD pathogenesis11
. Furthermore, short telomeres have previously been found to be associated with a higher risk of other age-related degenerative diseases, including dementia. 3–5, 12
Nevertheless, other puzzling epidemiological findings have been observed for PD: for example, smoking, an important risk factor in many aging-related disease, has been consistently shown to be inversely associated with PD13
, and PD patients appear to have on average a lower incidence of cancer.14
An important strength of the present study is its prospective design, which minimizes artifacts due to the effect of PD and its treatment on telomere length. Further, cases and controls were selected from the same well-characterized cohort, and analyses were adjusted for smoking and other potential confounders using prospectively collected and detailed information on the relevant covariates. The main limitation was the moderate sample size, which reduced the statistical power in analyses restricted to never smokers or the analyses that excluded men who already had symptoms of PD at the time of blood collection.
We did not find a significant correlation between age and telomere length. The modest correlation may be due in part to intra-individual variability, because telomere length varies widely even among individuals of the same age.5,9
In agreement with the study by Valdes et al,15
our results showed an association of smoking with telomere loss. Cigarette smoking is associated with shorter telomere length and a low risk of PD, and is a confounder of the association between telomere length and PD risk. In our analysis, adjustment for pack-years of smoking only slightly attenuated of the RRs of PD across quartiles of telomere length, suggesting that confounding by smoking is an unlikely explanation of the relation between telomere length and PD risk. On the other hand, we cannot exclude the possibility that telomere length is a biomarker for some effect of cigarette smoking that is important for PD protection.
A biological explanation for our findings is not readily available. Telomere length is determined by several biological factors, which are under genetic and environmental influence. These factors include, among many others, division rates of somatic cells, oxidative stress, and telomerase activity.16
One possible explanation for the relatively longer telomeres in PD is the activation of telomerase (normally inactive in somatic cells), although other proteins that regulate telomere function and length (e.g., TRF: telomere repeat binding factor 1 and 2; and TERC: telomerase RNA component) have been identified and linked to human diseases.17
Alternatively, the longer telomeres in individuals with PD may reflect a higher rate of apoptosis and thus a shorter lifespan of senescent cells (which have shorter telomeres) in peripheral blood. It is possible that besides endogenous factors, unknown environmental or lifestyle exposures that were not accounted for in our analysis influenced our results.
In summary, in this prospective study, we found no indication that there might be an increased risk of PD in men with shorter telomeres. Rather, unexpectedly, men with shorter telomeres had a lower risk of PD then those with longer telomeres. In spite of the modest sample size, restriction to men, and the other limitations discussed above, this finding is intriguing and warrants further epidemiologic studies to confirm or refute it.