Age-associated telomere shortening is a generally accepted finding based on large cross-sectional studies. It has been assumed that this characteristic telomere attrition is true at the individual level as well. It has also been speculated that the telomere attrition rate in blood cells of tumor patients is higher compared to controls. The present longitudinal study cohort demonstrated the expected decline in telomere length by time, but we also observed large individual differences. Actually, in about one third of all individuals an elongation of the telomeres occurred over a decade. Most interestingly, individuals displaying the longest telomeres at the first blood draw demonstrated the most pronounced telomere shortening over time, and vice versa. The average coefficient of variation for the method was ~6% and some of the variation in TL might be related to the technique itself. However, to make sure that the strong correlation was not based on the very highest or lowest RTL values, the correlation analysis was also made on individuals with RTL values <1 and >0.3. The result of the restricted correlation analysis was very similar to the result of the larger analysis, showing a strong correlation between telomere length at baseline and attrition rate.
A large variation in telomere attrition at the individual level has been observed in previous longitudinal studies on telomere length 
. In a very recent study by Aviv et al. 
, TL was measured in leukocytes collected on two occasions from 450 whites and 185 African Americans, participating in the Bogalusa Heart Study. The median time period between the first and second blood sampling was shorter compared to our study (~6 years vs. ~10 years), and the participants were fewer and younger (age range: 20.0–40.0 years at baseline). Nevertheless, they found that the age-dependent TL attrition rate was proportional to TL at baseline, which is in accordance to our present study. The majority of participants in their study displayed TL shortening (85.9% of African Americans and 88.0% of whites), whereas the rest displayed a stable or increased TL. Similar to our observation, they also found that the rate of TL shortening varied considerably among individuals.
One explanation to the variations in attrition rate could be differences in epigenetic regulation, with secondary effects on telomere maintenance. Another reason might be that telomerase act preferentially on short telomeres, which has been shown in mice models and cell culture systems 
. This would be in line with our observation of a very strong inverse correlation between individual TL at baseline and telomere attrition over time. Interestingly, we found a similar result in our separate family cohort. Hence, comparable data were obtained when analyzing telomere attrition rate at both the individual and at the family level. In the present study, individuals with the shortest TL actually elongated their telomeres over a decade, indicating that the TL maintenance machinery is focused on protecting the shortest telomeres. Nevertheless, other factors are likely to influence the TL attrition rate as well. In our study, the correlation value between blood RTL at baseline (sample 1) and attrition rate was r
−0.752 when analyzing the entire cohort. The corresponding r-squared value is hence 0.566, or ~57%. This means that the telomere length at time point 1 could explain 57% of the variation in attrition rate. Thus, 43% of the variation might well be explained by other factors, such as life style, oxidative stress, inflammation etc. In the study by Aviv et al. 
, oxidative stress was proposed as a potential candidate for causing proportional telomere shortening. We agree that oxidative stress is likely to be important for telomere attrition, but the theory does not explain why a subset of the cohort demonstrated TL elongation. We suggest that a cellular TL regulating mechanism, rather than environmental/life style factors, is the major factor determining the rate of telomere attrition over time.
The working hypothesis that blood cell TL can indicate a later development of a malignant tumor was not supported in the present study. This hypothesis emanates from data showing altered TL in cases with a variety of malignancies. In urinary bladder, head and neck, lung, and renal cell cancers, shortened blood telomeres have been described at diagnosis, whereas data on breast cancer indicate unchanged or longer telomeres compared to controls 
. Since no difference in TL existed between cases and controls, neither ≥9 (sample 1) nor 0–11 (sample 2) years before the appearance of a malignancy, we conclude that blood TL is not a prediagnostic biomarker for malignancy per se
. However, our cases suffered from a variety of tumors and we cannot exclude that blood TL might be a biomarker for specific tumor types. A support for this is a recent study indicating that short blood telomeres were associated with a decreased risk for melanoma but also an increased risk for basal cell carcinoma, whereas there was no trend for squamous cell carcinoma 
In the largest tumor group in our material, prostate cancer, the blood TL ≥9 years before diagnosis seemed to indicate a poor prognosis. All prostate cancer cases with long blood telomeres (>median) were alive five years after diagnosis compared to <60% in the group with short telomeres. However, in the sample taken 0–11 years before prostate cancer diagnosis, TL did not give prognostic information. Thus, since the same prostate cancer patients were studied at different time points ahead of the cancer diagnosis, a shift had occurred indicating differences in the rate of telomere loss. This shift is interesting, since for breast cancer, blood TL at diagnosis seems to be a strong prognostic biomarker, with longer telomeres associated with a worse prognosis 
. We have obtained similar data for renal cell carcinoma [Svenson et al., unpublished data] indicating that this feature is not unique for breast cancer. Unfortunately, in the present material the other cancer groups were too small to allow this type of statistical calculations. The biological background for these findings is unclear but it is tempting to speculate that factors responding to the presence of a tumor also have an impact on telomere maintenance, especially in immune reactive cells and their precursors. Due to few events in the cancer group a more definitive analysis of prediagnostic TL in relation to prognosis must await longer follow up times.
In conclusion, and similar to what have been observed in cultured cells in vitro,
human blood cells in vivo
seem to have a telomere maintenance system that gives priority to short telomeres. Based on human cross-sectional studies of age-associated telomere attrition, it has been speculated that TL at a certain age can predict a theoretical future life span. Our findings indicate that TL regulation through life might be more complex than previously known, complicating such life span predictions. We suggest that, at least in blood cells, the main TL regulator is a general mechanism that senses the telomere length similar to the counting mechanism demonstrated in cells from different species 
. However, it might well be possible to avoid excessive telomere loss by living a healthy life as recently indicated 
. Our data has important implications for our understanding of human telomere biology and for future analyses of telomere maintenance mechanisms in vivo.