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The rate of leukocyte telomere shortening predicts mortality from cardiovascular disease in elderly men

leukocyte telomere aging telomere length change tlc cellular senescence

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#1 Engadin

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Posted 08 May 2019 - 04:35 PM


 

 

INTRODUCTION

 

Understanding the aging process is central to preventing age-related disease burden and premature mortality. Many different measures have been suggested as having prognostic value for mortality. Cellular aging may offer insights into organismic aging relevant to diseases of aging such as CVD. Telomeres, the protective nucleoprotein structures capping the ends of eukaryotic chromosomes, can serve as markers of mitotic cell age and replicative potential. With every cell division, a portion of the telomere cap is not replicated due to the "end replication problem" - that is, DNA polymerase does not completely replicate the end of a DNA strand [1]. Hence, cells in certain older organisms, including humans, have shorter telomeres on average than cells in younger organisms.

 

Telomere length change (TLC) depends on many factors, prominent among them the rate of cell divisions and level of telomerase, a cellular ribonucleoprotein reverse transcriptase enzyme that replenishes telomeric DNA and thus lengthens the telomere. In cells lacking sufficient levels of telomerase, telomeres progressively shorten with successive cell divisions. If the telomere shortening represents a clock ticking forward on cells' lifespans, telomerase can slow or reverse this clock [2], making the two an intricately interdependent dynamic system. Indeed, in vitro studies show that telomeres can lengthen - activated B cell telomere length increases as these cells multiply in germinal centers in response to pathogenic challenge [3]. TLC in part reflects the balance between telomere elongation by telomerase action versus telomere shortening processes.

 

Cellular senescence may underlie the progression of diseases associated with organismic aging [4]. Mice bred without telomerase develop shorter telomeres, and show premature aging, including hair graying, impaired wound healing, reduced proliferation of lymphocytes, and, in later generations, early mortality and infertility [5]. Humans with a rare genetic disorder (dyskeratosis congenita) that leads to half the effective gene dosage of telomerase show early mortality and increased incidences of fibrosis, cancer, progressive bone marrow failure and other indications of premature aging, and other premature aging syndromes are also often characterized by shortened telomeres [4,6-8]. Despite these lines of evidence, among the general population of healthy humans without pathologic premature aging syndromes, little direct data exist to link cellular aging with organismic aging.

 

The strongest evidence that cellular aging, as reflected by shorter telomeres, might be associated with organismic aging has until now been derived from cross sectional studies. Shorter telomere length (TL) in leukocytes has been associated cross-sectionally with CVD and its risk factors, including pulse pressure [9-11], obesity [12,13], vascular dementia [14], diabetes [13,15,16], CAD [17], and myocardial infarction [18] although not in all studies [19]. TL has also been shown to predict CVD events (MI and stroke) in men under 73 years old [20]. Cawthon and colleagues found that TL predicted earlier mortality, particularly from CVD and infectious disease, in a sample of 143 healthy men and women 60 years and older [21]. This suggested that poor telomere maintenance may serve as a prognostic biomarker of risk of early mortality. Since then, additional studies have found blood TL predicts mortality, in large twin studies [22,23], and in Alzheimers [24], and stroke patients [25]. However, other reports, notably those with very elderly cohorts, have failed to find an association between TL and mortality [26].

 

A single TL assessment, however, leaves open the possibility that TL at birth, rather than rate of telomere attrition, accounts for this association with mortality. One might have expected, given the low rate of attrition throughout life, that TL at birth would be a strong predictor of TL later in life. However, twin studies indicate non-genetic factors can have significant effects on telomere length later in life; telomere length was similarly related in identical compared to fraternal male twins over 70 years old, suggesting a large non-genetic influence [27], and identical twins who exercised had longer leukocyte telomeres than the identical twin who did not [28]. Further, twin studies show that telomere length predicts mortality beyond genetic influences [22,23]. Hence, longitudinal studies that examine telomere changes over time within individuals are needed to test the prognostic value of the rate of telomere length change (TLC).

 

In one of the only published studies of TLC over time in humans, a study of 70 adults found that a small percentage (10%) of subjects showed leukocyte telomere length maintenance or lengthening over a ten year period [12]. No studies we are aware of in humans have systematically examined TLC within a short period of only a few years, and how this may or may not be linked to subsequent mortality. The current study examined TL and TLC in a high functioning sample of 70-79 year olds. We aimed to: 1) Describe the natural history of telomere length change over a 2.5 year period in a sample of elderly men and women; and 2) Test TL and particularly TLC as predictors of mortality. Lastly, we explored whether the combination of short TL and greater TLC predicted greater risk of subsequent mortality than either one indicator alone. We report here that TLC over the next 2.5 years did indeed predict 12-year mortality from cardiovascular disease in men. Hence we propose that the rate of leukocyte telomere shortening is a potentially useful prognostic for cardiovascular disease.

 

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Also tagged with one or more of these keywords: leukocyte telomere, aging, telomere length change, tlc, cellular senescence

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