Cell aging in relation to stress arousal and cardiovascular disease risk factors

Summary

We previously reported that psychological stress is linked to and possibly accelerates cellular aging, as reflected by lower PBMC telomerase and shortened telomeres. Psychological stress is a major risk factor for cardiovascular disease (CVD), with multiple behavioral and physiological mediators. Telomere shortness has been associated with CVD, but the relationship between low telomerase activity, a potential precursor to telomere shortening, and CVD risk factors has not been examined in humans. Here we examine whether telomere length and telomerase in leukocytes are associated with physiological signs of stress arousal and CVD risk factors in 62 healthy women. Low telomerase activity in leukocytes was associated with exaggerated autonomic reactivity to acute mental stress and elevated nocturnal epinephrine. Further, low telomerase activity was associated with the major risk factors for CVD —smoking, poor lipid profile, high systolic blood pressure, high fasting glucose, greater abdominal adiposity—as well as to a composite Metabolic Syndrome variable. Telomere length was related only to elevated stress hormones (catecholamines and cortisol). Thus, we propose that low leukocyte telomerase constitutes an early marker of CVD risk, possibly preceding shortened telomeres, that results in part from chronic stress arousal. Possible cellular mechanisms by which low telomerase may link stress and traditional risk factors to CVD are discussed. These findings may implicate telomerase as a novel and important mediator of the effects of psychological stress on physical health and disease.

Introduction

We recently reported that chronic psychological stress was associated with both shorter telomere length and lower telomerase activity in leukocytes (Epel et al., 2004). Telomeres are DNA-protein complexes that cap chromosomal ends and promote chromosomal stability. Telomere length is the downstream output of the actions of both lengthening and shortening activities in the cell (Blackburn, 2000). Most notably, the cellular enzyme telomerase adds telomeric repeat sequences to the chromosomal DNA ends, preserving not only telomere length but also healthy cell function, prolonged stem cell proliferation, and long-term immune function, independently of telomere length (Kim et al., 2003; Ly et al., 2005; Marrone et al., 2005).

Stress arousal is likely to be one pathway through which chronic stress may impact cellular aging (Sapolsky, 2004). Chronic life stress can lead to overexposure to stress responsive adrenal hormones, primarily cortisol and catecholamines, or to hyporesponsiveness, also reflecting dysregulation (McEwen, 1998). In addition to adrenal hormones, autonomic nervous system reactivity to stress, particularly heart rate variability, can serve as a physiological index of stress vulnerability, and is related to anxiety (Porges, 1995, Friedman Thayer, 1998). We thus examined whether telomerase levels and telomere length in peripheral blood mononucleocytes (PBMCs) are associated with two indices of stress arousal—nocturnal excretion of stress hormones (catecholamines and cortisol) and autonomic nervous system stress reactivity to a standardized stressor (vagal tone or heart rate variability).

Psychological stress has recently emerged as one of the major risk factors for CVD. The largest epidemiological study of risk factors for CVD to date, with almost 30,000 participants, across 52 countries, identified the top six modifiable risk factors: cigarette smoking, poor lipid profile, high blood pressure, diabetes, abdominal obesity, and an index of psychosocial stress (Yusef et al., 2004). The cellular mechanisms by which many of these physiological and behavioral risk factors, particularly stress, can lead to disease are not well understood.

However, there is now converging evidence from basic and clinical studies that telomere maintenance plays an important role in organismal longevity. Shorter telomeres in human leukocytes have been linked to age-related conditions and diseases including hypertension, greater pulse pressure, hypercholesterolemia (reviewed in Serrano and Andres, 2004), and increases in insulin resistance (Gardner et al., 2005). Moreover, in the only prospective study of telomere length and longevity, telomere length predicted earlier mortality, particularly from infections and CVD (Cawthon et al., 2003). It is unknown exactly how telomere maintenance might influence CVD processes. Telomerase increases telomere length. Although telomerase has not been examined in relation to CVD risk in humans, telomerase insufficiency leads to bone marrow failure (Marrone et al., 2005), while in animal studies and in vitro, telomerase insufficiency has been linked to cardiovascular pathobiology (Yang et al., 1999, Oh et al., 2003). These findings raise the possibility that telomerase may play an important role in early development of CVD in humans.

Given the inter-relationships between stress, telomere length and CVD risk factors, in the present study we also examined the relationship between cellular aging and CVD risk factors. We tested whether telomere length and telomerase were related to early development of the top CVD risk factors, in a sample of healthy young women (i.e. those without frank disease). Further, many CVD risk factors tend to be correlated, representing underlying insulin resistance, labeled as the Metabolic or Insulin Resistance Syndrome (Reaven, 1988). The Metabolic Syndrome tends to accrue with aging and is a well-established precursor to chronic diseases, most notably CVD (Lakka et al., 2002). Therefore, we examined whether cell aging was linked to this underlying syndrome, in addition to individual risk factors. We specifically tested the hypothesis that women with greater levels of cellular aging (i.e. shorter PBMC telomere length and lower telomerase activity) would have greater stress arousal and CVD risk factors, including level of Metabolic Syndrome.