Dynamics of telomerase activity in response to acute psychological stress☆
Introduction
The successful maintenance of telomeres, the protective caps at the ends of chromosomes, is critical to human health. Normal telomere maintenance requires the cellular enzyme telomerase. Telomerase is a cellular ribonucleoprotein reverse transcriptase enzyme that adds telomeric DNA to shortened telomeres, thus extending telomere length and protecting the chromosomes. Shortened telomeres and lower telomerase are linked to age-related risk factors and disease (Aviv et al., 2006, Benetos et al., 2001, Buchkovich and Greider, 1996, Gardner et al., 2005, Gidron et al., 2006, Hathcock et al., 2005, Honig et al., 2006, Hsu et al., 2007, Igarashi and Sakaguchi, 1997, Hsu et al., 2007, Honig et al., 2006, Hathcock et al., 2005, Gidron et al., 2006, Gardner et al., 2005, Folkman and Lazarus, 1985, Epel et al., 2004, Bakaysa et al., 2007, Benetos et al., 2001, Brouilette et al., 2003, Gardner et al., 2005, Jeanclos et al., 2000, Buchkovich and Greider, 1996, Nawrot et al., 2004, Buchkovich and Greider, 1996, Samani et al., 2001, Buchkovich and Greider, 1996, Samani et al., 2001, Sampson et al., 2006, Valdes et al., 2005) and several studies report that short telomeres predict early mortality (Bakaysa et al., 2007, Brouilette et al., 2003, Cawthon et al., 2003, Benetos et al., 2001, Brouilette et al., 2003, Buchkovich and Greider, 1996, Hathcock et al., 2005, Honig et al., 2006, Kimura et al., 2008, Martin-Ruiz et al., 2006). These findings highlight the importance of understanding how telomerase regulates telomere length in vivo.
Several studies have now shown that chronic life stress is linked to shorter telomeres (Damjanovic et al., 2007, Epel et al., 2004, Parks et al., 2009), and has been related to both dampened telomerase activity (Epel et al., 2004) and, paradoxically, elevated telomerase activity (Damjanovic et al., 2007). The cause of these different findings on telomerase activity under stress is unclear. While telomeres are thought to change slowly over time, telomerase is a dynamic enzyme that can increase quickly, and it is thus possible to examine how acute stress may impact telomerase activity in an experimental setting. In addition to protecting telomeres, telomerase has telomere-independent roles, important to cell survival in the face of physiological stress, and it could potentially be affected by acute psychological stress as well. In this study, we addressed whether acute psychological stress impacts telomerase activity, and whether this differs in individuals with high and low levels of chronic stress. Telomerase activity is under multiple modes of dynamic control. For example, upon mitogenic stimulation of resting immune T lymphocytes, telomerase activity is upregulated at least 18-fold three days later (Brouilette et al., 2003, Hathcock et al., 2005). One study assessed the telomerase activity increase after antigen stimulation of B lymphocytes, and found it was elevated as early as 12 h later (Igarashi and Sakaguchi, 1997). After phytohemagglutinin stimulation, telomerase in T cells becomes elevated within 2 days, potentially in the G1 phase (when cells are preparing for DNA replication) of even the first cell cycle the ensuing cell cycles associated with clonal proliferation (Buchkovich and Greider, 1996). It is unclear if telomerase changed earlier than these time periods, since immediate changes were not studied.
Acute psychological stress can promote increases in cortisol, catecholamines, and oxidative stress (Benetos et al., 2001, Gardner et al., 2005), factors that may regulate telomerase activity. For example, exposure to cortisol in vitro dampens telomerase activity three days later (Brouilette et al., 2003, Cawthon et al., 2003, Choi et al., 2008). UV irradiation of lens epithelial cells in vitro increases stress proteins as well as telomerase activity in a dose dependent fashion (Wu and Zhang, 2005), indicating that telomerase can change acutely. The greater the level of oxidative stress in cells in vitro, the greater the level of telomerase activity (Nishikawa et al., 2009). Under high oxidative stress (H2O2 exposure), telomerase translocates from the nucleus to the mitochondria and telomerase activity increases within 3 h (Saretzki, 2009). Although little is known about the physiological significance of this observation, it has been suggested that the telomerase response to oxidative stress may be cell-protective, rather than causing cell proliferation, at least in lens epithelial cells (Buchkovich and Greider, 1996, Cawthon et al., 2003, Choi et al., 2008, Colitz et al., 2004). Little is known about the kinetics of telomerase regulation in vivo, and whether telomerase activity might upregulate in response to acute stress. While changes over days may be due in part to reduction in transcription of hTERT (Choi et al., 2008) it is possible that through rapid post-translational changes, telomerase activity can upregulate within minutes.
Acute psychological stress affects the immune system in complex ways (Segerstrom and Miller, 2004), including changing the distribution of cell types in the circulation vs. in tissue (F. Dhabhar and McEwen, 1997). During acute stress, immune cells mobilize into and then traffic out of the bloodstream (F. Dhabhar and McEwen, 1997, Brouilette et al., 2003, Folkman and Lazarus, 1985, Honig et al., 2006, Damjanovic et al., 2007, Dhabhar et al., 1996; F. S. Dhabhar, 1998, Schedlowski et al., 1993). In contrast, chronic stress impairs such acute stress-induced immune cell redistribution, and suppresses and/or dysregulates immune function (Dhabhar and McEwen, 1997, Dhabhar, 2009, Dhabhar and McEwen, 2001). Given the known changes in immune cell composition in the blood during acute stress, such as the increases in lymphocytes and monocytes, and that telomerase activity levels differ depending on immune cell type (Lin et al., 2009), with B cells having the highest and CD8 cells having the lowest telomerase activity, it is possible that cell trafficking patterns might contribute to any observed changes in telomerase activity in circulating PBMCs during stress. Therefore, to investigate the sources of possible changes in telomerase activity during acute stress, it is important to concurrently measure changes in cell distribution during acute stress.
Our goal here was to test whether acute psychological stress affects PBMC telomerase activity levels, and whether this differs as a function of chronic stress exposure. We exposed healthy women who had high versus low levels of chronic stress to a standardized short-term laboratory stressor. We measured changes in their PBMC telomerase activity throughout the stressor, as well as two classic aspects of the human stress response: cortisol reactivity and psychological threat responses during the stressor. As described above, stress-induced redistributions of immune cells might cause changes in cell subsets present in peripheral blood during stress, which could impact the levels of telomerase activity as measured in the total PBMC population. Therefore, at each of the four blood draw points we also measured immune cell distributions using flow cytometry in a subset of 27 participants.
Section snippets
Recruitment
The sample was recruited in the San Francisco Bay Area, from the community and service centers for caregivers, such as support groups, neurology clinics, and adult daycare centers, as well as from notices in public places and electronic bulletin boards. The study requested healthy nonsmoking women. The caregivers were the primary caregiver for a husband or partner with dementia (typically Alzheimer’s disease or frontal-temporo-lobe dementia). They had to identify as the primary caregiver,
Sample description
One participant, a control, had telomerase activity values that were more than 4 SDs above the mean for the majority of samples (3 of the 4 samples), and was thus excluded from telomerase analyses. The final sample with complete telomerase measures, excluding this outlier as well as the 3 women with incomplete telomerase values, included 43 postmenopausal women, 22 who were caregivers and 21 controls. The women had a mean age of 62, ranging from 51 to 75 years. They were 84% Caucasian, 5%
Discussion
In this study, we examined whether leukocyte telomerase activity changes in response to acute psychological stress, and whether it is related to being a stressed caregiver, or to responding in the moment to the stressor with greater perceived threat or cortisol reactivity. We found that in response to the Trier Social Stress Test telomerase activity increased by around 18%. Further, telomerase activity increased more in those reacting with greater cortisol, and among controls, in those feeling
Limitations and conclusions
Strengths of this study are careful measurement of telomerase activity over time with a highly controlled standardized protocol and study sample, concurrently with psychological, hormonal, and immune cell responses during acute stress. This has revealed novel relationships. However, the study is limited by its sample size and by the fact that immune cell redistribution was measured on only a subsample of 27. It is also a limitation that we did not have a control group with no stress exposure,
Conflict of interest statement
All authors declare that there are no conflicts of interest.
Acknowledgments
This study was supported in part by an NIMH K08, NIA R56, and UCSF Academic Senate Grant and REAC Grant (ESE), Bernard and Barbro Foundation (EHB), the Carl & Elizabeth Naumann Fund Startup Grant (FSD), the UCSF Sandler Integrative Research Award (EHB) and the UCSF CCRC NIH Grant UL1 RR024131. Our sincere acknowledgments to Jean Tillie for flow cytometry, Alanie Lazaro for laboratory management, Wendy Wolfson, Hana Tylova, and Jessica Chan for study coordination, and Aoife O’Donovan for
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Please see Brief Commentary by Janice K. Kiecolt-Glaser and Ronald Glaser found on page 529 of this issue.