Cross-species Association Between Telomere Length and Glucocorticoid Exposure

Abstract

Context: Chronic exposure to glucocorticoids (GCs) or stress increases the risk of medical disorders, including cardiovascular and neuropsychiatric disorders. GCs contribute to accelerated aging; however, while the link between chronic GC exposure and disease onset is well established, the underpinning mechanisms are not clear.

Objective: We explored the potential nexus between GCs or stress exposure and telomere length.

Methods: In addition to rats exposed to 3 weeks of chronic stress, an iatrogenic mouse model of Cushing syndrome (CS), and a mouse neuronal cell line, we studied 32 patients with CS and age-matched controls and another cohort of 75 healthy humans.

Results: (1) Exposure to stress in rats was associated with a 54.5% (P = 0.036) reduction in telomere length in T cells. Genomic DNA (gDNA) extracted from the dentate gyrus of stressed and unstressed rats showed 43.2% reduction in telomere length (P = 0.006). (2) Mice exposed to corticosterone had a 61.4% reduction in telomere length in blood gDNA (P = 5.75 × 10-5) and 58.8% reduction in telomere length in the dentate gyrus (P = 0.002). (3) We observed a 40.8% reduction in the telomere length in patients with active CS compared to healthy controls (P = 0.006). There was a 17.8% reduction in telomere length in cured CS patients, which was not different from that of healthy controls (P = 0.08). For both cured and active CS, telomere length correlated significantly with duration of hypercortisolism (R2 = 0.22, P = 0.007). (4) There was a 27.6% reduction in telomere length between low and high tertiles in bedtime cortisol levels of healthy participants (P = 0.019).

Conclusion: Our findings demonstrate that exposure to stress and/or GCs is associated with shortened telomeres, which may be partially reversible.

Keywords: Cushing syndrome; allostatic load; cellular aging; cortisol; glucocorticoids; stress; telomere length.

Figure 1.

Telomere length in the rat T cells and hippocampus and its relationship with mean 3-week plasma corticosterone levels. (A) Telomere length was assessed in T-cell DNA obtained from rats exposed to 3-week chronic variable stress or no stress (N = 10 per group). (B) T-cell telomere lengths were correlated with mean 3-week plasma corticosterone levels calculated from 8 samplings during the CVS regimen. (C) Telomere length assessed in hippocampal DNA showed similar stress-induced reduction. (D) Similar association between hippocampal telomere length and corticosterone levels was observed. Bar graphs are presented as mean ± SEM. *P < 0.05 and **P < 0.01.

Figure 2.

Telomere length measurements in glucocorticoid-treated mice and cell line. (A) Telomere length was assessed in whole blood and hippocampal DNA of mice treated with corticosterone (CORT) or vehicle solution for 30 days (N = 12 per group). (B) Normalized gene expression levels of telomere-associated genes Tert and Dkc1 in the hippocampus of CORT-treated mice. (C) Dose-dependent reduction in telomere length was observed in the hippocampal cell line HT-22 treated with dexamethasone (DEX). (D) DEX-induced TLA was normalized following withdrawal of DEX from the media. Bar and line graphs are represented as mean ± SEM. *P < 0.05, **P < 0.01, and ***P < 0.001.

Figure 3.

Telomere length attrition (TLA) in patients with Cushing syndrome. (A) Telomere length was assessed in leukocyte DNA obtained from patients with active Cushing syndrome (N = 9), those who have been cured (N = 23), and healthy controls (N = 32). (B) Telomere length correlated significantly with the duration of hypercortisolism in patients with active Cushing syndrome and patients cured of the disorder. Bar graph is represented as mean ± SEM. *P < 0.05.

Figure 4.

Telomere length in healthy individuals. (A) Telomere length in leukocyte DNA was analyzed from 75 healthy participants whose DNA samples were divided into tertiles based on their mean 30-day bedtime salivary cortisol levels. Shorter overall telomere lengths were observed in the high cortisol tertile compared with the low cortisol tertile. (B) Telomere lengths correlated significantly with bedtime cortisol levels for all 75 participants. Bar graph is represented as mean ± SEM. *P < 0.05.