Cortisol Is Not Associated with Telomere Shortening or Chromosomal Instability in Human Lymphocytes Cultured under Low and High Folate Conditions

Abstract

Chronic psychological stress and nutritional deficiencies are factors that impact negatively on human health and disease risk. Chronic stress has been associated with accelerated leukocyte telomere shortening in numerous cohorts, however, a mechanistic link has proven elusive. This study tested the hypotheses that chronic exposure to the stress hormone, cortisol, causes telomere shortening and chromosome instability (CIN) in vitro, and that these effects would be further exacerbated by folate (vitamin B9) deficiency. Primary human lymphocytes were maintained in vitro for 12 days in medium containing either 25 nM folic acid (FA(low)) or 100 nM FA (FA(high)), together with either 0, 400, 1000 or 3500 nM cortisol. The interactive effects of cortisol and FA were examined by comparing telomere length (TL), biomarkers of DNA damage, and cytostasis. At day 12 TL was 5-17% longer in lymphocytes cultured in FA(low) conditions (mean ± SD;10.2% ± 1.6), compared with those in FA(high) medium (9.1% ± 1, p = 0.02). Refuting the hypothesis, TL was consistently greater in the presence of cortisol. The effect of FA deficiency on the frequency of DNA damage was significant for nucleoplasmic bridges, circular nuclei, micronuclei and nuclear buds, (p < 0.0001 – 0.001). The effect of cortisol, however, was negligible, only reaching statistical significance for the frequency of fused nuclei (p = 0.04). Cortisol was significantly associated with reduced cell division and growth and had an apparent protective effect on cell viability in the FA(low) conditions. Conclusions: Both chronic cortisol exposure, and folate deficiency, resulted in telomere elongation, however, the effect of cortisol was marginal relative to that of folate. Cortisol was not associated with increased chromosomal instability, but caused a significant reduction in cell division and growth. Together these results indicate that cortisol is not directly genotoxic and that the telomere shortening associated with increased psychological stress in vivo may not be explained by a direct effect of cortisol.

Increased Telomere Attrition After Renal Transplantation—Impact of Antimetabolite Therapy

“…Indeed, Paul et al 46 have reported decreasing telomere length with increasing folate, and a recent study has shown that folate deficiency results in telomere elongation. 47 Because telomere length is inversely associated with plasma homocysteine, this suggests that it may be an intermediary in the relationship between homocysteine and CVD. 22 However, although treatment with the two antimetabolite drugs was associated with markedly different folate levels, homocysteine levels did not change.…”

“…Although reports in the literature appear contradictory, homocysteine, folate and telomere attrition are consistently associated with each other. 21-24,45-47 Thus, the relationship between them should be investigated more thoroughly, preferably in cohorts undergoing premature aging, such as CKD patients.…”

Serum lipophilic antioxidants levels are associated with leucocyte telomere length among US adults

“…Other proposed mechanisms, particularly for the protective effect of lutein, zeaxanthin and vitamin C, include effects on immune-modulation, anti-inflammatory activity, modulation of apoptosis, and lymphocyte proliferation [ 25 , 40 , 41 ]. Several investigations conducted on other dietary components, including B vitamins like folate [ 42 – 44 ] point to their role in DNA methylation and consequently regulation of TL by DNA methylation [ 43 ].…”

Telomere length is inversely correlated with urinary stress hormone levels in healthy controls but not in un-medicated depressed individuals-preliminary findings

“…In vitro studies are somewhat inconsistent, with one showing that exposure to cortisol resulted in reduced telomerase activity, which could result in LTL shortening [13], while another found that exposure to cortisol increased telomere length [6]. In one of the few in vivo studies, four weeks of corticosterone exposure was found to significantly shorten telomeres in mice [12].…”

“…Accelerated LTL shortening is reported in several psychiatric illnesses and stress-related conditions [5], although underlying mechanisms are unknown [1,6]. Telomere shortening may occur with repeated mitoses, inflammation or oxidative stress [7] in the absence of adequate telomerase activity [1].…”