Subclinical inflammation, telomere shortening, homocysteine, vitamin B6, and mortality: the Ludwigshafen Risk and Cardiovascular Health Study

Abstract

Purpose Short telomeres and B vitamin deficiencies have been proposed as risk factors for age-related diseases and mortality that interact through oxidative stress and inflammation. However, available data to support this concept are insufficient. We aimed to investigate the predictive role of B vitamins and homocysteine (HCY) for mortality in cardiovascular patients. We explored potential relationships between HCY, B vitamins, relative telomere length (RTL), and indices of inflammation. Methods Vitamin B6, HCY, interleukin-6 (IL-6), high-sensitive-C-reactive protein (hs-CRP), and RTL were measured in participants of the Ludwigshafen Risk and Cardiovascular Health Study. Death events were recorded over a median followup of 9.9 years. Results All-cause mortality increased with higher concentrations of HCY and lower vitamin B6. Patients in the 4th quartile of HCY and vitamin B6 had hazard ratios (HR) for all-cause mortality of 2.77 (95% CI 2.28-3.37) and 0.41(95% CI 0.33-0.49), respectively, and for cardiovascular mortality of 2.78 (95% CI 2.29-3.39) and 0.40 (95% CI 0.33-0.49), respectively, compared to those in the 1st quartile. Multiple adjustments for confounders did not change these results. HCY and vitamin B6 correlated with age-corrected RTL (r = − 0.086, p < 0.001; r = 0.04, p = 0.031, respectively), IL-6 (r = 0.148, p < 0.001; r = − 0.249, p < 0.001, respectively), and hs-CRP (r = 0.101, p < 0.001; r = − 0.320, p < 0.001, respectively). Subjects with the longest telomeres had a significantly higher concentration of vitamin B6, but lower concentrations of HCY, IL-6, and hs-CRP. Multiple regression analyses identified HCY as an independent negative predictor of age-corrected RTL. Conclusions In conclusion, hyperhomocysteinemia and vitamin B6 deficiency are risk factors for death from any cause. Hyperhomocysteinemia and vitamin B6 deficiency correlate with increased mortality. This correlation might, at least partially, be explained by accelerated telomere shortening induced by oxidative stress and systemic inflammation in these circumstances.

The Importance of Telomere Shortening for Atherosclerosis and Mortality

“…While some studies reported an inverse association between telomere length and HCY [ 62 , 94 , 95 ], others did not [ 63 , 96 , 97 ]. In the prospective LURIC study, plasma HCY was identified as an independent predictor of all-cause mortality [ 66 ]. The unadjusted HR for death from all causes and from CVD was nearly three times higher in the fourth quartile of HCY than in the first quartile.…”

Serum Homocysteine and Intracranial Aneurysms

“…[13] Raised serum homocysteine is an independent risk factor for cardiovascular diseases [13,15,18]. Elevated serum homocysteine is associated with a rise in morbidity and mortality [18,19].…”

“…An increase in serum homocysteine results in oxidative stress and systemic inflammation which in turn leads to an accelerated telomere shortening [13,19]. Furthermore, elevated serum homocysteine damages endothelial cells [13].…”

Telomere shortening associates with elevated insulin and nuchal fat accumulation

“…Solid knowledge about the factors that influence RTL is important for a potential clinical use of this promising marker and an appropriate interpretation of results. Lifestyle factors, such as physical activity, nutrition and stress have been suggested as potential modulators of telomere length [3][4][5][6][7][8][9][10][11] . For example, regular endurance exercise induces telomerase, an enzyme that can prolong telomeres, and thus prevent telomere shortening [4][5][6][7] .…”

“…Nutritional factors also appear to be involved in telomere biology. Pusceddu et al have shown that vitamin B6, B12 and homocysteine relate to RTL and mortality in cardiovascular patients 11 . In contrast, in longitudinal studies various diets or food supplements, considered generally healthy have shown little or no effect on telomere attrition 8,9 . Obesity is a very common condition in Western societies that is associated with a broad range of metabolic alterations, elevated oxidative stress and chronic low-grade inflammation 10,12 .…”