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

European Journal of Nutrition https://doi.org/10.1007/s00394-019-01993-8 ORIGINAL CONTRIBUTION Subclinical inflammation, telomere shortening, homocysteine, vitamin B6, and mortality: the Ludwigshafen Risk and Cardiovascular Health Study Irene Pusceddu1 · Wolfgang Herrmann2 · Marcus E. Kleber3 · Hubert Scharnagl4 · Michael M. Hoffmann5 · Brigitte M. Winklhofer‑Roob6 · Winfried März3,4,7 · Markus Herrmann1,4 Received: 4 October 2018 / Accepted: 7 May 2019 © The Author(s) 2019 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. Keywords Telomere length · Homocysteine · Vitamin B6 · Inflammation · Mortality Introduction Winfried März and Markus Herrmann contributed equally. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00394-019-01993-8) contains supplementary material, which is available to authorized users. * Markus Herrmann Extended author information available on the last page of the article The accumulation of DNA damage is one of the most important factors of aging [1]. Functional telomeres and a sufficient supply with B vitamins are essential for the maintenance of genomic integrity and the prevention of premature aging [2, 3]. Vitamin B6, folate (B9), and B12 are essential co-factors in the one-carbon metabolism [4]. All three vitamins are involved in the degradation of homocysteine (HCY), which is a non-protein forming amino acid and a cytotoxic metabolite of the methionine cycle [4]. HCY is detoxified either by remethylation or by transsulfuration [4]. Prospective studies from around the world have firmly 13 Vol.:(0123456789) European Journal of Nutrition established elevated plasma HCY as a risk marker for mortality [5]. The toxic effects of HCY are at least partially mediated through oxidative damage to proteins [6] and DNA [7]. Therefore, an efficient detoxification of HCY is essential for genomic stability and cellular viability. Upon adequate availability of methionine, HCY is coupled to serine and subsequently catabolized to α-ketobutyrate and cysteine, a precursor of the principal antioxidant compound glutathione (GSH) [5]. This reaction is called transsulfuration and requires vitamin B6 as a co-factor for the enzymes cystathionine-β-synthase (CBS) and cystathionine-γ-lyase (CGL) [4]. When the exogenic supply with methionine is not sufficient, the conversion of HCY into methionine becomes activated. This reaction is called remethylation and requires 5-methyltetrahydrofolate (5-MTHF, vitamin B9) as substrate and vitamin B12 as co-factor for the methionine synthase [4]. Therefore, HCY is also considered as a functional marker of 5-MTHF and vitamin B12 availability. However, it also reflects the vitamin B6-dependent transsulfuration pathway, which transfers a sulfhydryl group from HCY to serine forming cysteine and it becomes activated in hyperhomocysteinemia (HHCY). Telomeres are protective nucleoprotein structures at the end of all chromosomes that ensure genomic stability and prevent the loss of coding DNA. They are composed of a non-coding, repetitive DNA sequence (TTAGGG) and associated proteins [1]. Due to the inability of the DNA polymerase to fully replicate the 3′ end of chromosomes, telomeres progressively shorten with every cell division until they become critically short, lose their protective properties, and send cells into senescence, or cause cell death [1]. Telomere length in blood leucocytes has been proposed as a biomarker of biological age. Prospective observational studies in healthy and high-risk populations have shown that short telomeres substantially increase the risk of all-cause and cardiovascular (CVD) mortality [8–10]. Environmental and lifestyle factors, such as exposure to UV radiation, smoking, stress, obesity, diet, and lack of physical activity, can modify the velocity of telomere shortening [2, 11]. Many of these factors are associated with increased oxidative stress. Oxidative stress is characterized by an excess of reactive oxygen species (ROS), such as peroxides and free radicals, which assault the DNA leading to base damage, DNA strand breaks, and accelerated telomere shortening [12]. Because of their impact on the cellular redox state, HCY and vitamin B6 deficiency are potential risk factors for premature telomere shortening and accelerated cellular aging. However, existing studies are inconsistent and mainly of cross-sectional nature. For example, a negative association between telomere length and HCY was found in some studies [13–16], but not in others [17–20]. Although HCY is an established risk factor for mortality [5], little is known about the association between vitamin B6 and mortality risk [21]. 13 Here, we investigated the predictive roles of plasma vitamin B6 and HCY concentrations for CVD and all-cause mortality in a large cohort of cardiovascular patients followed for a median period of 9.9 years. In addition, we explored potential relationshi (...truncated)