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. 2020 Jun;59(4):1399-1411.
doi: 10.1007/s00394-019-01993-8. Epub 2019 May 25.

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

Irene Pusceddu  1 , Wolfgang Herrmann  2 , Marcus E Kleber  3 , Hubert Scharnagl  4 , Michael M Hoffmann  5 , Brigitte M Winklhofer-Roob  6 , Winfried März  3   4   7 , Markus Herrmann  8   9
Affiliations

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

Irene Pusceddu et al. Eur J Nutr. 2020 Jun.

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 follow-up 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: Homocysteine; Inflammation; Mortality; Telomere length; Vitamin B6.

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Conflict of interest statement

Winfried März is affiliated with Synlab Holding Deutschland GmbH. There are no patents, products in development, or marketed products to declare. No other author has a competing interest to declare that interferes with, or could reasonably be perceived as interfering with, the full and objective presentation, peer review, editorial decision-making, or publication of this manuscript.

Figures

Fig. 1
Fig. 1
Kaplan–Meier plots. Cumulative survival according to quartiles of HCY (a); vitamin B6 (b)
Fig. 2
Fig. 2
RTL (a), hs-CRP (b), and IL-6 c in subjects with HCY below or above HCY the cohort median of 12.3 μmol/L
Fig. 3
Fig. 3
Key mechanisms underlying the relationship between B vitamins, homocysteine, and telomere function. Decreased vitamin B12 concentrations impair the remethylation of homocysteine to methionine through the methionine synthase, which is vitamin B12-dependent. MTHFR catalyzes the irreversible reduction of 5,10-methyleneTHF to 5-methylTHF, which is the methyl donor required for the conversion of homocysteine to methionine via methionine synthase. 5,10-MethyleneTHF can be regenerated from tetrahydrofolate produced in the methionine synthase reaction by the donation of a methyl group from the amino acid serine in a reaction catalyzed by SHMY, a vitamin B6-dependent enzyme. In addition, the methyl group from 5,10-methyleneTHF is used for the production of nucleotides. Hyperhomocysteinemia reduces the production of SAM, the universal methyl-donor group. The consequent reduced –CH3 availability impairs the methylation of DNA, subtelomeric regions, and proteins such as histones. Deficiency of vitamin B6 leads to impaired conversion of HCY to cystathionine, leading ultimately to decreased production of glutathione. Hyperhomocysteinemia and reduced glutathione induce the formation of reactive oxygen species that induce DNA damage, DNA breaks, NO deactivation, lipid peroxidation, and telomere uncapping leading to telomere dysfunction. CβS cystathionine-beta-synthase, CS cystathionase, H histone, Met methylated, MS methionine synthase, MTHFR methylenetetrahydrofolate reductase, NO nitric oxide, POT1 protection of telomeres 1, RAP1 repressor/activator protein 1, SAM S-adenosyl methionine, SAH S-adenosyl homocysteine, SHMT serine hydroxymethyl transferase, THF tetrahydrofolate, TIN2 TRF1 interacting protein 1, TPP1 TINT1/PIP1/PTOP 1, TRF1 telomere repeat binding factor 1, TRF2 telomere repeat binding factor 2
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