Date Published: April 1, 2018
Publisher: JKL International LLC
Author(s): Pedro Carrera-Bastos, Óscar Picazo, Maelán Fontes-Villalba, Helios Pareja-Galeano, Staffan Lindeberg, Manuel Martínez-Selles, Alejandro Lucia, Enzo Emanuele.
Endotoxemia-induced inflammation has been associated with insulin resistance and atherosclerosis, ultimately increasing the risk of coronary heart disease. Increased intestinal permeability is an important event leading to endotoxemia. This study aims to elucidate the possible association between endotoxin (lipopolysaccharide) and zonulin (a biomarker of intestinal permeability) levels and the risk of coronary heart disease, and thus healthy aging. Serum levels of zonulin, lipopolysaccharide and soluble CD14 (a protein that binds lipopolysaccharide) were measured in disease-free centenarians, young healthy controls and patients with precocious acute myocardial infarction. Disease-free centenarians had significantly lower levels of serum zonulin (P<0.01) and lipopolysaccharide (P<0.001) than young patients with acute myocardial infarction, and had significantly lower concentrations of serum lipopolysaccharide than young healthy controls (P<0.05). No significant differences were found for soluble CD14 between groups. Our findings may stimulate further research into the role played by intestinal permeability and endotoxemia not only in coronary heart disease but also in lifespan modulation.
As shown in Table 1, LPS levels were significantly lower in disease-free centenarians than in AMI patients (P<0.001, post-hoc Dunn’s test after Kruskal-Wallis test) and healthy young controls (P<0.05, post-hoc Dunn’s test after Kruskal-Wallis test). Zonulin levels were significantly lower in centenarians than in AMI patients (P<0.01), but no differences were found when centenarians were compared with healthy controls (P>0.05, post-hoc Tukey’s test after ANOVA). No significant differences were found between the groups in the levels of soluble CD14 (Table 1) (P>0.05). The aforementioned results remained essentially unchanged when analyzing men and women separately (data not shown). On the other hand, LPS levels correlated with those of zonulin within the group of centenarians (ρ=0.64, P<0.001) and AMI patients (ρ=0.48, P<0.001), but not within healthy young controls (ρ=0.19, P>0.05) (Table 2).
The present study shows that disease-free centenarians have lower serum zonulin and LPS levels than young AMI patients. Moreover, the two variables correlate with each other in centenarians and AMI patients, suggesting that intestinal hyperpermeability may cause endotoxemia, which in turn could lead to inflammation and hence insulin resistance, atherosclerosis and hypercoagulation [2, 4, 7, 8, 28, 29]. Regarding soluble CD14, although its levels have been found to be higher in patients with unstable angina , in individuals with the metabolic syndrome (which in turn is associated with an increased CHD risk) , and in HIV-infected patients (in whom CD14 levels are correlated with atherosclerosis  and coronary artery calcification ), no significant intergroup differences were found in the present study. Echoing our findings, other studies have yielded similar negative results [33, 34]. Thus, although more research is needed, our data suggest that serum levels of zonulin and LPS emerge as potential novel biomarkers of exceptional longevity. Indeed, the present cohort of centenarians has been the subject of previous research identifying other potential serum biomarkers of healthy exceptional longevity and thus of successful aging, i.e., irisin , vitamin D , eicosapentaenoic acid to arachidonic acid ratio , beclin-1 , or the combination of chemerin, fetuin-A, and fibroblast growth factors 19 and 21 . Our data, coupled with the fact that aging per se is typically associated with elevated circulating zonulin , endotoxemia , inflammation , insulin resistance  and atherosclerosis , suggest that measures taken to decrease intestinal permeability and LPS translocation may help to reduce the risk of CHD and contribute to healthy lifespan. Of interest, zonulin is identical to the precursor of haptoglobin , an acute-phase protein that scavenges the potent oxidant free hemoglobin  and has anti-inflammatory activity . Moreover, genetic variants of the haptoglobin gene have been associated with CHD  and longevity .