Age and genetic determinants of variation of circulating levels of the receptor for advanced glycation end products (RAGE) in the general human population

Abstract: In stark contrast to many other blood biomarkers, including a variety of inflammatory cytokines, the main factors affecting sRAGE variation in the general human population are virtually unknown. We examined the contribution of age, body composition, and putative genetic sources to the interindividual variation of sRAGE. Its plasma levels were measured in 1557 apparently healthy individuals from 359 nuclear families. Statistical analysis revealed that all the aforementioned factors are statistically significantly associated with sRAGE levels. The levels of sRAGE consistently decreased with age (R = −0.264, p = <0.001) and with the indices of obesity, such as BMI. However, of special interest was the highly significant and previously not reported independent correlation with fat free mass (p < 0.001). The putative genetic effects explained 0.291 ± 0.089 of sRAGE variation and were solely responsible for the phenotypic correlations with the obesity phenotypes (genetic correlations, −0.22 ± 0.09 and −0.33 ± 0.09). Taken together, these data suggest that although genetically determined to a substantial degree, the sRAGE levels also depend on age and obesity, which in turn, increase the risk for a variety of pathological conditions associated with sRAGE. Clearly, identifying the metabolic pathways and specific genetic factors is the next important stage in this research area.


Alex’s Notes: Advanced glycation endproducts (AGEs), both dietary and endogenous, are a well-known factor in the development and progression of several chronic and degenerative diseases, primarily through increasing oxidative stress and inflammation. The receptor for AGEs (RAGE) binds many ligands, obviously including AGEs, but also other regulators of inflammation. At the same time, however, a variation of the RAGE protein, called soluble RAGE or sRAGE, lacking the pro-inflammatory signaling ability is thought to be protective. The sRAGE proteins are hypothesized to bind to AGEs and neutralize some of the damage they may cause. Previous research has indeed shown that metabolic syndrome and its components are some of the strongest predictors of sRAGE concentrations, but data concerning its relationship to age and genetics is scarce.

The current study thus sought to examine the contribution of genetic and environmental factors to the variation in sRAGE plasma levels in a large population-based cohort of European ethnic origin.

The population studied included 1557 apparently healthy individuals (52% men) from 359 nuclear families ranging in age from 17 to 90 years living within Russia. They were all ethnically Caucasian and had lived for at least three generations under the same environmental conditions, thus limiting any bias to the results that would come from outside influences. Moreover, the study population was almost entirely involved in hard, manual agricultural work, essentially making them fall into the “extremely active” category for daily physical activity. In other words, these were otherwise healthy and physically active individuals. Blood samples were used to gather data on RAGE, and body composition was assessed with skinfold measurements.

From a statistical standpoint, initial analysis found that sRAGE variation displayed a highly significant correlation with age, with no differences between men and women. Additionally, sRAGE did not differ between healthy individuals and the 77 (5%) of the subjects with atherosclerosis. After adjustment for age and sex, further analysis revealed that all body composition measurements had a significant association with sRAGE. Since all the body composition variables were also significantly associated with one another (in addition to sRAGE), all were entered into a multivariate statistical model to isolate those that were independently associated with sRAGE.

It was found that only BMI and relative fat-free mass (RFFM; % of bodyweight that is not fat tissue) were significantly, independently associated with serum sRAGE concentrations.

Keeping these body composition parameters in the statistical model, the researchers further explored associations between sRAGE and environmental and genetic factors. It was found that, for the most part, the familial environment was not related to serum sRAGE, with the exception of a common household environment that explained about 22% of sRAGE variance. Heritability further explained about 29% of sRAGE variance.

Putting it all together

This study demonstrated that age, BMI, and even muscle mass(!) may reduce sRAGE as they increase (inverse association). The association with muscle mass had not previously been identified, and future work will have to clarify the molecular mechanisms behind it, as muscle is consistently seen as protective, not detrimental. Finally, genetics and a common family environment may explain about 29% and 22% of the variance in sRAGE, respectively, indicating that both your parents and where you live matter.

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