Search

Advanced glycation end product (AGE) accumulations as well as a high fat diet are associated with cardiovascular diseases. AGEs are recognized by several receptor molecules of which the receptor of AGEs (RAGE) is currently the most intensively studied. Activation of RAGE causes an unfavorable pro-inflammatory state. The hypothesis of this study was that metabolic stress due to a high fat diet results in the development of aortic valve stenosis and that knockout of RAGE should be protective. Six week old male C57BL/6N and C57BL/6N RAGE-/- mice (n=28) were randomly assigned to 4 groups and fed with normal or high fat diet for 32weeks. Weight gain was determined weekly. At the start of the experiment and after 2, 4 and 7months, echocardiographic assessments of the aortic valve were made. At the end of the experiment, plasma lipid levels and histological changes of the valves were determined. The high fat diet resulted in accelerated weight gain. However, after 7month, only C57BL/6 mice developed increased trans-aortic-valve velocities, leaflet thickness and reduced valve area index (p

Changes in the expression of fibrillar collagens and post-translational modifications with advanced glycation end-products (AGEs) are often associated with tissue aging. Less is known about age-related changes in mouse lung tissue. Therefore, we studied the expression level and AGE load of fibrillar collagens in lungs from young (≤ 6 months), adult (15 months) and old (≥ 25 months) mice. The mRNA expression level was reduced in adult and old mice compared with the young. Old mice also showed a reduced protein level, whereas the adults even had more collagen protein. Fractionating of the fibrillar collagens into enzyme-soluble and insoluble collagens revealed a reduced solubility of collagens in old age. The enzymatic solubility of fibrillar collagens correlated inversely with the AGE load in the insoluble collagen as detected by the AGE-related fluorescence. While the intensity of the AGE-related fluorescence was increased in fibrillar collagens in response to age, the fluorescing AGE variant argpyrimidine was less affected. In summary, aging causes a reduced expression, lower enzymatic solubility and increased AGE load of fibrillar collagens in mouse lung tissue, but not all changes occur gradually with age.

In order to identify hints of ageing in circulating hematopoietic stem cells (HSCs), putative senescence markers like the cellular level of carbonyl-modified proteins and senescence associated β-galactosidase activity were measured. Furthermore, the number of HSCs in the periphery and their proliferative capacity in vitro were analyzed in buffy coats of fifty five individuals: 27 young [age, 19–43 years; mean age 31] and 28 middle-aged individuals [age, 45–66 years; mean age 56]. The effect of humoral factors on cell proliferation in culture was studied by expansion of the cells in the presence of plasma pools from children and elderly donors. Using a multiplex flow cytometry method, the plasma pools used in the proliferation experiments were assayed for the presence or absence of 25 chemokines. Within the age range analyzed, no age-dependent differences in the number of isolated CD34+ cells were found. Both sources of progenitor cells were able to reach comparable cell density in culture, but cells from the middle-aged subjects proliferated only sufficiently in the presence of plasma obtained from older donors. Cells from middle-aged donors exhibited elevated levels of carbonyl-modified proteins and showed increased β-galactosidase activity in comparison to the cells from young donors. Our study shows that although two markers of ageing i.e. carbonylated proteins and senescent associated β-galactosidase activity are increased in HSCs from middle-aged donors, the number and proliferative capacity of HSCs are still maintained.