Sugar-derived AGEs accelerate pharyngeal pumping rate and increase the lifespan of Caenorhabditis elegans.

All living organisms are normally undergoing aging. Dietary habits constitute the main environmental factor that may accelerate or decelerate this process. Advanced glycation end products (AGEs) are constituents of dietary products that are consumed daily, such as bread and milk. Although AGEs have been widely regarded as toxic agents, recent studies seem to contradict this view: they either find no adverse effects of AGEs or even attribute beneficial properties to them. The aim of our study was to investigate the effects of sugar-derived AGEs on organismal lifespan using as a model the nematode Caenorhabditis elegans. Exposure to sugar-derived AGEs prolonged the lifespan of wild type animals; this lifespan extension was accompanied by an enhanced pharyngeal pumping rate. We demonstrate that elevation of the pharyngeal pumping rate depends on W06A7.4 and eat-4 expression, as well as on daf-16, which encodes a FOXO family transcription factor. Our results suggest that sugar-derived AGEs modulate the lifespan of C. elegans at least in part through transcriptional regulation of pharyngeal pumping throughout the animals' lifespan.

Adenosine triphosphate concentrations are higher in the brain of APOE3- compared to APOE4-targeted replacement mice and can be modulated by curcumin.

Curcumin from Curcuma longa may exert putative neuroprotective properties in the brain. Impaired mitochondrial function is implicated in Alzheimer's disease and the presence of the apolipoprotein (APO) E4 genotype, which is a risk factor for late-onset Alzheimer's disease, may aggravate mitochondrial malfunction. Here, we report that in the brain of 16-month-old APOE4-targeted replacement mice, adenosine triphosphate (ATP) concentrations were significantly lower than in APOE3 mice. A 3-month dietary supplementation of 0.2 % curcumin numerically increased ATP concentrations in APOE3 and significantly in APOE4 mice compared to the respective controls. Curcumin significantly induced the transcription of peroxisome proliferator-activated receptor (PPAR) γ and mitochondrial transcription factor A (TFAM) in APOE3, but not in APOE4 mice. Moreover, PPARγ coactivator (PGC)-1α and guanine-adenine repeat binding protein α (GABPa) mRNA was only increased in APOE3 mice. Consistent with these observations, protein expression of mitochondrial respiratory complexes, especially of complex IV, also appeared to be increased in APOE3 mice. In conclusion, we provide evidence that curcumin affects mitochondrial function and gene and protein expression in the murine brain despite its low bioavailability and carriers of the Alzheimer's disease-risk genotype APOE4 may be less responsive to dietary curcumin than APOE3 carriers.

Cathepsins D and L reduce the toxicity of advanced glycation end products.

Advanced glycation end product-modified proteins are known for accumulating during aging and in several pathological conditions such as diabetes, renal failure, and neurodegenerative disorders. There is little information about the intracellular fate of endocytosed advanced glycation end products (AGEs) and their influence on proteolytic systems. However, it is known that the lysosomal system is impaired during aging. Therefore, undegraded material may accumulate and play a considerable role in the development of diverse diseases. To investigate if AGEs can be degraded and to test whether they accumulate because of impaired lysosomal proteases we studied the effects of advanced glycation end products on the endosomal-lysosomal system. Five different types of AGEs were generated by bovine serum albumin incubation with glyoxal, methylglyoxal, glucose, fructose, and ribose. The first experiments revealed the uptake of AGEs by the macrophage cell line RAW 264.7. Further investigations demonstrated an increase in cathepsin D and L activity and an increase in mature cathepsins D and L. Increased activities were accompanied by the presence of more lysosomes, measured by staining with LysoTracker blue. To specify the roles of cathepsins D and L we used knockout cells to test the roles of both cathepsins on the toxicity of advanced glycation end products. In summary we conclude that both cathepsins are required for a reduction in advanced glycation end product-induced cytotoxicity.

Protein oxidative modifications in the ageing brain: consequence for the onset of neurodegenerative disease.

The free radical theory of ageing proposes the accumulation of altered, less active and toxic molecules of DNA, RNA, proteins and lipids caused by reactive oxygen species and reactive nitrogen species. Neurodegenerative disorders are characterized by an abnormal accumulation of oxidatively damaged macromolecules inside cells and in the extracellular space. Proteins involved in the formation of aggregates are ß-amyloid, tau, α-synuclein, parkin, prion proteins and proteins containing polyglutamine. These abnormal aggregated proteins influence normal cellular metabolism. Additionally, deposition of abnormal proteins induces oxidative stress and proteasomal as well as mitochondrial dysfunction that ultimately lead to neuronal cell death. This review focuses on the impact of oxidative and nitrative stress in the ageing brain and, consequently, on the generation of modified proteins, as these post-translational modifications are assumed to play an important role in the development of neurodegenerative diseases.