Energy metabolism, altered proteins, sirtuins and ageing: converging mechanisms?

The predominant molecular symptom of ageing is the accumulation of altered gene products. Nutritional studies show that ageing in animals can be significantly influenced by dietary restriction. Genetics has revealed that ageing may be controlled by changes in intracellular NAD/NADH ratio regulating sirtuin activity. Physiological and other approaches indicate that mitochondria may also regulate ageing. A mechanism is proposed which links diet, exercise and mitochondria-dependent changes in NAD/NADH ratio to intracellular generation of altered proteins. It is suggested that ad libitum feeding conditions decrease NAD availability which also decreases metabolism of the triose phosphate glycolytic intermediates, glyceraldehyde-3-phosphate and dihydroxyacetone-phosphate, which can spontaneously decompose into methylglyoxal (MG). MG is a highly toxic glycating agent and a major source of protein advanced-glycosylation end-products (AGEs). MG and AGEs can induce mitochondrial dysfunction and formation of reactive oxygen species (ROS), as well as affect gene expression and intracellular signalling. In dietary restriction–induced fasting, NADH would be oxidised and NAD regenerated via mitochondrial action. This would not only activate sirtuins and extend lifespan but also suppress MG formation. This proposal can also explain the apparent paradox whereby increased aerobic activity suppresses formation of glycoxidized proteins and extends lifespan. Variation in mitochondrial DNA composition and consequent mutation rate, arising from dietary-controlled differences in DNA precursor ratios, could also contribute to tissue differences in age-related mitochondrial dysfunction

Cytotoxicity of advanced glycation endproducts in human micro- and astroglial cell lines depends on the degree of protein glycation

Advanced glycation endproducts (AGEs) arise from the reaction of sugars with side chains and the N-terminus of proteins and are thought to be involved in the pathogenesis of several diseases by inducing oxidative stress, inflammation and cell death presumably mediated through activation of the receptor of AGE (RAGE). To address the question whether the cell damaging effect of AGE depends on the degree of its protein glycation, differential modified AGEs derived from incubating human serum albumin with increasing concentrations of methyl glyoxal were tested on cell viability, reactive oxygen species (ROS) formation, intracellular ATP levels, and activation of caspases 3/7 in two human glial cell lines, which were used as a model for human glia cells. All AGEs tested, regardless of their degree of modification, were found to induce ROS formation in both microglial (CHME-5) and astroglial cells (U373 MG), while only highly modified AGEs were able to decrease the cell viability and to induce apoptosis. This indicates that apoptotic events may be involved in the change of physiological parameters