Proposing a Role for Acetylation in the Damage of Aging

Researchers here investigate fruit flies in search of age-related changes in the cellular processes of metabolism that occur in mid-life, early signs of degeneration and damage accumulation. They find that an increase in acetylation that occurs with aging may act to both alter and raise the error rate of protein creation, leading to an increased number of damaged proteins and inappropriate levels of proteins in circulation. In support of this hypothesis, it is noted that more acetylation reduces fly life span, while suppressing the age-related rise in acetylation increases life span:

The aging process is accompanied by characteristic changes in physiology whose overall effect is to decrease the capacity for tissue repair and increase susceptibility to metabolic disease. In particular, the overall level of metabolic activity falls, and errors in the regulation of gene activity become more frequent. Researchers have now shown in the fruitfly Drosophila melanogaster that such age-dependent changes are already detectable in middle age. Genetic investigation of the signal pathways involved in mediating this effect identified a common process - the modification of proteins by the attachment of so-called acetyl groups (CH3COO−) to proteins - that links the age-related changes at the metabolic and genetic levels. Most studies of the aging process employ comparisons between young and old individuals belonging to the same species. "However, in aged animals, many of the potentially relevant physiological operations no longer function optimally, which makes it difficult to probe their interactions. That is why we chose to look in Drosophila to see whether we could find any characteristic metabolic changes or other striking modifications in flies on the threshold of old age and, if so, ask how these processes interact with each other."

Resarchers first made the surprising discovery that middle-aged male flies (7 weeks old) actually consume more oxygen than their younger counterparts. This points to a metabolic readjustment which is accompanied by an increase in mitochondrial activity, and indeed, the researchers noted a rise in the intracellular concentration of acetyl-CoA in these flies. Acetyl-CoA is a metabolite that is produced in the mitochondria, which participates in large number of processes in energy metabolism. Furthermore, it is an important source of acetyl groups for the chemical modification of proteins. "Acetyl groups are attached to specific positions in certain proteins by dedicated enzymes, and can be removed by a separate set of enzymes. These modifications modulate the functions of the proteins to which they are added, and our experiments have shown that many proteins are much more likely to be found in acetylated form in middle-aged flies than in younger individuals."

Strikingly, this is true not only for proteins that are involved in basic metabolism, but also for proteins that are directly responsible for regulating gene expression. "We were able to show that the histones in middle-aged flies are overacetylated. This reduces the packing density of the DNA, and with it the stringency of gene regulation. The overall result is a rise in the level of errors in the expression of the genetic information, because genetic material that should be maintained in a repressed state can now be reactivated. In the prime of their lives, fruitflies begin to produce a surfeit of acetylated proteins, which turns out to be too much of a good thing."

Taken together, these findings indicate that changes in acetylation may be a key factor in the process of natural aging, reflecting alterations in basic metabolism as well as modifying gene regulation. "A rise in the level of protein acetylation seems to be linked to a decrease in life expectancy. For inhibition of an acetylase enzyme which specifically attaches acetyl groups to histones, or attenuation of the rate of synthesis of acetyl-CoA - which reduces the supply of acetyl groups - reverses many of the age-dependent modifications seen in these animals, and both interventions are associated with a longer and more active lifespan." The researchers are now planning to look for comparable effects in mammals. "If that turns out to be the case, then the enzymes that specifically acetylate histones might well be interesting targets for the development of novel therapeutic agents that correct age-dependent dysregulation. Partial inhibitors that reduce enzyme activity without completely blocking it would probably be most effective in this context."



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