This study shows that metabolism, acetyl‐CoA levels and histone acetylation are increased during midlife in Drosophila, which correlates with changes in the transcriptome. Depleting the enzymes that link metabolism and histone acetylation reduces midlife acetyl‐CoA levels, transcriptome changes and increases life span.
A collaborative study by 2 research groups at LMU’s Biomedical Center has shown in the fruitfly Drosophila melanogaster that 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.
As we age, the efficiency of the mitochondria progressively declines. Mitochondria also possess their own genome, and mutations in this mitochondrial DNA have been linked to a reduction in lifespan. Paradoxically, however, several studies have shown that reducing levels of mitochondrial activity – by restricting food intake, for instance – can actually extend lifespan. “These findings imply that the primary cause of aging cannot simply lie in a reduction in overall metabolic activity, so the whole issue must be more complicated than that,” Imhof points out. 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,” he explains.
Histone acetylation is changed during midlife, while cooler temperature reverses midlife‐associated metabolic and histone acetylation levels
The 2 teams first made the surprising discovery that middle-aged male flies (7 wks old) consume more oxygen than their younger conspecifics. 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 acetylCoA in these flies. Furthermore, it is an important source of acetyl groups for chemical modification of proteins. “..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. In the cell nucleus, the genomic DNA molecules are wrapped around “spools” made of proteins called histones. These spools or “nucleosomes” are tightly packed together, and keep the nuclear DNA in a compact, condensed form. Various chemical modifications of the nucleosomal histones – including acetylation – regulate the accessibility of the DNA to the enzymes required for gene expression, and thus determine which genes are active at any given time. “We were able to show that the histones in middle-aged flies are overacetylated,” Imhof says. “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.” And Ladurner adds: “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.”
Genetic attenuation of ATPCL reduces midlife histone acetylation and promotes Drosophila life span
These findings indicate 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,” says Ladurner. “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,” says Imhof. “Partial inhibitors that reduce enzyme activity without completely blocking it would probably be most effective in this context.” http://www.en.uni-muenchen.de/news/newsarchiv/2016/imhof_alterung.html
http://embor.embopress.org/content/early/2016/01/18/embr.201541132
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