Epigenetic research on the potential molecular causes of aging has piqued the curiosity of many people who want to know if it’s possible to slow aging or, perhaps, stop it altogether. The process of aging comes along with physiological changes that decrease the body’s ability to repair tissue and increase vulnerability to metabolic diseases. Overall, metabolic activity levels are reduced and missteps in gene activity regulation occur more often as one ages. In a new article published in EMBO Reports, Munich researchers at the Ludwig Maximilian University investigated middle aged fruit flies known as Drosophila melanogaster, and uncovered new insights into how histone modifications may play a role in aging.
Two groups of researchers at LMU’s Biomedical Center, one team led by Professor of Molecular Biology, Axel Imhof, and another led by Professor of Physiological Chemistry, Andreas Ladurner, worked on fruit flies together to demonstrate that age-dependent physiological changes can be measured in middle age. After investigating the signal pathways that play a part as mediators of this age-dependent effect, they found that a particular histone modification known as histone acetylation was the link between physiological alterations related to age and genetic and metabolic levels.
Mitochondria, known as the “powerhouse” of the cells, convert nutrients so that they may be used as an energy source. Naturally, as we get older, these organelles get progressively less efficient. Mutations in the genome of the mitochondria have been connected to reduced lifespan. However, numerous studies have revealed that reducing caloric intake – which, in turn, decreases mitochondrial activity – is actually associated with an increase in 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 noted. Many studies that investigate aging make comparisons between old and young individuals of 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,” Imhof explained.
In a previous study on histone modifications and aging, researchers at the University of Pennsylvania pinpointed abnormal transcription that is significantly increased in older cells using a budding yeast single-cell organism model.
In this study, the researchers found that the male flies that were middle-aged (7 weeks) consumed extra oxygen compared to the younger male flies. This metabolic readjustment suggested that mitochondrial activity rose, which was in fact confirmed by the researchers who discovered an increase in intracellular concentration of acetyl coenzyme A (acetyl-CoA). The metabolite known as acetyl-CoA is produced in the mitochondria and is involved in numerous energy metabolism processes. In terms of its involvement in epigenetic mechanisms, acetyl-CoA is a key source of acetyl groups necessary for histone acetylation.
Histone acetylation is a popular histone modification defined as the addition of acetyl groups to histone proteins, around which DNA is wound. Acetyl groups are joined to various positions on histones via enzymes known as histone acetyltransferases (HATs). When the acetyl groups are removed by other enzymes called histone deacetylases (HDACs), the epigenetic modification is termed histone deacetylation. Measuring histone modifications allows researchers insight into gene expression.
Overall, the experiments conducted by Ladurner and his colleagues demonstrated that midlife flies showed “changes in the metabolome, elevated acetyl‐CoA levels, alterations in protein—notably histone—acetylation, as well as associated transcriptome changes.” Importantly, they concluded that it is more likely that proteins will be acetylated in middle-aged flies compared to younger flies.
Interestingly, this is not only the case for proteins linked to basic metabolism, but also for histone proteins that help regulate the expression of genes. These histone proteins are modified by the addition or removal of acetyl groups and can loosen or tighten the packaging of DNA. This makes the DNA more or less available to transcription, impacting the expression of particular genes.
“We were able to show that the histones in middle-aged flies are overacetylated,” Imhof said. “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.”
Shifts in histone modification marks, specifically histone acetylation, might play a crucial role in aging. In this case, basic metabolism changes and the modification of gene regulation related to aging appear to be controlled by histone acetylation.
According to Ladurner, “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.” Specifically, the researchers decreased the activity of histone H4 K12‐specific acetyltransferase Chameau and found that this alleviated the aging-associated changes and promoted longevity.
The team is now focusing on illuminating these same results in mammals in future studies. Imhof suggested that if histone acetylation is a key component to the natural aging process, then enzymes that catalyze the acetylation of histones might pose as targets to develop new therapies in order to correct the dysregulation connected to aging.
Source: Peleg, S. et al. (2016). Life span extension by targeting a link between metabolism and histone acetylation in Drosophila. EMBO reports. 17(2).
Reference: The Ludwig-Maximilians-Universitaet (LMU). Harbringers of aging. 29 Jan 2016. Web.