Aging: The environment affects the genome

Researchers have studied how "aging" E. coli bacteria mutate. The study very surprisingly showed that the bacteria accumulated mutations in very specific places on their genome as they aged. Many of these sites code for so-called transcription factors that can turn several genes on or off simultaneously. The result shows that aging cells "explore" new ways to survive.

But why are aging bacteria and the way they mutate important at all? New findings like these challenge our understanding of how aging or starving organisms adapt, says Senior Scientist Morten Nørholm from The Novo Nordisk Foundation Center for Biosustainability – DTU Biosustain – at Technical University of Denmark:

"If we can understand what happens in cells when we get old, we may also be able to understand why we develop age-related diseases like cancer," he says.

The study is the first to have investigated these kinds of mutations in aging bacteria and has recently been published in the journal Nature Scientific Reports.

The study also indicated that genes that are very active are also most likely to mutate.

"Our findings suggest that the environment can activate some mechanism, which then triggers specific mutations in specific genes as we get older. If this is the case, it is actually somewhat controversial, because this means that our DNA is directly influenced by the environment. We would like to investigate this mechanism further to understand the aging process," says Morten Nørholm.

In addition, the study found that most mutated building blocks are G’s. DNA consists of four bases: A, T, G and C, of which G mutated most frequently under these conditions.

"Now we know how the risk genes mutate, and ultimately it could mean that you can replace the G’s to make the gene more robust. Initially, you would probably only change the DNA for research purposes. But in theory, you would be able to make potential cancer genes more resistant to mutations," he says.

An organism, which is under selection pressure due to an unfavourable environment will try to mutate to survive. But as the cell does not have the energy to divide, the mutations need to improve the chance of survival and growth BEFORE they have been embedded in the DNA permanently.

The situation is seen in for example so-called dormant cells, which suddenly begin to grow after a long period of ‘hibernation’. This is only possible if the cells acquire new properties, although they are not dividing. The phenomenon is called retro-mutagenesis.

According to this theory, only mutations that are actively read by the decoding machinery of the cell and, hence, result in mutant proteins, will be incorporated as a permanent change in the DNA.

In order to show that the bacteria were exposed to retro-mutagenesis, the researchers cultivated E. coli bacteria on a growth medium with a type of sugar (maltose) that the bacteria could not grow on. After 4 days, some bacteria, however, began to grow as reddish colonies, because the microbes were now able to break down maltose. Two months after the inoculation the researchers sequenced the bacteria's genomes.

The researchers studied 96 mutants and found 4-5 mutations in each genome sequenced. The mutations were mostly located on the transcribed strand of the DNA, which meant that retro-mutagenesis had taken place. Most mutations were located in very specific locations, which influence the sugar metabolism. This suggested that a genetic program was activated, which allowed the cells to ‘explore’ their chances of survival:

"It is very interesting that the cell can activate a master switch that leads to mutations. But it makes perfect sense. In principle, the cell could also ‘choose’ to turn on all of its genes to survive, but this would cost too much energy. Therefore, it instead ‘chooses’ only to use energy to turn on certain master switches in the hope that this can provide useful changes to the DNA," says Morten Nørholm.