Ageing is a major public health concern in Europe: one in five citizens is forecasted to be over the age of 65 by 2030. Consequently, the burden of age-related diseases is also likely to increase. The EU-funded MetAGEn project sought to shed light on the underlying processes that produce ageing. “If we could cure cancer, lifespan would only increase 2 or 3 years, since it is a disease of old age, and people with cancer have a host of other chronic diseases,” says project coordinator Martin Denzel, director of the Denzel Lab at the Max Planck Institute for Biology of Ageing in Cologne, Germany. “We need to understand ageing so that we can understand the dominant risk factors that occur with age.”
Denzel’s group focuses on one aspect of ageing, the loss of protein homeostasis. As individuals age, the process of making, modifying and degrading proteins becomes faulty. This incremental process is believed to underlie many age-related diseases. The group discovered that the hexosamine pathway appears to play a decisive role in regulating protein homeostasis in the nematode Caenorhabditis elegans. The team found that when this pathway is upregulated in the tiny worms, protein homeostasis is improved, leading to longer lifespans in the nematodes. So why isn’t this pathway upregulating all the time? “It’s costly,” adds Denzel, “it’s using all currencies of energy: fructose, glutamine, UTP, acetyl CoA, all these are used to build up the final product. You can activate this pathway and have the gas pedal pressed down all the time in worms with a plentiful food supply, but it’s not a beneficial situation when trade-offs are encountered in the wild.”
Experiments carried out for the MetAGEn project found that this hexosamine pathway also exists in mammalian neuronal cells, suggesting the possibility of exploiting it to treat human age-related diseases. “When we activated the hexosamine pathway, it led to a strong protection, suppressing the formation of toxic protein aggregations that are linked to neurodegeneration in people,” explains Denzel. The group is now working with a German company to identify small molecule drugs that may activate this pathway. The work was supported by the European Research Council, which allowed the team to adapt their genetic screening methods to mouse cells. “This is an example of what you can do with an ERC grant, the freedom to try something crazy,” notes Denzel. The group used newly discovered haploid embryonic cells to identify point mutations relevant to drug resistance in cancers.
The researchers are now focusing on this haploid screening technology to further understand the hexosamine pathway. “We have really exciting data in that area,” says Denzel, “There’s a new player we’re trying to understand.” This work has led to the development of a spinout company to carry on this research, Acus Laboratories GmbH, headed by one of the postdocs from Denzel’s lab and supported by a further ERC grant.
MetAGEn, ageing, protein, homeostasis, nematode, hexosamine, upregulated, Caenorhabditis elegans, lifespan