Cancer drug makes fruit flies live longer
【LWBS 2015 06 26 A】(SpringRain Edited from University College London Institute of Healthy Ageing and the Max Planck Institute for Biology of Ageing) Adult fruit flies given a cancer drug live 12% longer than average, according to a University College London (UCL)-led study researching healthy ageing. The drug targets a specific cellular process that occurs in animals, including humans, delaying the onset of age-related deaths by slowing the ageing process.
The study, published in Cell and funded by the Max Planck Society and Wellcome Trust, shows for the first time that a small molecule drug, which limits the effects of a protein called Ras, can delay the ageing process in animals. The treated fruit flies outlived the control group by staying healthier for longer.
Humans, yeasts and fruit flies began to evolve separately millions of years ago. Nevertheless, the cellular processes which regulate cell division and cell death – and therefore the mechanism of ageing – are similar in all of them.
Scientists at the Max Planck Institute for Biology of Ageing in Cologne and University College London have now succeeded in controlling this mechanism, thus extending life expectancy in fruit flies by around twelve percent. They achieved this with the help of a cancer drug called Trametinib. Human cells contain the same molecular switches that Trametinib targets in fruit flies. It is therefore conceivable that the substance could be used to develop future anti-ageing drugs to extend life expectancy in humans.
To ensure a long and healthy life in humans, researchers have to understand the ageing process at the cellular level more precisely. A scientific study has now shown how Ras proteins can be manipulated to prolong the lifespans of animals.
Ras proteins play a key role in the regulation of cell processes. As molecular switches within the cellular signalling network, they control vital functions such as cell division, cell death, specialisation and metabolism. They regulate these intracellular processes via the Ras-Erk-ETS signal pathway. This network has been conserved over hundreds of millions of years of evolution and is present in single-cell organisms such as yeasts, in insects such as the fruit fly (Drosophila), as well as in mammals such as mice and humans.
It was already known that inhibition of this signal pathway can prolong the life expectancy of yeast cells. However, to achieve this, the scientists had thus far manipulated the DNA directly in order to deactivate individual genes within the Ras signal pathway. However, no substance was known that could slow the ageing process at this interface. Recent work by the research team has now filled this gap.
The scientists took advantage of the fact that the Ras-Erk-ETS signal pathway has been thoroughly researched in the context of cancer treatment. This is because overactivation of Ras is carcinogenic: in around a third of cancer patients, the Ras proteins of cancer cells are mutated, resulting in uncontrolled cellular division. Many cancer researchers have therefore focused on this signal pathway - and many drugs have already been developed to interfere with Ras signalling in order to check cancerous growth.
The researchers administered one of those substances, Trametinib, to fruit flies in the form of a food additive. Even a small dose, which is approximately equivalent to a daily dose of the drug in a human patient, increased the fruit flies’ average life expectancy by eight percent. With a moderate dose, the flies lived twelve percent longer on average.
Any drug suitable for anti-ageing applications must be effective even if it is administered during an advanced phase of life. The scientists successfully demonstrated this property. In a substudy, they administered the substance for the first time to Drosophila that were 30 days old – a ripe old age for this species. At this point, egg laying, i.e. the insects’ fertile phase, has ceased. Even when a moderate dose of the substance was given to the flies at this late point in their lifespan, it still increased their average life expectancy by seven percent. The researchers observed no adverse effects on the insects’ digestive system or food intake.
“Our findings indicate what substance classes could be used to slow the ageing process in humans,” explains Nazif Alic of UCL. “The Ras-Erk-ETS signal pathway could serve as a target for those substances.” The aim now is to investigate this pathway more closely. “The study suggests that inhibition of this signal pathway has positive effects on longevity and mortality,” says Cathy Slack, who researches at University College London and at the Max Planck Institute for Biology of Ageing. Slack emphasises that Trametinib has been approved by the FDA as a drug for the treatment of skin cancer and is therefore already in clinical use.
In mammals, Ras acts as a mediator for the insulin/IGF-1 signal pathway, which modulates life expectancy. Ras activation has effects on both the PI3/Akt and Erk/Mapk signal pathways. Until now, it was assumed that the PI3/Akt branch is primarily responsible for modulating lifespan. The findings show, however, that the Erk branch is also important in this regard. Two transcription factors controlled by Ras-Erk appear to be key mediators of these effects: Pnt, a gene expression activator, and Aop, a repressor. It therefore appears likely that life expectancy can be regulated via both branches of the signal pathway.
Co-first author, Dr Nazif Alic, UCL Institute of Healthy Ageing, said: “Our aim is to understand the mechanisms of ageing and alter the processes that lead to loss of function and to disease. We studied this molecular pathway in flies because they are reasonably complex and yet age more quickly than mammals. We were able to extend their lifespan both genetically and by using a cancer drug to target the Ras pathway, which provides us with the first evidence for the anti-ageing potential of drugs developed to dampen this pathway.”
Co-first author, Dr Cathy Slack, UCL Institute of Healthy Ageing, said: “Identifying the importance of the Ras-Erk-ETS pathway in animal ageing is a significant step on the way to developing treatments that delay the onset of ageing. The pathway is the same in humans as it is in flies and, because the Ras protein plays a key role in cancer, many small molecule drugs already exist, some of which have been approved for clinical use. With support from pharma, we can refine these molecules over the next 10-20 years to develop anti-ageing treatments which don’t have the adverse effects of cancer drugs.”
Principal Investigator, Professor Dame Linda Partridge, Director of the UCL Institute of Healthy Ageing and the Max Planck Institute for Biology of Ageing, said: “My groups study the changes in diet and genetic make-up that can slow down ageing, with the aim of identifying drug targets for a broad-spectrum, preventative medicine for the diseases of human ageing. Death still seems to be inevitable, but we now have evidence to suggest it is possible to develop pharmacological treatments to keep us healthier for longer. Our next step is to investigate the effects of targeting the Erk-Ras-ETS pathway in more complex animals, such as mice, with a view to developing a drug regime that could be suitable for testing in humans. This project complements other work we are doing into the ways in which the ageing process acts as a risk factor for neurodegenerative disease.”