BRITISH scientists have made an exciting advance in the study of ageing after successfully extending the lives of several different organisms by switching on the cellular equivalent of an “energy saver” mode.
Researchers led by scientists at the MRC Laboratory of Medical Sciences in London and Imperial College London found that directly activating a crucial energy-sensing enzyme could increase lifespan in yeast, worms and fruit flies.
The findings, published in the scientific journal Aging Cell, provide new evidence that a biological system called AMPK could eventually become an important target in the search for treatments designed to help people remain healthier for longer.
In some of the laboratory organisms studied, lifespan was extended by more than 25 per cent.
The research has a strong British contribution, involving scientists from the MRC Laboratory of Medical Sciences, Imperial College London, Queen Mary University of London and the Francis Crick Institute, alongside researchers at the University of Cologne and University of Lyon.
The work was primarily funded by the UK’s Medical Research Council.
At the centre of the discovery is an enzyme known as AMP-activated protein kinase, or AMPK, which acts as one of the body’s cellular energy sensors.
When cells begin running short of energy, such as during exercise, fasting or other forms of stress, AMPK helps them conserve resources.
It reduces energy-intensive activities, while encouraging processes that generate energy from existing stores of fat and sugar.
Dr Helena Cochemé, who leads the Redox Metabolism Group at the MRC Laboratory of Medical Sciences, compared the mechanism to putting a mobile phone into “energy saving mode”.
Scientists have long been interested in AMPK because of its central role in metabolism and its possible relationship with ageing.
However, previous research has frequently involved substances such as the diabetes medicine metformin, which can activate AMPK indirectly and have other effects on cells. That has made it difficult for scientists to determine precisely how much of any observed benefit is actually caused by AMPK.
The British-led team instead used a compound known as 991, which directly targets and activates AMPK.
They tested it in three very different laboratory organisms, fission yeast, nematode worms and fruit flies.
All are widely used in ageing research because their relatively short lifespans allow scientists to study the biological effects of potential treatments far more quickly than would be possible in mammals.
The researchers found that direct activation of AMPK using 991 extended lifespan across all three organisms.
Crucially, experiments involving worms and yeast genetically lacking the relevant AMPK activity did not show the same lifespan-extending effect, providing evidence that AMPK itself was responsible for the results.
Dr Cochemé said the fact that lifespan could be extended in three distantly related species was “very exciting”, describing the research as the first demonstration that directly targeting AMPK with a drug could produce longevity benefits in living organisms.
The scientists also took an initial step towards determining whether the findings might eventually translate to mammals.
Mice treated with 991 for three weeks did not undergo a lifespan experiment, so the researchers have not demonstrated that the compound makes mice live longer.
However, analysis of proteins in their livers found biological changes associated with AMPK activation and processes linked with longevity, including changes involving energy metabolism, mitochondrial activity and mTOR signalling.
The researchers described this as a “pro-longevity” protein profile, providing a reason to investigate the approach further in mammals.
Professor David Carling, who leads the Cellular Stress Group at the MRC Laboratory of Medical Sciences, said directly activating AMPK allowed researchers to produce a much cleaner experimental result than using substances which affect the enzyme indirectly.
The next major challenge will be to establish whether direct AMPK activation can improve health and extend lifespan in mice.
Researchers say future animal studies are likely to use newer compounds similar to 991 which have better properties for use in mammals.
There is still a considerable distance to travel before the discovery could lead to an anti-ageing treatment for people.
Professor Filipe Cabreiro, who leads the Host-Microbe Co-Metabolism Group at the MRC Laboratory of Medical Sciences and also has a laboratory at the University of Cologne, stressed that the field remained “a long way” from human anti-ageing clinical trials.
Ageing itself is not technically classified as a disease, and findings in yeast, worms and flies cannot simply be assumed to work in people.
But the potential prize is considerable.
Age is one of the biggest risk factors for conditions including heart disease, cancer, diabetes and dementia. Rather than simply attempting to increase the number of years people live, scientists are increasingly interested in extending healthspan, the period of life spent in good health.
If researchers can eventually manipulate fundamental biological processes involved in ageing, it could potentially help delay several age-related diseases rather than treating each one separately.
The latest discovery adds another chapter to Britain’s formidable record in biomedical research, with UK laboratories playing a leading role in investigating one of medicine’s biggest questions, whether it may one day be possible to intervene in the ageing process itself.
For now, there is no suggestion that people should take existing medicines in an attempt to reproduce the laboratory findings, and considerably more research will be required before scientists know whether directly activating AMPK can safely produce similar benefits in humans.
But after demonstrating lifespan extension across three remarkably different organisms, Britain’s scientists have provided an intriguing new clue in the global quest to help people live not merely longer lives, but healthier ones.
Read the full publication in Aging Cell.
