The study, published today in Aging Cell, found strong evidence that triggering a protein governing energy level may help organisms live longer, in some cases by over 25%.
Researchers from the MRC Laboratory of Medical Sciences (MRC LMS), Imperial College London, University of Cologne and their collaborators used a drug to specifically activate an important metabolic sensor in cells.
They achieved anti-ageing effects across a range of species including yeast, worms and flies.
The AMPK enzyme
Adenosine monophosphate-activated protein kinase (AMPK) is a special metabolic enzyme inside cells that monitors energy levels in real time.
When energy depletes, for instance during exercise, fasting or stress, AMPK turns off intensive cellular processes like building new proteins or storing fat.
Instead, AMPK turns on energy-generating processes, such as burning existing fat and sugar for fuel.
The role of AMPK in the metabolism
Since AMPK plays a central role in controlling metabolism, disruption can lead to metabolic diseases, such as type 2 diabetes and obesity, while increased AMPK activity can provide health benefits.
Several medicines and treatments including the anti-diabetic drug Metformin and weight-loss drugs like Semaglutide are known to activate AMPK.
But many of these work indirectly, making it much more challenging to confirm and interpret biological results with certainty in the laboratory and in the clinic.
Targeting AMPK using 991
To overcome this hurdle, the team used a specific drug, called 991, to target AMPK directly.
They turned to a range of model organisms:
- fission yeast (S. pombe)
- nematode worms (C. elegans)
- fruit flies (Drosophila)
These model systems are extremely valuable in the ageing field, due to their comparatively short lifespans.
‘Energy saver mode’
Dr Helena Cochemé, who leads the Redox Metabolism Group at MRC LMS, said:
For example, worms and flies in the lab live for around three weeks and three months respectively, compared to roughly three years for mice, so you can make progress and discoveries much more rapidly and efficiently than in mammalian systems.
The fact that we can extend lifespan in yeast, worms and flies is very exciting.
Our study is the first demonstration that directly targeting AMPK using a drug can have longevity benefits in living organisms.
AMPK is effectively the body’s equivalent to the ‘energy saving mode’ on a mobile phone.
If a treatment works successfully in three such distantly related species, then these results give us confidence that in the longer-term, the effects could be translated to mammals and eventually humans.
Next steps
Professor David Carling, who leads the Cellular Stress Group at MRC LMS, said:
By switching-on AMPK specifically using a direct activator, it is possible to achieve a much cleaner result, avoiding potential side-effects.
Now that we have very solid, convincing evidence from the laboratory model organisms, the next step will be to show that we can also improve health and extend lifespan in mice.
Direct AMPK activators have already been used safely in clinical trials for the treatment of specific metabolic diseases.
This opens the door for using AMPK activators to treat a range of human diseases in the future.
Healthier for longer
Professor Filipe Cabreiro, who leads the Host-Microbe Co-Metabolism Group at the MRC LMS, alongside a laboratory at the University of Cologne in Germany, said:
The field is still a long way from anti-ageing clinical trials in humans.
This is because ageing in not technically classified as a disease.
But improving health in older age would be hugely beneficial from a societal and healthcare perspective, since ageing is a major risk factor for so many diseases, such as heart disease, diabetes, cancer and dementia.
The ability to make individuals healthier for longer, for instance by pharmacologically targeting energy balance through AMPK, would be a major biomedical breakthrough.
Research collaboration
The research also involved contributions from scientists at:
- Queen Mary University of London
- the Francis Crick Institute
- University of Lyon
This study was primarily funded by the Medical Research Council (MRC) UK.