Switching on the cell’s “low fuel” sensor directly made yeast, worms and flies live longer

Every cell needs to know how much energy it has. One of the main sensors is an enzyme called AMPK (AMP-activated protein kinase). When fuel runs low, a by-product of energy use called AMP builds up, AMPK switches on, and the cell shifts from building and storing to saving and burning: it makes more mitochondria (its power plants), burns fat, recycles worn parts and slows growth. Fasting and exercise both activate AMPK. In many animals, turning AMPK up genetically makes them live longer.

The diabetes drug metformin is often described as an AMPK activator, and it is being proposed for trials against aging itself. But metformin acts indirectly: it disturbs the cell’s energy balance, which then turns on AMPK, and it affects many other things along the way, including gut bacteria. In worms and flies, for example, metformin’s effect on lifespan works through their bacteria. So it is hard to say how much of metformin’s benefit really comes from AMPK.

A direct switch

A team from London, Cologne and Lyon used an experimental compound called 991, which binds directly to AMPK in a pocket between two of its parts and switches it on, without changing the cell’s energy levels. It had only been used in mammalian cells. The researchers first checked that it fits and activates the AMPK of yeast, worms and flies, whose versions of the enzyme are very similar to ours. It did, and at concentrations about a thousand times lower than metformin needs (micromolar against millimolar) in fly cells.

What they found

• Longer lives in three species. Added to the food, 991 extended the lifespan of fruit flies, roundworms (C. elegans) and fission yeast.
• It worked through AMPK. In yeast and worms that lack a working AMPK, 991 did not extend life (in the yeast it even shortened it). That is good evidence the effect runs through AMPK itself.
• Not through bacteria or eating less. Flies on 991 had less body fat but did not eat less, and their egg-laying was unchanged. In worms, 991 did not change the growth of the bacteria they feed on, and it worked on two different bacterial strains, unlike metformin.
• Dose matters. Higher doses shortened lifespan, so more is not better.
• First signs in mammals. Mice injected with 991 packed into tiny particles for three weeks showed liver protein changes that fit AMPK activation (more energy production, more new mitochondria, reduced activity of the growth regulator mTOR). This was a short test of molecular changes, not a lifespan study.

What to keep in mind

Yeast, worms and flies are where many longevity drugs start, and many of those never work in mammals. The mouse part of this study was small (three mice per group in the main comparison) and lasted three weeks. The paper is a short report, and the exact gains in lifespan are given in its figures.

Why it matters

The authors note that drug companies have already developed similar direct AMPK activators for diabetes and fatty liver disease, which bind to the same pocket and work better in mammals. One of them has been given to people in trials and was reported to be safe. This makes it realistic to test the idea in mice next, which is what the authors propose: a proper mouse lifespan study with these second-generation drugs.