THE ARISING · Longevity & Healthspan · Long Reads
A Direct AMPK Activator Extended Lifespan in Yeast, Worms and Flies
An Aging Cell study from London and Cologne shows a compound called 991 lengthened life in three species by switching on the cell's energy sensor. Higher doses shortened life; mouse liver proteins were studied, but mammalian lifespan was not.
Fasting and exercise share a hidden switch inside every cell: an enzyme called AMPK that senses when energy runs low. For years, scientists suspected flipping that switch could slow aging. Now a drug that turns it on directly has extended lifespan in three very different species.
Our research desk reported that a compound called 991, a direct AMPK activator, lengthened life in fission yeast, nematode worms and fruit flies. It credited a team from the MRC Laboratory of Medical Sciences, Imperial College London and the University of Cologne, publishing in Aging Cell.
We confirmed the paper, led by Eliano dos Santos with senior authors David Carling, Filipe Cabreiro and Helena Cochemé. It appears in the October 2026 issue. Its title says it plainly: direct pharmacological activation of AMPK extends lifespan in yeast, worms and flies.
The details are more nuanced than the headline. In flies, low doses extended female lifespan, but a higher dose shortened it. In yeast, a low dose helped and a higher dose harmed. In worms, the benefit disappeared in animals lacking the worm version of AMPK, which supports the idea that the drug works through that switch.
Our desk missed one piece. The team also gave 991 to mice for three weeks, delivered by nanoparticle injection. Liver proteins shifted toward a profile linked to longevity, including signs of better mitochondrial production and reduced mTOR activity. Lifespan was not measured, and only three mice per group were analyzed.
Two more details deserve attention. In flies, the benefit appeared only on a defined laboratory diet; in standard yeast-based food, 991 did not activate AMPK at all. And egg-laying in treated flies was unchanged, which suggests the drug did not simply buy longevity by suppressing reproduction, a common trade-off in aging research.
Metformin, the diabetes drug in the planned TAME aging trial, touches AMPK, but only indirectly and alongside many other effects. That makes it hard to know what produces any benefit. A clean, direct activator lets researchers test the switch itself.
The paper cites human metabolic-disease trials of a different direct AMPK activator, PXL-770. That does not establish the safety of 991 or show a human anti-aging benefit.
• Use the switch you already control: regular exercise is one of the most reliable natural activators of AMPK. • Do not seek out 991 or similar research compounds; 991 remains a research compound, and this study does not establish safe human dosing or longevity benefit. • If you take metformin for diabetes or prediabetes, keep doing so as prescribed; this study does not change that decision. • Anyone considering off-label metformin for longevity should discuss the evidence and side effects with their physician first.
• Narrow dose window. Higher doses shortened life in two species, a real warning for anyone extrapolating. • Mouse data are preliminary. Three weeks, a few animals, liver proteins only, no lifespan or healthspan. • Mechanism is still unclear, the authors say, beyond pointing to AMPK.
• A mouse lifespan and healthspan study with oral dosing or second-generation activators. • Whether any direct AMPK activator from metabolic-disease trials is repurposed for aging research. • Independent replication, ideally through the NIA Interventions Testing Program.