Direct Pharmacological Activation of AMPK Extends Lifespan in Yeast, Worms and Flies

  • Aging Cell. 2026 Oct;25(10):e70721. doi: 10.1111/acel.70721.
Eliano Dos Santos  1  2 ,  Marie Blickling  3 ,  Fiona C Leiper  1  2 ,  John-Patrick Alao  4 ,  Claudia Lennicke  1  2 ,  Andrea Foley  1  2 ,  Jon R Wilson  5 ,  Steven J Gamblin  5 ,  Bénédicte Chazaud  6 ,  Giovanna Lollo  7  8 ,  Rémi Mounier  6 ,  Gaëtan Juban  6 ,  Charalampos Rallis  4 ,  David Carling  1  2 ,  Filipe Cabreiro  2  3  9 ,  Helena M Cochemé  1  2
Affiliations
  • 1. MRC Laboratory of Medical Sciences (LMS), London, UK.
  • 2. Institute of Clinical Sciences, Imperial College London, London, UK.
  • 3. CECAD Research Cluster, University of Cologne, Köln, Germany.
  • 4. School of Biological and Behavioural Sciences, Queen Mary University of London, London, UK.
  • 5. The Francis Crick Institute, London, UK.
  • 6. Institut NeuroMyoGène, Physiopathologie et Génétique du Neurone et du Muscle, Université Claude Bernard Lyon 1, Inserm U1315, CNRS UMR 5261, Université de Lyon, Lyon, France.
  • 7. Laboratoire d'Automatique, de Génie des Procédés et de Génie Pharmaceutique, Université Claude Bernard Lyon 1, CNRS UMR 5007, Villeurbanne, France.
  • 8. Institut Universitaire de France (IUF), Paris, France.
  • 9. Center for Molecular Medicine Cologne (CMMC), University of Cologne, Köln, Germany.
PMID: 42810392 DOI: 10.1111/acel.70721
Abstract

AMP-activated protein kinase (AMPK) is a key evolutionarily conserved sensor of energy homeostasis and plays a central role in metabolic health and disease. AMPK has also been implicated in ageing; however, most in vivo drug studies rely on the use of indirect activators, such as metformin, which have complex modes-of-action, therefore making conclusions on the specific role of AMPK more challenging. Here, we demonstrate that direct activation of AMPK with the compound 991 extends lifespan in Drosophila melanogaster, Caenorhabditis elegans and Schizosaccharomyces pombe. In mice, 991 treatment induces a pro-longevity proteomic profile, highlighting the potential for translation to mammals. Overall, our study provides important proof-of-principle for AMPK as a pharmacological target with longevity benefits.

Keywords
Caenorhabditis elegans; Drosophila melanogaster; Schizosaccharomyces pombe; AMPK; ageing; energy metabolism; lifespan; pharmacology.
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