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

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.

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Journal
Aging Cell
Published
2026-09-29
DOI
https://doi.org/10.1111/acel.70721
Primary Topic
Metabolism, Diabetes, and Cancer
Type
article
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article

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

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Aging Cell
Metabolism, Diabetes, and Cancer
article

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

A. Reghan Foley, David Carling, Charalampos Rallis, Fiona C. Leiper, Giovanna Lollo, Marie Blickling, Filipe Cabreiro, Steve J. Gamblin, Jon R. Wilson, Bénédicte Chazaud, Rémi Mounier, Claudia Lennicke, Helena M. Cochemé, John Patrick Alao, Eliano dos Santos, Gaëtan Juban
article en

Abstract

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.

Aging CellVol. 25(10)
Université Claude Bernard Lyon 1 (FR), TH Köln - University of Applied Sciences (DE), Centre National de la Recherche Scientifique (FR), Inserm (FR), Queen Mary University of London (GB), University of Cologne (DE), Institut Universitaire de France (FR), The Francis Crick Institute (GB), Institut NeuroMyoGène (FR), Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (DE), Laboratoire d'Automatique, de Génie des Procédés et de Génie Pharmaceutique (FR), MRC London Institute of Medical Sciences (GB), Imperial College London (GB)
Openalex Percentile: Top 19%
Metabolism, Diabetes, and Cancer
DOIOpen Access PDFOpenAlex
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