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

Eliano Dos Santos, Marie Blickling, Fiona C Leiper, John-Patrick Alao, Claudia Lennicke, Andrea Foley, Jon R Wilson, Steven J Gamblin, Bénédicte Chazaud, Giovanna Lollo, Rémi Mounier, Gaëtan Juban, Charalampos Rallis, David Carling, Filipe Cabreiro, Helena M Cochemé

MRC Laboratory of Medical Sciences (LMS), London, UK.MRC Laboratory of Medical Sciences (LMS), London, UK. · pubmed

Paper

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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Research summary

Direct pharmacological activation of AMPK with compound 991 extends lifespan in yeast, worms, and flies, and induces pro-longevity proteomic profiles in mice. This study is relevant because it provides direct evidence that targeting a specific conserved metabolic sensor (AMPK) rather than using indirect activators like metformin can extend lifespan across multiple model organisms, offering a clearer mechanistic pathway for developing longevity interventions.

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