Direct Pharmacological Activation of AMPK Modestly Extends Life in Short-Lived Species
AMPK is the target of a range of interventions known to modestly slow aging in short-lived species. Like much of the complex array of evolved machinery that responds to various forms of cellular stress with improved maintenance, repair of damage, and a consequent slowing of aging, AMPK is involved in the regulation of energy metabolism. Many of these interventions, such as metformin, are far from robust. The animal data is mixed. One might argue that this is in part because the effects on the behavior of AMPK are indirect, as researchers do in this paper. Still, their direct approach to activating AMPK still produces only a modest effect on life span, and does so in species known to be far more receptive to life extension via metabolic alteration than is the case for humans. One wouldn't expect great things to emerge from attempting this in our species.
AMP-activated protein kinase (AMPK) is a fundamental sensor of metabolic status and stress, which is universal throughout eukaryotes. AMPK plays a central role in energy homeostasis and is therefore an attractive therapeutic target in health and disease. AMPK consists of a heterotrimer, with a catalytic α subunit and regulatory β and γ subunits, and displays strong evolutionary conservation across eukaryotes, as evident from sequence alignments between the human, fly, worm, and yeast orthologues. Maximal kinase activity of AMPK requires phosphorylation of a conserved threonine in the α subunit.
Many studies utilise pharmacological targeting of AMPK, for instance by the anti-diabetic drug metformin, which activates AMPK indirectly by altering the cellular AMP/ADP:ATP ratio. To overcome the complexity and non-specificity of metformin, studies with direct AMPK activators are essential to fully appreciate the therapeutic potential of AMPK in health and ageing. Here, we apply the direct AMPK activator compound 991 in yeast, worms, flies and mice to investigate its potential pro-longevity effects. 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.