![]() Two of the most widely used medicines in the world, metformin 18, the mostly commonly used drug for type 2 diabetes, and salicylate 19, the active ingredient in aspirin and salsalate, also activate AMPK, suggesting that some of their beneficial effects may be mediated in part by AMPK. Many of these herbal medicines such as resveratrol 15 and berberine 15, 16, 17 are being reformulated to enhance their bioavailability and efficacy. This interest has been stimulated in part by the discovery that AMPK is activated by physiological regulators that are associated with health and longevity such as caloric restriction 10 and exercise 11, hormones such as leptin 12 and adiponectin 13 and many natural products that have been used as traditional herbal medicines (reviewed in ref. Over the last 30 years since formally naming AMPK 9, interest in the enzyme as a drug target has continued to grow. However, a pivotal step in identifying a unifying mechanism that could link these changes to multiple branches of metabolism followed the discovery that the AMP-activated protein kinase (AMPK) provided a common regulatory mechanism for inhibiting both cholesterol (through phosphorylation of HMG-CoA reductase (HMGR)) and fatty acid (through phosphorylation of acetyl-CoA carboxylase (ACC)) synthesis 8 (Box 1). Given their central role as a measure of cellular energy balance, a number of enzymes were known for many years to be regulated by alterations in adenine nucleotides 7. Therefore, developing new pharmacological strategies that mimic a low energy state, such as that elicited by exercise and caloric restriction, could be potentially beneficial for treating chronic metabolic diseases.Īt the cellular level, the balance between energy intake and demand can be inferred by the relative levels of the adenine nucleotides AMP, ADP and ATP that are continuously produced and consumed through numerous metabolic reactions 6. And although lifestyle interventions that target this energy imbalance through caloric restriction and/or endurance exercise can reduce ageing, obesity and related diseases, implementing and maintaining these changes for prolonged periods is challenging given the pervasiveness of calorically dense foods and sedentary lifestyle-enabling technologies. This energy imbalance contributes to a global epidemic of overweight and obesity 4 that accelerates ageing and also increases the risk of developing type 2 diabetes, cardiovascular disease (CVD), non-alcoholic fatty liver disease (NAFLD), chronic kidney disease and certain cancers 5. Perhaps the greatest threat to future health is a chronic energy imbalance in which intake exceeds expenditure 3. Despite these positive developments, there are substantial risks that challenge continued improvements in human health. Importantly, the number of years spent in good health is also increasing 2. Dramatic improvements in health care coupled with an increased standard of living, including better nutrition and education, have led to a remarkable increase in human lifespan 1.
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