Aging comes with breakdowns in energy metabolism: cells sense nutrients less well, mitochondria run less efficiently, and the daily rhythms of macronutrient use blur. AMPK, or AMP-activated protein kinase, serves as the central regulator of metabolism: it switches on when a cell runs low on energy and kicks off processes that conserve resources. Calorie restriction and some geroprotective interventions activate AMPK, and in long-lived mutant worms and flies this pathway is often boosted. Yet direct and specific pharmacological AMPK activators have barely been studied in the context of aging. MK-8722 is a potent and highly specific activator of all AMPK isoforms that has shown benefits in models of metabolic disease, but its effect on lifespan and healthy aging remained unknown.
The study used two models: the nematode Caenorhabditis elegans and mice of the C57BL/6JRj strain. Wild-type worms and mutants for the csb-1 gene (a model of Cockayne progeria) received MK-8722 at a concentration of 70 µM from the late larval stage L4, with transfer to fresh plates containing the drug on day 5 and day 10. Lifespan was assessed manually by survival and automatically by mobility on scanners. To check specificity, the researchers used worms with an AMPK knockout (aak-2) and worms with a permanently active form of the enzyme. Mice at 18 months of age received purified chow with MK-8722 at a dose of 50 ppm (about 4 mg/kg per day) for 6 months. The animals were measured for body mass, body composition (EchoMRI), food intake, energy expenditure, respiratory quotient, glucose levels, liver enzymes, and a frailty index. After euthanasia, metabolomic analysis of liver and kidneys was performed, along with RNA sequencing of the liver.
In wild-type worms and csb-1(ok2335) mutants, treatment with MK-8722 extended lifespan by about 13%. The effect disappeared in worms lacking AMPK and in worms with a permanently active enzyme, confirming that it works specifically through AMPK. The drug did not affect daily or total fecundity, either by self-fertilization or by mating. Automated analysis showed that MK-8722 pushed back the age at which 25% of worms died and increased the period of high mobility. In mice receiving MK-8722, body mass and body fat percentage rose less over 6 months, and the effect was stronger in females. In females on the drug, food intake dropped by about 8%. Fasting glucose levels in mice on MK-8722 did not decline with age, unlike in controls. The respiratory quotient during the dark period was higher, indicating better preservation of the circadian rhythm of metabolism. In serum, free fatty acids and markers of liver damage (AST and ALT) decreased. In kidneys and liver, levels of ATP, creatine phosphate, and hexose phosphates rose, as did bile acids, including lithocholic acid. The liver transcriptome showed upregulation of steroid biosynthesis genes and downregulation of interferon inflammatory signaling.
The work shows for the first time that a direct pharmacological AMPK activator can extend lifespan and improve health in models of normal aging. This supports the idea that AMPK is a key target for geroprotective interventions. The link between AMPK activation and increased lithocholic acid levels suggests bidirectional regulation: lithocholic acid activates AMPK, and AMPK in turn boosts bile acid synthesis. This could be part of a shared mechanism through which calorie restriction and pharmacological AMPK activators slow aging.
A promising direction will be studying the long-term effects of MK-8722 on mouse lifespan, especially given the observed hypertrophy of the heart and kidneys. It is important to find out whether these changes are pathological or reversible, as data on their similarity to an "athlete's heart" suggest. It is also worth testing MK-8722 in models of Cockayne progeria with UV-induced phenotypes, which are closer to the human disease. Understanding the role of bile acids, especially lithocholic acid, in geroprotection could lead to new combination strategies.
The results could influence drug development against age-related metabolic disorders and, possibly, clinical trials of AMPK activators. For gerontology, this is a step toward pharmacologically reproducing the effects of calorie restriction.
The immediate steps include measuring the lifespan of mice treated with MK-8722 and assessing the reversibility of heart and kidney hypertrophy. It is also necessary to test the drug's effects on UV-irradiated csb-1 worms and in mouse models of Cockayne syndrome.
In gerontology, the question remains open whether the geroprotective effects of calorie restriction can be reproduced pharmacologically without side effects. This work links AMPK activation to increased levels of lithocholic acid, a known mediator of calorie restriction, and shows that such a strategy can improve health without obvious harm to reproductive function. The unresolved problem remains the long-term safety of AMPK activators because of heart and kidney hypertrophy.
Lithocholic acid, whose levels rose in mice on MK-8722, was recently recognized as a powerful geroprotector: giving it to old mice reproduced many of the effects of calorie restriction and extended lifespan.
In Peter Watts's novel Blindsight, vampires have a super-efficient metabolism that lets them survive on minimal resources. AMPK activation, as in this work, is a step toward similar metabolic thrift, though without the vampire genes.
Not published on arXiv. Here are its page, the PDF and the formalization: you can check it yourself, not only read our account.