If couch-potato lab mice had beach-body dreams and if they could speak, they might tell you they’re thrilled by advances in the science of exercise and calorie-restriction (CR) mimetics.
In recent studies conducted at research centers across the United States, mice have chowed down, fattened up, exercised only if they felt like it, and still managed to lose body fat, improve their blood lipids, increase muscle power, avoid blood sugar problems, and boost heart function.
How did these mice get so lucky? They were given mimetics, experimental drugs that “mimic” the effects of exercise and calorie reduction in the body without the need to break a sweat or eat less.
“The mice looked like they’d done endurance training,” said Thomas Burris, PhD, a University of Florida pharmacodynamics professor and coauthor of a September 2023 study of the exercise mimetic SLU-PP-332, published in the Journal of Pharmacology and Experimental Therapeutics.
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Enter the exercise mimetics. Unlike CR mimetics, exercise mimetics affect mitochondria — the tiny power plants in muscle and every other cell in the body. They switch on genes that encourage the growth of more mitochondria and encourage them to burn fatty acids, not just glucose, for fuel.
In mice, this can keep them from gaining weight, increase insulin sensitivity, and boost exercise endurance. “We can use a drug to activate the same networks that are activated by physical activity,” said Ronald Evans, PhD, professor and director of the Gene Expression Laboratory at the Salk Institute for Biological Studies in La Jolla, California.
Among notable mimetics moving into human studies is ASP0367, a drug in a class called PPAR delta modulators first developed in Evans’ lab. ASP0367 was licensed to the pharmaceutical company Mitobridge, later acquired by Astellas. Astellas is currently running a phase 2/3 human trial of the investigational drug in people with the rare genetic disorder primary mitochondrial myopathy.
“We can use a drug to activate the same networks that are activated by physical activity.”
At the University of Florida, Burris and team hope to soon move the exercise mimetic SLU-PP-332 into human studies. “It targets a receptor called ERR that I’ve been working on since the 1980s,” Burris said. “We knew from genetic studies that ERR has a role in exercise’s effects on mitochondrial function in muscle.” The calorie mimetics he’s studying also activate genes for making more mitochondria and driving them to burn fatty acids. “This generates a lot of energy,” he said. In a January 2024 study in Circulation, Burris found the drug restores heart function in mice experiencing heart failure. “Very little heart function was lost,” he said. It’s had no serious side effects.
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The field has hit some bumps. Some feel inevitable — such as otherwise healthy people misusing the drugs. GW1516, an early experimental exercise mimetic studied by Evans and abandoned because it triggered tumor growth in lab studies, is used illegally by elite athletes as a performance-enhancing drug despite warnings from the US Anti-Doping Agency. Burris worries that future CR mimetics could be misused the same way.
Full story:
https://www.medscape.com/viewarticle/diet-and-exercise-pill-are-real-how-mimetics-work-2024a10004rt
Related thread: Much discussion about Exercise and Caloric Restriction Mimetics, What about Sleep Mimetics?
Details on the Exercise and Caloric Restriction Mimetics mentioned in the story:
A brand-new kind of drug, tested in mice, shows promising new results that could lead to the development of a new weight-loss drug that mimics exercise.
The new compound, developed and tested by a University of Florida professor of pharmacy and his colleagues, leads obese mice to lose weight by convincing the body’s muscles that they are exercising more than they really are, boosting the animals’ metabolism.
It also increases endurance, helping mice run nearly 50% further than they could before. All without the mice lifting a paw.
Jan/2024:
A Synthetic ERR Agonist Alleviates Metabolic Syndrome
Physical exercise induces physiologic adaptations and is effective at reducing the risk of premature death from all causes. Pharmacological exercise mimetics may be effective in the treatment of a range of diseases including obesity and metabolic syndrome. Previously, we described the development of SLU-PP-332, an agonist for the estrogen-related receptor (ERR)α , β, and γ nuclear receptors that activates an acute aerobic exercise program. Here we examine the effects of this exercise mimetic in mouse models of obesity and metabolic syndrome. Diet-induced obese or ob/ob mice were administered SLU-PP-332, and the effects on a range of metabolic parameters were assessed. SLU-PP-332 administration mimics exercise-induced benefits on whole-body metabolism in mice including increased energy expenditure and fatty acid oxidation. These effects were accompanied by decreased fat mass accumulation. Additionally, the ERR agonist effectively reduced obesity and improved insulin sensitivity in models of metabolic syndrome. Pharmacological activation of ERR may be an effective method to treat metabolic syndrome and obesity. SIGNIFICANCE STATEMENT: An estrogen receptor-related orphan receptor agonist, SLU-PP-332, with exercise mimetic activity, holds promise as a therapeutic to treat metabolic diseases by decreasing fat mass in mouse models of obesity.
Paywalled Paper: A Synthetic ERR Agonist Alleviates Metabolic Syndrome - PubMed
Mannoheptulose
Open Access Papers:
An Avocado Extract Enriched in Mannoheptulose Prevents the Negative Effects of a High-Fat Diet in Mice
Glycolytic inhibition: an effective strategy for developing calorie restriction mimetics
Calorie restriction mimetics encompass a growing research field directed toward developing treatments that mimic the anti-aging effects of long-term calorie restriction without requiring a change in eating habits. A wide range of approaches have been identified that include (1) intestinal inhibitors of fat and carbohydrate metabolism; (2) inhibitors of intracellular glycolysis; (3) stimulators of the AMPK pathway; (4) sirtuin activators; (5) inhibitors of the mTOR pathway, and (6) polyamines. Several biotech companies have been formed to pursue several of these strategies. The objective of this review is to describe the approaches directed toward glycolytic inhibition. This upstream strategy is considered an effective means to invoke a wide range of anti-aging mechanisms induced by CR. Anti-cancer and anti-obesity effects are important considerations in early development efforts. Although many dozens of candidates could be discussed, the compounds selected to be reviewed are the following: 2-deoxyglucose, 3-bromopyruvate, chrysin, genistein, astragalin, resveratrol, glucosamine, mannoheptulose, and d-allulose. Some candidates have been investigated extensively with both positive and negative results, while others are only beginning to be studied.
