Researchers have found scientific evidence that calorie restriction can increase the longevity of laboratory animals, but translating these benefits to humans is difficult, especially considering that most people have difficulty following the type of diet. excessively restrictive diet that would be necessary to prolong life.
For this reason, science continues to search for simpler and more accessible techniques that obtain the same effects of calorie restriction on longevity and, specifically, scientists try to identify the molecular mechanisms linked to this phenomenon. A new study published in Nature and conducted by researchers from the Chinese Academy of Sciences and Xiamen University has identified a potential mimic of calorie restriction: a bile acid called lithocholic acid (LCA).
If the findings of these experts are confirmed in new studies, it would open the possibility of developing drugs capable of simulating the action of this acid to live longer in a healthy way and without the need to make nutritional sacrifices, or run the risk of suffering from malnutrition or an irreversible loss of muscle mass.
Improvements in markers of healthy aging
Human beings produce bile acids to facilitate the absorption of fats during digestion, but after being secreted in the intestine, these molecules are modified by bacterial enzymes and generate a wide spectrum of chemical variants whose impact is still barely understood. One of the secondary metabolites produced by intestinal bacteria from bile acids is lithocholic acid.
The idea that lithocholic acid may offer health benefits has surprised some gastroenterologists, since it had always been considered harmful because in high doses it can damage the liver. Researchers have even used it in animal models to induce liver damage and study protective treatments. However, recent studies suggest that LCA at low concentrations may have positive biological effects unrelated to its toxicity.
Previous studies showed that mice on a low-calorie diet had greater activity of a protein called AMPK in their muscles, as well as fewer signs of muscle atrophy. In cultured cells, serum from fasted mice also activates AMPK. The authors of the new research identified hundreds of metabolites that are significantly altered in the serum of mice during caloric restriction. After several filtering processes and tests on cultured cells, they identified LCA as an AMPK activator.
Mice given small amounts of LCA through their drinking water showed an increase in AMPK activity, as well as improvements in markers of healthy aging, such as increased grip strength and physical endurance. The authors suggest that elevated levels of LCA could be responsible for some benefits seen in calorie-restricted mice. However, the results showed that although LCA extended the life of fruit flies and nematode worms, it did not have a statistically significant effect on the longevity of mice, suggesting that other key components are still missing.
The findings could be considered “a milestone connecting caloric intake to aging-related diseases.”
In a complementary study that has also been published in the journal Nature, the same authors explored how LCA activates AMPK and verified that LCA activity depends on signals from sirtuins, a family of enzymes associated with aging. They identified a protein that binds to LCA and activates sirtuins, initiating a signaling pathway that also activates AMPK when glucose levels are low.
David Sinclair, a biologist at Harvard Medical School, stated in a comment for Nature collected by C&EN that these findings could be considered “a milestone connecting caloric intake with diseases related to aging.” For his part, Vijay Yadav, a researcher in longevity and metabolism at Rutgers University, pointed out in an email that LCA “could be a component that mediates the effects of caloric restriction in some tissues,” although he doubts that it acts on its own. only. Additionally, he cautions that the study did not examine whether LCA-treated mice developed liver damage.
Sheng-Cai Lin, lead author of the study, stated in an email collected by C&EN that LCA appears to act through the same pathway as the well-known drug metformin. Lin noted that since they observed pro-health effects, they were not worried about possible liver damage. Yadav cautions, however, that LCA detoxification pathways vary between species, meaning its toxicity profile could be different in humans and precautions need to be taken in future studies.
