Lithocholic Acid in Calorie Restriction
Researchers here argue for lithocholic acid, a bile acid produced when the gut microbiome processes bile, to be a player in the ability of calorie restriction to slow aging and extend life in short-lived species. Researchers have in the past noted that providing lithocholic acid to yeast slows cell aging, while centenarians exhibit a gut microbiome that produces more lithocholic acid. While reading this, it is worth remembering that while the mechanisms described exist, it is ever challenging to determine how much of the benefits of calorie restriction or an altered gut microbiome derive from pathways involving lithocholic acid. Therapies that target this could be interesting, or could be poor options. It is hard to tell without trying.
Generally speaking, bile is less interesting than is longevity, but that might soon change. Consisting mainly of water, bilirubin (a breakdown product of haemoglobin), cholesterol, and bile acids, this yellow-green fluid is synthesized in the liver, stored in the gallbladder and released into the small intestine to emulsify dietary fats and increase the absorption of fat-soluble vitamins. Gut-resident bacteria, such as species of Clostridium and Lactobacillus, convert primary bile acids into the secondary bile acids deoxycholic acid and LCA, some of which is reabsorbed into the bloodstream.
Previous work has identified bile acids as health-promoting compounds. Dafachronic acids, which are structurally related to LCA, extend the lifespans of nematode worms (Caenorhabditis elegans) and LCA extends the lifespans of yeast (Saccharomyces cerevisiae) and fruit flies. In mammals, LCA is not known to extend lifespan, but it does alter physiology in ways that are consistent with improved health, such as lowering levels of liver triglycerides, blood glucose, and systemic inflammation - in part, by activating the bile-acid receptor TGR5. LCA is also implicated in the lifespan-extending effects of transplanting gut microbiota from young mice into old mice, but how the bile acid might impart health benefits is unclear.
In a recent study researchers gave LCA to old mice for a month. These mice experienced health benefits reminiscent of those induced by calorie restriction, including improved muscle regeneration, grip strength, and sensitivity to insulin. These effects were dependent on AMPK. Interestingly, LCA raised levels of the hormone GLP-1 without causing muscle loss, unlike today's popular weight-loss drugs that bind to the GLP-1 receptor. In nematodes and flies, LCA activated AMPK, increased stress resistance and extended lifespan - benefits that were negated when the gene encoding AMPK was deleted in the animals.
After ruling out TGR5 as the mediator of LCA's effects, the researchers turned their attention to the enzyme SIRT1. They demonstrated that LCA stimulates SIRT1 to upregulate AMPK. The involvement of gut microbiota in the production of LCA and the benefits of calorie restriction might explain why faecal transplants from young animals improve the health and increase the lifespans of older animals, and why some mice do not respond to calorie restriction.