Caloric restriction (CR) is an effective dietary intervention that delays aging and improves metabolic health. Previous studies have reported that lithocholic acid (LCA), a secondary bile acid, increases significantly in serum during CR. LCA has been shown to mimic the anti-aging effects of CR across multiple model organisms, including elevating muscle NAD⁺ levels, enhancing grip strength and exercise endurance in aged mice, and extending lifespan in nematodes and fruit flies. However, concerns about the safety of LCA persist. Multiple studies have demonstrated that high doses of LCA are hepatotoxic, capable of inducing cholestasis, bile duct obstruction, liver injury, and even cell death in isolated hepatocytes. These observations raise fundamental questions. What accounts for the seemingly contradictory roles of LCA in promoting health versus causing liver damage? At what dose can its benefits be preserved without eliciting toxicity? And can these benefits extend to primates?
Now, a team led by Professor Sheng-Cai Lin at Henan University and Xiamen University reports in Life Metabolism the first systematic evaluation of LCA at CR-mimetic doses in both mice and non-human primates. The study demonstrates that LCA possesses a safe and effective dose window in cynomolgus macaques, and that at CR-equivalent concentrations, LCA not only lacks hepatotoxicity but also markedly alleviates fatty liver in both species.
Using obese mice, the researchers administered 1 g/L LCA in drinking water to achieve a serum concentration of approximately 1 μmol/L, which matches CR levels. Rather than observing toxicity, they found that after 4 weeks, hepatic triglycerides declined, fatty liver eased, and glucose metabolism improved. Liver-specific AMPKα-knockout mice confirmed that these benefits depended on AMPK activation. When the dose was escalated to 250 mg/kg/day, hepatic LCA reached about 14 μmol/L and caused overt liver damage. This confirmed that the safety of LCA is strictly dose-dependent. The team then moved to a non‑human primate model of fatty liver. Because macaques rejected the mouse formulation, they developed a phospholipid‑coated preparation in fish oil. When given the mouse‑equivalent dose converted by body surface area at 9.6 mg/kg, serum LCA spiked above 6 μmol/L. Within one week, ALT and AST rose significantly, showing that standard dose conversion is unreliable. A full titration in macaques identified two safe regimens at 0.25 mg/kg and 0.5 mg/kg twice daily. These maintained steady‑state serum levels around 0.8 to 1 μmol/L withoutliver toxicity. Over 13 weeks, treated fatty‑liver macaques showed significant histological improvement in hepatic steatosis, while body weight, lipids, and glucose remained stable. Neither dose caused ALT, AST, creatinine, or blood count abnormalities.
Together, these findings challenge the view that LCA is merely a toxic bile acid. They instead establish that at CR-mimetic concentrations, LCA acts through hepatic AMPK to alleviate fatty liver without detectable toxicity. The work identifies a safe and effective dose window in primates for the first time and suggests that LCA may hold therapeutic promise for metabolic dysfunction‑associated steatotic liver disease, but only with careful dose calibration. Because the study was performed in early‑stage fatty liver models without overt hyperglycaemia or hypertriglyceridaemia, its relevance to more advanced disease remains to be established. Future work will need to determine full pharmacokinetic profile of LCA in primates, including tissue distribution and sex differences. Longer-term and more severe disease models will also be needed before human trials can be designed.
DOI
10.1093/lifemeta/loag023