Lithocholic acid (LCA), a bile acid produced through calorie restriction (CR), has been shown to mimic some of the metabolic benefits of CR, including improved muscle performance and lifespan extension. The recent study published in Nature highlights the significant role of LCA in activating AMPK, a critical enzyme associated with anti-aging processes and the improvement of overall health.
Calorie restriction (CR) is a non-pharmacological dietary approach that has long been associated with various metabolic benefits. Studies in different organisms, ranging from yeast and fruit flies to mice and humans, have demonstrated that CR not only extends lifespan but also reduces the risks of aging-related conditions. Some of the diseases that CR helps alleviate include insulin resistance, muscle atrophy, central obesity, and various forms of cardiovascular disease.
At a cellular level, CR induces several metabolic changes, including alterations in cholesterol, free fatty acids, vitamins, and other essential metabolites. One of the primary mechanisms through which CR exerts its effects is by activating adenosine monophosphate-activated protein kinase (AMPK), an enzyme that regulates cellular energy balance. AMPK is pivotal in delaying aging processes by influencing multiple pathways, including the activation of sirtuins, autophagy, and mitochondrial biogenesis. This makes AMPK a key player in promoting health and longevity.
AMPK also plays a significant role in controlling oxidative stress, inflammation, and neurodegeneration, all of which contribute to aging. Due to its involvement in these anti-aging processes, AMPK has become a prime target for extending lifespan and improving overall health. The use of CR mimetics (CRMs) like metformin and resveratrol, which activate AMPK, has shown promise in replicating the benefits of CR without the need to drastically reduce caloric intake.
The focus of the study was to identify the specific metabolites involved in the benefits of CR, especially those that can mimic CR’s positive effects on aging. To do this, the researchers used metabolomics to analyze serum from mice subjected to CR and compared it with control serum from ad libitum-fed mice. By identifying metabolites that were modified during CR, the study aimed to uncover the mechanisms that contribute to CR’s health benefits.
The study utilized mass spectrometry-based techniques to assess 1,215 metabolites, of which 695 were found to be altered by CR. Some of these modifications included reductions in phenylalanine, long-chain fatty acids, and tyrosine, while levels of short-chain fatty acids, bile acids, and acyl-carnitine were found to increase. Among these, lithocholic acid (LCA) emerged as a key metabolite that could activate AMPK, leading to significant health benefits.
The researchers discovered that LCA, a bile acid that naturally increases during CR, could activate AMPK at physiological concentrations. When introduced into various cell types, including human embryonic kidney (HEK293T) cells, mouse embryonic fibroblasts (MEFs), primary hepatocytes, and primary myocytes, LCA effectively activated AMPK and inhibited mTORC1, another critical pathway involved in aging. Additionally, LCA treatment resulted in the increased translocation of TFEB (transcription factor EB) into the nucleus, further confirming its role in promoting anti-aging processes.
Interestingly, the serum from CR-treated mice contained about 1.1 μM of LCA, compared to only 0.3 μM in the control serum. This confirmed that LCA production is upregulated during CR, independent of other bile acids like muricholate. The researchers also found that LCA did not induce changes in energy levels or activate AMPK through the TGR5 receptor, suggesting that it is a specific metabolite in CR serum responsible for activating AMPK.
Further experiments showed that supplementing LCA in aged mice for one month led to significant improvements in muscle performance. The treated mice displayed increased oxidative muscle fibers, enhanced muscle regeneration, and better overall strength. Additionally, LCA-treated mice demonstrated improvements in glucose tolerance and insulin sensitivity, showing that LCA could also help prevent age-related metabolic issues.
LCA was identified as a crucial metabolite induced by CR that has the potential to activate AMPK, which in turn promotes a range of anti-aging processes. This discovery underscores the role of LCA in mimicking the benefits of calorie restriction, including improved muscle performance, enhanced glucose metabolism, and extended lifespan.
The research confirms that LCA can be considered a CR mimetic, offering similar health benefits without requiring drastic caloric intake reductions. The study suggests that LCA could serve as a promising therapeutic target for aging-related diseases, particularly those related to muscle deterioration and metabolic dysfunction.
In conclusion, lithocholic acid presents a compelling avenue for future research into aging and longevity. By mimicking the effects of calorie restriction, LCA may provide a novel strategy to improve healthspan and mitigate the aging process, potentially extending lifespan in a wide variety of organisms.
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