A groundbreaking study reveals that lithocholic acid (LCA), a metabolite produced during calorie restriction (CR), may hold the key to improving health and extending lifespan. This discovery mimics the well-documented benefits of CR, offering promising new avenues for anti-aging research.
Calorie restriction (CR) has long been recognized for its health benefits, including improved lifespan and better management of age-related conditions. Now, a new study published in Nature provides compelling evidence that one of the mechanisms behind CR’s benefits may be the production of lithocholic acid (LCA). This bile acid, generated when the body undergoes CR, appears to activate key metabolic pathways that could slow aging and improve overall health.
CR is a non-pharmacological dietary intervention that has been shown to enhance the body’s metabolic health. By reducing caloric intake without malnutrition, CR induces a variety of physiological changes, such as alterations in cholesterol, fatty acid levels, and the presence of certain vitamins. Numerous studies across species—from yeast and flies to primates—have shown that CR promotes longevity and health improvements, including reduced inflammation, better protein homeostasis, and decreased oxidative damage.
Beyond these general benefits, CR has been associated with improving conditions like insulin resistance, central obesity, and muscle deterioration—common challenges as we age. The key to these benefits may lie in CR’s activation of AMP-activated protein kinase (AMPK), an enzyme that plays a central role in maintaining energy balance and regulating aging processes.
AMPK is considered one of the primary drivers of aging-related cellular processes, including mitochondrial function, protein maintenance (proteostasis), and autophagy—the process by which the body removes damaged cells. Research has shown that AMPK also helps protect against neurodegeneration and inflammation, further reinforcing its critical role in aging.
In the search for substances that can mimic the effects of CR without requiring drastic dietary changes, researchers have identified a group of compounds known as CR mimetics (CRMs). These include substances like metformin and resveratrol, both of which have been shown to activate AMPK and extend lifespan in model organisms. The latest study points to LCA as another potential CRM.
The study explored how CR-induced changes in serum metabolites could be responsible for its health benefits. By analyzing the serum of CR-treated mice, researchers identified 1,215 metabolites, with 695 undergoing notable modifications. Among these metabolites, LCA stood out for its ability to activate AMPK, making it a potential key player in CR’s health benefits.
LCA was shown to activate AMPK at concentrations as low as 1 μM in various cell types, including liver and muscle cells. Notably, this effect was independent of TGR5, a receptor known to influence bile acid signaling, and did not involve large changes in calcium levels. These findings suggest that LCA acts through a specific pathway, distinct from other known CR mechanisms.
Further experiments in aged mice revealed that LCA treatment led to significant improvements in muscle performance. Aged mice given LCA showed an increase in oxidative muscle fibers, which are more efficient and less prone to fatigue than glycolytic fibers. LCA also improved muscle regeneration following damage, demonstrating its potential to counteract one of the hallmarks of aging: muscle deterioration.
In addition to these benefits, LCA treatment also improved glucose metabolism, alleviating age-related insulin resistance and glucose intolerance. The treatment increased levels of glucagon-like peptide 1 (GLP-1), a hormone that regulates glucose levels and plays a role in appetite control. These improvements in muscle health and glucose regulation suggest that LCA has the potential to promote both healthspan (the period of life spent in good health) and lifespan.
With these findings, LCA emerges as a promising new compound in the field of anti-aging research. By mimicking the metabolic effects of CR, LCA offers a new approach to improving health and extending lifespan without requiring drastic changes to diet or lifestyle. While more research is needed to fully understand its effects, the evidence points to LCA as a powerful tool for enhancing the body’s natural ability to combat aging.
As interest in longevity and healthspan grows, LCA could pave the way for new treatments that help people live longer, healthier lives. Scientists are excited by the potential of LCA and its ability to activate AMPK, a pathway that plays a key role in the aging process.
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