Qu Q, Chen Y, Wang Y, Long S, Wang W, Yang HY, Li M, Tian X, Wei X, Liu YH, Xu S, Zhang C, Zhu M, Lam SM, Wu J, Yun C, Chen J, Xue S, Zhang B, Zheng ZZ, Piao HL, Jiang C, Guo H, Shui G, Deng X, Zhang CS, Lin SC. Lithocholic acid phenocopies anti-ageing effects of calorie restriction. Nature. 2024 Dec 18; Epub 2024 Dec 18 PubMed.
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University of California, San Diego
These two studies by Qi et al. from Dr. Sheng-Cai Lin's group revealed a fundamental mechanism by which lithocholic acid mediates the pro-longevity effects of caloric restriction through the activation of AMPK, a key metabolic regulator. The discovery of LCA as a metabolic mediator of CR, and its effects across biochemical, cellular, and organismal levels, is truly striking. Moreover, the mechanistic study elegantly uncovered the molecular pathway underlying LCA-mediated AMPK activation: LCA binds to its receptor, TULP3, which activates sirtuins. These, in turn, inhibit vacuolar H⁺-ATPase on lysosomes, leading to AMPK activation. This novel signaling axis highlights the complex interplay between the deacetylation and phosphorylation of AMPK in response to glucose and nutrient-sensing signals.
Given AMPK’s well-established role in regulating glucose and lipid metabolism in the brain, these findings offer exciting new insights into neural health and disease. Alzheimer's disease in particular is associated with impaired glucose utilization and disrupted lipid metabolism, contributing to neuronal metabolic dysfunction and neuroinflammation. Both AMPK and sirtuins have been reported to directly and indirectly impact neuronal health, with both pathways linked to lysosomal function. Future investigations into the LCA-TULP3–sirtuin–v-ATPase–AMPK signaling pathway in neurons and glial cells during aging and neurological disorders could uncover new mechanistic insights into health and disease, while also informing potential translational strategies.
View all comments by Xu ChenChina Medical University
These are two remarkable papers from scientists in Lin's lab, who have continued their previous studies showing that the lysosomal AMPK pathway is inherently active in higher organisms. Organisms can not only resist hunger, but also become "empowered" from hunger.
They decided to screen metabolic changes caused by calorie restriction (CR) in mice to look for compounds that could turn on AMPK. This is a difficult task. Calorie restriction is widely recognized in the field of aging research as a way to extend life and delay aging. AMPK is known to be turned on by CR and plays a crucial role in its beneficial effects. In mammals, a family of seven enzymes called deacetylases (or SIRT1-7) fights many of the biological processes that lead to aging, including cellular senescence, DNA damage, and impaired tissue repair. Their response requires the ubiquitous metabolite molecule NAD+, whose levels decrease with age and rise due to CR. The hypothesis supported by some scientists that deacetylase-mediated CR is beneficial is supported by a wealth of data, but it is not without its critics.
This brings us to the work of Lin and his colleagues. To find molecules that mediate CR and are beneficial to health, they started by studying the sera of calorie-restricted mice. Through metabolomic identification and subsequent investigation, they finally found the molecular analogue of CR, lithocholic acid, and verified the effect of LCA on delaying aging and extending life in worms, flies, and mice. In addition, further exploration found the molecular target of LCA, TULP3, which binds LCA to activate SIRT1. This is where the study gets even more interesting. Finally, they analyzed the specific mechanism of life extension through the TULP3-sirtuin-v-ATPase-AMPK axis.
This discovery fills in the gaps in how the body senses metabolic signals caused by calorie restriction and how CR plays a role in delaying aging. Whether LCA can be used as a new longevity drug needs to be validated in clinical trials. At the same time, the analysis of the life-prolonging mechanism of LCA also provides a new theory and target for the development of such drugs.
View all comments by Liu CaoColumbia University
This work is thought-provoking. However, lithocholic acid is highly toxic—the most toxic of the bile acids. Therefore, new therapeutic agents will be required. I am concerned that this article will inspire attempts to use Lithocholic acid for self-medication.
View all comments by Michael ShelanskiMake a Comment
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