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AI-Predicted mTOR Inhibitor Reduces Cancer Cell Proliferation and Extends the Lifespan of C. elegans.

ABSTRACT: The mechanistic target of rapamycin (mTOR) kinase is one of the top drug targets for promoting health and lifespan extension. Besides rapamycin, only a few other mTOR inhibitors have been developed and shown to be capable of slowing aging. We used machine learning to predict novel small molecules targeting mTOR. We selected one small molecule, TKA001, based on in silico predictions of a high on-target probability, low toxicity, favorable physicochemical properties, and preferable ADMET profile. We modeled TKA001 binding in silico by molecular docking and molecular dynamics. TKA001 potently inhibits both TOR complex 1 and 2 signaling in vitro. Furthermore, TKA001 inhibits human cancer cell proliferation in vitro and extends the lifespan of Caenorhabditis elegans, suggesting that TKA001 is able to slow aging in vivo.

SUBMITTER: Vidovic T

PROVIDER: S-EPMC10177929 | biostudies-literature | 2023 Apr

REPOSITORIES: biostudies-literature

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AI-Predicted mTOR Inhibitor Reduces Cancer Cell Proliferation and Extends the Lifespan of <i>C. elegans</i>.

Vidovic Tinka T Dakhovnik Alexander A Hrabovskyi Oleksii O MacArthur Michael R MR Ewald Collin Y CY

International journal of molecular sciences 20230425 9

The mechanistic target of rapamycin (mTOR) kinase is one of the top drug targets for promoting health and lifespan extension. Besides rapamycin, only a few other mTOR inhibitors have been developed and shown to be capable of slowing aging. We used machine learning to predict novel small molecules targeting mTOR. We selected one small molecule, TKA001, based on in silico predictions of a high on-target probability, low toxicity, favorable physicochemical properties, and preferable ADMET profile. ...[more]

PMID: 37175557

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Project description:Phosphatidylcholine is one of the major phospholipids comprising cellular membrane and is known to have several health-promoting activities, including the improvement of brain function and liver repair. In this paper, we examine the in vivo effect of dietary supplementation with phosphatidylcholine on the response to environmental stressors and aging in C. elegans. Treatment with phosphatidylcholine significantly increased the survival of worms under oxidative stress conditions. However, there was no significant difference in response to stresses caused by heat shock or ultraviolet irradiation. Oxidative stress is believed to be one of the major causal factors of aging. Then, we examined the effect of phosphatidylcholine on lifespan and age-related physiological changes. Phosphatidylcholine showed a lifespan-extending effect and a reduction in fertility, possibly as a tradeoff for long lifespan. Age-related decline of motility was also significantly delayed by supplementation with phosphatidylcholine. Interestingly, the expressions of well-known longevity-assuring genes, hsp-16.2 and sod-3, were significantly upregulated by dietary intervention with phosphatidylcholine. DAF-16, a transcription factor modulating stress response genes, was accumulated in the nucleus by phosphatidylcholine treatment. Increase of the ROS level with phosphatidylcholine suggests that the antioxidant and lifespan-extending effects are due to the hormetic effect of phosphatidylcholine. Phosphatidylcholine also showed a protective effect against amyloid beta-induced toxicity in Alzheimer's disease model animals. Experiments with long-lived mutants revealed that the lifespan-extending effect of phosphatidylcholine specifically overlapped with that of reduced insulin/IGF-1-like signaling and required DAF-16. These findings showed the antioxidant and antiaging activities of phosphatidylcholine for the first time in vivo. Further studies focusing on the identification of underlying cellular mechanisms involved in the antiaging effect will increase the possibility of using phosphatidylcholine for the development of antiaging therapeutics.

Dataset Information

AI-Predicted mTOR Inhibitor Reduces Cancer Cell Proliferation and Extends the Lifespan of C. elegans.

Publications

AI-Predicted mTOR Inhibitor Reduces Cancer Cell Proliferation and Extends the Lifespan of <i>C. elegans</i>.

Similar Datasets

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