# Mendelian Randomization and mTOR **URL:** \ **Category:** General\ **Tags:** rapamycin\ **Created:** [July 17, 2024, 2:08am UTC](https://www.rapamycin.news/t/mendelian-randomization-and-mtor/15036 "2024-07-17T02:08:59Z")\ **Posts on this page:** 3\ **Page:** 1
**Author:** ![A\_User](https://www.rapamycin.news/user_avatar/www.rapamycin.news/a_user/32/40991_2.png) [@A\_User](https://www.rapamycin.news/u/A_User)\ **Post date:** [July 17, 2024, 2:08am UTC](https://www.rapamycin.news/t/mendelian-randomization-and-mtor/15036/1 "2024-07-17T02:08:59Z")
Post all of your Mendelian Randomization studies related to mTOR here so we know what diseases rapamycin might causally impact. If you don’t understand a study result feel free to ask so someone might explain. [Causal Association Between mTOR-Dependent Protein Levels and Alzheimer’s Disease: A Mendelian Randomization Study](https://content.iospress.com/articles/journal-of-alzheimers-disease/jad230128), 2023. > Most previous studies supported that the mammalian target of rapamycin (mTOR) is over-activated in Alzheimer’s disease (AD) and exacerbates the development of AD. It is unclear whether the causal associations between the mTOR signaling-related protein and the risk for AD exist. Objective:This study aims to investigate the causal effects of the mTOR signaling targets on AD. Methods:We explored whether the risk of AD varied with genetically predicted AKT, RP-S6K, EIF4E-BP, eIF4E, eIF4A, and eIF4G circulating levels using a two-sample Mendelian randomization analysis. The summary data for targets of the mTOR signaling were acquired from published genome-wide association studies for the INTERVAL study. Genetic associations with AD were retrieved from the International Genomics of Alzheimer’s Project. We utilized the inverse variance weighted as the primary approach to calculate the effect estimates. Results:The elevated levels of AKT (OR = 0.910, 95% CI=0.840-0.986, p = 0.02) and RP-S6K (OR = 0.910, 95% CI=0.840-0.986, p = 0.02) may decrease the AD risk. In contrast, the elevated eIF4E levels (OR = 1.805, 95% CI=1.002-1.174, p = 0.045) may genetically increase the AD risk. No statistical significance was identified for levels of EIF4-BP, eIF4A, and eIF4G with AD risk (p \> 0.05). Conclusion:There was a causal relationship between the mTOR signaling and the risk for AD. Activating AKT and RP-S6K, or inhibiting eIF4E may be potentially beneficial to the prevention and treatment of AD. [Causal association between mTOR-dependent EIF-4E and EIF-4A circulating protein levels and type 2 diabetes: a Mendelian randomization study](https://www.nature.com/articles/s41598-020-71987-8), 2020. > The mammalian Target of Rapamycin complex 1 (mTORC1) nutrient-sensing pathway is a central regulator of cell growth and metabolism and is dysregulated in diabetes. The eukaryotic translation initiation factor 4E (EIF-4E) protein, a key regulator of gene translation and protein function, is controlled by mTORC1 and EIF-4E Binding Proteins (EIF4EBPs). Both EIF4EBPs and ribosomal protein S6K kinase (RP-S6K) are downstream effectors regulated by mTORC1 but converge to regulate two independent pathways. We investigated whether the risk of type 2 diabetes varied with genetically predicted EIF-4E, EIF-4A, EIF-4G, EIF4EBP, and RP-S6K circulating levels using Mendelian Randomization. We estimated the causal role of EIF-4F complex, EIF4EBP, and S6K in the circulation on type 2 diabetes, based on independent single nucleotide polymorphisms strongly associated (p = 5 × 10–6) with EIF-4E (16 SNPs), EIF-4A (11 SNPs), EIF-4G (6 SNPs), EIF4EBP2 (12 SNPs), and RP-S6K (16 SNPs). The exposure data were obtained from the INTERVAL study. We applied these SNPs for each exposure to publically available genetic associations with diabetes from the DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) case (n = 26,676) and control (n = 132,532) study (mean age 57.4 years). We meta-analyzed SNP-specific Wald-estimates using inverse variance weighting with multiplicative random effects and conducted sensitivity analysis. Mendelian Randomization (MR-Base) R package was used in the analysis. The PhenoScanner curated database was used to identify disease associations with SNP gene variants. EIF-4E is associated with a lowered risk of type 2 diabetes with an odds ratio (OR) 0.94, 95% confidence interval (0.88, 0.99, p = 0.03) with similar estimates from the weighted median and MR-Egger. Similarly, EIF-4A was associated with lower risk of type 2 diabetes with odds ratio (OR) 0.90, 95% confidence interval (0.85, 0.97, p = 0.0003). Sensitivity analysis using MR-Egger and weighed median analysis does not indicate that there is a pleiotropic effect. This unbiased Mendelian Randomization estimate is consistent with a protective causal association of EIF-4E and EIF-4A on type 2 diabetes. EIF-4E and EIF-4A may be targeted for intervention by repurposing existing therapeutics to reduce the risk of type 2 diabetes. ---
**Author:** ![Neo](https://www.rapamycin.news/letter_avatar_proxy/v4/letter/n/9fc348/32.png) [@Neo](https://www.rapamycin.news/u/Neo)\ **Post date:** [September 19, 2024, 1:47pm UTC](https://www.rapamycin.news/t/mendelian-randomization-and-mtor/15036/2 "2024-09-19T13:47:40Z")
This one seems key for this thread: > [@Evaluating the life-extending potential and safety profile of rapamycin: a Mendelian Randomization study of the mTOR pathway](https://www.rapamycin.news/t/evaluating-the-life-extending-potential-and-safety-profile-of-rapamycin-a-mendelian-randomization-study-of-the-mtor-pathway/9854): > > Results: Our findings suggest that genetically proxied mTOR inhibition may increase the odds of attaining top 1% longest lifespan in the population (OR=1.24, OR\* 95%CI\*=1-1.53, pvalue=0.048). Moreover, mTOR inhibition significantly reduced body mass index (BMI), basal metabolic rate (BMR), height, and age at menopause, while increasing bone mineral density. Interestingly, there was generally little evidence linking mTOR inhibition to cardiovascular disease incidence, with the exception of weak evidence for a protective effect against heart failure (OR=0.94, OR\* 95%CI\*=0.89-0.99, p-value=0.039). Chronic mTOR inhibition did not causally affect prostate cancer incidence but increased the risk of developing type 2 diabetes. A higher-than-expected (p-value = 0.05) number of genes in the mTOR pathway were causally associated with BMR. Conclusions: This study highlights the potential lifespan-extending effects of mTOR inhibition and its significant influence on metabolic risk factors and d… ---
**Author:** ![A\_User](https://www.rapamycin.news/user_avatar/www.rapamycin.news/a_user/32/40991_2.png) [@A\_User](https://www.rapamycin.news/u/A_User)\ **Post date:** [March 14, 2025, 1:55pm UTC](https://www.rapamycin.news/t/mendelian-randomization-and-mtor/15036/3 "2025-03-14T13:55:43Z")
This seems important: ![image](https://www.rapamycin.news/uploads/default/original/3X/8/8/88bb296b153c15b169c55a432e21d25007be0946.png) [https://x.com/JohnKastelein/status/1892563413043204393#m](https://x.com/JohnKastelein/status/1892563413043204393#m) And: ![image](https://www.rapamycin.news/uploads/default/original/3X/3/8/3805c299200eb40e62d643877f85b7b28d85c9b4.png) The takeaway seem to be careful about MR drug target that doesn’t have any known biological mechanism? I wonder if MR researchers like kastelein have noticed a lot of false hits from e.g multiple comparison problem when just playing around with the MR tools (do p-values have to be much lower?) ?