Evaluating the life-extending potential and safety profile of rapamycin: a Mendelian Randomization study of the mTOR pathway

Objective The mechanistic target of rapamycin (mTOR) pathway plays an integral role in cellular metabolism, growth, and aging. While rapamycin and its analogs inhibit the mTOR pathway, extending lifespan in various organisms, the long-term safety and efficacy of these compounds in humans remain understudied. Methods Utilizing two mTOR expression QTL instruments derived from the eQTLgen and MetaBrain studies, we sought to explore the potential causal relationship between mTOR expression inhibition in blood and brain cortex (mimicking chronic rapamycin use), and its effects on longevity, cardiometabolic disease, prostate cancer and anthropometric risk factors. Subsequently, we extended the selection of instruments to 47 other members of the mTOR pathway. To complement this Mendelian randomization (MR) evidence, we conducted genetic colocalisation and sampling-based enrichment testing. 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, OR95%CI=1-1.53, p-value=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, OR95%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 disease. Members of the mTOR complex, especially mTORC1, play a disproportionate role in influencing BMR and BMI, which provides valuable insight for potential therapeutic target development. ### Competing Interest Statement T.R.G. receives funding from Biogen for unrelated research. ### Funding Statement This work was funded by the UK Medical Research Council (MRC) as part of the MRC Integrative Epidemiology Unit (MC\_UU\_00032/03). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes GWAS summary statistics availability is provided by relevant publications. We accessed the following summary statistics via OpenGWAS: ebi-a-GCST005350, ebi-a-GCST006288, ebi-a-GCST006414, ebi-a-GCST006906, ebi-a-GCST009541, ieu-a-7, ieu-a-26, ieu-a-89, ieu-a-798, ieu-b-40, ieu-b-85, ukb-b-17422, ukb-b-16446.