A Trans-Omic Mendelian Randomization Study of Parental Lifespan Uncovers Novel Aging Biology and Drug Candidates for Human Healthspan Extension

The study of parental lifespan has emerged as an innovative tool to advance aging biology and our understanding of the genetic architecture of human longevity and healthspan. Here, we leveraged summary statistics of a genome-wide association study including over one million parental lifespans to identify genetically regulated genes from the Genotype-Tissue Expression project through a combination of multi-tissue transcriptome-wide association analyses and genetic colocalization. Mendelian randomization (MR) analyses also identified circulating proteins and metabolites causally associated with parental lifespan that may offer new drug repositioning opportunities for healthspan such as drugs targeting apolipoprotein-B-containing lipoproteins. Liver expression of HP , the gene encoding haptoglobin, and plasma haptoglobin levels were causally linked with parental lifespan. Phenome-wide MR analyses were used to map genetically regulated genes, proteins and metabolites with the disease-related phenome in the UK Biobank and FinnGen. Altogether, this study identified novel biological determinants of aging and potential therapeutic targets for human healthspan extension. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement NP holds a doctoral research award from the Fonds de recherche du Quebec: Sante. (FRQS). BJA and ST hold junior scholar awards from the FRQS. PM holds a FRQS Research Chair on the Pathobiology of Calcific Aortic Valve Disease. YB holds a Canada Research Chair in Genomics of Heart and Lung Diseases. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Because the data included in this manuscript was obtained from publicly available sources, no ethical approval was obtained for this specific project. Analyses performed with the UK Biobank dataset were conducted under UK Biobank data application number 25205. This project was approved by the IRB of the Quebec Heart and Lung Institute. All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived. 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 and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes URLs for external datasets and statistical software are included in the manuscript.