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.