Aging is a complex process with universal occurrence in higher animals, multiple contributing genetic pathways, and extensive downstream consequences for society. To date, most knowledge about aging is derived from a limited set of short-lived models. In contrast, lifespan variation across the tree of life can be dramatic, even among closely related species. For example, the bowhead whale, pink cockatoo, and greater mouse-eared bat all exhibit extraordinary longevity compared to their relatives. Using the genomes of hundreds of mammals and birds, our ongoing work has identified candidate pathways, genes, and amino acid residues that show signals of purifying or positive selection in long-lived organisms.
To understand the relevance of these genetic signals to human longevity and healthspan, we will analyze the UK Biobank genotype and phenotype data for concordance with our comparative genomics results. We will use population genetics methods to study the signals of selection for longevity and healthy aging in the UK Biobank cohort, and demographic analysis to associate genotypes with biomarkers and clinical outcomes. If these results are concordant with our comparative genomics results, they would provide powerful evidence of the human relevance of longevity pathways used by non-model organisms.
We are also interested in integrating our comparative findings into the broader architecture of aging in humans, and plan to combine multiple types of “omics” data with socioeconomic factors, biomarkers, and clinical data to build a multi-modal model of aging and healthspan using causal network analysis. Our model aims to predict medical outcomes and diagnoses, discover mechanistic insights into aging, and suggest candidate pathways for targeted health and longevity intervention.
This research will be disseminated through a series of peer-reviewed publications. The resulting manuscripts will emphasize the health impacts and public benefit of this work.
