Approved Research

Genomic Translation of Aging-Related Associations from Model Systems to Humans

Lay summary

While there has been much progress in using model organisms, such as worms and mice, to understand biological processes that underlie aging-related disease and health outcomes, the translation of findings in those model organisms from biological experiments to human relevance occurs very slowly. Collaboration with human population scientists and genetic epidemiologists can accelerate the translation and the interpretation of analytical findings to establish human relevance for the findings as well as generate hypotheses to move research forward into the clinical area. Our project focuses on research to prevent aging-related disease and promote greater health and resilience in older age, through several sub-projects born out of collaborations between biologists and population scientists. The overall aim of the project is to interrogate research findings from model organisms in the existing, large scale UKB data to study relevance to specific sub-groups of individuals based on gender and different environmental and behavioral conditions.

Findings from this work will be used to generate additional hypotheses for experimental and mechanism-based studies. Over the course of five years (2020-2025), we will examine (1) variation in the ALDH4a1 gene for associations with aging-related functional decline, (2) genetic variants underlying a mitochondrial derived peptide for associations with cognitive decline, (3) genetic variation underlying HMGCS2 enzyme levels for relationships with metabolic outcomes, and (4) smoking exposure effects on cognition, with a focus on differences by gender. With the transdisciplinary collaborations for these sub-projects, we expect that results from this work will facilitate on-going research and move closer towards bringing bench science to intervention studies focused on aging-related disease prevention.

Scope extension:

Several sub-studies are proposed for completion within this application, all of which will involve collaborations between population-scientists and biologists, and in which we will leverage the large scale, UKB data to test hypotheses on genomic associations derived from model systems (e.g., mice, worms). Our main aims are focused on interrogating findings derived from model organisms in UKB human population data to establish relevance to human aging, under natural human conditions, using empirically-driven approaches. Projects planned focus on evaluating (1) variation in the ALDH4a1 gene for associations with aging-related functional decline, (2) genetic variants underlying a mitochondrial derived peptide for associations with cognitive decline, (3) genetic variation underlying HMGCS2 enzyme levels for relationships with metabolic outcomes, and (4) smoking exposure effects on cognitive functioning, with a focus on differences by gender.

We additionally would expand project 1 to evaluate additional gene candidates, and project 2 to evaluate interactions between mitochondrial derived peptides with nuclear variants on additional aging-related health outcomes, including indicators of inflammation, metabolic dysfunction, functional decline, frailty, and accelerated aging. A project 5 would focus on evaluating genetic and environmental factors underlying behaviors and lifestyle related to health in aging, including an evaluation of genetic homophily.