Comparative genomics of longevity and Alzheimer's disease

The overarching goal of this Program Project Grant (PPG), “Comparative Genomics of Longevity and Alzheimer’s disease” is to identify mechanisms responsible for health and longevity, with the focus on genome/epigenome stability and Alzheimer’s disease (AD) and related dementias (ADRD), in long-lived mammalian species. Mammals differ over 100-fold in their maximum lifespans, from 2 years in a shrew to over 200 years in the bowhead whale. Characterization of the processes responsible for this disparity in lifespan will enable the development of interventions to prevent or cure age-related diseases including AD and ADRD. The central hypothesis of this PPG is that long-lived species have evolved more efficient mechanisms to maintain genome/epigenome stability and prevent Alzheimer’s and ADRD, which can be adapted to extend human healthspan. In the previous phase of the PPG, we generated exciting data that support our hypothesis. Specifically, we identified DNA double strand break repair as a mechanism that strongly correlates with longevity; improved DNA repair in mouse cells by specific amino acid changes; showed that the naked mole rat hyaluronan synthase 2 gene improves mouse health and lifespan and delays ADRD pathology; showed that mutation rates are lower in long-lived species; developed epigenetic clocks for naked mole rats; discovered mechanisms responsible for longevity and genome stability in the longest-lived mammal, the bowhead whale; identified omics profiles of long-lived species; identified a potential mechanism for sporadic AD in degu; and generated new mouse models with genes from long-lived mammals. In the next cycle we will expand our studies to developing interventions and applying novel omics techniques. This PPG is comprised of four integrated projects and three cores. Project 1 (Gorbunova; Garcia) is focused on mechanisms responsible for more efficient genome/epigenome stability and developing anti-aging and AD and ADRD interventions. Project 2 (Seluanov; O’Banion) develops novel animal models of AD resilience (naked mole rat) and sporadic AD (degu). Project 3 (Vijg; Fang) investigates mutations and epimutations in animals with diverse lifespans and in AD models using novel, high throughput single-molecule approaches. Project 4 (Gladyshev; Tyshkovskii) uses multi-omics to identify genes and pathways involved in genome/epigenome stability across species and developing aging, longevity and AD biomarkers. The research team consists of investigators dedicated to longevity research who are experts in comparative biology and DNA repair (Gorbunova), long-lived rodents (Seluanov), AD and ADRD (O’Banion), mutagenesis and single-cell approaches (Vijg), comparative genomics and biomarkers (Gladyshev; Tyshkovskiy); cutting-edge omics techniques, proteomics, and mass spectrometry (Garcia); long-read sequencing (Fang) and bioinformatics (Zhang, Core C). Moreover, we developed a collection of primary cells and tissues, and animal colonies, to facilitate comparative studies of longevity and AD (Seluanov, Core B). This assembly of expertise uniquely positions our team to achieve unprecedented insight into the biology of longevity.