A key hallmark of aging is an overall increase in genomic instability. Accumulating evidence has revealed widespread reactivation of transposable elements (TE) during aging across taxonomically-distant model organisms. Yet, the relationship between this aberrant reactivation and age-related functional decline is largely unknown, at the cellular, organ and organism levels. We hypothesize that the progressive loss of transposon repression contributes to the widespread age-related functional decline at the organismal level. The African turquoise killifish (Nothobranchius furzeri), an emerging naturally short-lived vertebrate model organism, provides a unique opportunity to investigate this link, and the investigators have previously developed a powerful genome-to-phenotype toolkit for this species. In this proposal, we propose to leverage the African turquoise killifish as a tractable short-lived model organism to rapidly interrogate the molecular and organismal impact of increased TE activity on vertebrate aging in vivo. To test our hypothesis, we propose (i) to characterize the repetitive element landscape in the genome of the African turquoise killifish and TE activation patterns, and (ii) to explore the impact of conserved changes in TE regulation with aging and age-related disease on the aging process. The completion of this project will advance the understanding of vertebrate aging. Ultimately, these findings will help define therapeutic targets for development of new treatments for age-associated diseases that have a heavy economic burden, and more importantly, cause extreme suffering to patients and their families.
Understanding how gene regulation processes deteriorate during aging will provide a handle to help delay functional decline and age-related diseases. The progressive buildup of damage to our genomes is a hallmark of the aging process, and accumulating evidence suggests that increased activation of endogenous mobile DNA elements (or `transposons'), which act as parasites to our genome, is a major contributor to age-related genomic damage.!This project aims at understanding how the progressive age-related loss of transposon control contributes to age- related functional decline by leveraging a powerful new model organism, the African turquoise killifish, the shortest-lived Vertebrate that can be bred in captivity.
