Characterization of a positive influence of retrotransposons on longevity

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Project Summary The primary goal of this project is to characterize how DNA sequences known as retrotransposons promote longevity of non-dividing cells exposed to stress conditions. Retrotransposons are mobile DNA elements that can insert copies of themselves at new sites in genomes, causing genetic damage or increasing genetic variation. Many cellular factors inhibit retrotransposons to prevent their mobility in order to maintain genome stability. The project is part of a long-term goal to understand how retrotransposons influence cellular functions in order to manipulate retrotransposons to improve human health. Investigating the contribution of retrotransposons to aging and basic cellular functions in mammals is challenging, due to the many thousands of these elements present in mammalian genomes. This project will use an exceptional model system in budding yeast in which cells that completely lack retrotransposons can be compared to cells that have different copy numbers of retrotransposons. Mammalian and yeast retrotransposons are both activated with age, have similar mutagenic effects, and are regulated by common factors, such as DNA damage, oxidative stress, and a process for recycling cellular components termed autophagy. Aging of mammals and yeast is also regulated by common factors, such as growth signaling, autophagy, mitochondrial function, and DNA replication stress. The project will build upon the novel observation that retrotransposon expression can increase longevity of non-dividing yeast cells in conditions of moderate DNA damage, DNA replication stress, and oxidative stress. The first goal is to identify cellular processes altered by the presence of retrotransposons that are responsible for lifespan extension. The contributions of autophagy and mitochondria to retrotransposon-dependent lifespan extension will be tested in particular, based on preliminary data that retrotransposons reduce mitochondrial activity, reduce reactive oxygen species levels, and provide resistance to a chemical inducer of autophagy. This will involve analysis of mutants with defects in autophagy and mitochondria, cell biology methods to measure alterations in these cellular functions, and analysis of genome-wide gene expression changes due to retrotransposons. The second goal is to use retrotransposons with defects in specific aspects of their expression and replication to determine what features of retrotransposons promote lifespan and associated changes in cellular functions. The advantages of this yeast system will identify specific steps in retrotransposon expression responsible for altering particular cellular processes that increase lifespan. This will enable the design of experiments in mammalian models in which activation or inhibition of particular aspects of retrotransposon expression is expected to produce changes in specific cellular functions relevant to aging.