tRNA-derived short and long RNAs in aging

ABSTRACT Some of the most novel insights in aging have come from studies in model organisms like S. cerevisiae. While a lot has been done about gene (mRNA) expression changes that accompany aging, not much has been done about short RNA changes that may accompany aging. To address this, we sequenced the short RNAome in young and old yeast and discovered that there was a significant induction of a family of short RNAs derived from tRNAs, called tRF-5s or tiR-5s or tRNA halves, that are created by cleavage of tRNAs in the anticodon loop. In addition, we discovered a strong induction of extended transcripts spanning the tRNA loci in the aged yeast compared to the young yeast. In this exploratory project we propose to investigate the tRNA halves and the extended tRNA transcripts to determine if they contribute to lifespan or to the proteostasis that is associated with aging. In Aim 1 we will focus on the tiR-5s, overexpressing or depleting them to study effects on lifespan and proteostasis. We will also determine how the tRNA halves accumulate with age and whether mutations in yeast that advance aging advance the accumulation of the tRNA halves. In Aim 2 we will turn to the extended tRNA transcripts, defining their start and end points, how they accumulate and whether their overexpression contributes to lifespan changes or aging-associated dysregulation of proteostasis. These exploratory studies will define whether these short RNAs and/or the abnormally extended tRNA transcripts contribute to determination of lifespan or to specific disturbances in proteostasis that accompany aging. A positive result will lead to more in depth studies exploring the mechanism by which these tRNA based short and long RNAs are produced and how they contribute to the aging phenotype. This project brings together an expert on yeast aging (Dr. Jeffrey Smith) and an expert on tRNA fragments (Dr. Anindya Dutta) to explore what could be a novel mechanism of aging.