# Chromosome duplication causes premature aging via defects in ribosome quality control

## TL;DR

Extra chromosomes in yeast cause early aging by disrupting ribosome quality control, leading to protein issues and shorter lifespan.

## Contribution

This study reveals that chromosome duplication causes premature aging through ribosome quality control defects in yeast.

## Key findings

- Chromosome duplication disrupts quiescence and shortens lifespan in yeast.
- Aneuploidy causes protein aggregation and ribosome profile abnormalities.
- Improving ribosome quality control reduces aneuploidy-related aging defects.

## Abstract

Down syndrome, caused by an extra copy of Chromosome 21, causes lifelong problems. One of the most common phenotypes among people with Down syndrome is premature aging, including early tissue decline, neurodegeneration, and shortened life span. Yet the reasons for premature systemic aging are a mystery and difficult to study in humans. Here we show that chromosome amplification in wild yeast also produces premature aging and shortens life span. Chromosome duplication disrupts nutrient-induced cell-cycle arrest, entry into quiescence, and cellular health during chronological aging, across genetic background and independent of which chromosome is amplified. Using a genomic screen, we discovered that these defects are due in part to aneuploidy-induced dysfunction in Ribosome Quality Control (RQC). We show that aneuploids entering quiescence display aberrant ribosome profiles, accumulate RQC intermediates, and harbor an increased load of protein aggregates compared to euploid cells. Although they maintain proteasome activity, aneuploids also show signs of ubiquitin dysregulation and sequestration into foci. Remarkably, inducing ribosome stalling in euploids produces similar aging phenotypes, while up-regulating limiting RQC subunits or poly-ubiquitin alleviates many of the aneuploid defects. We propose that the increased translational load caused by having too many mRNAs accelerates a decline in translational fidelity, contributing to premature aging.

Syndromes caused by chromosome amplification, such as Down syndrome, are characterized by premature aging, but the reason behind this is unclear. This study shows that chromosome amplification in yeast disrupts quiescence and lifespan due to defects in the ribosome quality control pathway, leading to protein aggregation and accelerated aging.