Single-Cell Analyses Identify Independent Aging Processes that Compete to Determine Cellular Fate in Budding Yeast -- scRNA-seq

In budding yeast, two distinct aging trajectories, characterized by either ribosomal DNA (rDNA) instability or mitochondrial decline, have been proposed to be mutually exclusive. Here, we systematically dissect the heterogeneity among aging yeast cells by combining single-cell transcriptomics with longitudinal fluorescence microscopy.

Our data reveals distinct transcriptional responses that emerge in aging cells, highlighted by loss of rDNA silencing, a hypoxia response, and the Environmental Stress Response (ESR). Contrary to expectation, we establish that ESR induction is not caused by rDNA instability but is instead a consequence of an early decline in mitochondrial membrane potential (MMP). However, the ESR is merely a biomarker of this decline and not itself a determinant of lifespan.