An aging-independent replicative lifespan in a symmetrically dividing eukaryote

Abstract

The replicative lifespan (RLS) of a cell--defined as the number of generations a cell divides before death--has informed our understanding of the molecular mechanisms of cellular aging. Nearly all RLS studies have been performed on budding yeast and little is known about the mechanisms of aging and longevity in symmetrically dividing eukaryotic cells. Here, we describe a multiplexed fission yeast (Schizosaccharomyces pombe) lifespan micro-dissector (FYLM); a microfluidic platform for performing automated micro-dissection and high-content single-cell analysis in well-defined culture conditions. Using the FYLM, we directly observe continuous and robust replication of hundreds of individual fission yeast cells for over seventy-five cell divisions. Surprisingly, cells die without any classic hallmarks of cellular aging such as changes in cell morphology, increased doubling time, or reduced sibling health. Genetic perturbations and longevity-enhancing drugs can further extend the replicative lifespan (RLS) via an aging-independent mechanism. We conclude that despite occasional sudden death of individual cells, fission yeast does not age. These results highlight that cellular aging and replicative lifespan can be uncoupled in a eukaryotic cell.