Modeling premature aging in yeast via the expression of Progerin

The budding yeast, Saccharomyces cerevisiae, is an excellent model for studying mechanisms governing aging, with many genetic and biochemical pathways highly conserved. Here, we established a model of premature aging by expressing galactose inducible EGFP fusions of the cytotoxic protein Progerin, and its wild type form, Lamin A (LMNA), in yeast. Progerin is the driving force behind the incurable disease Hutchinson-Gilford Progreria Syndrome, which causes children to age 8 times faster than normal. We observed that EGFP-Progerin and EGFP-LMNA both localized to the yeast nuclear membrane. Progerin expression, but not LMNA, caused yeast cells to grow slowly, experience increased genome instability, and exhibit reduced chronological lifespan. The Lamin A protein had a half-life of 4 hours in yeast, whereas Progerin remained stable for 24 hours, with Progerin accumulating in mother cells, parallel to other long lived asymmetrically retained proteins (LARPS). The select segregation of LARPS into mother cells is associated with the aging program, as this potentially protects daughter cells, ensuring a pristine start and a full lifespan. Using flow cytometry with cells stained with Wheat Germ Agglutinin to score buds scars and relative yeast age, we confirmed that Progerin, but not LMNA, was retained specifically in aging mother cells. Taken together, expression of Progerin in yeast cells mimics what is observed in human cells, establishing yeast as a powerful model to discover genetic mechanisms driving premature and normal aging.