A programmable fate decision landscape underlies single-cell aging in yeast

Area of Science:

• Cellular and Molecular Biology
• Aging Research
• Yeast Genetics

Background:

• Cellular aging is characterized by conserved processes like chromatin instability and mitochondrial decline.
• Distinct signaling pathways govern chromatin and mitochondrial function, but their interplay in cellular aging remains unclear.

Purpose of the Study:

• To investigate the mechanism determining the dominant aging process (chromatin vs. mitochondrial) in individual cells.
• To elucidate the role of interactions between chromatin silencing and mitochondrial pathways in shaping the aging process.
• To explore the potential for manipulating these pathways to extend cellular lifespan.

Main Methods:

• Utilized a quantitative model to describe the epigenetic landscape of yeast replicative aging.
• Analyzed the interactions between chromatin silencing and mitochondrial pathways.
• Employed genetic engineering strategies guided by the aging model to create novel aging states.

Main Results:

• Identified an epigenetic landscape with multiple equilibrium states representing distinct terminal aging phenotypes.
• Demonstrated that the landscape structure drives single-cell differentiation towards specific aging states early in life.
• Showed that this fate determination is robust and insensitive to intracellular noise.
• Successfully engineered a long-lived equilibrium state with an extended lifespan.

Conclusions:

• Interactions between chromatin and mitochondrial pathways establish an epigenetic landscape that dictates cellular aging trajectories.
• Cellular aging fate is established early and is largely predetermined by this landscape.
• Targeting the epigenetic landscape offers a viable strategy for extending cellular lifespan.