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

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Science  17 Jul 2020:
Vol. 369, Issue 6501, pp. 325-329
DOI: 10.1126/science.aax9552

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Programmed aging in yeast cells

Following the fate of individual yeast cells has revealed aging to be more of a programmable decision process rather than a simple accumulation of deleterious events. Li et al. combined single-cell studies and mathematical modeling to show that yeast cells showed two different forms of aging: one with less ribosomal DNA silencing, in which nucleoli were degraded, and another with less heme accumulation and hemedependent transcription, in which mitochondria were more affected. Overexpression of the lysine deacetylase Sir2, which contributes to ribosomal DNA silencing, led to a third cell-aging fate in which the average life span was extended. If other cells age in similar ways, then this study may provide new ways to consider dynamics of aging and strategies to extend the health span.

Science this issue p. 325

Abstract

Chromatin instability and mitochondrial decline are conserved processes that contribute to cellular aging. Although both processes have been explored individually in the context of their distinct signaling pathways, the mechanism that determines which process dominates during aging of individual cells is unknown. We show that interactions between the chromatin silencing and mitochondrial pathways lead to an epigenetic landscape of yeast replicative aging with multiple equilibrium states that represent different types of terminal states of aging. The structure of the landscape drives single-cell differentiation toward one of these states during aging, whereby the fate is determined quite early and is insensitive to intracellular noise. Guided by a quantitative model of the aging landscape, we genetically engineered a long-lived equilibrium state characterized by an extended life span.

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