PT  - JOURNAL ARTICLE
AU  - Yang Li
AU  - Yanfei Jiang
AU  - Julie Paxman
AU  - Richard O’Laughlin
AU  - Lorraine Pillus
AU  - Lev S. Tsimring
AU  - Jeff Hasty
AU  - Nan Hao
TI  - An epigenetic landscape governs early fate decision in cellular aging
AID  - 10.1101/630921
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 630921
4099  - http://biorxiv.org/content/early/2019/05/07/630921.short
4100  - http://biorxiv.org/content/early/2019/05/07/630921.full
AB  - 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 cell fate arises in isogenic cells is unknown. Here, we show that interactions between the chromatin silencing and mitochondrial pathways lead to an epigenetic landscape with multiple equilibrium states that represent different types of terminal cellular states. Interestingly, the structure of the landscape drives single-cell differentiation towards 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 engineer a new “long-lived” equilibrium state that is characterized by a dramatically extended lifespan.