PT - JOURNAL ARTICLE AU - Yang Li AU - Meng Jin AU - Richard O’Laughlin AU - Lev S. Tsimring AU - Lorraine Pillus AU - Jeff Hasty AU - Nan Hao TI - Multi-generational silencing dynamics control cell aging AID - 10.1101/102210 DP - 2017 Jan 01 TA - bioRxiv PG - 102210 4099 - http://biorxiv.org/content/early/2017/01/22/102210.short 4100 - http://biorxiv.org/content/early/2017/01/22/102210.full AB - Cellular aging plays an important role in many diseases 1, such as cancers 2, metabolic syndromes 3 and neurodegenerative disorders 4. There has been steady progress in identifying age-related factors such as reactive oxygen species and genomic instability 5, yet an emerging challenge is to reconcile the mechanistic contributions of these factors with the fact that genetically identical cells can age at significantly different rates. Single-cell analyses to unravel the interplay of aging dynamics and variability hold the promise to answer that challenge 6–8. We have used novel microfluidic technologies to track the replicative aging of single yeast cells, revealing that cells show sporadic waves of silencing loss in the heterochromatic ribosomal DNA (rDNA) during early phases of aging, followed by sustained loss of silencing preceding cell death. Isogenic cells have different lengths of the early intermittent silencing phase that largely determine their final lifespans. Combining computational modeling and experimental approaches, we found that the intermittent silencing dynamics is important for longevity and is dependent on the conserved Sir2 deacetylase, whereas either sustained silencing or sustained loss of silencing shortens lifespan. These findings reveal a new dynamics-based control of cell aging that could guide the design of temporally controlled nutriceutical strategies to extend lifespan.