RT Journal Article SR Electronic T1 Multi-generational silencing dynamics control cell aging JF bioRxiv FD Cold Spring Harbor Laboratory SP 102210 DO 10.1101/102210 A1 Yang Li A1 Meng Jin A1 Richard O’Laughlin A1 Lev S. Tsimring A1 Lorraine Pillus A1 Jeff Hasty A1 Nan Hao YR 2017 UL http://biorxiv.org/content/early/2017/01/22/102210.abstract 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.