Multi-generational silencing dynamics control cell aging

Cellular aging plays an important role in many diseases, such as cancers, metabolic syndromes and neurodegenerative disorders. There has been steady progress in identifying aging-related factors such as reactive oxygen species and genomic instability, yet an emerging challenge is to reconcile the contributions of these factors with the fact that genetically identical cells can age at significantly different rates. Such complexity requires single-cell analyses designed to unravel the interplay of aging dynamics and cell-to-cell variability. Here we use novel microfluidic technologies to track the replicative aging of single yeast cells and reveal that the temporal patterns of heterochromatin silencing loss regulate cellular lifespan. We found that cells show sporadic waves of silencing loss in the heterochromatic ribosomal DNA (rDNA) during the 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, for the first time, that the temporal patterns of a key molecular process can directly influence cellular aging and thus could provide guidance for the design of temporally controlled strategies to extend lifespan.\n\nSignificanceAging is an inevitable consequence of living, and with it comes increased morbidity and mortality. Novel approaches to mitigating age-related chronic diseases demand a better understanding of the biology of aging. Studies in model organisms have identified many conserved molecular factors that influence aging. The emerging challenge is to understand how these factors interact and change dynamically to drive aging. Using multidisciplinary technologies, we have revealed a sirtuin-dependent intermittent pattern of chromatin silencing during yeast aging that is crucial for longevity. Our findings highlight the important role of silencing dynamics in aging, which deserves careful consideration when designing schemes to delay or reverse aging by modulating sirtuins and silencing.