Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 114, Issue 42, Pages 11253-11258Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1703379114
Keywords
replicative aging; single-cell analysis; microfluidics; chromatin silencing; computational modeling
Categories
Funding
- National Science Foundation [MCB-1616127]
- University of California Cancer Research Coordinating Committee
- Department of Defense
- Air Force Office of Scientific Research
- National Defense Science and Engineering Graduate Fellowship [32 CFR 168a]
- Human Frontier Science Program Fellowship [LT000840/2014-C]
- San Diego Center for Systems Biology National Institutes of Health Grant [P50-GM085764]
- Div Of Molecular and Cellular Bioscience
- Direct For Biological Sciences [1616127] Funding Source: National Science Foundation
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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 microfluidic technologies to track the replicative aging of single yeast cells and reveal that the temporal patterns of heterochromatin silencing loss regulate cellular life span. We found that cells show sporadic waves of silencing loss in the heterochromatic ribosomal DNA 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 life spans. 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 life span. These findings reveal 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 life span.
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