• Altmetrics
  • Sign-up for PNAS eTOC Alerts

Multigenerational silencing dynamics control cell aging

  1. Nan Haoa,b,c,2
  1. aSection of Molecular Biology, Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093;
  2. bBioCircuits Institute, University of California, San Diego, La Jolla, CA 92093;
  3. cThe San Diego Center for Systems Biology, La Jolla, CA 92093;
  4. dDepartment of Bioengineering, University of California, San Diego, La Jolla, CA 92093;
  5. eMoores Cancer Center, University of California, San Diego, La Jolla, CA 92093
  1. Edited by Jasper Rine, University of California, Berkeley, Berkeley, CA, and approved September 5, 2017 (received for review February 27, 2017)


Aging 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.


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.


  • ?1Y.L., M.J., and R.O. contributed equally to this work.

  • ?2To whom correspondence should be addressed. Email: nhao{at}ucsd.edu.
  • Author contributions: Y.L., M.J., R.O., L.S.T., L.P., J.H., and N.H. designed research; Y.L. and R.O. performed research; Y.L., M.J., R.O., and P.B. analyzed data; and Y.L., M.J., R.O., L.S.T., L.P., J.H., and N.H. wrote the paper.

  • The authors declare no conflict of interest.

  • This article is a PNAS Direct Submission.

  • This article contains supporting information online at www.danielhellerman.com/lookup/suppl/doi:10.1073/pnas.1703379114/-/DCSupplemental.

Freely available online through the PNAS open access option.

Online Impact

  • 864971864 2018-01-22
  • 258841863 2018-01-22
  • 957295862 2018-01-22
  • 553518861 2018-01-22
  • 983792860 2018-01-22
  • 539694859 2018-01-22
  • 956115858 2018-01-22
  • 730379857 2018-01-22
  • 346624856 2018-01-22
  • 201609855 2018-01-22
  • 72549854 2018-01-21
  • 795928853 2018-01-21
  • 752345852 2018-01-21
  • 566508851 2018-01-21
  • 615722850 2018-01-21
  • 689612849 2018-01-21
  • 846903848 2018-01-21
  • 674896847 2018-01-21
  • 11197846 2018-01-21
  • 986896845 2018-01-21