Review Article | Published:

Cellular senescence: when bad things happen to good cells

Nature Reviews Molecular Cell Biology volume 8, pages 729740 (2007) | Download Citation

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Abstract

Cells continually experience stress and damage from exogenous and endogenous sources, and their responses range from complete recovery to cell death. Proliferating cells can initiate an additional response by adopting a state of permanent cell-cycle arrest that is termed cellular senescence. Understanding the causes and consequences of cellular senescence has provided novel insights into how cells react to stress, especially genotoxic stress, and how this cellular response can affect complex organismal processes such as the development of cancer and ageing.

Key points

  • Cellular senescence is a multifaceted process that arrests the proliferation of cells that are at risk of neoplastic transformation.

  • Many stimuli elicit a senescence response. These include dysfunctional telomeres, DNA damage, the expression of certain oncogenes, perturbations to chromatin organization and strong mitogenic signals.

  • Two powerful tumour suppressor pathways, controlled by the p53 and retinoblastoma (pRB) proteins, are important for establishing and maintaining the senescence growth arrest. These pathways respond to somewhat different stimuli but interact and cooperate to control the senescence response.

  • There is now substantial evidence that cellular senescence is a barrier to malignant tumorigenesis in vivo.

  • In mammalian organisms, cells that express markers of senescence have been shown to accumulate with age and at sites of certain age-related pathologies. There is also mounting evidence that cellular senescence contributes to ageing. Although this evidence is still mainly circumstantial, it suggests that the senescence response might be an example of evolutionary antagonistic pleiotropy.

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Acknowledgements

The authors thank colleagues and the members of their laboratories for stimulating discussions. The F.d'A.d.F. group is supported by the Associazione Italiana per la Ricerca sul Cancro, the Association for International Cancer Research and the Human Frontier Science Program. The J.C. group is supported by the US National Institute of Aging, the National Cancer Institute and the Department of Energy.

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Affiliations

  1. Life Sciences Division, Lawrence Berkeley National Laboratory, 1 Cyclotron Road, Berkeley, California 94720, USA; and Buck Institute for Age Research, 8001 Redwood Boulevard, Novato, California 94945, USA.  jcampisi@lbl.gov

    • Judith Campisi
  2. IFOM Foundation, FIRC Institute of Molecular Oncology, Via Adamello 16, 20139 Milan, Italy.  fabrizio.dadda@ifom-ieo-campus.it

    • Fabrizio d'Adda di Fagagna

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The authors declare no competing financial interests.

Glossary

Renewable tissue

A tissue in which cell proliferation is important for tissue repair or regeneration. Renewable tissues typically contain, but sometimes recruit, mitotic cells upon injury or cell loss.

Antagonistic pleiotropy

The hypothesis that genes or processes that were selected to benefit the health and fitness of young organisms can have unselected deleterious effects that manifest in older organisms and thereby contribute to ageing.

Mitotic cell

A cell that has the ability to proliferate. In vivo, mitotic cells often exist in a reversible growth-arrested state that is termed quiescence or G0 phase, but such cells can be stimulated to proliferate in response to appropriate physiological signals.

Post-mitotic cell

A cell that has permanently lost the ability to proliferate, usually due to differentiation.

Quiescence

A reversible non-dividing state from which cells can be stimulated to proliferate in response to physiological signals.

Senescent phenotype

The combination of changes in cell behaviour, structure and function that occur upon cellular senescence. For most cell types, these changes include an essentially irreversible growth arrest, resistance to apoptosis and many alterations in gene expression.

Oncogene

A gene that contributes to the malignant transformation of cells. Oncogenes can be cellular or viral in origin. Cellular oncogenes are usually mutant or overexpressed forms of normal cellular genes. Viral oncogenes can also originate from cellular genes, acquiring mutations during viral capture, but they can also be distinctly viral in origin.

Chromatin

The DNA and complex of associated proteins that determine the accessibility of large DNA regions to the transcription machinery and other large protein complexes.

Euchromatin

Chromatin that is in an open conformation and hence accessible. Also termed active chromatin.

Heterochromatin

Chromatin that is in a closed conformation and hence inaccessible. Also termed silent or inactive chromatin. Chromatin probably exists in many forms between the extremes of euchromatin and heterochromatin.

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