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  • Review Article
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Forging a signature of in vivo senescence

An Erratum to this article was published on 16 July 2015

This article has been updated

Key Points

  • Although the term 'cellular senescence' was originally used to define the state of irreversible proliferative arrest by cultured cells that had reached their replicative limit, it is now widely used to describe states of cell cycle arrest in different in vivo biological settings, including age-associated loss of regenerative capacity, tumour suppression, inflammation, wound healing and embryogenesis.

  • A central problem in the senescence field is the lack of a uniform definition of cellular senescence, coupled with inconsistent application of biomarkers to identify and enumerate senescent cells in vivo.

  • Although frequently used in various combinations to denote putatively senescent cells in vivo, senescence-associated biomarkers — such as robust expression of lysosomal β-galactosidase and the cyclin D-dependent kinase inhibitor p16INK4A, activation of the DNA-damage response, alterations in paracrine secretion and changes in heterochromatin — are individually nonspecific. There is no consensus on which amalgamation of these biomarkers describes the senescent state.

  • Many cancer-associated stress factors activate senescence biomarkers, supporting the roles of senescence-associated processes in tumour suppression. A commonly used senescence marker, the tumour suppressor p16INK4A, progressively increases during organismal ageing and may indeed restrict longevity in certain animal models, but it is unclear whether its expression marks the accumulation of senescent cells per se or, instead, accompanies proliferative arrest in response to many forms of cellular stress.

  • We advocate that 'cellular senescence' should be strictly defined as stress-induced proliferative arrest accompanied by the failure to re-enter the cell division cycle in response to mitogenic and oncogenic stimuli. More-specific descriptors could then be applied to characterize many of the diverse phenotypes that define complex and possibly distinct cellular states currently aggregated under the umbrella term 'senescence'.

Abstract

'Cellular senescence', a term originally defining the characteristics of cultured cells that exceed their replicative limit, has been broadened to describe durable states of proliferative arrest induced by disparate stress factors. Proposed relationships between cellular senescence, tumour suppression, loss of tissue regenerative capacity and ageing suffer from lack of uniform definition and consistently applied criteria. Here, we highlight caveats in interpreting the importance of suboptimal senescence-associated biomarkers, expressed either alone or in combination. We advocate that more-specific descriptors be substituted for the now broadly applied umbrella term 'senescence' in defining the suite of diverse physiological responses to cellular stress.

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Figure 1: Stress triggers and biomarkers of senescence.
Figure 2: The CDKN2A–CDKN2B locus.
Figure 3: Senescence in vivo.

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Change history

  • 16 July 2015

    In the version of this article that was originally published, the figure permission credit line was missing from the legend of Figure 2. The following credit line has now been added to the online versions of the article: "Figure adapted with permission from REF. 71, Elsevier, and REF. 174, Wiley Periodicals.".

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Acknowledgements

The authors thank J. Sage, K. Dorshkind, C. Burd, A. Banito and J. Morris for comments and criticisms on the manuscript.

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Glossary

mTOR

A serine/threonine kinase incorporated into mTOR complex 1 (mTORC1) and mTORC2, which act as nutrient sensors and regulators of translation.

APC/C

(Anaphase-promoting complex/cyclosome). A multi-subunit ubiquitin ligase complex that degrades cyclins A and B, depending on two alternative substrate selectivity factors, CDC20 and CDH1, that function during mitosis and G1 phase, respectively.

Foci

A nonspecific term frequently used to designate discrete, punctate topological sites (for example, of chromosomal DNA damage or heterochromatinization), which can also be described as speckles, detected by microscopy and usually with the aid of fluorescence-based antibodies.

CDKN2A

(Cyclin-dependent kinase inhibitor 2A; also known as the INK4A–ARF locus). Originally used to designate the gene encoding p16INK4A, the locus is now recognized to encode a second, unrelated alternative reading frame (ARF) protein as well.

Ataxia telangiectasia mutated

(ATM). A serine/threonine kinase that acts as a sensor of DNA damage and that phosphorylates various substrates during the different phases of the cell cycle to activate checkpoint responses that arrest the growth of cells with DNA damage.

γH2AX

A phosphorylated histone variant that decorates chromatin sites of DNA damage and is required for the assembly of repair proteins during the DNA-damage response.

Heterochromatin protein 1

(HP1). A family of proteins that bind to trimethylated Lys9 on histone H3, which is important in gene silencing.

Dyskeratosis congenita

A rare inherited disorder presenting with variable degenerative ageing phenotypes accompanied by reduced telomere maintenance and shortened lifespan; it is most commonly triggered by mutations affecting X-linked DKC1, which encodes the telomerase cofactor dyskerin.

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Sharpless, N., Sherr, C. Forging a signature of in vivo senescence. Nat Rev Cancer 15, 397–408 (2015). https://doi.org/10.1038/nrc3960

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