Review
Hallmarks of Cellular Senescence

https://doi.org/10.1016/j.tcb.2018.02.001Get rights and content

Highlights

The phenotype associated with cellular senescence is highly variable and heterogeneous.

Senescent cells show common marks, but mechanisms behind these marks are not widely conserved among all the senescence programs.

Lack of universal or program-specific markers is a major limitation for the identification and the targeting of senescent cells in vitro and in vivo.

Technological advancements or more systematic approaches need to address difficulties associated with the study of cellular senescence.

Cellular senescence is a permanent state of cell cycle arrest that promotes tissue remodeling during development and after injury, but can also contribute to the decline of the regenerative potential and function of tissues, to inflammation, and to tumorigenesis in aged organisms. Therefore, the identification, characterization, and pharmacological elimination of senescent cells have gained attention in the field of aging research. However, the nonspecificity of current senescence markers and the existence of different senescence programs strongly limit these tasks. Here, we describe the molecular regulators of senescence phenotypes and how they are used for identifying senescent cells in vitro and in vivo. We also highlight the importance that these levels of regulations have in the development of therapeutic targets.

Section snippets

The Complexity of the Senescence Phenotype

The functional decline of an organism throughout its life affects multiple organs and is accompanied by the appearance of several diseases. This general decline of functional capabilities is known as aging (see Glossary) and is fairly conserved among species [1].

A main feature of aged organisms is the accumulation of cellular senescence [1], a state of permanent cell cycle arrest in response to different damaging stimuli [2] (Box 1). Excessive and aberrant accumulation of senescent cells in

DNA Damage Response

In the presence of DNA damage, cells activate a robust response, the DDR. Double-strand DNA breaks (DSBs) are powerful activators of DDR, and can lead to cellular senescence when unresolved. DSBs promote the recruitment and binding of ATM kinase to the DNA damage site 8, 9. This recruitment drives phosphorylation of the histone H2AX, which facilitates the assembly of specific DNA repair complexes (Figure 1) [10]. Histone methylation can also contribute to the assembly of damage response

Cell Size and Shape

A key feature of in vitro senescence is the enlarged and irregularly shaped cell body. Activation of the mTOR pathway is necessary for the enlargement of the cell body of senescent endothelial cells [68]. mTORC1 is known to integrate various stress signals and to modulate cell growth accordingly [112], and mTORC1 activation occurs in response to senescence-inducing stimuli [113]. In normal aging, the decline in growth factors, such as GDF11, might also contribute to the activation of mTORC1 and

Implications for Senescence Interventions

Among the various biological functions in which cellular senescence is involved, its role in diseases such as cancer and aging has made it an attractive therapeutic target. Strategies to interfere with senescent cells are mostly based on the markers listed above (Figure 3). Two main approaches are currently under development: (i) specific elimination of senescent cells; and (ii) inhibition of the SASP.

The first approach focuses on identifying compounds that can specifically induce senescent

Concluding Remarks

Since the discovery of senescent cells by Hayflick and Moorhead in 1961 [160], the scientific community has struggled to identify universal and unequivocal markers characterizing the senescence state. The difficulty in identifying such markers reflects the complexity of the senescence phenotype and the existence of highly heterogeneous senescence programs (see Outstanding Questions). Currently, the only possibility resides in combining the measurement of multiple hallmarks in the same sample [3]

Glossary

Aging
functional decline or an organism throughout life [1].
Alternative splicing
process that allows a gene to encode different mRNA products by differentially using exons and excluding introns in a primary transcript to give rise to different processed mRNAs.
Apoptosis
normal physiological form of cell death [82].
Autophagy
intracellular degradation system. It can degrade nonspecific (general autophagy) or specific (selective autophagy) targets [149].
Caveolae
cholesterol-enriched microdomains of the

References (163)

  • W. Huang

    Histone deacetylase 3 represses p15INK4b and p21 WAF1/cip1 transcription by interacting with Sp1

    Biochem. Biophys. Res. Commun.

    (2006)
  • B.-H. Koo

    Distinct roles of transforming growth factor-β signaling and transforming growth factor-β receptor inhibitor SB431542 in the regulation of p21 expression

    Eur. J. Pharmacol.

    (2015)
  • C.D. Wiley

    Mitochondrial dysfunction induces senescence with a distinct secretory phenotype

    Cell Metab.

    (2016)
  • T. Kuilman

    Oncogene-induced senescence relayed by an interleukin-dependent inflammatory network

    Cell

    (2008)
  • A. Toso

    Enhancing chemotherapy efficacy in pten-deficient prostate tumors by activating the senescence-associated antitumor immunity

    Cell Rep.

    (2014)
  • H. Chen

    MacroH2A1 and ATM play opposing roles in paracrine senescence and the senescence-associated secretory phenotype

    Mol. Cell

    (2015)
  • J.C. Acosta

    Chemokine signaling via the CXCR2 receptor reinforces senescence

    Cell

    (2008)
  • J.L. Stow et al.

    Intracellular trafficking and secretion of inflammatory cytokines

    Cytokine Growth Factor Rev.

    (2013)
  • Y.Y. Sanders

    Histone modifications in senescence-associated resistance to apoptosis by oxidative stress

    Redox Biol.

    (2013)
  • L.H. Boise

    Bcl-X, a Bcl-2-related gene that functions as a dominant regulator of apoptotic cell death

    Cell

    (1993)
  • C. Correia-Melo et al.

    Mitochondria: are they causal players in cellular senescence?

    Biochim. Biophys. Acta

    (2015)
  • B.N. Nicolay et al.

    The multiple connections between pRB and cell metabolism

    Curr. Opin. Cell Biol.

    (2013)
  • D. Muñoz-Espín et al.

    Cellular senescence: from physiology to pathology

    Nat. Rev. Mol. Cell Biol.

    (2014)
  • N.E. Sharpless et al.

    Forging a signature of in vivo senescence

    Nat. Rev. Cancer

    (2015)
  • P. Lecot

    Context-dependent effects of cellular senescence in cancer development

    Br. J. Cancer

    (2016)
  • L. Zou

    Single- and double-stranded DNA: Building a trigger of ATR-mediated DNA damage response

    Genes Dev.

    (2007)
  • A. Celeste

    Genomic instability in mice lacking histone H2AX

    Science

    (2002)
  • M.K. Ayrapetov

    DNA double-strand breaks promote methylation of histone H3 on lysine 9 and transient formation of repressive chromatin

    Proc. Natl. Acad. Sci.

    (2014)
  • S. Bekker-Jensen

    Spatial organization of the mammalian genome surveillance machinery in response to DNA strand breaks

    J. Cell Biol.

    (2006)
  • C. Lukas

    Distinct spatiotemporal dynamics of mammalian checkpoint regulators induced by DNA damage

    Nat. Cell Biol.

    (2003)
  • G.A. Turenne

    Activation of p53 transcriptional activity requires ATM’s kinase domain and multiple N-terminal serine residues of p53

    Oncogene

    (2001)
  • D.J. Baker

    Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders

    Nature

    (2011)
  • M. Velicescu

    Cell division is required for de novo methylation of CpG islands in bladder cancer cells

    Cancer Res.

    (2002)
  • S. Venturelli

    Differential induction of apoptosis and senescence by the DNA methyltransferase inhibitors 5-azacytidine and 5-aza-2′-deoxycytidine in solid tumor cells

    Mol. Cancer Ther.

    (2013)
  • B. Zhu

    Atorvastatin treatment modulates p16 promoter methylation to regulate p16 expression

    FEBS J.

    (2017)
  • K. Pan

    HBP1-mediated transcriptional regulation of DNA methyltransferase 1 and its impact on cell senescence

    Mol. Cell Biol.

    (2013)
  • J. Li

    Regulatory mechanisms of tumor suppressor P16 INK4A and their relevance to cancer

    Biochemistry

    (2011)
  • M. Barzily-Rokni

    Synergism between DNA methylation and macroH2A1 occupancy in epigenetic silencing of the tumor suppressor gene p16(CDKN2A)

    Nucleic Acids Res.

    (2011)
  • X. Wang

    The proximal GC-rich region of p16INK4a gene promoter plays a role in its transcriptional regulation

    Mol. Cell. Biochem.

    (2007)
  • N. Ohtani

    Opposing effects of Ets and Id proteins on p16INK4a expression during cellular senescence

    Nature

    (2001)
  • E. Passegue

    JunB suppresses cell proliferation by transcriptional activation of p16INK4a expression

    EMBO J.

    (2000)
  • Q. Gan

    PPAR accelerates cellular senescence by inducing p16INK4 expression in human diploid fibroblasts

    J. Cell Sci.

    (2008)
  • Y. Huang

    B-MYB delays cell aging by repressing p16 INK4α transcription

    Cell. Mol. Life Sci.

    (2011)
  • Y. Kotake

    YB1 binds to and represses the p16 tumor suppressor gene

    Genes Cells

    (2013)
  • D. Zhu

    Modulation of the expression of p16INK4a and p14ARF by hnRNP A1 and A2 RNA binding proteins: Implications for cellular senescence

    J. Cell. Physiol.

    (2002)
  • G.E. Guo

    Hydrogen peroxide induces p16INK4a through an AUF1-dependent manner

    J. Cell. Biochem.

    (2010)
  • H.H. Al-Khalaf et al.

    P16INK4A positively regulates p21WAF1 expression by suppressing AUF1-dependent mRNA decay

    PLoS One

    (2013)
  • A. Bisio

    The 5′-untranslated region of p16INK4a melanoma tumor suppressor acts as a cellular IRES, controlling mRNA translation under hypoxia through YBX1 binding

    Oncotarget

    (2015)
  • Y. Lu

    The interplay between p16 serine phosphorylation and arginine methylation determines its function in modulating cellular apoptosis and senescence

    Sci. Rep.

    (2017)
  • A. Ko

    Dynamics of ARF regulation that control senescence and cancer

    BMB Rep.

    (2016)
  • Cited by (1398)

    • Senescence and fibrosis in salivary gland aging and disease

      2024, Journal of Oral Biology and Craniofacial Research
    View all citing articles on Scopus
    View full text