Biogerontology (2009) 10:229233 DOI 10.

1007/s10522-008-9207-x

EDITORIAL

Cell senescence: the future of ageing?

Lynne S. Cox

Received: 24 November 2008 / Accepted: 3 December 2008 / Published online: 30 December 2008 Springer Science+Business Media B.V. 2008

This special Cell Senescence issue of Biogerontology results from a lively and successful 2 day international workshop held at Oriel College, Oxford, UK on July 78th 2008, which set out to provide a forum for discussion and dissemination of the latest and most exciting ndings in senescence research, and for which I had the privilege of acting as main organiser. It followed on 10 years (almost to the day) from a previous workshop of the same name also held at Oriel College (Kill 1998). In the intervening decade, research on cellular senescence has progressed rapidly, with the identication of the genetic mutation leading to human premature ageing Hutchinson Gilford syndrome (De Sandre-Giovannoli et al. 2003; Eriksson et al. 2003), production of various model systems to study ageing, identication of triggers of senescence and key molecular components, together with a growing appreciation that senescence has an important role in tumour suppression (e.g. Campisi 2005). This greater understanding at all levels from the organism through to the molecule has laid the intellectual basis for development of therapies with the long-term goal of modulating senescence. Ageing, and research into the causes of ageing, is rapidly moving up the political agenda as demographic change makes huge nancial calls on the
L. S. Cox (&) Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, UK e-mail: lynne.cox@bioch.ox.ac.uk

economies of industrialised and developing countries. This was emphasised at the meeting in presentations by Professor Nigel Brown, then Head of Science and Technology at the BBSRC, and Dr Evan Harris MP, Liberal Democrat Spokesman for Science, who made a very strong case for evidence-based policy and decision making in politics. These presentations reinforced the responsibilities of the scientic research community to communicate with other end-users, including the pharmaceutical industry and the funders and policy makers who decide the strategic direction of, and investment into, our research.

Do senescent cells exist in vivo? Controversy has surrounded the idea of cellular senescence ever since it was rst mooted by Leonard Hayick in 1965 (Hayick 1965). One of the main objections to the hypothesis was the absence of evidence that senescence occurs in vivo: this has been strongly refuted by recent studies that clearly demonstrate the presence of a large number of cells with a characteristically senescent phenotype in the skin of naturally aged baboons (Herbig et al. 2006; Jeyapalan et al. 2007). John Sedivy (Brown University, Providence, RI, USA) took this further, describing powerful new experimental tools for identifying senescent cells. Immunological defects in ageing were addressed by Arne Akbar (University College, London, UK), who described a decit in subcutaneous T-cell migration in

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older subjects, together with possible molecular mechanisms and even potential modes of correcting the decit (see also Vukmanovic-Stejic et al. 2008 for an alternative experimental model for investigating T-cell accumulation in cutaneous tissue). Immunosenescence was further explored by Donald Palmer (Royal Vetinary College, London, UK) who described not only thymic atrophy with age (Aw et al. 2008), but also suggested a potential new model system based on evolutionary conservation of thymic involution in the zebra sh. Senescence as a feature of other organ systems was also explored. Failure of energy metabolism in the vascular endothelium with ageing was discussed in the context of IGF-BP3 upregulation by Pidder Jansen-Durr (Institute for Biomedical Ageing Research, Innsbruck, Austria), and the paper from his lab in this special issue (Unterluggauer et al. 2008) shows how HSP70 is a major target for AGE modication in senescent human cells. The theme of IGF signalling in ageing tissues was further explored by Gillian Butler-Brown (INSERM, Paris, France), in terms of increasing the pool of satellite cells in muscle with exercise, to correct for satellite cells loss which contributes to muscle loss in the elderly (see also Bigot et al. 2008).

role of RecQ proteins in maintaining stability. In addition to these generally well-accepted model systems, Ilaria Bellantuono (Shefeld University, UK) presented new data on stem cell ageing in Down syndrome (DS), showing the utility of studying DS as a segmental progeria, and emphasising the importance of Notch signalling. Her paper in this special issue (Holmes et al. 2008) examines telomere length maintenance in human foetuses compared with pre-term infants, and demonstrates a more rapid rate of telomere loss after birth.

The interplay between DNA structure, epigenetic effects and signalling in senescence Model systems of ageing have provided insights into some molecular mechanisms underlying ageing. This was further explored in a session devoted to mechanisms. Brad Johnson (University of Pennsylvania, Philadelphia, USA) gave a fascinating talk on DNA quadruplex-forming potential (Hershman et al. 2008) and its impact on gene expression in senescence. Thomas von Zglinicki (Newcastle University, UK) then described the link between nuclear DNA repair and mitochondrial dysfunction, using a systems modelling approach (see also Ahmed et al. 2008). Olivier Toussaint (University of Namur, Belgium) discussed increases in TGFb1 levels in senescence. Debacq-Chaineaux and colleagues take this work through to examining the impact of COX-2 overexpression in p53 and ATF-2-mediated senescence on oxidative damage (Zdanov et al. 2008). Signalling in senescence was also addressed by Peter Adams (Fox Chase Cancer Center, Philadelphia, PA, USA), who showed the importance of Wnt signalling in preventing senescencehe also described his recent work on establishment of senescent chromatin (Adams 2007). Telomere attrition contributes to human senescence through the p53 pathway (Deng et al. 2008). The contribution of telomeric maintenance mechanisms to preventing DNA instability, and resulting in cancer when such mechanisms fail, was discussed by Dominique Broccoli (Curtis and Elizabeth Anderson Cancer Institute, Savannah, GA, USA) (see McCord and Broccoli 2008). Sandy Chang (MD Anderson Cancer Center, Houston, TX, USA) further described telomeric maintenance, dissecting the role of POT1, and in doing so, identifying human dyskeratosis

Models of human ageing To dissect the mechanistic basis of normal ageing, the use of model systems is extremely valuable. Of these, the progeroid Werner syndrome (WS) and HutchinsonGilford progeria syndrome (HGPS) are widely accepted models of premature human ageing. Ian Kill (Brunel University, UK) presented data on failure of cell motility in HGPS, while Lynne Cox (University of Oxford, UK) described collaborative work with Robert Saunders (Open University, UK) on the discovery of a WRN orthologue in Drosophila (Saunders et al. 2008) and presented new data on its exonuclease activity (Boubriak et al. 2008). Vilhelm Bohr (NIA, Bethesda, MD, USA) gave a thorough overview of the role of RecQ helicases in DNA repair, showing some very interesting results on deciency of double strand break repair in RothmundThompson syndrome. The review article in this edition (Singh et al. 2008) demonstrates the importance of chromosomal instability in Cell Senescence and premature human ageing, and the critical

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congentia as a useful experimental system for studying stem cell exhaustion. Richard Faragher (Brighton University, UK) proposed a novel hypothesis to explain the pro-inammatory phenotype of senescent cells.

Can senescence be modulated experimentally and in the clinic? In the nal scientic session, possible interventions in senescence were discussed. David Kipling (Cardiff University, UK) described work on p38 MAP kinase inhibitors, particularly showing reversion of the WS senescent phenotype in vitro (Davis et al. 2005). Davis and Kipling take this further in their paper in this special edition, assessing the importance of p38 MAP kinase signalling in WS compared with Ataxia Telengiectasia, more commonly known as a DNA repair disease but one which can shed valuable insights into premature ageing (Davis and Kipling 2008). Nicol Keith (Glasgow University, UK) described a cellbased screen for inhibitors of the telomerase promoter (see Keith et al. 2007). Finally, Leslie Gordon (Brown University, Providence, RI, USA) gave a very interesting presentation on the worlds rst clinical trial for HutchinsonGilford Progeria, using farnesyl transferase inhibitors (FTIs, see http://www.progeriaresearch. org/rst-ever_progeria_clinical_drug_trial_reaches_ 1-year_mark.html). Such studies, remarkable though they are and of extreme signicance to those affected by the devastating childhood onset progeria, might be thought to relate only to a tiny number of individuals. However, the lessons from HGPS are likely to extend widely to normal ageing. For example, Scafdi and Misteli have proposed that accumulation of progerin in normal individuals may be associated with physiological ageing (Scafdi and Misteli 2006). In summary, this meeting highlighted several key ideas in senescence research. Firstly, senescence does occur in many different tissues and new tools are in development for detection of senescent cells. Secondly, progeroid syndromes aid investigation of the molecular basis of normal ageing, with DNA stability (including telomere maintenance, DNA repair and nuclear integrity) a common theme. In terms of molecular mechanisms, the IGF axis continues to be central in many aspects of ageing, but this is joined by p38 MAPK stress signalling and developmental

switches Notch and Wnt. The nal, and perhaps key question is whether senescence can usefully be modulated. The presentations at the meeting strongly suggested that it can, supported by two very recent and important papers in which the cardiovascular phenotypes of HGPS can be at least partially reversed in mice on FTI treatment (Capell et al. 2008; Sagelius et al. 2008). Since this meeting, a further important advance has been made in understanding HGPS, in that lamin A prenylation has been shown to be caused not only by farnesyltransferase but also through the action of geranylgeranyltransferase (Varela et al. 2008). Using a combination of aminobisphosphonates and statins, these authors noted marked phenotypic improvements in a mouse model of HGPS (Varela et al. 2008). Together, these studies reinforce the validity of the HGPS FTI clinical trial, suggest further therapeutic strategies and hold out hope for affected families. The role of funders is often marginalised at scientic meetings. Here, contributions were invited from representatives of the academic funders of the meeting: BBSRC, Research into Ageing and SPARC in the UK, and The Ellison Medical Foundation and National Institute on Ageing in the USA. This close integration of funders and researchers has helped to pave the way for a more synergistic understanding of how and why ageing research is conducted in the lab and what aspects are most likely to attract funding. So did this meeting address its aims of bringing together some of the worlds leading researchers in the eld of cellular senescence to discuss world class science, of providing a condential forum for discussion of novel data, and of forging new links that should lead to further exciting work in the eld? Yes: the highly positive feedback from delegates suggests that such small network meetings full an essential role in getting key scientists to talk informally with each other and establish trust and understanding that will lead to much productive international collaborative research in the future. The papers in this special edition of Biogerotnology provide only a small snapshot of the work discussed at the meeting, but act as testament to the quality of current research on cell senescence.
Acknowledgments I wish to thank all members of the organising committee for their help and support: Nicky Hewson and Richard Faragher (both at Brighton University, UK), Robert Saunders (Open University, UK), Dominique Broccoli (Curtis and Elizabeth Anderson Cancer Institute,

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232 Savannah, GA, USA), David Kipling (Cardiff University, UK) and Ian Kill (Brunel University, UK). We are very grateful to all our sponsors: this meeting was supported by the Biotechnology and Biological Sciences Research Council (BBSRC) [Work 1705], The Ellison Medical Foundation (USA), Research into Ageing (UK), National Institute on Ageing (USA), SPARC (UK), together with our commercial sponsors: Ageing Cell, Anachem, Applied Biosystems, Bioline, BMG Labtech, Dojindo, Fermentas Life Sciences, NBS Biologicals, Promega, VWR, and of course, Biogerontology, without whose support this special issue would not be possible.

Biogerontology (2009) 10:229233 Gilford progeria. Science 300:2055. doi:10.1126/science. 1084125 Deng Y, Chan SS, Chang S (2008) Telomere dysfunction and tumour suppression: the senescence connection. Nat Rev Cancer 8:450458. doi:10.1038/nrc2393 Eriksson M, Brown WT, Gordon LB, Glynn MW, Singer J, Scott L, Erdos MR, Robbins CM, Moses TY, Berglund P, Dutra A, Pak E, Durkin S, Csoka AB, Boehnke M, Glover TW, Collins FS (2003) Recurrent de novo point mutations in lamin A cause HutchinsonGilford progeria syndrome. Nature 423:293298. doi:10.1038/nature01629 Hayick L (1965) The limited in vitro lifetime of human diploid cell strains. Exp Cell Res 37:614636. doi: 10.1016/0014-4827(65)90211-9 Herbig U, Ferreira M, Condel L, Carey D, Sedivy JM (2006) Cellular senescence in aging primates. Science 311:1257. doi:10.1126/science.1122446 Hershman SG, Chen Q, Lee JY, Kozak ML, Yue P, Wang LS, Johnson FB (2008) Genomic distribution and functional analyses of potential G-quadruplex-forming sequences in Saccharomyces cerevisiae. Nucleic Acids Res 36:144 156. doi:10.1093/nar/gkm986 Holmes DK, Bellantuono I, Walkinshaw SA, Alrevic Z, Johnston TA, Subhedar NV, Chittick R, Swindell R, Wynn RF (2008) Telomere length dynamics differ in foetal and early post-natal human leukocytes in a longitudinal study. Biogerontology. doi 10.1007/s10522-008-9194-y Jeyapalan JC, Ferreira M, Sedivy JM, Herbig U (2007) Accumulation of senescent cells in mitotic tissue of aging primates. Mech Ageing Dev 128:3644 Keith WN, Thomson CM, Howcroft J, Maitland NJ, Shay JW (2007) Seeding drug discovery: integrating telomerase cancer biology and cellular senescence to uncover new therapeutic opportunities in targeting cancer stem cells. Drug Discov Today 12:611621. doi:10.1016/j.drudis. 2007.06.009 Kill IR (1998) Ageing research in the UK: plenty of proliferative potential. Cellular Senescence: the future of ageing. Oxford, United Kingdom, 1617 July 1998. Mol Med Today 4:466467. doi:10.1016/S1357-4310(98)01360-4 McCord RA, Broccoli D (2008) Telomeric chromatin: roles in aging, cancer and hereditary disease. Mutat Res 647: 8693. doi:10.1016/j.mrfmmm.2008.08.005 Sagelius H, Rosengardten Y, Schmidt E, Sonnabend C, Rozell B, Eriksson M (2008) Reversible phenotype in a mouse model of HutchinsonGilford progeria syndrome. J Med Genet. doi:10.1136/jmg.2008.060772 Saunders RD, Boubriak I, Clancy DJ, Cox LS (2008) Identication and characterization of a Drosophila ortholog of WRN exonuclease that is required to maintain genome integrity. Aging Cell 7:418425. doi:10.1111/j.14749726.2008.00388.x Scafdi P, Misteli T (2006) Lamin A-dependent nuclear defects in human aging. Science 312:10591063. doi:10. 1126/science.1127168 Singh DK, Ahn B, Bohr VA (2008) Roles of RECQ helicases in recombination based DNA repair, genomic stability and aging. Biogerontology. doi:10.1007/s10522-008-9205-z Unterluggauer H, Micutkova L, Lindner H, Sarg B, Hernebring M, Nystrom T, Jansen-Durr P (2008) Identication of Hsc70

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