Bagley, MC & Davis, T - New Dynamics of Ageing

School of ChemistryOverview of TalkThe New Science of Ageing:A combined genetic and small moleculeapproach1. Introduction – general background and biology2. Interdisiplinarity – biology, chemistry, social science3. Project Goals – dissection of stress-induced cell ageing4. Results & Discussion – current outputs and problems5. Conclusions – Werner syndrome? The future?3

School of ChemistryIntroduction – the ageing story so far1) Life expectancy in the UK increased greatly over 20 th century. This isa great success story and is due to improved living conditions, publichealth and biomedicineAn individual living today who is 65 has a significantly greater remaininglife expectancy than if they had reached that birthday ten or twenty yearsago2) This “success” brings many challenges as not all individuals show“successful ageing” – and there is a large increase in age-related diseasee.g. strokes, macular degeneration, heart disease, and othersThese are often chronic and withoutcure resulting in a significant social andhealthcare cost (morbidity) – whatbiogerontology calls reduced“healthspan”morbidity4age

School of ChemistryIncrease health-span not just lifespanacb6Output Item: The contribution of Biogerontology to quality ageing : Bagley M., Davis T., Latimer J. andKipling D. (2011), Quality in Ageing and Older Adults. 12(1): 26-32

School of ChemistryPeer-reviewed articleThe contribution of biogerontology to quality ageingMark C BagleyReader in Organic Chemistry, School of Chemistry, Cardiff University, UKTerence DavisSenior Research Fellow, School of Medicine, Cardiff University, UKJoanna LatimerProfessor of Sociology, School of Social Sciences, and ESRC Centre for theEconomic and Social Aspects of Genomics, Cardiff University, UKDavid KiplingProfessor of Biological Gerontology, School of Medicine, Cardiff University, UKPresentation at the UnitedNations International Day ofOlder People „Promoting Activeand Healthy Ageing’Conference. Temple of Peace,Cardiff, Wales 2010Quality in Ageing and Older Adults 2011, 12, 26-32.Copies available7

School of ChemistryWhat do we know about human ageing?Ageing:The universal, progressive, and intrinsicaccumulation of deleterious changes.Why are we bothered about ageing?The physiological effectiveness of anorganism is compromised, ultimately leadingto death.What causes it?UnknownHow can we understand it?Model species vs. human genetic diseasesUniversal vs. species-specific

School of ChemistryWerner Syndrome

School of ChemistryWerner SyndromeCharles W. Otto Werner, German physician(1879–1936)Rare, autosomal recessive genetic diseasePremature ageing of a subset of tissuesFeatures include: osteoporosis, bilateralcataracts, type II diabetes, thymic atrophy,an overall aged appearanceElevated risk of atherosclerosis andpredominantly mesenchymal cancersAffected tissues are mainly those containingcells that are division-competent during lifeThus may be due to accelerated cell ageingGeorge Martin and GermanWerner individual (age 36)American Werner syndromeindividual (age ~50)

School of ChemistryCell ageing – a possible mechanismFinite lifespan of normal human cellsin culture – divide ~50 timesSenescence– is viable cell cycle arrest– may act as a barrier to cancerformationSenescent cells– remain metabolically active– display altered patterns ofgene expression, includingsecreted proteins

School of ChemistrySenescence as an Ageing MechanismPhysiological cell loss(wear-and-tear, wounding, haemodynamic stress)Standard cellsReplacement cell divisionProgressive accumulation of senescent cellsYoung humanfibroblastsSenescentmorphologyAltered cellularmicroenvironmentReduced divisioncapacity12Aged tissue

School of ChemistrySenescence as an Ageing MechanismPhysiological cell loss(wear-and-tear, wounding, haemodynamic stress)Young humanfibroblastsSenescentmorphologyReplacement cell divisionProgressive accumulation of senescent cellsWS cellsAltered cellularmicroenvironmentReduced divisioncapacity13Accelerated AgeingKipling et al. Science 2004, 305, 1426-31

School of ChemistrySenescence as an Ageing Mechanism• WS cells in culture have a shortenedreplicative lifespan• They show slow growth rate,elongated cell cycle and sensescentmorphology of aged normalfibroblastsYoung humanfibroblastsSenescentmorphology• They enter senescence prematurelyafter only 15-20 PDWS cellsAltered cellularmicroenvironmentReduced divisioncapacity14Accelerated AgeingKipling et al. Science 2004, 305, 1426-31

Preventing accelerated WS cell ageingJ. Gerontol. 2005, 60A, 1386.SB20358015Output Item: Use of p38 MAPK inhibitors for thetreatment of Werner syndrome, Bagley, M. C.; Davis,T.; Murziani, P. G. S.; Widdowson, C. S.; Kipling, D.Pharmaceuticals 2010, 3, 1842.

School of ChemistryTreating age-related diseases with p38 inhibitors16Relevance to normal ageingThere are environmental and clinicalfactors (such as cancer, infection,periodontal disease, stress) that canactivate p38 in normal individuals.This could link extrinsic lifecoursefactors with a fundamentalmechanism of ageingProblems using p38 inhibitorsp38 a major cellular signalling ‘hub’and regulates a very large number ofdownstream pathways.Its nodal role perhaps explainstoxicity/side effect issuesp38 inhibitors not specific enough

School of ChemistryOverview of TalkThe New Science of Ageing:A combined genetic and small moleculeapproach1. Introduction – general background and biology2. Interdisiplinarity – biology, chemistry social science3. Project Goals – dissection of stress-induced cell ageing4. Results & Discussion – current outputs and problems5. Conclusions – Werner syndrome? The future?17

School of ChemistryProf David KiplingSchool of MedicineThe TeamDNA DamageDr Mark C BagleySchool of ChemistryCellbiologyChemistryDr Terry DavisSchool of MedicineCellbiologyAgeingProf Joanna LatimerSchool of Social ScienceAgeing-related diseaseintervention18Ageing therapeuticsSocialimplications

School of ChemistryWhat Use is Chemistry to Clinical Medicine?DrugDiscoverySynthesis andscreeningDiseasePathophysiologychemogenomics19

Example: BIRB 796 p38 Inhibitor Synthesis20Bagley, M. C.; Davis, T.; Dix, M. C.; Widdowson, C. S.; Kipling, D. Org. Biomol. Chem. 2006, 4, 4158.

School of ChemistryComparing different p38 inhibitorsSCIBS initiativeVX-745RO3201195BIRB 796UR-1375621All synthesized by the Bagley team.

School of ChemistryOverview of TalkThe New Science of Ageing:A combined genetic and small moleculeapproach1. Introduction – general background and biology2. Interdisiplinarity – biology, chemistry social science3. Project Goals – dissection of stress-induced cell ageing4. Results & Discussion – current outputs and problems5. Conclusions – Werner syndrome? The future?22

School of ChemistryStress-induced Cell Growth ArrestEnvironmental stressDNA replication stressWernersyndromeStress LoadPremature ageing is consistent withaccelerated replicative senescencedue to endogenous stressp38a MAPKMK2/323Cell cycle arrestChronic illnessPro-inflammatorycytokinebiosynthesis

School of ChemistryScientific RationaleEnvironmental stressDNA replication stressWernersyndromeStress Loadp38a MAPKINHIBITORSMK2/3Selection Criteria :• Efficacy• Kinase selectivity• Cellular potency• Mammalian model24Cell cycle arrestChronic illnessPro-inflammatorycytokinebiosynthesis

School of ChemistryConfirming the role of p38a signallingVX-745DNA replication stressStress LoadUR13756JNKVX-745UR13756p38a MAPKMK2/325Growth arrestGrowth arrest

School of ChemistrySelectivity of p38a kinase inhibitorsBIRB 796DNA replication stressStress LoadJNKBIRB 796SB203580p38a MAPKSB203580MK2/3Data suggestsinvolvement of JNK26Growth arrestGrowth arrest

School of ChemistryOverview of TalkThe New Science of Ageing:A combined genetic and small moleculeapproach1. Introduction – general background and biology2. Interdisiplinarity – biology,chemistry social science3. Project Goals – dissection of stress-induced cell ageing4. Results & Discussion – current outputs and problems5. Conclusions – Werner syndrome? The future?27

School of ChemistryThe effect of JNK inhibitorsPrevious data suggested possible role for JNK activityThus synthesized JNK inhibitorsThis data points finger at MK2Output item28Effects of diaminopyridine inhibitors on the growth and morphology of Werner syndrome fibroblasts.Davis, T.; Kipling, D.; Bagley, M.C.; et al. Chem. Cent. J. 2011, 5, in review.

School of ChemistryMK2 – a new target??DNA replication stressStress LoadMK2 inhibitorsp38a MAPKMK2/329Growth arrestKey Biological Hypotheses:Does MK2 inhibition ameliorate the slowgrowth in WS cells?Does MK2 inhibition modulate senescenceresulting from oxidative stress?

School of ChemistryMK2 Inhibitors in WS cells• CMPD 2 confirmed as MK2 inhibitor• Little effect on growth rate at 2.5 mM(which is less than [IC50])• Cells undergo a dramaticmorphological change at 10 mM30Davis, T.; Bagley, M. C.; Murziani, P.; Rokicki, M.; Widdowson, C.S.; Zayed, J. M.; Bachler, M. A.; Kipling, D.Bioorg. Med. Chem. Lett. 2007, 17, 6832–6835.

School of ChemistryMK2 Inhibitors in WS cellsKey Biological Hypotheses:Does MK2 inhibition ameliorate the slow growth in WS cells?Does MK2 inhibition modulate senescence resulting from oxidative stress?....could not be studied using existing chemical toolsAssemble more recently disclosed inhibitors of MK2 as chemical tools forstudy of the WS phenotype:Problem: NO CHEMIST31Davis, T.; Bagley, M. C.; Murziani, P.; Rokicki, M.; Widdowson, C.S.; Zayed, J. M.; Bachler, M. A.; Kipling, D.Bioorg. Med. Chem. Lett. 2007, 17, 6832–6835.

School of ChemistrySocial issues with “extended life”?“(normal) ageing is a disease” – misfit between biomedical and regulatoryfunding structures and anti-ageing science – forcing ageing to be renamed asdisease?Tensions between:Postponing those ageing effects that are correlated with disabling diseases oflater life, while at the same supporting and valuing older people.Prolongevity (the immortalists) movement & adding quality of life to yearsmovement.Social, cultural and ethical aspects of anti-ageing scienceand medicine (Qualitative evidence: Joanna Latimer)32• Interviews, discussions and site visits with ageing scientists;• Analysis of the literature (scientific and social studies);• Interviews and discussions with skeptics of ageing science.

School of ChemistrySocial issues with “extended life”?• Discusses how ageism is endemic to some aspects of health care andmedicine.• Explores how biogerontology could contribute to the social inclusion ofolder people, particularly in relation to health care.• Defining the ways that biogerontology is reconceptualising what it is to age,and to be old, can help reinclude ageing and the aged in health careeducation, policy and practice.33Output itemAgeing science, health care and social inclusion of older people.Latimer J., Bagley M., Davis T. and Kipling D. Quality in Ageing & Older Adults(2011), 12(1):11-16.

School of ChemistryPeer-reviewed articleAgeing science, health care and social inclusion of olderpeopleJoanna LatimerProfessor of Sociology, School of Social Sciences, and ESRC Centre for theEconomic and Social Aspectsof Genomics, Cardiff University, UKTerence DavisSenior Research Fellow, School of Medicine, Cardiff University, UKMark C BagleyReader in Organic Chemistry, School of Chemistry, Cardiff University, UKDavid KiplingProfessor of Biological Gerontology, School of Medicine, Cardiff University, UKQuality in Ageing and Older Adults 2011, 12, 11-16.Presentation at the UnitedNations International Day ofOlder People „Promoting Activeand Healthy Ageing’Conference. Temple of Peace,Cardiff, Wales 2010Copies available34

School of ChemistrySummary of output items to dateJournal PublicationsOutput 1: Use of p38 MAPK inhibitors for the treatment of Werner syndrome,Bagley MC, Davis T, Murziani PGS, Widdowson CS, Kipling D. Pharmaceuticals(2010), 3:1842-1872.Output 2: The contribution of biogerontology to quality ageing.Bagley MC, Davis T, Latimer J, Kipling D. Quality in Ageing & Older Adults (2011),12(1):26-32.Output 3: Ageing science, health care and social inclusion of older people.Latimer J, Bagley MC, Davis T, Kipling D. Quality in Ageing & Older Adults (2011),12(1):11-16.Output 4: Effects of diaminopyridine inhibitors on the growth and morphologyof Werner syndrome fibroblasts.Davis T, Dix MC, Rokicki MJ, Brook AJC, Kipling D, Bagley MC. Chem. Cent. J.(2011), 5: in review.35

School of ChemistryOverview of TalkThe New Science of Ageing:A combined genetic and small moleculeapproach1. Introduction – general background and biology2. Interdisiplinarity – biology,chemistry social science3. Project Goals – dissection of stress-induced cell ageing4. Results & Discussion – current outputs and problems5. Conclusions – Werner syndrome? The future?36

School of ChemistryIs there a link between stress and ageing?Can we intervene in ageing in WS?Yes!Will this lead to a clinical treatment?Maybe…..Can we intervene in the otherclinical symptoms of this syndrome?Maybe…..Can we intervene in ageing in you and I?No not yet, but we have good evidencethat the senescence of somatic cells is acausal agent of normal ageing and thatthis could be prevented with smallmolecule inhibitors37

School of ChemistryZoomer Nation – a new ageing visionMoses Znaimerhttp://www.zoomermag.com/tag/moses-znaimer• promotes a positive vision of elderly people• fights for elderly peoples‟ rights• elderly people contributing to the economy of allrather than simply “recipients” of Healthcare• promotes social inclusion by highlightingbenefits rather than problemsA new vision ofageing Canada38http://www.carp.ca/2011/10/21/the-future-of-ageing/

School of ChemistryAcknowledgementsPeopleFundingDr Matt Dix BBSRCDr Caz Widdowson EPSRCDr Paola Murziani SPARCMr Michal Rokicki BBSRC, ESRC(NDA)Ms Leanne Walker ESRC(NDA)BBSRC Anglo-Japanese Partnering AwardWellcome TrustThe Nuffield FoundationThe Royal Society39