Claudio Franceschi CIG Centro Interdipartimentale “L. Galvani” University of Bologna ITALY

1. Claudio Franceschi CIG Centro Interdipartimentale “L. Galvani” University of Bologna ITALY La ricerca per la qualità della vita: la priorità "salute" del 7° Programma QuadroFerrara, 25 ottobre 2006 Aula Magna - Palazzo Bevilacqua Costabili Via Voltapaletto, 11 Nona tappa del "Viaggio della Ricerca in Italia"

2. Coordinator of the EU Integrated Project GEHA Genetic of Healthy Ageing (2004-2009) devoted to study nuclear and mitochondria genetics of healthy aging and longevity • PARTNER OF THE FOLLOWING EU PROJECTS • GENAGE(1999-2001) coordinatated by Prof. B. Clark, University of Aarhus, Denmark) devoted to the identification of human longevity genes; • PROTAGE(2001-2003) coordinated by Prof. Bertrand Friguet, University of Paris VII) devoted to the study of proteasome, comprehensive of its activity and genetic polymorphisms in ageing and longevity; • ECHA(2002-2004) coordinated by Prof. G. De Benectis, University of Calabria) devoted to identification of human frailty and longevity genes; • FUNCTIONAGE(2002-2004), coordinated by Prof. Olivier Toussaint, University of Namur) devoted to optimize the microchips for the study and diagnosis of the inflammatory status in elderly subjects affected by age-related pathologies. • T-CIA(2003-2005) coordinated by Prof. Graham Pawelec, University of Tubingen) related to the study of specific immunity T cell-mediated during ageing. • PROTEOMAGE (2006-2010) coordinatated by Prof. B. Clark, University of Aarhus, Denmark) devoted to study the proteomics of ageing. • LINKAGE (2005-2008) coordinated by Prof. Olivier Toussaint, University of Namur) devoted to coordinate and fund the study of ageing in Europe.

3. R&D investments in Europe and the USA • The proportion of gross national product allocated to R&D is smaller in the UE (1,94 %) than in the USA (2,8 %) and in Japan (2,98 %) • The 3% objective is still far • (Lisbonne 2000, Barcelone 2002) Source : Third European Report on S&T Indicators, 2003

7. European Research Area - Combining three concepts *: – the creation of an"internal market" in research (free movement of knowledge, researchers and technology) – therestructuringof theEuropean research fabric (improved coordination of national research activities and policies through integration of Europe’s research efforts and capacities) – the development of aEuropean research policy (taking into account other EU and national policies) * COM(2002) 565 final, THE EUROPEAN RESEARCH AREA : PROVIDING NEW MOMENTUM

8. Coordination of Research • Policy level • open method of coordination • Policy support oriented research • Legislation (e.g. COM (2004) 178 Directive*) • * 3rd country researchers in Europe Programme level • CREST initiatives • ERA-NET • Article 169 Project level • New Instruments • Traditional Instruments (CAs)

9. Legal basis Article 169 of the Treaty : “In implementing the multiannual framework programme, the Community may make provision, in agreement with the Member States concerned, for participation in research and development programmes undertaken by several Member States, including participation in the structures created for the execution of those programmes”

24. CARE-LINKAGE COORDINATION OF AGEING RESEARCH IN EUROPE Spetses May 21st 2006 GEHA GEnetics of Healthy Aging an Integrated Project of EU 6FP Claudio Franceschi CIG Centro Interdipartimentale “L. Galvani” University of Bologna ITALY

25. The equation of longevity L=E+G+S Longevity=Environment+Genetics+ Stocasticity Longevity is a very complex trait

26. Genetics and Longevity • Parents of centenarians lived longer than people of the same cohort • Siblings of centenarians have a “risk” to reach 100 several times higher than that of people of the same cohort • Offspring of centenarians have a lower mortality and are protected from CVD and cancer • A strong familiar component of longevity

27. Genetics and Longevity The survival advantage of centenarian offspring is not shared by their spouses despite the fact that they shared the same environment for most of their life Thus the strong familiar component of longevity is likely a genetic component and long living sibs should be highly enriched in longevity genes

28. GEHA GEnetics of Healthy Aging Integrated Project of EU 6thFP 7.2 M €, 25 Units Recruitment and Genome Scanning (nuclear and mitochondrial genomes) of 2650 90+ sibpairs and 2650 young controls collected in 11 countries May 1st 2004- April 30th 2009 (www.geha.unibo.it)

29. GEHA GEnetics of Healthy Aging Coordinator:Prof. Claudio Franceschi Project Manager:Dr. Alessandra Malavolta Scientific Manager:Dr. Silvana Valensin

30. The GEHA Consortium 25 partners from 11 European countries and China

32. GEHA EU Integrated Project supported through Priority 1 (Life Sciences, Genomics and Biotechnology for Health) of European Union's FP6 Project Number:  LSHM-CT-2004-503270 GEHA is the largest project in Europe to study the genetic determinants of human longevity

33. The aim of GEHA is to identify genes involved in healthy aging and longevity in humans, which allow individuals to survive to advanced old age in good cognitive and physical function and in the absence of major age-related diseases and disabilities

34. GEHA : a multi disciplinary project • The GEHA Consortium involves: • demographers • geriatricians • geneticists • genetic epidemiologists • molecular biologists • bioinfomaticians • statisticians

35. 12 Workpackages(WP)

36. GEHA Infrastructures (www.geha.unibo.it) • DATABASES: • Phenotype database • Genotype database • mtDNA database • Centralized facilities for: • - DNA extraction, quality controland banking • Data analysis, mathematical modelling, • advanced statistics Genetic Platforms

37. GEHA DNA Time Schedule Total time = ?

38. GEHA Infrastructures (www.geha.unibo.it) GEHA Biobank one of the largest biobank in Europe on old subjects GEHA MitoBank at the end of the project the largest biobank and database on mtDNA in Europe

39. GEHA Infrastructures (www.geha.unibo.it) GEHA Biobank - Coordination among Biobanks in Italy - Coordination among Biobanks in Europe

40. mtDNA 16569 bp • Maternally inherited • Does not Recombine • High mutation rate (particularly the D-loop) • Several mtDNAs per mitochondrion, several mitochondria per cell • Homoplasmic status: same mtDNAs per cell, tissue or organ • Heteroplasmic status: different mtDNAs per cell, tissue or organ 37 genes: 13 OXPHOS subunits 22 tRNA 2 rRNA D-loop or Control Region (16024-576): regulative region

41. mtDNA variants (haplogroups) are not neutral and adaptation to cold climates likely played a major role Wallace D.C.; 2005, Annu Rev. Genet.

42. D-loopmtDNA mutations described in cells and tissues from old people The high incidence of C150T transition in the D-loop of centenarians is an example of a rare mutation selected through maternal inheritance or somatic event(s) Zhang et al, PNAS, 100, 1116-21, 2003

43. The design of the GEHA Project allows to perform both linkage and association studies according to the most advanced genetic approaches the GEHA consortium has facilities which allow to use high throughput (Affymetrix, Illumina) or smaller scale (Sequenom) platforms

44. GEHA approach to increase the power of the genetic analysis

45. The candidate region 11p15.5 IGF2 SIRT3 H-RAS TH PMSD13 INS

46. The number of samples1599 individuals from three populations in a case-control association study using existing DNA collections and stringent quality-check • The number of markersdouble selection of tag- and ht-SNPs, quality check with the CEPH families and the original HapMap data. 356 markers were used for genotyping, with a density comparable to 250’000 markers on the whole genome • The technologyhigh throughput technology genotyping, 384 plate format and 48-plex analysis

47. Sample Design