Claudio Franceschi

CIG Centro Interdipartimentale

“L. Galvani”University of Bologna

ITALY

La ricerca per la qualità della vita: la priorità "salute" del 7° Programma Quadro Ferrara, 25 ottobre 2006Aula Magna - Palazzo Bevilacqua Costabili Via Voltapaletto, 11 Nona tappa del "Viaggio della Ricerca in Italia"

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.

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

– the creation of anthe creation of an "internal market" in research"internal market" in research (free movement of knowledge, researchers and technology)(free movement of knowledge, researchers and technology)

– the restructuring of the European research fabric(improved coordination of national research activities and policies through integration of Europe’s research efforts and capacities)

– the development of athe development of a European research policyEuropean research policy (taking into account other EU and national policies)(taking into account other EU and national policies)

European Research Area -European Research Area - Combining three concepts Combining three concepts *::

* * COM(2002) 565 final, THE EUROPEAN RESEARCH AREA : PROVIDING NEW MOMENTUM

Coordination of Research Coordination of Research

Policy levelopen method of coordinationPolicy support oriented research Legislation (e.g. COM (2004) 178 Directive*) * 3rd country researchers in Europe

Programme levelCREST initiativesERA-NETArticle 169

Project levelNew InstrumentsTraditional Instruments (CAs)

Legal basisLegal basis

“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”

Article 169 of the Treaty : :

CARE-LINKAGECOORDINATION OF AGEING

RESEARCH IN EUROPESpetses May 21st 2006

GEHAGEnetics of

HealthyAging

an Integrated Project of EU 6FP

Claudio Franceschi

CIG Centro Interdipartimentale

“L. Galvani”University of Bologna

ITALY

L=E+G+SLongevity = Environment + Genetics + Stocasticity

The equation of longevity

Longevity is a very complex trait

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

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

GEHAGEnetics 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 controlscollected in 11 countries

May 1st 2004- April 30th 2009

(www.geha.unibo.it)

GEHAGEnetics of Healthy Aging

Coordinator: Prof. Claudio FranceschiProject Manager: Dr. Alessandra Malavolta

Scientific Manager: Dr. Silvana Valensin

25 partners from 11 European countries and China

The GEHA Consortium

Participant name Short name Country

CIG - University of Bologna, C. Franceschi UNIBO IT

University of Montpellier UM1, J.M. Robine CRLC FR

CAU Kiel Centre for Functional Genomics S. Schreiber, A. Nebel

CAU DE

Foundation Jean Dausset, Hélène Blanché CEPH FR

Istituto Superiore di Sanità, A. Stazi ISS IT

Leiden University Medical Centre, E. Slagboom, R. Westendorp

LUMC NL

Max Planck Institute for Demographic Research, J. Vaupel MPIDR DE

National Hellenic Research Foundation, E. Gonos NHRF GR

National Public Health Institute, L. Peltonen KTL FI

Nencki Istitute for Experimental Biology, E. Sikora NENCKI PL

University of Belfast, QUB, I.M.Rea QUB UK

University of Calabria, G. De Benedictis UNICAL IT

IFOM Institute of Milan, P.G. Pelicci IFOM IT

University of Sassari, L. Deiana UNISS IT

Catholic University of Louvain, M. Poulain UCL BE

Fac. Univ. Notre Dame de la Paix O. Toussaint FUNDP BE

University of Newcastle, T. Kirkwood UNEW UK

University of Southern Denmark, K. Christensen, B. Jeune

SDU DK

Tampere School of Public Health, A. Hervonen TAMPERE FI

Research Innovation s.r.l. A. Leon R&I IT

Istituto Nazionale Ricovero e Cura AnzianiL. Spazzafumo

INRCA IT

University of Aarhus, P. Kristensen UAAR DK

Bejing Genomics Institute, L. Bolund, B. Liu BGI CN

Eppendorf Array Technologies, J. Remacle EAT BE

Institute of Gerontology, V. Bezrukov Inst. Geront. Ukraine

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

GEHA

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

The GEHA Consortium involves:

demographers

geriatricians

geneticists

genetic epidemiologists

molecular biologists

bioinfomaticians

statisticians

GEHA : a multi disciplinary project

12 Workpackages (WP)

European Commission

WP1 WP2 WP3

1

WP4 WP5 WP6 WP7 WP8

1 18 17 4 3 12 7

WP9

11

WP10

20

Research Organizationand Standard

Recruitment

Database

Ethics

ASPanalysis

LD Mapping and candidate gene work

mtDNAanalysis

Dataanalysis

Training

Demonstration

Steering Committee

WP11

1

Management

1

Research Organization

WP12

Assessment of Progress and Results

GEHA Infrastructures (www.geha.unibo.it)

DATABASES:1.Phenotype database2.Genotype database3.mtDNA database

Centralized facilities for: - DNA extraction, quality control and banking

-Data analysis, mathematical modelling,advanced statistics

Genetic Platforms

t 0

t 1

t 2

t 3

t 4

t 5

t 6

t 7

t 8

t 9

t 10

1-2 weeks

2-3 weeks

2-3 months

?

?

?

?

?

?

Variable

GEHA DNA Time Schedule

t0

Contact with Trios

Interviewand BloodSampling

Several TriosGrouped

Recruitment Units

Shipmentto KTL

KTL, Helsinki

PID GID

DNA Extraction

t1 t2 t3 t4 t5

DNA QualityCheck

t6

DNA Aliquottingand Plating

t7 t8 t9

Shipment toGenotypingUnits

Genotyping Units

t10

Genetic and mtDNA Analysis

Steering Committee

GEHA Coordinator

Authorization forDNA shipment

Total time = ?

GEHA Infrastructures (www.geha.unibo.it)

GEHA Biobankone 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

GEHA Infrastructures (www.geha.unibo.it)

GEHA Biobank

- Coordination among Biobanks in Italy- Coordination among Biobanks in Europe

mtDNA16569 bp

37 genes: 13 OXPHOS subunits 22 tRNA 2 rRNAD-loop or Control Region (16024-576): regulative region

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

Wallace D.C.; 2005, Annu Rev. Genet.

mtDNA variants (haplogroups) are not neutraland adaptation to cold climates likely played a major role

Zhang et al, PNAS, 100, 1116-21, 2003

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)

D-loop mtDNA mutations described in cells and tissues from old people

The design of the GEHA Project allows to perform

both linkage and association studiesaccording to the most advanced

genetic approaches

the GEHA consortium has facilities which allow to use

high throughput (Affymetrix, Illumina)or smaller scale (Sequenom)

platforms

GEHA approach to increase the power of the genetic analysis

H-RASH-RASSIRT3SIRT3 IGF2IGF2

INSINS

THTH

The candidate region 11p15.5The candidate region 11p15.5

PMSD13PMSD13

1.1. The number of samplesThe number of samples1599 individuals from three populations in a case-control association study using existing DNA collections and stringent quality-check

2.2. The number of markersThe 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

3.3. The technologyThe technologyhigh throughput technology genotyping, 384 plate format and 48-plex analysis

CENTENARIANS CONTROLSmales females males females

Central Italy 40 267 221 131

total = 307 total = 352

Germany 76 299 94 282

total = 375 total = 376

South Italy 30 62 48 49

total = 92 total = 97

  TOTAL = 774 TOTAL = 825

  TOTAL sample = 1599

Sample DesignSample Design