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Elisa Cevenini

La medicina del domani: invecchiare con successo Workshop di medicina anabiotica & medicina anti-ageing: from bench to bedside. Elisa Cevenini. Systems Biology and Longevity. CIG, C entro I nterdipartimentale “Luigi G alvani” Università di Bologna, Italy. Riviera di Taormina

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Elisa Cevenini

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  1. La medicina del domani: invecchiare con successo Workshop di medicina anabiotica & medicina anti-ageing: from bench to bedside Elisa Cevenini Systems Biology and Longevity CIG, Centro Interdipartimentale “Luigi Galvani” Università di Bologna, Italy Riviera di Taormina December 6-7, 2007

  2. Jeanne Calment, who died in 1997, lived to be 122 years and 164 days old

  3. How to study human longevity ?

  4. How to study human longevity ? • Centenarians and/or their offspring 2. Very old sibpairs 3. MZ and DZ Twins 5. Longitudinal studies on cohorts of different age

  5. the model of centenarians selection remodelling + Centenarians represent an extreme phenotype: 1:7-10,000 WORKING HYPOTHESIS: centenarians are likelynot simply the more robustbutthose people who adapted and remodelled better and quicker

  6. Immunological and Genetic Studies in Centenarians • The result of an extensive collaborations among several groups: • S. Salvioli, M. Capri, S. Valensin, E. Mariani,AND MANY OTHERS • (Univ. of Bologna and Modena) • - F. Olivieri, F. Marchegiani, M. Cardelli, E. Mocchegiani (INRCA Ancona) • - P. Sansoni, R. Vescovini, F. Fagnoni (University of Parma) • - G. De Benedictis, G. Passarino, G. Rose (Univ. of Calabria) • D. Monti, A. Cossarizza (Univ. of Florence and Modena) • G. Paolisso, M. Barbieri (Univ. of Naples) • L. Deiana, G. Baggio, G. Pes, C. Carru (Univ. Sassari) • C. Caruso, D. Lio (Univ. of Palermo) • R. Paganelli (University of Chieti) • M. Rea (University of Belfast) • B. Jeune, Q. Tan, K. Christensen (Univ. of Odense) • J. Vaupel, A. Yashin (MPI for Demography, Rostock) • G. Attardi (CALTECH Pasadena) • G. Pawelec (University of Tubingen) • J. Powell, D. Mazzatti (UNILEVER, UK)

  7. Most centenarians are remarkably healthy

  8. Centenarian phenotype well preserved: • cell proliferation (fibroblasts) • telomere length (fibroblasts) • hemopoiesis (CD34+ hemopoietic stem cells) • proteasome activity • anthropometric parameters • glucose metabolism

  9. CLINICAL CHARACTERISTICS OF THE STUDY GROUPS (n=466) CONTROLS CENTENARIANS n = 298 n = 168 148/150 51/117 *p<0.01 vs control group Paolisso et al., Exp. Gerontol., 37, 149-156, 2001

  10. INSULINE RESISTANCE IN THE WHOLE POPULATION (n=466) p for trend < 0.01 20-40 40-50 50-60 60-70 70-80 80-90 90-100 >100 Paolisso et al., Exp. Gerontol., 37:149-156, 2001

  11. IGF-1 plasma levels are low in centenarians Bonafè et al., J Clin Endocrinol Metabol 2003

  12. Centenarians, Genetics and Human 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 • Astrong familiar component of longevity

  13. Centenarians, Genetics and Human Longevity The survival advantage of offspring of long-living sibs 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

  14. 1697 FHS offspring members were grouped as following: • Neither parent survived 85 years (n=705) • One parent survived 85 years (n=804) • Both parents survived 85 years (n=188) • Score for cardiovascular risk factors was most favorable in individuals • with both parents surviving to 85 or older and was progressively worse • in those with one or no long-lived parent

  15. GEHA GEnetics of Healthy Aging Integrated Project of EU 6thFP 25 Partners Recruitment and Genome Scanning (nuclear and mitochondrial genomes) of 2650 90+ sibpairs and 2650 young controls collected in 11 countries and China May 1st 2004- April 30th 2009 (www.geha.unibo.it) Coordinator:Prof. Claudio Franceschi Project Manager:Dr. Alessandra Malavolta Scientific Manager:Dr. Silvana Valensin

  16. The genetics of human longevity very old sibpairs should derive from families where longevity is running and their DNA is likely “enriched” in longevity genes 2100 complete trios are recruited so far (October 31, 2007)

  17. GEHA LOGISTIC AND SAMPLE SIZE • 2650 sib pairs 90+ years old (for a total of 5300 subjects) • 2650 Younger Controls from the same geographic areas 7950 samples from 11 European countries All samples are centralized at KTL inHelsinki • extraction • quality control • repository DNA

  18. GEHA DESIGN younger CONTROLS(mean age: 62 years) 90+ SIBS genetically unrelated ethnically-matched SIB1 90+SIB1’ 90+ SIB2 90+ SIB2’ 90+ … SIBn 90+ SIBn’ 90+ 2 CASE-CONTROL ASSOCIATION STUDIES – LD mapping genome-wide (hypothesis-free) or region-focused (hypothesis- or data-driven) 1 LINKAGE analysis (ASP Analysis) genome-wide (hypothesis-free) non parametric (no assumption on the model of heritability of the trait)

  19. 1. ASSOCIATION STUDIES Association analysis is expected to be more powerful for the detection ofcommonalleles that confermodestdisease risks Today it is possible to perform genome-wide association studies using high throughput technologies and several hundred thousands SNPs (300K Illumina 500 K Affimetrix)

  20. 2. LINKAGE ANALYSIS looks for co-inheritance of chromosomal regions with the trait in families It is more powerful than association analysis for identifyingrare high-riskdisease alleles

  21. The advantage of LINKAGE STUDIES is that • they are not influenced by population admixture • The advantage of ASSOCIATION (CASE-CONTROL) • STUDIES is that they require less genotyping • to obtain equivalent power

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

  23. Mitochondrial DNA analyses Inherited variability Haplogroups (J) and sub haplogroups Epigenetic variability Heteroplasmy at position C150T

  24. HETEROGEITY OF HUMAN POPULATIONS • human longevity is a unique source of information • Humans areoutbredpopulations • The environment isrich of antigenic stimuli(bacteria, viruses, parasites) • Development(both in utero and after birth) is a long process • Lifespanis quite long • Cultural/anthropological determinantshave a strong impact on lifespan

  25. HETEROGEITY OF HUMAN POPULATIONS • human longevity is a unique source of information • Genderdifferences are marked • Genomeis different from that of model systems • Information on diseasesis quite large and detailed • Demographic dataare extensive • Several cell types are mitotically competentand stem cells repair occurs in several tissues

  26. Franceschi et al., 2007

  27. Owing to the heterogeneity of the centenarian phenotype genetic studies must be replicated in different populations

  28. Is human longevity population-specific? -Human populations are genetically heterogeneous - Genes potentially involved in longevity interact with the environment, dominated in humans by evolutionary history,socialand cultural factors Associations between genetic variability and longevity may be difficult to replicate in different populations.

  29. Example of positive replications: - ApoE gene - PON1 gene - mtDNA haplogroup J - mtDNA 150T mutation (polymorphism)

  30. Example of negative replications: - CEPT gene • MTP gene - mtDNA haplogroup J - mtDNA 150T mutation (polymorphism)

  31. The Impact of Geography and Demography • 2. Increased Homozygosity • 3. The impact of mtDNA • 4. The Complex Timing of Alleles involved in Longevity • 5. Remodelling versus Antagonistic Pleiotropy The unusual genetics of longevity

  32. WORKING HYPOTHESIS The phenotype of aged subjects is the result of the capability of the body to respond and to adapt to non repaired damages and their signalling capability REMODELLING accumulation of damages (mutations) + adaptative response

  33. STRESSORS MAINTENANCE SYSTEMS (Defence and Repair) ADAPTATION Successful REMODELLING Unsuccessful REMODELLING LONGEVITY DISEASE and DEATH

  34. STRESSORS MAINTENANCE SYSTEMS (Defence and Repair) Change in body microenvironment Changes in gene expression Changes in protein abundance, composition interaction Progressive change of internal milieu

  35. Human aging and longevity are at the intersection of two Darwinian processes: • - the first occurssomatically at the level of single soma (individual remodelling) • the second occurred at the level of • H. sapiens as a species (evolutionary and ecological constraints) • - these two Darwinian processes are not coordinated

  36. The unusual immunology and genetics of ageing and longevity AdaptationRemodelling Antagonist Pleiotropy The levelling off of morbidity/mortality at very advanced age

  37. Age-related remodelling gene expression profiling in peripheral blood T cells in collaboration with D. Mazzatti and J Powell, UNILEVER, UK (EU T-CIA project coordinated by G. Pawelec)

  38. Data set • 25 arrays 19K: 5 age groups • A: 20 to 30 years old • B: 30 to 40 years old • C: 40 to 60 years old • D: 60 to 80 years old • E: 80 to >90 years old

  39. Pathways significance analysis the 1600 probes were embedded in KEGG pathway database, and a significance analysis was performed onto each KEGG pathway based on the ratio of significant probes (hypergeometric function test).

  40. Biclustering of 1600 significant genes

  41. Top 50 genes

  42. K-means clustering of the significant gene set: 8 clusters

  43. K-means clustering of the significant gene set: 12 clusters

  44. The 16 genes among 1600 significant that are found to be among the 156 genes that discriminate the different T cell populations(naïve, effectors and memory).

  45. AGE-GROUPS gene profiling 1-way ANOVA selection RED - upregulated; GREEN - downregulated

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