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Why do we age so differently?

Genetic and Molecular Determinants of Human Ageing and Longevity - DNA repair, pro- and antioxidant and insulin/IGF-1 signaling pathways. M.Sc. Mette Sørensen Ph.D. student at SDU Supervisors: Associate Professor Lene Christiansen Professor Kaare Christensen

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Why do we age so differently?

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  1. Genetic and Molecular Determinants of Human Ageing and Longevity- DNA repair, pro- and antioxidant and insulin/IGF-1 signaling pathways M.Sc. Mette Sørensen Ph.D. student at SDU Supervisors: Associate Professor Lene Christiansen Professor Kaare Christensen Associate Professor Tinna Stevnsner Professor Vilhelm A. Bohr VELUX FONDEN Why do we age so differently? Funded by:

  2. Presentation Outline • Background • Genetic influence on ageing and longevity • Candidate biological pathways • Single nucleotide polymorphisms – SNPs • The purposes and the status of the project • Subproject 1 – Association study of genetic variations in candidate genes/pathways with longevity and aging → Golden Gate chip and more. • Subproject 2 – Functional studies of genetic variation • Pilot study of rs4880 2

  3. Genetic factors influence age-related diseases and age-related physical and cognitive functions Genetic factors contribute to the variation in lifespan by approximately 25%. The contribution is minimal before age 60 years and most profound from 85 years and onwards Candidate biological pathways for ageing and longevity: Lipid metabolism Immune response Cell cycle regulation Insulin metabolism Antioxidants DNA repair ....... Genetic Influence on Ageing and Longevity

  4. Single Nucleotide Polymorphisms (SNPs) Estimate: 3 -15 • 106 SNPs in the human genome (1/200-1/1000 nucleotides) Person A . . . GAA GGA CGA GAA . . . Person B . . . GAA GGA TGA GAA . . . Person A . . . Glu Ala Arg Glu . . . Person B . . . Glu Ala Stop Consequences; amino acid substitution, Splice site etc.

  5. The Purpose of Subproject 1 Investigate the association of genetic variation in candidate genes composing DNA repair, pro/antioxidant and insulin/IGF-1 signaling pathways with human longevity and ageing (e.g. disease prevalence, physical and cognitive abilities) • Longitudinal study: 1651 individuals of The Danish 1905 birth cohort • Follow-up time: 10 years, age at death 92-100+ • Interviews and assessments of functional and cognitive abilities • Cross sectional study: 800 individuals of the Study of Middle Aged Danish Twins, age 42-65 • Interviews and assessments of functional and cognitive abilities 5

  6. Status of Subproject 1 Literature search → choosing 168 candidate genes Association studies of longevity and/or age-related diseases Relevant for premature aging syndromes Animal research (e.g. knock outs) Additional genes to cover the pathways Database search → choosing 1536 SNPs Association candidate SNPs Functional SNPs (non-synonymous, splice site etc.) Tagging SNPs to cover the genetic variation Linkage disequilibrium (the non-random association of alleles at two or more loci). Purification of 2400 DNA samples for Golden Gate chip (1536 SNPs * 2400 individuals)

  7. Genotyping (Aros Biotechnology), finish in May 2009 Data Analysis is started – Genome Studio, Plink Next: Data Analysis Additional genotyping (Taqman, SNPlex methods): In depth of possible Golden Gate chip findings Additional SNPs (impossible via Golden Gate chip)

  8. The Purpose of Subproject 2 Investigate the functional consequences of SNPs Findings via the Golden Gate Chip Recombinant variant RecQ helicases; genes are on Golden Gate chip, made in corroboration with the Aarhus group

  9. Pilot study of the SOD2-rs4880 SNP and longevity in the 1905 cohort,Background: Epidemiology: rs4880 has been shown to be associated the several age-related diseases (e.g. cardiomyopathy, atherosclerosis and Alzheimer's). Animal research: SOD2 knock outs → Decreased life span (D. melanogaster) or neonatal lethality (m. musculus) Over expression → Increased life span (D. melanogaster and m. musculus) Molecular biology: rs4880 in the mitochondrial targeting sequence → less transport of T variant precursor protein into the mitochondrial matrix 4 x more processed MnSOD / MnSOD activity in C variant cells than in T cells 60% lower O2.- levels in C cells than in T cells

  10. Pilot study of the SOD2-rs4880 SNP andlongevity in the 1905 cohort,(one of) the result(s): Increased survival of SOD2-rs4880 CC/CT individuals: Mortality risk (CC/CT vs. TT): 0.91, P = 0.002

  11. Published in Spring 2009:

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