Genetic and Molecular Determinants of Human Ageing and Longevity - DNA repair, pro- and antioxidant and insulin/IGF-1 signaling pathways - PowerPoint PPT Presentation

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Genetic and Molecular Determinants of Human Ageing and Longevity - DNA repair, pro- and antioxidant and insulin/IGF-1 signaling pathways

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Title: Genetic and Molecular Determinants of Human Ageing and Longevity - DNA repair, pro- and antioxidant and insulin/IGF-1 signaling pathways


1
Genetic and Molecular Determinants of Human
Ageing and Longevity - DNA repair, pro- and
antioxidant and insulin/IGF-1 signaling pathways
Why do we age so differently?
  • 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

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 Influence on Ageing and Longevity
  • 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
  • .......

4
Single Nucleotide Polymorphisms (SNPs)
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.
  • Estimate 3 -15 106 SNPs in the human genome
    (1/200-1/1000 nucleotides)

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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