Title: Genetic and Molecular Determinants of Human Ageing and Longevity - DNA repair, pro- and antioxidant and insulin/IGF-1 signaling pathways
1Genetic 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
2Presentation 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
3Genetic 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
- .......
4Single 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)
5The 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
6Status 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)
8The 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
9Pilot 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
10Pilot 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
11Published in Spring 2009