Biosocial Surveys (2008) / Chapter Skim
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1 Biological Indicators and Genetic Information in Danish Twin and Oldest-Old Surveys--Kaare Christensen, Lise Bathum, and Lene Christiansen
1 Biological Indicators and Genetic Information in Danish Twin and Oldest-Old Surveys--Kaare Christensen, Lise Bathum, and Lene Christiansen
Pages 15-41
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From page 15... ...
findings from other studies -- in particular, genetic association studies, which constitute a research field that suffers from many false positive findings due to multiple testing in many small-scale studies. Second, we decided to obtain more detailed biological indicators from individuals who were identified through the survey as particularly informative for a given research purpose, meaning that we used the survey as a screening instrument for follow-up ancillary studies.
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Finally, a new biological indicator, perceived age based on photographs, is described and we show how this biological indicator -- which is at the other end of the biological spectrum from molecular indicators of aging -- correlates to environmental exposures and predicts survival. CHALLENGES IN THE SEARCH FOR DETERMINANTS OF HEALTHY AGING AND LONGEVITY A large ongoing research effort is under way to identify the genetic, environmental, and behavioral determinants of extreme survival (longevity)
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These studies comprised a home-based two-hour multidimensional interview focusing on health issues, assessment of functional and cognitive abilities, and DNA sampling. Biological Indicators in LSADT Full Blood Samples on Selected Individuals in 1997 Shortly after the interview in 1997, a trained phlebotomist collected a blood sample from all same-sex twin pairs in which both members were alive and willing to participate.
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(80%) 421 265 161 134 94 1995 1997 1999 2001 2003 2005 Full blood from Blood spots / cheek brushes from all intact twin pairs FIGURE 1-1 Overview of the Longitudinal Study of Aging Danish Twins (LSADT)
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August 2005 1998 2000 2003 1998 FIGURE 1-2 Overview of the Danish 1905 Cohort Study. All nonproxy participants were eligible for blood spots/cheek brushes at all waves.
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Of these, around 80 percent agreed to blood spots and 20 percent to cheek brushes. Full Blood Samples from All Participants in 2005 To obtain comparable data to a Danish centenarian study conducted 10 years earlier, that of the 1895-1896 cohort (Andersen-Ranberg, Schroll, and Jeune, 2001)
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. IMPORTANT FINDINGS DUE TO INCLUSION OF BIOLOGICAL INDICATORS IN THE DANISH SURVEYS Studies of Candidate Genes for Healthy Aging Using the Full Surveys A very large number of candidate genes have been investigated for putative associations with human aging and longevity (Christensen, Johnson, and Vaupel, 2006)
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, thus confirming the lack of association between MTP and longevity and illustrating the necessity of replication studies in identifying genes that affect human longevity (Beekman et al., 2006)
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. Not only has ApoE-4 been shown to be a risk factor for cardiovascular diseases and Alzheimer disease per se, but also several studies have found that the ApoE-4 carrier is more susceptible to some environmental exposures, making this an example of a geneenvironment interaction.
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. ApoE-4 also seems to modulate the effect of other risk factors for cognitive decline.
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KAARE CHRISTENSEN, LISE BATHUM, and LENE CHRISTIANSEN 25 c2 c3 0.15 1.00 0.95 0.90 0.10 Allele Frequency Allele Frequency 0.85 0.80 0.75 0.05 0.70 0.65 0.00 0.60 0 25 50 75 100 0 25 50 75 100 Age Age c4 0.25 0.20 Allele Frequency 0.15 0.10 0.05 0.00 0 25 50 75 100 Age FIGURE 1-4 The frequencies of apolipoprotein E alleles vary with age. Frequencies of the three common ApoE alleles -- ApoE-2, ApoE-3, and ApoE-4 -- are shown, taken from data in 13 published studies.
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is also a biologically plausible candidate for successful aging and longevity. This is because the genotype accounts for approximately half of the variance in the circulating ACE level and from the II (homozygous insertion)
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ACE genotype has been hypothesized to be associated with longevity since a German study found an increased frequency of the DD genotype in octogenarians (Luft, 1999) , which was to some degree supported in LSADT data (Frederiksen et al., 2003)
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One physiological function of the enzyme appears to be the elimination of toxic oxidized lipids in lipoproteins, whereby it confers protection against atherosclerosis and coronary heart disease. Recent studies have demonstrated a progressive decrease of PON1 activity with age, which may be related to oxidative stress conditions developing with increased age.
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further corroborated the initial finding. One of the biggest challenges to genetic association studies are false positive findings (Ioannidis, 2003)
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Currently we are reexamining the blood samples using new and improved methods of measurement of telomere length to test if the lack of association could be due to methodological problems. X Inactivation Although females have two X chromosomes, only one of them is active in each cell; the other is inactivated in early embryonic life and stays so throughout life (a phenomenon called X inactivation)
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���������Our studies indicate that the peripheral blood cells from LSADT monozygotic female twins show a strong tendency for the same cell line to become predominant in two co-twins, which suggests that X-linked genetic factors influence human hematopoietic stem cell kinetics and potentially organismal survival. The fact that females have two cell lines with different potentials could be one of the reasons why women live longer than men (Christensen et al., 2000)
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Individuals whose spiral test was positive were recontacted, and 119 twin pairs were interviewed and examined by a movement disorder specialist. The study revealed a nearly complete concordance for monozygotic twins for essential tremor and a substantial lower concordance rate for dizygotic twins, indicating a high heritability for essential tremor, and hence a good candidate for a phenotype to be used in linkage studies (Lorenz et al., 2004)
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Biometrical models confirmed that the twin similarity is best explained by a model including additive genetic factors and nonfamily environment, and that the heritability (i.e., the proportion of the variance explained by genetic factors) of perceived age is about 60 percent, with no sex or age differences.
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We also made high-quality pictures of 100 selected pairs, including facial imprint of the facial structure, to shed light on which immediate and distant factors are the basis for perceived age and its association with health and survival.
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Some 70 papers based on LSADT and the Danish 1905 Cohort Study have been published in international peer-reviewed journals, and half of the papers include biological indicators, even though their inclusion was not started until some years after the study had been launched. LSADT and the Danish 1905 Cohort Study aim at identifying the determinants of healthy aging and longevity.
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���We feel that our most important research is a result of extending our surveys beyond the traditional items, and hence we feel that supplementing our epidemiological surveys with the collection of biological markers and indicators has brought us new insight and has helped us to think outside the box in our research field of healthy aging and longevity. ACKNOWLEDGMENTS This research was supported by a grant from the Danish National Research Foundation and the National Institute on Aging (P01-AG08761)
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. ������������������������� X-linked genetic factors regulate hematopoietic stem-cell kinetics in females.
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gene polymorphism in relation to physical performance, cognition, and survival: A follow-up study of elderly Danish twins. Annals of Epidemiology����� 57-65.
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. Telomere length in white blood cells is not associated with morbidity or mortal ity in the oldest old: A population-based study.
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. Vascular genetic factors and human longevity.
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. Evaluating ����������� whole genome amplification via multiply-primed rolling circle amplification for SNP genotyping of samples with low DNA yield.
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