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jtitle_s:("Age (dorer)")
1.  Evidence from case–control and longitudinal studies supports associations of genetic variation in APOE, CETP, and IL6 with human longevity 
Age  2012;35(2):487-500.
In this study, we investigated 102 single-nucleotide polymorphisms (SNPs) covering the common genetic variation in 16 genes recurrently regarded as candidates for human longevity: APOE; ACE; CETP; HFE; IL6; IL6R; MTHFR; TGFB1; APOA4; APOC3; SIRTs 1, 3, 6; and HSPAs 1A, 1L, 14. In a case–control study of 1,089 oldest-old (ages 92–93) and 736 middle-aged Danes, the minor allele frequency (MAF) of rs769449 (APOE) was significantly decreased in the oldest-old, while the MAF of rs9923854 (CETP) was significantly enriched. These effects were supported when investigating 1,613 oldest-old (ages 95–110) and 1,104 middle-aged Germans. rs769449 was in modest linkage equilibrium (R2 = 0.55) with rs429358 of the APOE-ε4 haplotype and adjusting for rs429358 eliminated the association of rs769449, indicating that the association likely reflects the well-known effect of rs429358. Gene-based analysis confirmed the effects of variation in APOE and CETP and furthermore pointed to HSPA14 as a longevity gene. In a longitudinal study with 11 years of follow-up on survival in the oldest-old Danes, only one SNP, rs2069827 (IL6), was borderline significantly associated with survival from age 92 (P-corrected = 0.064). This advantageous effect of the minor allele was supported when investigating a Dutch longitudinal cohort (N = 563) of oldest-old (age 85+). Since rs2069827 was located in a putative transcription factor binding site, quantitative RNA expression studies were conducted. However, no difference in IL6 expression was observed between rs2069827 genotype groups. In conclusion, we here support and expand the evidence suggesting that genetic variation in APOE, CETP, and IL6, and possible HSPA14, is associated with human longevity.
Electronic supplementary material
The online version of this article (doi:10.1007/s11357-011-9373-7) contains supplementary material, which is available to authorized users.
PMCID: PMC3592963  PMID: 22234866
Human longevity; Candidate gene association study; Case–control data; Longitudinal data
2.  Lipid metabolism in long-lived families: the Leiden Longevity Study 
Age  2010;33(2):219-227.
Mechanisms underlying the variation in human life expectancy are largely unknown, but lipid metabolism and especially lipoprotein size was suggested to play an important role in longevity. We have performed comprehensive lipid phenotyping in the Leiden Longevity Study (LLS). By applying multiple logistic regression analysis we tested for the first time the effects of parameters in lipid metabolism (i.e., classical serum lipids, lipoprotein particle sizes, and apolipoprotein E levels) on longevity independent of each other. Parameters in lipid metabolism were measured in offspring of nonagenarian siblings from 421 families of the LLS (n = 1,664; mean age, 59 years) and in the partners of the offspring as population controls (n = 711; mean age, 60 years). In the initial model, where lipoprotein particles sizes, classical serum lipids and apolipoprotein E were included, offspring had larger low-density lipoprotein (LDL) particle sizes (p = 0.017), and lower triglyceride levels (p = 0.026), indicating that they displayed a more beneficial lipid profile. After backwards regression only LDL size (p = 0.014) and triglyceride levels (p = 0.05) were associated with offspring from long-lived families. Sex-specific backwards regression analysis revealed that LDL particle sizes were associated with male longevity (increase in log odds ratio (OR) per unit = 0.21; p = 0.023). Triglyceride levels (decrease OR per unit = 0.22; p = 0.01), but not LDL particle size, were associated with female longevity. Due to the analysis of a comprehensive lipid profile, we confirmed an important role of lipid metabolism in human longevity, with LDL size and triglyceride levels as major predicting factors.
PMCID: PMC3127468  PMID: 20811950
Human longevity; Triglycerides; HDL cholesterol; LDL cholesterol; Lipoprotein particle size; Apolipoprotein E
3.  Gene set analysis of GWAS data for human longevity highlights the relevance of the insulin/IGF-1 signaling and telomere maintenance pathways 
Age  2011;35(1):235-249.
In genome-wide association studies (GWAS) of complex traits, single SNP analysis is still the most applied approach. However, the identified SNPs have small effects and provide limited biological insight. A more appropriate approach to interpret GWAS data of complex traits is to analyze the combined effect of a SNP set grouped per pathway or gene region. We used this approach to study the joint effect on human longevity of genetic variation in two candidate pathways, the insulin/insulin-like growth factor (IGF-1) signaling (IIS) pathway and the telomere maintenance (TM) pathway. For the analyses, we used genotyped GWAS data of 403 unrelated nonagenarians from long-lived sibships collected in the Leiden Longevity Study and 1,670 younger population controls. We analyzed 1,021 SNPs in 68 IIS pathway genes and 88 SNPs in 13 TM pathway genes using four self-contained pathway tests (PLINK set-based test, Global test, GRASS and SNP ratio test). Although we observed small differences between the results of the different pathway tests, they showed consistent significant association of the IIS and TM pathway SNP sets with longevity. Analysis of gene SNP sets from these pathways indicates that the association of the IIS pathway is scattered over several genes (AKT1, AKT3, FOXO4, IGF2, INS, PIK3CA, SGK, SGK2, and YWHAG), while the association of the TM pathway seems to be mainly determined by one gene (POT1). In conclusion, this study shows that genetic variation in genes involved in the IIS and TM pathways is associated with human longevity.
Electronic supplementary material
The online version of this article (doi:10.1007/s11357-011-9340-3) contains supplementary material, which is available to authorized users.
PMCID: PMC3543749  PMID: 22113349
Genetics; Aging; Longevity; Gene set analysis; Insulin/IGF-1 signaling; Telomere maintenance
4.  C-reactive protein and glucose regulation in familial longevity 
Age  2011;33(4):623-630.
Earlier, we showed that the offspring from exceptionally long-lived families have a more favorable glucose metabolism when compared with controls. As chronic low-grade inflammation has been regarded as a strong risk factor for insulin resistance, we evaluated if and to what extent the favorable glucose metabolism in offspring from long-lived families could be explained by differences in subclinical inflammation, as estimated from circulating levels of C-reactive protein. We found no difference between the two groups in C-reactive protein levels or in the distribution of C-reactive protein haplotypes. However, among controls higher levels of C-reactive protein were related to higher glucose levels, whereas among offspring levels of C-reactive protein were unrelated to glucose levels. It is a limitation of the current study that its cross-sectional nature does not allow for assessment of cause–effect relationships. One possible interpretation of these data is that the offspring from long-lived families might be able to regulate glucose levels more tightly under conditions of low-grade inflammation. To test this hypothesis, our future research will be focused on assessing the robustness of insulin sensitivity in response to various challenges in offspring from long-lived families and controls.
PMCID: PMC3220397  PMID: 21246407
C-reactive protein; Insulin resistance; Humans; Longevity

Results 1-4 (4)