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jtitle_s:("Age (dodr)")
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.  High serum glucose levels are associated with a higher perceived age 
Age  2011;35(1):189-195.
Estimating perceived age by facial photographs is a good estimate of health in elderly populations. Previously, we showed that familial longevity is marked by a more beneficial glucose metabolism already at middle age. As glucose is also related to skin aging, this study aimed to investigate the association between glucose metabolism and perceived age. Perceived age was assessed using facial photographs and non-fasted glucose and insulin were measured in 602 subjects from the Leiden Longevity Study. Non-diabetic subjects (n = 569) were divided in three strata according to their glucose levels, and diabetic subjects (n = 33; as a proxy of long-term hyperglycemic exposure) were included as a fourth stratum. Considered confounding factors were gender, chronological age, current smoking, body mass index, photo-damage score, and insulin levels. Perceived age was increased from 59.6 years (SE = 0.3) in the first stratum to 61.2 years (SE = 0.6) in diabetic subjects (p for trend = 0.002). In non-diabetic subjects only, perceived age was increased from 59.6 years (SE = 0.3) in the first stratum to 60.6 years (SE = 0.3) in the third stratum (p for trend = 0.009). Continuously, perceived age increased 0.40 years (SE = 0.14, p = 0.006) per 1 mmol/L increase in glucose level in non-diabetic subjects. The present study demonstrates that, also among non-diabetic subjects, higher glucose levels are associated with a higher perceived age. Future research should be focused on elucidating possible mechanisms linking glucose levels to perceived age.
Electronic supplementary material
The online version of this article (doi:10.1007/s11357-011-9339-9) contains supplementary material, which is available to authorized users.
PMCID: PMC3543736  PMID: 22102339
Perceived age; Serum glucose levels; Diabetes; Aging
5.  Morphometric skin characteristics dependent on chronological and biological age: the Leiden Longevity Study 
Age  2011;34(6):1543-1552.
The effect of chronological age on skin characteristics is readily visible, and its underlying histological changes have been a field of study for several years. However, the effect of biological age (i.e. a person’s rate of ageing compared to their chronological age) on the skin has so far only been studied in facial photographs. Skin biopsies obtained from middle-aged offspring of nonagenarian siblings that are genetically enriched for longevity were compared to their partners who represent the general Dutch population. Though of the same chronological age, the offspring were previously observed to be of a younger biological age than their partners. The biopsies were analysed on several aspects epidermal and elastic fibre morphology. We investigated whether these skin characteristics were dependent on chronological age, familial longevity (the difference between the offspring and partners) and Framingham heart risk scores, adjusted for external stressors. A decreased thickness and flattening of the epidermis as well as an increased amount of elastic fibres in the reticular dermis were observed with chronological age (P < 0.001, P < 0.001 and P = 0.03, respectively), but no effect of familial longevity was found. The Framingham heart risk score was associated with some skin characteristics. A slower rate of skin ageing does not mark offspring from nonagenarian siblings. Epidermal and elastic fibre morphometric characteristics are not a potential marker for familial longevity in middle-aged subjects enriched for familial longevity.
Electronic supplementary material
The online version of this article (doi:10.1007/s11357-011-9314-5) contains supplementary material, which is available to authorized users.
PMCID: PMC3528376  PMID: 21909657
Skin ageing; Chronological age; Biological age; Familial longevity; Epidermis; Elastic fibres
6.  Handgrip strength at midlife and familial longevity 
Age  2011;34(5):1261-1268.
Low handgrip strength has been linked with premature mortality in diverse samples of middle-aged and elderly subjects. The value of handgrip strength as marker of “exceptional” human longevity has not been previously explored. We postulated that the genetic influence on extreme survival might also be involved in the muscular strength determination pathway. Therefore, the objective of this study was to assess the muscle strength in a sample of middle-aged adults who are genetically enriched for exceptional survival and comparing them to a control group. We included 336 offspring of the nonagenarian from the Leiden Longevity Study who were enriched for heritable exceptional longevity, and 336 of their partners were used as controls. The Leiden Longevity study was a prospective follow up study of long-living siblings pairs together with their offspring and their partners. Handgrip strength was used as a proxy for overall muscle strength. No significant difference in handgrip strength was seen between the offspring of the nonagenarian and their partners after adjustment for potential confounders including body compositions, sum score of comorbidities, medication use, smoking and alcohol history. The main determinants of midlife handgrip strength were age, gender, total body percentage fat and relative appendicular lean mass. Although midlife handgrip strength has previously been shown to be an important prognostic indicator of survival, it is not a marker of exceptional familial longevity in middle-aged adults. This finding suggests that genetic component of susceptibility to extreme survival is likely to be separate from that of muscular strength.
PMCID: PMC3448992  PMID: 21833741
Handgrip strength; Ageing; Sarcopenia; Familial longevity; Muscle
7.  Parental longevity correlates with offspring’s optimism in two cohorts of community-dwelling older subjects 
Age  2011;34(2):461-468.
Dispositional optimism and other positive personality traits have been associated with longevity. Using a familial approach, we investigated the relationship between parental longevity and offspring’s dispositional optimism among community-dwelling older subjects. Parental age of death was assessed using structured questionnaires in two different population-based samples: the Leiden Longevity Study (n = 1,252, 52.2% female, mean age 66 years, SD = 4) and the Alpha Omega Trial (n = 769, 22.8% female, mean age 69 years, SD = 6). Adult offspring’s dispositional optimism was assessed with the Life Orientation Test—Revised (LOT-R). The association between parental age of death and levels of optimism in the offspring was analysed using linear regression analysis within each sample and a meta-analysis for the overall effect. In both samples, the parental mean age of death was positively associated with optimism scores of the offspring. The association remained significant after adjustment for age, gender, living arrangement, body mass index, smoking status, education and self-rated health of the offspring. The pooled B coefficient (increase in LOT-R score per 10-year increase in parental mean age of death) was 0.30 (SE = 0.08, p < 0.001). In conclusion, parental longevity was positively associated with optimism in adult offspring, suggesting a partial linked heritability of longevity and optimism.
PMCID: PMC3312631  PMID: 21472382
Longevity; Dispositional optimism; Personality; Maternal inheritance

Results 1-7 (7)