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.
Human longevity; Candidate gene association study; Case–control data; Longitudinal data
Transitions between disability states in older people occur frequently. This study investigated predictors of disability transitions in the oldest old and was performed in the Leiden 85-plus study, a population-based prospective cohort study among 597 participants aged 85 years. At baseline (age 85 years), data on sociodemographic characteristics and chronic diseases were obtained. Disabilities in basic activities of daily living (BADL) and instrumental activities of daily living (IADL) were measured annually for 5 years with the Groningen Activities Restriction Scale (GARS). Mortality data were obtained. A statistical multi-state model was used to assess the risks of transitions between no disabilities, IADL disability, BADL disability, and death. At baseline, 299 participants (50.0 %) were disabled in IADL only, and 155 participants (26.0 %) were disabled in both BADL and IADL. During 5-year follow-up, 374 participants (62.6 %) made >1 transition between disability states, mostly deterioration in disability. Males had a lower risk of deterioration [hazard ratio (HR), 0.75 (95 % CI, 0.58–0.96)] compared to females. No gender differences were observed for improvement [HR, 0.64 (95 % CI, 0.37–1.11)]. Participants with depressive symptoms were less likely to improve [HR, 0.50 (95 % CI, 0.28–0.87)]. Participants with depressive symptoms [HR, 1.46 (95 % CI, 1.12–1.91)], >1 chronic disease [HR, 1.60 (95 % CI, 1.27–2.01)], and with cognitive impairment [HR, 1.60 (95 % CI, 1.20–2.13)] had the highest risk of deteriorating. Disability is a dynamic process in the oldest old. Deterioration is more common than improvement. Older men are less likely to deteriorate than women. The presence of depressive symptoms, chronic disease, and cognitive impairment predicts deterioration.
Elderly/aged; Disability in activities of daily living; Recovery of function; Transitions between disability states
This study aimed to explore the prognosis of very old people depending on their cardiovascular disease (CVD) history. This observational prospective cohort study included 570 participants aged 85 years from the general population with 5-year follow-up for morbidity, functional status, and mortality. At baseline, participants were assigned to three groups: no CVD history, “minor” CVD (angina pectoris, transient ischemic attack, intermittent claudication, and/or heart failure), or “major” CVD (myocardial infarction [MI], stroke, and/or arterial surgery). Follow-up data were collected on MI, stroke, functional status, and cause-specific mortality. The composite endpoint included cardiovascular events (MI or stroke) and cardiovascular mortality. At baseline, 270 (47.4 %) participants had no CVD history, 128 (22.4 %) had minor CVD, and 172 (30.2 %) had major CVD. Compared to the no CVD history group, the risk of the composite endpoint increased from 1.6 (95 % confidence interval [CI], 1.1–2.4) for the minor CVD group to 2.7 (95 % CI, 2.0–3.9) for the major CVD group. Similar trends were observed for cardiovascular and all-cause mortality risks. In a direct comparison, the major CVD group had a nearly doubled risk of the composite endpoint (hazard ratio, 1.8; 95 % CI, 1.2–2.7), compared to the minor CVD group. Both minor and major CVD were associated with an accelerated decline in cognitive function and accelerated increase of disability score (all p < 0.05), albeit most pronounced in participants with major CVD. CVD disease status in very old age is still of important prognostic value: a history of major CVD (mainly MI or stroke) leads to a nearly doubled risk of poor outcome, including cardiovascular events, functional decline, and mortality, compared with a history of minor CVD.
Aged 80 and over; Cardiovascular disease; Prevention; Cardiovascular morbidity; Functional status; Mortality
The low percentages of naïve T cells commonly observed in elderly people are thought to be causally associated with mortality, primarily from infectious disease, and are taken as a hallmark of “immunosenescence”. Whether low levels of naive cells actually do associate with mortality has, however, not been tested in longitudinal studies. Here, we present correlations between peripheral T-cell phenotypes and 8-year survival in individuals from the population-based prospective Leiden 85-plus Study. Counter-intuitively, we found that a lower frequency of naïve CD8+ T cells (characterized as CD45RA+CCR7+CD27+CD28+) at baseline (>88 years) correlated with significantly better survival, while there was a tendency for the reciprocal accumulation of late-differentiated effector memory cells (CD45RA−CCR7−CD27−CD28−) also to associate with better survival. These findings suggest that better retention of memory cells specific for previously encountered antigens may provide a survival advantage in this particular population. Given the prevalence of Cytomegalovirus (CMV) and its reported association with immunosenescence, we tested whether memory for this potential pathogen was relevant to survival. We found that individuals mounting an exclusively pro-inflammatory ex vivo response (TNF, IFN-γ, IL-17) to the major CMV target molecules pp65 and IE1 had a significant survival advantage over those also having anti-inflammatory responses (IL-10). These findings suggest that higher levels of naïve T cells may not necessarily be associated with a survival advantage and imply that the nature of immunosurveillance against CMV may be crucial for remaining longevity, at least in the very elderly.
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The online version of this article (doi:10.1007/s11357-012-9425-7) contains supplementary material, which is available to authorized users.
Immunosenescence; T-cell subsets; Mortality; CMV
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.
Genetics; Aging; Longevity; Gene set analysis; Insulin/IGF-1 signaling; Telomere maintenance
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.
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The online version of this article (doi:10.1007/s11357-011-9339-9) contains supplementary material, which is available to authorized users.
Perceived age; Serum glucose levels; Diabetes; Aging
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.
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The online version of this article (doi:10.1007/s11357-011-9314-5) contains supplementary material, which is available to authorized users.
Skin ageing; Chronological age; Biological age; Familial longevity; Epidermis; Elastic fibres
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.
Handgrip strength; Ageing; Sarcopenia; Familial longevity; Muscle
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.
Longevity; Dispositional optimism; Personality; Maternal inheritance
Increasing evidence suggests that pro-inflammatory cytokines are at play in lowering peripheral thyroid hormone levels during critical illness. Conversely, thyroid hormones have been suggested to enhance production of inflammatory cytokines. In view of these considerations, we hypothesized a mutual association between triiodothyronine and pro-inflammatory cytokines. Therefore we evaluated the relation between both circulating and induced inflammatory markers and serum thyroid function parameters in the Leiden 85-plus Study. We found that higher circulating levels of inflammatory markers were associated with lower levels of free serum triiodothyronine. In turn, higher serum free triiodothyronine levels were related to higher production capacity of pro-inflammatory cytokines after stimulation with lipopolysaccharide. By combining in vivo and ex vivo data, we were able to demonstrate for the first time the existence of a potential feedback mechanism between thyroid function and immune production capacity. We conclude that maintenance of normal thyroid function might be important for a preserved immune response in elderly human populations.
Thyroid; Inflammation; Aging; Humans