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jtitle_s:("Age (dodr)")
1.  Disability transitions in the oldest old in the general population. The Leiden 85-plus study 
Age  2013;36(1):483-493.
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.
PMCID: PMC3889888  PMID: 23990275
Elderly/aged; Disability in activities of daily living; Recovery of function; Transitions between disability states
2.  Lower proportion of naïve peripheral CD8+ T cells and an unopposed pro-inflammatory response to human Cytomegalovirus proteins in vitro are associated with longer survival in very elderly people 
Age  2012;35(4):1387-1399.
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.
Electronic supplementary material
The online version of this article (doi:10.1007/s11357-012-9425-7) contains supplementary material, which is available to authorized users.
PMCID: PMC3705124  PMID: 22661297
Immunosenescence; T-cell subsets; Mortality; CMV
3.  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
4.  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
5.  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
6.  Responsiveness of the innate immune system and glucose concentrations in the oldest old 
Age  2011;34(4):983-986.
Patients with diabetes mellitus show increased risk of infectious disease as well as disturbances in innate immunity. In critical care settings, hyperglycemia is associated with increased risk of sepsis. It is unclear whether elevated glucose concentrations and innate immunity are associated in a non-clinical setting. We aimed to assess the association between glucose concentrations and innate immune response in the oldest old, who are at increased risk of both disturbed glucose metabolism as well as infectious disease. This study was part of the Leiden 85-plus Study. In 562 subjects aged 85 years old of the general population, venous blood samples were taken for measurement of morning glucose, C-reactive protein (CRP) and glycated hemoglobin (HbA1c). The innate immune response was assessed by performing ex vivo whole blood lipopolysaccharide (LPS) stimulation for production capacity of tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6), interleukin 1-beta (IL1-β), interleukin 10 (IL-10) and interleukin 1 receptor antagonist (IL-1Ra). Using linear regression analysis, cross-sectional analysis between glucose and cytokine production capacity was performed. We found a significant negative association between glucose concentrations, but not HbA1c, and cytokine response capacity in four out of five measured cytokines (all p < 0.05). Both glucose and HbA1c were positively associated with circulating levels of CRP. Higher glucose concentrations in non-diabetic elderly are associated with lower innate immune response. As elderly show increased vulnerability for disturbances in glucose metabolism as well as infectious disease, this relation could be of clinical significance.
PMCID: PMC3682070  PMID: 21833742
Aging; Glucose; Cytokine response; Innate immunity
7.  Serum triiodothyronine levels and inflammatory cytokine production capacity 
Age  2011;34(1):195-201.
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.
PMCID: PMC3260363  PMID: 21350816
Thyroid; Inflammation; Aging; Humans
8.  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 1-8 (8)