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,... Show moreTransitions 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. Show less
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... Show moreThis 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. Show less
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 ... Show moreThe 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. Show less
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... Show moreIncreasing 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. Show less
Soerensen, M.; Dato, S.; Tan, Q.H.; Thinggaard, M.; Kleindorp, R.; Beekman, M.; ... ; Christiansen, L. 2012
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;... Show moreIn 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 (R (2) = 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. Show less
