CMV-independent increase in CD27-CD28+ CD8+ EMRA T cells is inversely related to mortality in octogenarians.

Cytomegalovirus (CMV) seropositivity in adults has been linked to increased cardiovascular disease burden. Phenotypically, CMV infection leads to an inflated CD8 T-lymphocyte compartment. We employed a 8-colour flow cytometric protocol to analyse circulating T cells in 597 octogenarians from the same birth cohort together with NT-proBNP measurements and followed all participants over 7 years. We found that, independent of CMV serostatus, a high number of CD27-CD28+ CD8 EMRA T-lymphocytes (TEMRA) protected from all-cause death after adjusting for known risk factors, such as heart failure, frailty or cancer (Hazard ratio 0.66 for highest vs lowest tertile; confidence interval 0.51-0.86). In addition, CD27-CD28+ CD8 EMRA T-lymphocytes protected from both, non-cardiovascular (hazard ratio 0.59) and cardiovascular death (hazard ratio 0.65). In aged mice treated with the senolytic navitoclax, in which we have previously shown a rejuvenated cardiac phenotype, CD8 effector memory cells are decreased, further indicating that alterations in T cell subpopulations are associated with cardiovascular ageing. Future studies are required to show whether targeting immunosenescence will lead to enhanced life- or healthspan.

A meta-analysis of genome-wide association studies identifies multiple longevity genes.

Human longevity is heritable, but genome-wide association (GWA) studies have had limited success. Here, we perform two meta-analyses of GWA studies of a rigorous longevity phenotype definition including 11,262/3484 cases surviving at or beyond the age corresponding to the 90th/99th survival percentile, respectively, and 25,483 controls whose age at death or at last contact was at or below the age corresponding to the 60th survival percentile. Consistent with previous reports, rs429358 (apolipoprotein E (ApoE) ε4) is associated with lower odds of surviving to the 90th and 99th percentile age, while rs7412 (ApoE ε2) shows the opposite. Moreover, rs7676745, located near GPR78, associates with lower odds of surviving to the 90th percentile age. Gene-level association analysis reveals a role for tissue-specific expression of multiple genes in longevity. Finally, genetic correlation of the longevity GWA results with that of several disease-related phenotypes points to a shared genetic architecture between health and longevity.

Longitudinal changes in global and domain specific cognitive function in the very-old: findings from the Newcastle 85+ Study.

OBJECTIVE: Ageing is associated with changes in cognition in some, but not all domains. In young-old adults, defined as persons aged 65-84 years, baseline cognitive function has been shown to impact on cognitive trajectories. Whether similar patterns occur in the very-old, defined as persons aged 85 years and over, is not known. METHODS: Longitudinal changes (5 years' follow-up) in global and domain specific cognitive function including memory, attention and speed were investigated in participants from the Newcastle 85+ Study (n = 845). At baseline, participants were grouped using Mini-Mental State Examination cut-off scores and dementia status into the following: not impaired, mildly impaired or severely impaired/dementia groups. RESULTS: Only a limited number of cognitive measures showed significant decline in performance over time. Where observed, change generally occurred only in the severely impaired group. In the severely impaired group, small differences in baseline age were associated with poorer performance over time on most measures. Education was not protective against cognitive decline in any group. CONCLUSIONS: There are individuals who maintain a high level of cognitive function or only show mild impairments even into their ninth decade of life. This group of successful cognitive agers may provide insight for identifying predictors of cognitive integrity in later life. In individuals with severe impairment, cognitive performance shows significant decline over time, especially in measures of attention and speed. Further work to identify those individuals at highest risk of cognitive decline is necessary to implement early support and intervention strategies in this rapidly expanding age group. © 2017 The Authors. International Journal of Geriatric Psychiatry published by John Wiley & Sons Ltd.

Serum Thyroid Function, Mortality and Disability in Advanced Old Age: The Newcastle 85+ Study.

CONTEXT: Perturbations in thyroid function are common in older individuals but their significance in the very old is not fully understood. OBJECTIVE: This study sought to determine whether thyroid hormone status and variation of thyroid hormones within the reference range correlated with mortality and disability in a cohort of 85-year-olds. DESIGN: A cohort of 85-year-old individuals were assessed in their own homes (community or institutional care) for health status and thyroid function, and followed for mortality and disability for up to 9 years. SETTING AND PARTICIPANTS: Six hundred and forty-three 85-year-olds registered with participating general practices in Newcastle and North Tyneside, United Kingdom. MAIN OUTCOMES: All-cause mortality, cardiovascular mortality, and disability according to thyroid disease status and baseline thyroid hormone parameters (serum TSH, FT4, FT3, and rT3). Models were adjusted for age, sex, education, body mass index, smoking, and disease count. RESULTS: After adjustment for age and sex, all-cause mortality was associated with baseline serum rT3 and FT3 (both P < .001), but not FT4 or TSH. After additional adjustment for potential confounders, only rT3 remained significantly associated with mortality (P = .001). Baseline serum TSH and rT3 predicted future disability trajectories in men and women, respectively. CONCLUSIONS: Our study is reassuring that individuals age 85 y with both subclinical hypothyroidism and subclinical hyperthyroidism do not have a significantly worse survival over 9 years than their euthyroid peers. However, thyroid function tests did predict disability, with higher serum TSH levels predicting better outcomes. These data strengthen the argument for routine use of age-specific thyroid function reference ranges.

Micronutrient intake and food sources in the very old: analysis of the Newcastle 85+ Study.

A number of socio-economic, biological and lifestyle characteristics change with advancing age and place very old adults at increased risk of micronutrient deficiencies. The aim of this study was to assess vitamin and mineral intakes and respective food sources in 793 75-year-olds (302 men and 491 women) in the North-East of England, participating in the Newcastle 85+ Study. Micronutrient intakes were estimated using a multiple-pass recall tool (2×24 h recalls). Determinants of micronutrient intake were assessed with multinomial logistic regression. Median vitamin D, Ca and Mg intakes were 2·0 (interquartile range (IQR) 1·2-6·5) µg/d, 731 (IQR 554-916) mg/d and 215 (IQR 166-266) mg/d, respectively. Fe intake was 8·7 (IQR 6·7-11·6) mg/d, and Se intake was 39·0 (IQR 27·3-55·5) µg/d. Cereals and cereal products were the top contributors to intakes of folate (31·5 %), Fe (49·2 %) and Se (46·7 %) and the second highest contributors to intakes of vitamin D (23·8 %), Ca (27·5 %) and K (15·8 %). More than 95 % (n 756) of the participants had vitamin D intakes below the UK's Reference Nutrient Intake (10 µg/d). In all, >20 % of the participants were below the Lower Reference Nutrient Intake for Mg (n 175), K (n 238) and Se (n 418) (comparisons with dietary reference values (DRV) do not include supplements). As most DRV are not age specific and have been extrapolated from younger populations, results should be interpreted with caution. Participants with higher education, from higher social class and who were more physically active had more nutrient-dense diets. More studies are needed to inform the development of age-specific DRV for micronutrients for the very old.

Macronutrient intake and food sources in the very old: analysis of the Newcastle 85+ Study.

Food and nutrient intake data are scarce in very old adults (85 years and older) - one of the fastest growing age segments of Western societies, including the UK. Our primary objective was to assess energy and macronutrient intakes and respective food sources in 793 85-year-olds (302 men and 491 women) living in North-East England and participating in the Newcastle 85+ cohort Study. Dietary information was collected using a repeated multiple-pass recall (2×24 h recalls). Energy, macronutrient and NSP intakes were estimated, and the contribution (%) of food groups to nutrient intake was calculated. The median energy intake was 6·65 (interquartile ranges (IQR) 5·49-8·16) MJ/d - 46·8 % was from carbohydrates, 36·8 % from fats and 15·7 % from proteins. NSP intake was 10·2 g/d (IQR 7·3-13·7). NSP intake was higher in non-institutionalised, more educated, from higher social class and more physically active 85-year-olds. Cereals and cereal products were the top contributors to intakes of energy and most macronutrients (carbohydrates, non-milk extrinsic sugars, NSP and fat), followed by meat and meat products. The median intakes of energy and NSP were much lower than the estimated average requirement for energy (9·6 MJ/d for men and 7·7 MJ/d for women) and the dietary reference value (DRV) for NSP (≥18 g/d). The median SFA intake was higher than the DRV (≤11 % of dietary energy). This study highlights the paucity of data on dietary intake and the uncertainties about DRV for this age group.

Deconstructing Complex Multimorbidity in the Very Old: Findings from the Newcastle 85+ Study.

OBJECTIVES: To examine the extent and complexity of the morbidity burden in 85-year-olds; identify patterns within multimorbidity; and explore associations with medication and healthcare use. Participants. 710 men and women; mean (SD) age 85.5 (0.4) years. METHODS: Data on 20 chronic conditions (diseases and geriatric conditions) ascertained from general practice records and participant assessment. Cluster analysis within the multimorbid sample identified subgroups sharing morbidity profiles. Clusters were compared on medication and healthcare use. RESULTS: 92.7% (658/710) of participants had multimorbidity; median number of conditions: 4 (IQR 3-6). Cluster analysis (multimorbid sample) identified five subgroups sharing similar morbidity profiles; 60.0% (395/658) of participants belonged to one of two high morbidity clusters, with only 4.9% (32/658) in the healthiest cluster. Healthcare use was high, with polypharmacy (≥5 medications) in 69.8% (459/658). Between-cluster differences were found in medication count (p = 0.0001); hospital admissions (p = 0.022); and general practitioner (p = 0.034) and practice nurse consultations (p = 0.011). Morbidity load was related to medication burden and use of some, but not all, healthcare services. CONCLUSIONS: The majority of 85-year-olds had extensive and complex morbidity. Elaborating participant clusters sharing similar morbidity profiles will help inform future healthcare provision and the identification of common underlying biological mechanisms.

Respiratory health and disease in a U.K. population-based cohort of 85†year olds: The Newcastle 85+ Study.

BACKGROUND: People aged 85 years and older are the fastest growing age group worldwide. This study assessed respiratory health, prevalence of respiratory disease and use of spirometry in respiratory diagnosis in a population-based cohort of 85 year olds to better understand respiratory health and disease in this sector of society. METHODS: A single year birth-cohort of 85 year olds participated in a respiratory assessment at their home or residential institution including self-reporting of symptoms and measurement of spirometry. General practice medical records were reviewed for respiratory diagnoses and treatments. FINDINGS: In the 845 participants, a substantial burden of respiratory disease was seen with a prevalence of COPD in medical records of 16.6% (n=140). A large proportion of the cohort had environmental exposures through past or current smoking (64.2%, n=539) and occupational risk factors (33.6%, n=269). Spirometry meeting reliability criteria was performed in 87% (n=737) of participants. In the subgroup with a diagnosis of COPD (n=123), only 75.6% (n=93) satisfied Global Initiative in Obstructive Lung Disease (GOLD) criteria for airflow obstruction, and in a healthy subgroup without respiratory symptoms or diagnoses (n=151), 44.4% (n=67) reached GOLD criteria for airflow obstruction and 43.3% (n=29) National Institute of Health and Care Excellence criteria for at least moderate COPD. INTERPRETATION: Spirometry can be successfully performed in the very old, aged 85 years, and may help identify respiratory diseases such as COPD. However interpretation in this age group using current definitions of COPD based on spirometry indices may be difficult and lead to overdiagnosis in a healthy group with transient symptoms.

Antihypertensive drug use and risk of cognitive decline in the very old: an observational study - the Newcastle 85+ Study.

OBJECTIVES: Older adults are a fast growing group in society and are at high risk of hypertension, cognitive decline and dementia. Antihypertensive drugs, particularly calcium channel blockers (CCB), have been associated with a decreased risk of cognitive decline and dementia. We used observational data to examine the association between antihypertensive drug class and change in cognitive function. METHODS: The Newcastle 85+ Study is a population-based cohort study recruiting individuals aged 85 (born in 1921) via general/family practices in Newcastle/North Tyneside, United Kingdom. Data, including blood pressure, antihypertensive drug use and cognitive function [assessed using the Standardized Mini-Mental State Exam (SMMSE)], were collected at baseline and 3-year follow-up. RESULTS: The study population comprised 238 participants with a diagnosis of hypertension, prescribed antihypertensive drug treatment and with baseline and follow-up SMMSE assessment. There was an association between CCB use and less cognitive decline over 3 years (rate of decline was lower by 1.29 SMMSE points (95% confidence interval 0.16-2.42; P = 0.03) compared with those taking other antihypertensive classes after adjustment for age, sex, years of education, baseline SMMSE score, smoking, BMI, baseline blood pressure, and incident cerebrovascular event. This finding was even stronger in the cognitively intact (SMMSE >24), wherein rate of cognitive decline was lower by 1.33 SMMSE points (95% confidence interval 0.30-2.37; P = 0.01), but was not seen for other antihypertensive classes. CONCLUSION: Findings provide support for an association between CCB use and a lower rate of cognitive decline in very old adults with hypertension.

Age-related frailty and its association with biological markers of ageing.

BACKGROUND: The relationship between age-related frailty and the underlying processes that drive changes in health is currently unclear. Considered individually, most blood biomarkers show only weak relationships with frailty and ageing. Here, we examined whether a biomarker-based frailty index (FI-B) allowed examination of their collective effect in predicting mortality compared with individual biomarkers, a clinical deficits frailty index (FI-CD), and the Fried frailty phenotype. METHODS: We analyzed baseline data and up to 7-year mortality in the Newcastle 85+ Study (n = 845; mean age 85.5). The FI-B combined 40 biomarkers of cellular ageing, inflammation, haematology, and immunosenescence. The Kaplan-Meier estimator was used to stratify participants into FI-B risk strata. Stability of the risk estimates for the FI-B was assessed using iterative, random subsampling of the 40 FI-B items. Predictive validity was tested using Cox proportional hazards analysis and discriminative ability by the area under receiver operating characteristic (ROC) curves. RESULTS: The mean FI-B was 0.35 (SD, 0.08), higher than the mean FI-CD (0.22; SD, 0.12); no participant had an FI-B score <0.12. Higher values of each FI were associated with higher mortality risk. In a sex-adjusted model, each one percent increase in the FI-B increased the hazard ratio by 5.4 % (HR, 1.05; CI, 1.04-1.06). The FI-B was more powerful for mortality prediction than any individual biomarker and was robust to biomarker substitution. The ROC analysis showed moderate discriminative ability for 7-year mortality (AUC for FI-CD = 0.71 and AUC for FI-B = 0.66). No individual biomarker's AUC exceeded 0.61. The AUC for combined FI-CD/FI-B was 0.75. CONCLUSIONS: Many biological processes are implicated in ageing. The systemic effects of these processes can be elucidated using the frailty index approach, which showed here that subclinical deficits increased the risk of death. In the future, blood biomarkers may indicate the nature of the underlying causal deficits leading to age-related frailty, thereby helping to expose targets for early preventative interventions.

A comparison of subjective and objective measures of physical activity from the Newcastle 85+ study.

BACKGROUND: Little is known about physical activity (PA) in the very old, the fastest growing age group in the population. We aimed to examine the convergent validity of subjective and objective measures of PA in adults aged over 85 years. METHODS: A total of 484 participants aged 87-89 years recruited to the Newcastle 85+ study completed a purpose-designed physical activity questionnaire (PAQ), which categorised participants as mildly active, moderately active and very active. Out of them, 337 participants wore a triaxial, raw accelerometer on the right wrist over a 5-7-day period to obtain objective measures of rest/activity, PA intensity and PA type. Data from subjective and objective measurement methods were compared. RESULTS: Self-reported PA was significantly associated with objective measures of the daily sedentary time, low-intensity PA and activity type classified as sedentary, activities of daily living and walking. Objective measures of PA were significantly different when low, moderate and high self-reported PA categories were compared (all P < 0.001). CONCLUSION: The Newcastle 85+ PAQ demonstrated convergent validity with objective measures of PA. Our findings suggest that this PAQ can be used in the very old to rank individuals according to their level of total PA.

The enduring effect of education-socioeconomic differences in disability trajectories from age 85 years in the Newcastle 85+ Study.

OBJECTIVE: Little is known about disability progression in very old age despite this being vital for care planning. We investigate whether distinct trajectories of disability are evident from age 85 to 90 and their association with socio-economic status (SES). METHODS: The Newcastle 85+ Study recruited people born in 1921 through participating general practices in Newcastle and North Tyneside. Participants underwent a health assessment (HA) at baseline, 18, 36 and 60 months and a GP record review (GPRR) at baseline, 36 and 60 months. Disability was measured via difficulty in 17 Activities of Daily Living. Trajectory identification was assessed by gender stratified, mortality adjusted, group-based trajectory modelling (GBTM) and the impact of life-course SES (level of education; occupational class; deprivation) on trajectory membership evaluated (adjusting for confounding variables). RESULTS: 851 participants agreed to HA and GPRR, 840 (98.7%) with complete disability data. Four distinct trajectories were evident for both sexes. A disability-free trajectory between age 85 and 90 was identified in men only (9% of the sample). The most disabled trajectories had severe disability at age 85 progressing to profound disability by age 90. After adjusting for confounders education remained significant; men and women with most education being less likely to be in the most disabled trajectory (Men: OR=0.80, 95% CI 0.65-0.98; women: OR=0.59, 95% CI 0.42-0.83). CONCLUSION: Distinct disability trajectories are evident in the very old and these are influenced by education, suggesting SES disadvantages cumulate throughout the life-course to create health and mortality inequalities later.

Serum osmolarity and haematocrit do not modify the association between the impedance index (Ht(2)/Z) and total body water in the very old: the Newcastle 85+ study.

PURPOSE OF THE RESEARCH: Bioelectrical impedance is a non-invasive technique for the assessment of body composition; however, information on its accuracy in the very old (80+years) is limited. We investigated whether the association between the impedance index and total body water (TBW) was modified by hydration status as assessed by haematocrit and serum osmolarity. MATERIALS AND METHODS: This was a cross-sectional analysis of baseline data from the Newcastle 85+Cohort Study. Anthropometric measurements [weight, height (Ht)] were taken and body mass index (BMI) calculated. Leg-to-leg bioimpedance was used to measure the impedance value (Z) and to estimate fat mass, fat free mass and TBW. The impedance index (Ht2/Z) was calculated. Blood haematocrit, haemoglobin, glucose, sodium, potassium, urea and creatinine concentrations were measured. Serum osmolarity was calculated using a validated prediction equation. PRINCIPAL RESULTS: 677 men and women aged 85 years were included. The average BMI of the population was 24.3±4.2kg/m2 and the prevalence of overweight and obesity was 32.6% and 9.5%, respectively. The impedance index was significantly associated with TBW in both men (n=274, r=0.76, p<0.001) and women (n=403, r=0.96, p<0.001); in regression models, the impedance index remained associated with TBW after adjustment for height, weight and gender, and further adjustment for serum osmolarity and haematocrit. The impedance index values increased with BMI and the relationship was not modified by hydration status in women (p=0.69) and only marginally in men (p=0.02). MAJOR CONCLUSIONS: The association between the impedance index and TBW was not modified by hydration status, which may support the utilisation of leg-to-leg bioimpedance for the assessment of body composition in the very old.

Improving retention of very old participants in longitudinal research: experiences from the Newcastle 85+ study.

BACKGROUND: People aged 85 and over are often excluded from research on the grounds of being difficult to recruit and problematic to retain. The Newcastle 85+ study successfully recruited a cohort of 854 85-year-olds to detailed health assessment at baseline and followed them up over 3 phases spanning 5 years. This paper describes the effectiveness of its retention strategies. METHODS: Primary retention strategies involved meticulous management of contact information and active maintenance of contact with participants between research visits and between phases of the study. For statistical analysis, data on post-inclusion attrition over the 3 follow-up phases was separated into 'death' and 'withdrawal' categories, with sub-categories 'health' and 'non-health' reasons created for 'withdrawal'. Multinomial logistic regression was used to determine if particular socio-demographic and health characteristics were associated with post-inclusion attrition due to withdrawal at each of the 3 phase-to-phase transition points. RESULTS: For both sexes, at successive follow-up phases there was a decrease in attrition due to withdrawal and an increase due to death. Withdrawal was most prevalent between baseline and phase 2. Across the 5 years of the study total post-inclusion (post-baseline) attrition due to death accounted for a 40% (344/854) loss to cohort and total post-inclusion attrition due to withdraw a 19% (166/854) loss to cohort, with health reasons for withdrawal becoming more dominant over time. Adjusting for sex, parsimonious modelling showed only occupational class (National Statistics Socio-economic Classification) to be associated with withdrawal and only between baseline and phase 2 (routine/manual compared to managerial (OR 3.41; 95% CI [1.23 to 9.44]). CONCLUSION: Following successful recruitment, we retained a high proportion of participants from a very old age group over 5 years of longitudinal research. No strong predictors of post-inclusion attrition due to withdrawal were found, suggesting the general effectiveness of our retention strategies.

Utility of NT-proBNP as a rule-out test for left ventricular dysfunction in very old people with limiting dyspnoea: the Newcastle 85+ Study.

BACKGROUND: Guidelines advocate using B-type natriuretic peptides in the diagnostic work-up of suspected heart failure (HF). Their main role is to limit echocardiography rates by ruling out HF/LV dysfunction where peptide level is low. Recommended rule-out cut points vary between guidelines. The utility of B-type natriuretic peptides in the very old (85+) requires further investigation, with optimal cut points yet to be established. We examined NT-proBNP's utility, alone and in combination with history of myocardial infarction (MI), as a rule-out test for LV dysfunction in very old people with limiting dyspnoea. DESIGN: Cross-sectional analysis. SETTING: Population-based sample; North-East England. PARTICIPANTS: 155 people (aged 87-89) with limiting dyspnoea. MEASURES: Dyspnoea assessed by questionnaire. Domiciliary echocardiography performed; LV systolic/diastolic function graded. NT-proBNP measured (Roche Diagnostics). Receiver operating characteristic analyses examined NT-proBNP's diagnostic accuracy for LV dysfunction. RESULTS: AUC for LVEF less than or equal to 50% was poor (0.58, 95% CI 0.49-0.65), but good for LVEF less than or equal to 40% (0.80, 95% CI 0.73-0.86). At ESC cut point (125 ng/l), few cases of systolic dysfunction were missed (NPV 94-100%, depending on severity), but echocardiography (88%) and false positive rates (56-81 per 100 screened) were high. At NICE cut point (400 ng/l), echocardiography (51%) and false positive rates (33-45) were lower; exclusionary performance was good for LVEF less than or equal to 40% (1 case missed per 100 screened, 15% of cases; NPV 97%), but poor for LVEF less than or equal to 50% (16 cases missed per 100 screened, 45% of cases; NPV 68%). Incorporating isolated moderate/severe diastolic dysfunction into target condition increased the proportion of cases missed (lower NPV), whilst improving case detection. Incorporating MI history as an additional referral prompt slightly reduced the number of cases missed at expense of higher echocardiography and false positive rates. CONCLUSIONS: High echocardiography rates and poor exclusionary performance for mild degrees of systolic dysfunction and for diastolic dysfunction limit NT-proBNP's utility as a rule-out test for LV dysfunction in very old people with limiting dyspnoea. Incorporating MI history as an additional echocardiography prompt yields no overall benefit compared to using NT-proBNP level alone.

Genome-wide association meta-analysis of human longevity identifies a novel locus conferring survival beyond 90 years of age.

The genetic contribution to the variation in human lifespan is ∼ 25%. Despite the large number of identified disease-susceptibility loci, it is not known which loci influence population mortality. We performed a genome-wide association meta-analysis of 7729 long-lived individuals of European descent (≥ 85 years) and 16 121 younger controls (<65 years) followed by replication in an additional set of 13 060 long-lived individuals and 61 156 controls. In addition, we performed a subset analysis in cases aged ≥ 90 years. We observed genome-wide significant association with longevity, as reflected by survival to ages beyond 90 years, at a novel locus, rs2149954, on chromosome 5q33.3 (OR = 1.10, P = 1.74 × 10(-8)). We also confirmed association of rs4420638 on chromosome 19q13.32 (OR = 0.72, P = 3.40 × 10(-36)), representing the TOMM40/APOE/APOC1 locus. In a prospective meta-analysis (n = 34 103), the minor allele of rs2149954 (T) on chromosome 5q33.3 associates with increased survival (HR = 0.95, P = 0.003). This allele has previously been reported to associate with low blood pressure in middle age. Interestingly, the minor allele (T) associates with decreased cardiovascular mortality risk, independent of blood pressure. We report on the first GWAS-identified longevity locus on chromosome 5q33.3 influencing survival in the general European population. The minor allele of this locus associates with low blood pressure in middle age, although the contribution of this allele to survival may be less dependent on blood pressure. Hence, the pleiotropic mechanisms by which this intragenic variation contributes to lifespan regulation have to be elucidated.

Acquisition of aberrant DNA methylation is associated with frailty in the very old: findings from the Newcastle 85+ Study.

Frailty is a major health problem in older people and, as the population ages, identification of its underlying biological mechanisms will be increasingly important. DNA methylation patterns within genomic DNA change during ageing and alterations in DNA methylation, particularly at gene promoter regions, can lead to altered gene expression. However the importance of altered DNA methylation in frailty is largely unknown. Using cross-sectional data from the Newcastle 85+ Study (all participants aged 85 years) frailty was operationalized by the Fried model. DNA methylation levels were assessed by highly quantitative pyrosequencing at the gene promoter associated CpG islands from a panel of five age-related methylation marker loci and at LINE-1 repetitive elements (as a surrogate for genome-wide methylation). While genome-wide methylation (as assessed at LINE-1 elements) showed no association with frailty status, there was a clear association between CpG island methylation and frailty. When compared to participants with CpG island methylation levels in the combined middle two (referent) quartiles, those in the lowest quartile had significantly decreased odds of frailty [odds ratio 0.47 (95 % CI 0.26-0.85); n = 321, p = 0.013]. Overall this study suggests a potential role for age-related changes in CpG island methylation in the development of frailty.

Reactive oxygen species production and mitochondrial dysfunction in white blood cells are not valid biomarkers of ageing in the very old.

Reliable and valid biomarkers of ageing (BoA) are needed to understand mechanisms, test interventions and predict the timing of adverse health events associated with ageing. Since increased reactive oxygen species (ROS) production and mitochondrial dysfunction are consequences of cellular senescence and may contribute causally to the ageing of organisms, we focused on these parameters as candidate BoA. Superoxide levels, mitochondrial mass and mitochondrial membrane potential in human peripheral blood mononuclear cells (PBMCs) and subpopulations (lymphocytes and monocytes) were measured in participants from the Newcastle 85+ study, a population-based study of the very old (aged 85 years and older). The intra- and inter-assay precision expressed as coefficient of variation (CV) for all parameters was acceptable (3% to 12% and 5 to 22% respectively). All parameters were stable in the short-term (1 week interval) in a sample of control individuals in the PBMCs and lymphocyte subpopulation, however they were unstable in the monocyte subpopulation; this rendered monocytes unreliable for further analysis. There was a significant association between superoxide levels and mitochondrial mass (positive in lymphocytes, p = 0.01) and between superoxide levels and mitochondrial membrane potential (negative in PBMCs, p = 0.01; positive in lymphocytes, p = 0.05). There were also significant associations between superoxide levels and mitochondrial parameters with other markers of oxidative stress-induced cellular senescence (p≤0.04), however some were in the opposite direction to expected. No associations were found between the measured parameters and age-related outcomes, including cognitive impairment, disability, co-morbidity and survival - questioning the validity of these parameters as candidate BoA in the very old.

The contribution of diseases to the male-female disability-survival paradox in the very old: results from the Newcastle 85+ study.

BACKGROUND: Explanations for the male-female disability-survival paradox - that woman live longer than men but with more disability - include sex differences in diseases and their impact on disability and death. Less is known about the paradox in the very old. We examine sex differences in the presence and impact of disabling and fatal diseases accounting for the male-female disability-survival paradox in very late life. METHODS: We use data from the Newcastle 85+ Study, a cohort of people born in 1921 and all recruited at age 85 in 2006. Participants underwent a health assessment (HA) at baseline, 18 months, 36 months, 60 months, and a review of their GP records (GPRR) at baseline and 36 months. We used multi-state modelling to assess the impact of specific diseases on disability and death. Disability (measured via ADLs/IADLs) was categorised as no disability (difficulty with 0 activities), or disabled (difficulty with one or more activities). Diseases were ascertained from review of general practice records and cognitive impairment which was defined as an sMMSE of 21 or less (from health assessment). RESULTS: In participants who had complete HA and GPRR, women had more arthritis (RR = 1.2, 95% CI: 1.1-1.3) and hypertension (RR = 1.2, 95%CI 1.0-1.3), more disability, and were more likely disabled at all follow-ups. From multistate models, women with cerebrovascular disease (HR: 2.6, 95% CI: 2.1-3.4) or respiratory disease (HR: 2.0, 95% CI: 1.4-3.0) were more likely to become disabled than those without but this did not hold for men (sex difference p<0.01). Men were more likely to die from respiratory disease (HR: 2.2, 95% CI: 1.8-2.8) but this did not hold for women (p = 0.002). CONCLUSION: The disability-survival paradox was still evident at age 85 and appears due to sex differences in the types of diseases and their impact on the disability pathway.