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Covid-19 endangers lives, has disrupted normal life, changed the way medicine is practised and is likely to alter our world for the foreseeable future. Almost two years on since the presumptive first diagnosis of COVID-19 in China, more than two hundred and fifty million cases have been confirmed and more than five million people have died globally, with the figures rising daily. One of the most striking aspects of COVID-19 illness is the marked difference in individuals' experiences of the disease. Some, most often younger groups, are asymptomatic, whereas others become severely ill with acute respiratory distress syndrome (ARDS), pneumonia or proceed to fatal organ disease. The highest death rates are in the older and oldest age groups and in people with co-morbidities such as diabetes, heart disease and obesity. Three major questions seem important to consider. What do we understand about changes in the immune system that might contribute to the older person's risk of developing severe COVID-19? What factors contribute to the higher morbidity and mortality in older people with COVID-19? How could immunocompetence in the older and the frailest individuals and populations be supported and enhanced to give protection from serious COVID-19 illness?

Societal and medical advances have extended life expectancy for people globally. Despite the significance of wellbeing for everyone, the challenge for medicine, society, and governments is to make the added years as healthy and productive as possible. People who age exceptionally well interest us. Current ninety-year-olds and centenarians are the survivors of their generation and are the fastest growing population group in Europe and the developed world. We want to know what gives them their determination to go forward; how have they remained healthy and escaped the dangers of illness and degenerative disease throughout their long lives? This chapter discusses some lifestyle and behavioral factors that associate with good quality longevity and describes links and evidence with known epigenetic mechanisms. It seems possible that exceptional ninety-year-olds and centenarians may have actively or intuitively adopted a range of behaviors and lifestyles that have contributed, through epigenetic mechanisms, to their aging-well-phenotype.

More and more people are living into the 90s or becoming centenarians. But, the gift of increased 'age span' seldom equates with an improved 'health-span'. Governments across the world are expressing concern about the epidemic of chronic disease, and have responded by initiating policies that make prevention, reduction and treatment of chronic disease, a public health priority. But understanding, how to age long and well, with the avoidance of chronic disease and later life complex disease morbidity is challenging. While inherited genes have an undoubted role to play in the chance of maintaining good health or conversely a predilection to developing disease and chronic ill health, there is increasing evidence that behavioural and environmental life-style choices may contribute up to 50% of the variability of human lifespan. Physical exercise is readily available to everyone, and is a simple cheap and effective form of life-style intervention. Exercise appears to help maintain good health and to reduce the risk of developing chronic disease and ill health. Evidence suggests that physical activity improves well-being across many health domains through out life, continues to offer important health benefits in older age groups and tracks with a 'healthy ageing' profile. Although many of the molecular pathways remain to be fully identified, here we discuss how physical activity and exercise is understood to produce changes in the human epigenome, which have the potential to enhance cognitive and psychological health, improve muscular fitness, and lead to better ageing with improved quality of life in older age.

Multi-drug resistance (MDR) may compromise the successful management of haematological malignancies, impairing the effectiveness of chemotherapy. The P-glycoprotein (P-gp) drug efflux pump, encoded by the gene ABCB1 (MDR1), is the most widely studied component in MDR. A single nucleotide polymorphism (SNP) has been identified within ABCB1, rs1045642 (C3435T), which may alter P-gp substrate specificity and have an impact on the effectiveness of treatment, and hence overall survival (OS). We estimated the frequency of this SNP in the Northern Irish population and investigated its impact on the OS of patients with plasma cell myeloma (PCM). There was no significant difference in the frequency of rs1045642 between the PCM cohort and an age- and gender-matched control population. Findings within the PCM cohort suggest that rs1045642 genotype influences OS (p = 2 x 10(-2)). If confirmed in larger studies, these results suggest that genotyping rs1045642 may be a useful predictor of outcome in PCM and could indicate modified treatment modalities in certain individuals.

Human longevity is a complex trait and increasingly we understand that both genes and lifestyle interact in the longevity phenotype. Non-genetic factors, including diet, physical activity, health habits, and psychosocial factors contribute approximately 50 % of the variability in human lifespan with another 25 % explained by genetic differences. Family clusters of nonagenarian and centenarian siblings, who show both exceptional age-span and health-span, are likely to have inherited facilitatory gene groups, but also have nine decades of life experiences and behaviours which have interacted with their genetic profiles. Identification of their shared genes is just one small step in the link from genes to their physical and psychological profiles. Behavioural genomics is beginning to demonstrate links to biological mechanisms through regulation of gene expression, which directs the proteome and influences the personal phenotype. Epigenetics has been considered the missing link between nature and nurture. Although there is much that remains to be discovered, this article will discuss some of genetic and environmental factors which appear important in good quality longevity and link known epigenetic mechanisms to themes identified by nonagenarians themselves related to their longevity. Here we suggest that exceptional 90-year old siblings have adopted a range of behaviours and life-styles which have contributed to their ageing-well-phenotype and which link with important public health messages.

Glutathione and glutathione peroxidase activity are important components in the complex body defense against oxidative damage. In this study, we have measured malondialdehyde (MDA) as a marker of oxidative stress, the antioxidant glutathione (GSH), and activity of the antioxidant enzyme (GSHPx), in a cohort of free-living elderly subjects from the Belfast Elderly Longitudinal Free-living Aging STudy (BELFAST), hypothesizing that free-living Senieur-approximated nonagenarians might demonstrate enhanced antioxidant defense mechanisms. The main finding in the BELFAST octo/ nonagenarians was that plasma antioxidant glutathione increased in nonagenarian compared with septo/octogenarian subjects (P = .015), whereas conversely antioxidant glutathione peroxidase activity fell in the nonagenarian group (P < .0001). In the same subject group, malondialdehyde, a measure of lipid peroxidation, showed no change across the age groups (P = .73). These results might overall represent a situation in which elderly survivors in the BELFAST study have evolved a sort of free radical/antioxidant equilibrium as a mechanism of successful aging.

Background. PON1, an arylesterase, associated with high density lipoprotein (HDL), protects low density lipoprotein (LDL) against oxidative modification. Common polymorphisms PON1 55 (L/M) and 192 (Q/R) in the PON1 gene associate with atherosclerosis and heart disease. Because long-lived people seem protected from premature vascular death, we conducted a pooled statistical analysis to assess any association between these polymorphisms and longevity in a large combined group of Italian centenarians and octo/nonagenarians from Northern Ireland (NI). Materials and methods. Separated DNA was available from 1479 subjects from Italy and Northern Ireland (NI). In Italy 308 centenarians (males 67, females 241, mean age 100.8, SD2.1 years) and 579 young controls (males 347, females 232, mean age 40.7, SD 12.7 years) were included in the study. In NI, 296 octo/nonagenarians (males 92, females 204, mean age 89.8, SD 5.7 years) and 296 young sex-matched subjects (mean age 13.0, SD 1.4 years) had available DNA. PON1 55 (L/M) and 192 (Q/R) polymorphisms were studied using a PCR-RFLP approach. Results. There was a significant difference in PON1 192 genotypes in Italian centenarians compared to younger controls (X2=6.8, df=2, p=0.03) and a similar but non significant trend between octo/nonagenarian and young subjects in NI (X2=4.0, df=2, p=0.14). Using logistic regression analysis on the combined Italian and Irish datasets, there was a small survival advantage for centenarian and octo/nonagenarian subjects who were heterozygous for PON1 192 R allele, (OR 1.3, CI 1-1.6; p=0.04) with a stepwise increase for RR homozygous subjects (OR 1.7, CI 1.1-2.6; p=0.02), compared to QQ subjects. Comparing R and Q alleles there was a survival advantage for octo/nonagenarian/centenarian subjects who carried the R allele (OR 1.3, CI 1.1-1.5; p=0.007), but there was no sex-specific effect (p=0.77). LL, LM and MM genotypes of PON 55 polymorphisms showed similar frequencies in Italy (39.9, 47.0, 13.1%) and Ireland (39.5, 48.6, 11.9%) with no age or sex-related differences. The PON1 192R/Q and PON55L/M loci were in strong linkage disequilibrium with a Lewontin's D′ coefficient −0.928 (elderly) and −0.965 (young). There was a significant difference in haplotype frequency of these linked loci in older compared to younger subjects (Likelihood Ratio X2=9.60, df=3, p=0.02). Conclusion. These data suggest a modest association between the 192R allele and longevity in two very elderly populations in two European countries. Being homozygous for 192 RR further enhances survival advantage but this effect was not found to be sex specific. This finding is of interest because the 192R allele has previously been associated with increased risk of coronary heart disease. On the other hand, the 192R allele shows higher enzymatic activity, using paraoxon as substrate, and we postulate that its role in the metabolism of potentially toxic chemicals or other metabolic pathways may be important in survival to very old age.

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked Files. This article is open access. 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 (

Background: The β2-integrin CD11b (Mac-1) plays a crucial role in the firm attachment of leucocytes to the endothelium during the inflammatory response. Objective: This study aimed to determine whether the increased incidence of infections witnessed in elderly individuals compared to their younger counterparts was associated with deficiencies in basal expression and/or upregulation of CD11b. Methods: Flow cytometry was used to measure CD11b expression, before and after in vitro tumour necrosis factor alpha (TNF-α) stimulation, on neutrophils, monocytes and lymphocytes from healthy volunteers aged less than 36 years and Senieur-approximated 70–85 and over 85 year olds. The TNF-α levels in serum were measured using a commercially available enzyme-linked immunoassay technique. Results: The basal expression of CD11b on monocytes and lymphocytes was highest in the 70–85-year-olds and lowest in the >85-year-olds. Following in vitro stimulation using low (10 IU) and high (100 IU) TNF-α concentrations, subjects >85 years consistently showed significantly lower increases in CD11b expression on each of the three cell types. The maximal increase in CD11b expression was in the 70–85-year age group for neutrophils and monocytes and in Conclusions: The results of this study suggest that CD11b expression on leucocytes may not be consistent throughout life. Such age-related changes could compromise the inflammatory response, rendering individuals >85 years old more susceptible to infections. Alternatively, the lower levels of CD11b expression in this group may represent downregulation and protection against excess leucocyte activation within the vascular system and may, therefore, provide a mechanism for successful ageing.

P-selectin is an adhesion molecule found in the alpha granules of platelets. Activation occurs in response to a range of inflammatory and thrombotic agents resulting in rapid up-regulation. Flow cytometry methods have recently been described for the analysis of platelet P-selectin expression in whole blood. While introducing these methods into our laboratory it was noted that expression could be stimulated, in vitro, in a number of ways. This study shows that red cell lysis, the anticoagulant K3 EDTA and the time elapse between blood collection and antibody labelling had statistically significant effects on P-selectin expression. Post-labelling fixation, with CellFIX, caused no significant effect. We conclude that blood for P-selectin analysis should be collected in sodium citrate and that red cell lysis and centrifugation should be avoided. When comparing samples, the time between collection and labelling should be standardized. The relatively high CV for the assay indicates that all samples should be labelled and analysed in duplicate with the mean level reported.

This cross-sectional study assessed relationships between plasma homocysteine, 'thermolabile' methylenetetrahydrofolatereductase (MTHFR) genotype, B vitamin status and measures of renal function in elderly (70-89 years) and nonagenarian (90+ years) subjects, with the hypothesis that octo/nonagenarian subjects who remain healthy into old age as defined by 'Senieur' status might show reduced genetic or environmental risk factors usually associated with hyperhomocysteinaemia. Plasma homocysteine was 9.1 micromol/l (geometric mean [GM]) for all elderly subjects. Intriguingly, homocysteine was significantly lower in 90+ (GM; 8.2 micromol/l) compared to 70-89-year-old subjects (GM; 9.8 micromol/l) despite significantly lower glomerular filtration rate (GFR) and serum B12 in nonagenarian subjects and comparable MTHFR thermolabile (TT) genotype frequency, folate and B6 status to 70-89-year-olds. For all elderly subjects, the odds ratio and 95% confidence intervals for plasma homocysteine being in the highest versus lowest quartile was 4.27 (2.04-8.92) for age90 compared90 years, 3.4 (1.5-7.8) for serum folate10.7 compared10.7nmol/l, 3.0 (0.9-10.2) for creatinine140 compared140 umol/l and 2.1 (1.0-4.4) for male sex. This study shows that plasma homocysteine does not invariably increase with age. Compared to similarly enlisted 70-89-year-olds, apparently well, mentally alert, community-living 90+ year olds approximating 'Senieur' status, show lower homocysteine, which is unexplained by renal function, TT genotype and B vitamin status, suggesting that lower homocysteine may be associated with survival.

Interleukin 12 (IL-12), a central cytokine acting on T and natural killer (NK) cells, directs proliferation of activated T lymphocytes towards a Th1 phenotype. The heterodimeric molecule IL-12p70, equates with IL-12 biological activity, while IL-12p40 may antagonize IL-12 and inhibit cytotoxic T lymphocyte (CTL) generation in vitro. This study characterizes age-related changes in serum total IL-12, IL-12p70 and IL-12p40 relating them with CD3(+), NK and related subsets from subjects, aged 30-96 years. Total IL-12, IL-12p40 and the IL-12p40/IL-12p70 ratio, but not IL-12p70, increased significantly with age (P

Aging is associated with changes in lymphocyte subsets and unexplained HLA-DR upregulation on T-lymphocytes. We further investigated this activation, by measuring early (CD69), middle (CD25), and late (HLA-DR) T-lymphocyte activation markers on CD3+ lymphocytes, across subjects (20-100 years) together with serum tumor necrosis factor (TNF-alpha), interferon-gamma (IFN-gamma), and soluble interleukin-2 receptor (sIL-2R). HLA-DR was present as a CD3+ HLA-DR+ subset that constituted 8% of total lymphocytes, increased twofold with age and included CD4+, CD8+, and CD45RA+ phenotypes. HLA-DR was also expressed on a CD8+ CD57+ subset. The CD3+ CD25+ subset constituted 13% of lymphocytes, fell with age but was weakly associated with the CD3+ HLA-DR+ subset especially in older subjects. A small 3-5% CD3+ CD69+ subsets showed no age effect. Serum sIL-2R, TNF-alpha, but not IFN-gamma, were associated with CD3+ HLA-DR+ lymphocytes, TNF-alpha with CD8+ CD57+ count and sIL-2R and IFN-gamma with the CD3+ CD25+/CD3+ CD4+ ratio. The study confirms age-related upregulation of HLA-DR on CD3+ lymphocytes, shows some evidence for associated upregulation of CD25 on CD3+ cells in older subjects, and links serum TNF-alpha, IFN-gamma, and sIL2-R to T-lymphocyte activation.

Aging has been shown to be accompanied by various changes in the lymphocyte subset distribution in the elderly. We have investigated more fully, and in a large number of subjects, age-related changes within several subpopulations bearing natural killer (NK) cell-associated surface antigens and changes in several cytokines involved in NK cell expansion. A total of 229 healthy subjects from all decades of life from 20 to 98 years of age was included in this cross-sectional study. A significant increase with age was found in both the absolute counts and the proportions of CD3−CD(16+56)+, CD3+CD(16+56)+, CD57+CD8+, CD57+CD8(low)+, and CD57+CD8− cells, whereas the CD57+CD8(high)+ subset, which may represent the cytolytic T cell population more precisely, showed less change with age. Some evidence is also provided to suggest that these expanded NK cell populations are in an activated state. Soluble IL-2 receptor levels were also found to increase significantly with age and correlated with certain NK cell subsets. Although the functions of some of these subsets remain to be elucidated, their expansion in the elderly may represent a remodeling of the immune system with increasing age, with an increase in non-MHC-restricted cells perhaps compensating for the previously reported decline in T and B cells in the elderly. Alternatively, increased numbers of these cells may be a direct result of cytokine dysregulation or increased antigenic or neoplastic cell challenge.

Several authors have shown that neutrophil generation of reactive oxygen species (ROS) declines with advancing age. Similar changes have also been suggested in monocytes. In both cases alterations in second messenger activity have been implicated as the most likely explanation for these observations. The aim of this study was to investigate the effect of age on phagocyte ROS generation, stimulated by the direct activation of protein kinase C (PKC). Venous blood was drawn from normal healthy subjects, cells were separated on a double density gradient into mononuclear and polymorphonuclear (pmn) cells. Phorbol myristate acetate (PMA) was employed as a cell stimulus. Superoxide generation was measured by cytochrome c reduction and myeloperoxidase (MPO) products by measurement of peak luminol chemiluminescence (CL). Fifty-eight subjects, 25 males and 33 females, were studied, median age 49 years (range 26-88 years). Polymorphonuclear cell superoxide generation was significantly higher in males and there was a trend towards higher pmn MPO product generation in males. Using Spearman's ranked correlation coefficient, monocyte superoxide generation was negatively correlated with age (r = -0.473, P0.001). No changes in the generation of MPO products was found. There were also trends towards a negative correlation of pmn cytochrome c reduction and peak luminol CL with age in males but not females. Since PMA directly activates protein kinase C, reduced monocyte superoxide generation with increasing age appears to be related to alterations in the ROS generating system downstream of the cell receptor. Impaired monocyte superoxide generation may have implications for non-specific defence against certain infections and early tumour growth in the elderly. Factors underlying these changes in monocyte function therefore require further study.

To measure anthropometric variables of weight, height, body mass index (BMI) and triceps skin fold thickness (TSF) and produce local percentiles for90 y old subjects. To assess prevalence of conventional measures of under nutrition (BMI at or below 18.5 kg/m2) or over nutrition (BMI values30 kg/m2) in this age group.Community cross-sectional study.Belfast, Northern Ireland.238 subjects90 y of age who were apparently well, mentally competent and recruited from all areas of Belfast.Mean weight was significantly heavier in male 63.9 (s.d. 9.1) kg compared to female subjects 54.4 (s.d. 11.9) kg (P0.0001). Men were significantly taller than women with mean height of 162 (s.d. 5.9) cm compared to 150 (s.d. 6.7) cm in women (P0.0001). Increasing age was associated with a fall in weight (P = 0.06 female; P = 0.09 male) and in height for women (P = 0.04). Mean BMI was 24.3 (s.d. 3.0) kg/m2 for men and 24.6 (s.d. 5.4) kg/m2 for women with no sex or age differential. 10% of females had values for BMI18.5 kg/m2. 11% of female and 2% of male subjects had BMI values30 kg/m2. TSF values were 11.7 (s.d. 4.1) mm in male and 12.3 (s.d. 4.5) mm in female subjects with no age or sex-related difference.Local percentiles for anthropometric variables are presented for subjects90 y. Both BMI and TSF show no sex or age-related difference. Ten percent of females have BMI values consistent with either under nutrition or over nutrition.

Background: Natural Killer Cells (NK) play an important role in detection and elimination of virus-infected, damaged or cancer cells. NK cell function is guided by expression of Killer Immunoglobulin-like Receptors (KIRs) and contributed to by the cytokine milieu. KIR molecules are grouped on NK cells into stimulatory and inhibitory KIR haplotypes A and B, through which NKs sense and tolerate HLA self-antigens or up-regulate the NK-cytotoxic response to cells with altered HLA self-antigens, damaged by viruses or tumours. We have previously described increased numbers of NK and NK-related subsets in association with sIL-2R cytokine serum levels in BELFAST octo/nonagenarians. We hypothesised that changes in KIR A and B haplotype gene frequencies could explain the increased cytokine profiles and NK compartments previously described in Belfast Elderly Longitudinal Free-living Aging STudy (BELFAST) octo/nonagenarians, who show evidence of ageing well.Results: In the BELFAST study, 24% of octo/nonagenarians carried the KIR A haplotype and 76% KIR B haplotype with no differences for KIR A haplogroup frequency between male or female subjects (23% v 24%; p=0.88) or for KIR B haplogroup (77% v 76%; p=0.99). Octo/nonagenarian KIR A haplotype carriers showed increased NK numbers and percentage compared to Group B KIR subjects (p=0.003; p=0.016 respectively). There were no KIR A/ B haplogroup-associated changes for related CD57+CD8 (high or low) subsets. Using logistic regression, KIR B carriers were predicted to have higher IL-12 cytokine levels compared to KIR A carriers by about 3% (OR 1.03, confidence limits CI 0.99–1.09; p=0.027) and 14% higher levels for TGF-ß (active), a cytokine with an anti-inflammatory role, (OR 1.14, confidence limits CI 0.99–1.09; p=0.002).Conclusion: In this observational study, BELFAST octo/nonagenarians carrying KIR A haplotype showed higher NK cell numbers and percentage compared to KIR B carriers. Conversely, KIR B haplotype carriers, with genes encoding for activating KIRs, showed a tendency for higher serum pro-inflammatory cytokines compared to KIR A carriers. While the findings in this study should be considered exploratory they may serve to stimulate debate about the immune signatures of those who appear to age slowly and who represent a model for good quality survivor-hood.© 2013 Rea et al.; licensee BioMed Central Ltd.

OBJECTIVE: To study whether individual Human Leucocyte Antigens (HLA) at the HLA 1 or 11 loci or the phenotypic combination A1B8Cw7DR3 were associated with longevity. DESIGN: Direct comparison of the > 90-year-old subjects with a control group. SETTING: Northern Ireland population with little migratory mobility. SUBJECTS: The > 90-year-old group (79 females, 38 males) was compared with a control group consisting of 150 unrelated blood donors (81 females, 69 males). MEASUREMENTS: Human Leucocyte Antigen (HLA) Class 1 typing was carried out on 117 nonagenarians (mean age 93.7 years) and 150 younger controls (mean age 33.7 years) using conventional serological methods; HLA DR typing was carried out on 102 of the 117 > 90-year-old subjects, together with the 150 control subjects, and performed using restriction fragment length polymorphisms. The frequency of the phenotypic combination A1B8Cw7DR3 was measured in both groups. RESULTS: There were no significant differences in the HLA antigen frequencies between the very elderly groups and the younger subjects at the A, B, C, and DR loci. The phenotypic combination A1B8Cw7DR3 was significantly increased (×3) in nonagenarian men compared with young men but not between elderly women and young women. There was a trend for increased representation of this phenotype in elderly men compared with women of the same age. CONCLUSIONS: The frequency of the supratype A1B8Cw7DR3 was significantly increased in very elderly men but not in elderly women. Since this phenotypic combination has been associated with immune surveillance and/or hyperactivity in Caucasians, there is the suggestion that it could influence longevity through immune mechanisms but that sex differences may exist in its influence and expression.

In 2004, the integrated European project GEHA (Genetics of Healthy Ageing) was initiated with the aim of identifying genes involved in healthy ageing and longevity. The first step in the project was the recruitment of more than 2500 pairs of siblings aged 90years or more together with one younger control person from 15 areas in 11 European countries through a coordinated and standardised effort. A biological sample, preferably a blood sample, was collected from each participant, and basic physical and cognitive measures were obtained together with information about health, life style, and family composition. From 2004 to 2008 a total of 2535 families comprising 5319 nonagenarian siblings were identified and included in the project. In addition, 2548 younger control persons aged 50-75years were recruited. A total of 2249 complete trios with blood samples from at least two old siblings and the younger control were formed and are available for genetic analyses (e.g. linkage studies and genome-wide association studies). Mortality follow-up improves the possibility of identifying families with the most extreme longevity phenotypes. With a mean follow-up time of 3.7years the number of families with all participating siblings aged 95years or more has increased by a factor of 5 to 750 families compared to when interviews were conducted. Thus, the GEHA project represents a unique source in the search for genes related to healthy ageing and longevity. In 2004, the integrated European project GEHA (Genetics of Healthy Ageing) was initiated with the aim of identifying genes involved in healthy ageing and longevity. The first step in the project was the recruitment of more than 2500 pairs of siblings aged 90years or more together with one younger control person from 15 areas in 11 European countries through a coordinated and standardised effort. A biological sample, preferably a blood sample, was collected from each participant, and basic physical and cognitive measures were obtained together with information about health, life style, and family composition. From 2004 to 2008 a total of 2535 families comprising 5319 nonagenarian siblings were identified and included in the project. In addition, 2548 younger control persons aged 50-75years were recruited. A total of 2249 complete trios with blood samples from at least two old siblings and the younger control were formed and are available for genetic analyses (e.g. linkage studies and genome-wide association studies). Mortality follow-up improves the possibility of identifying families with the most extreme longevity phenotypes. With a mean follow-up time of 3.7years the number of families with all participating siblings aged 95years or more has increased by a factor of 5 to 750 families compared to when interviews were conducted. Thus, the GEHA project represents a unique source in the search for genes related to healthy ageing and longevity.

Nonagenarians are the fastest growing sector of populations across Western European and the developed world. They are some of the oldest members of our societies and survivors of their generation and may help us understand how to age not only longer, but better. The Belfast Longevity Group enlisted the help of 500 community-living, mobile, mentally competent, 'elite' nonagenarians, as part of an ongoing study of ageing. We assessed some immunological, cardiovascular, nutritional and genetic factors and some aspects of their interaction in this group of 'oldest old'. Here we present some of the evidence related to genetic and nutritional factors which seem to be important for good quality ageing in nonagenarians from the Belfast Elderly Longitudinal Free-living Ageing STudy (BELFAST).

Paraoxonase 1 (PON1) has been suggested as a plausible candidate gene for human longevity due to its modulation of cardiovascular disease risk, by preventing oxidation of atherogenic low-density lipoprotein. The role of the PON1 192 QJR polymorphism has been analyzed for association with survival at old age in several populations, albeit with controversial results. To reconcile the conflicting evidence, we performed a large association study with two samples of 2357 Germans and 1025 French, respectively. We combined our results with those from seven previous studies in the largest and most comprehensive meta-analysis on PON1 192 Q/R and longevity to-date, to include a total of 9580 individuals. No significant association of PON1 192 Q/R with longevity was observed, for either R allele or carriership. This finding relied on very large sample sizes, is supported by different analysis methods and is therefore considered very robust. Moreover, we have investigated a potential interaction of PON1 192 Q/R with APOE epsilon 4 using data from four populations. Whereas a significant result was found in the German sample, this could not be confirmed in the other examined groups. Our large-scale meta-analysis provided no evidence that the PON1 192 Q/R polymorphism is associated with longevity, but this does not exclude the possibility of population-specific effects due to the influence of, and interaction between, different genetic and/or environmental factors (e.g. diet). (C) 2010 Elsevier Ireland Ltd. All rights reserved.

Introduction: Centenarians are reservoirs of genetic and environmental information to successful ageing and local centenarian groups may help us to understand some of these secrets. The current centenarian cohort in Belfast survived the 1970s epidemic of death from coronary heart disease in Northern Ireland, where cardiovascular mortality was almost highest in the world. These centenarians provided an opportunity to assess biological and genetic factors important in cardiovascular risk and ageing. Methods: Thirty-five (27 female, 8 male) centenarians, participants of the Belfast Elderly Longitudinal Free-living Ageing STudy (BELFAST), were community-living and of good cognition at enrolment. Results: Centenarians showed median Body Mass Index (BMI) at 25.7, systolic blood pressure 140mmHg and diastolic blood pressure 90mmHg respectively, and fasting glucose of 5.54mmol/l with no sex-related difference. Lipoproteins showed median cholesterol 5.3, High Density Lipoprotein (HDL) 1.10 and Low Density Lipoprotein (LDL) 3.47mmol/l respectively. Centenarian smokers showed no different blood pressure or lipid measurements compared with non-smokers. Malondialdehyde, a measure of lipid peroxidation, was low at 1.19 umol/l, and measures of antioxidant status showed variable results. Male centenarians did not carry any of the vascular risk genotypes studied ApoE4 for Apolipoprotein E (ApoE), DD for Angiotensin-Converting Enzyme (ACE), and TT for Methylene Tetrafolate-dehydrogenase reductase (MTHFR), though this is not true for female centenarians. Conclusions: This small local study shows, that Belfast centenarians carry a reasonably favourable risk profile with respect to cardiovascular disease. There is also some evidence suggesting that vascular risk factors and genotypes may be tolerated differently between the male and female centenarians. Maintaining an optimal cardiovascular risk profile seems likely to improve the chance of becoming a centenarian, especially for males.

Udgivelsesdato: 2007-Apr The aim of the 5-year European Union (EU)-Integrated Project GEnetics of Healthy Aging (GEHA), constituted by 25 partners (24 from Europe plus the Beijing Genomics Institute from China), is to identify genes involved in healthy aging and longevity, which allow individuals to survive to advanced old age in good cognitive and physical function and in the absence of major age-related diseases. To achieve this aim a coherent, tightly integrated program of research that unites demographers, geriatricians, geneticists, genetic epidemiologists, molecular biologists, bioinfomaticians, and statisticians has been set up. The working plan is to: (a) collect DNA and information on the health status from an unprecedented number of long-lived 90+ sibpairs (n = 2650) and of younger ethnically matched controls (n = 2650) from 11 European countries; (b) perform a genome-wide linkage scannning in all the sibpairs (a total of 5300 individuals); this investigation will be followed by linkage disequilibrium mapping (LD mapping) of the candidate chromosomal regions; (c) study in cases (i.e., the 2650 probands of the sibpairs) and controls (2650 younger people), genomic regions (chromosome 4, D4S1564, chromosome 11, 11.p15.5) which were identified in previous studies as possible candidates to harbor longevity genes; (d) genotype all recruited subjects for apoE polymorphisms; and (e) genotype all recruited subjects for inherited as well as epigenetic variability of the mitochondrial DNA (mtDNA). The genetic analysis will be performed by 9 high-throughput platforms, within the framework of centralized databases for phenotypic, genetic, and mtDNA data. Additional advanced approaches (bioinformatics, advanced statistics, mathematical modeling, functional genomics and proteomics, molecular biology, molecular genetics) are envisaged to identify the gene variant(s) of interest. The experimental design will also allow (a) to identify gender-specific genes involved in healthy aging and longevity in women and men stratified for ethnic and geographic origin and apoE genotype; (b) to perform a longitudinal survival study to assess the impact of the identified genetic loci on 90+ people mortality; and (c) to develop mathematical and statistical models capable of combining genetic data with demographic characteristics, health status, socioeconomic factors, lifestyle habits.

In this study, we have assessed any change in the frequency of the GG homozygotes of the 174 IL-6 polymorphism with increasing age, arguing that if IL-6 tracks with functional disability and age-related diseases, then there may be attrition or reduction in the frequency of homozgyous subjects, who produce higher levels of IL-6 in serum, in older survivors in a population. We have tested this hypothesis in a large group of free-living, mentally competent, nonagenarian and octogenarian subjects from the Belfast Elderly Longitudinal Ageing Study—BELFAST study and found that the frequency of GG homozygotes with IL-6-174C/G polymorphism decreases with age by about 10%, compared with young controls. In addition we find that CC homozygotes have higher serum levels of IL-6 levels compared with GG (P=0.055), with reciprocal and significant changes in the anti-inflammatory IL-10 (P=0.05). Both IL-6 and IL-10 were spontaneously produced from separated mononuclear cell monolayers in elderly subjects, with significantly higher levels of secreted IL-10 supernatant levels (P=0.05) at 20 h, for G allele subjects carrying the IL-6-174C/G polymorphism. In conclusion, in the BELFAST study, there appears to be a reduction in the frequency of GG homozygotes in the octo/nonagenarian age group and a higher serum IL-6 level associated with CC homozygotes with reciprocal changes for the anti-inflammatory cytokine IL-10.

Cytokines, the central regulators of leucocyte growth and differentiation, are produced by a wide variety of cell types, target various cell subsets and exhibit numerous biological activities. Cytokine dysregulation is believed to play a role in the remodelling of the immune system in old age, however, previous reports of cytokine levels in elderly subjects have been conflicting, possibly due to methodologies employed. We used the relatively new technique of intracellular cytokine detection by flow cytometry to measure cytokine production in CD3+ lymphocytes from young and elderly subjects, but applied it to whole blood, thereby eliminating the need for laborious cell separation techniques and maintaining cells in their normal physiological environment. We found the assay to be very reproducible with acceptable intra- (2.9%) and inter- (6.3%) assay CVs. The percentages of CD3+ cells producing TNF-alpha and IFN-gamma were significantly higher in elderly compared to young people (p=0.0049; p=0.0026, respectively) after stimulation with PMA and ionomycin. Absolute counts of CD3+IFN-gamma+ and CD3+TNF-alpha+ cells were also significantly higher in the elderly group (p=0.039; p=0.051) respectively. There was no significant difference between the age groups for the percentage or numbers of IL-2-producing CD3+ cells on stimulation. CD3+ cells expressing TNF-alpha were highly associated with CD3+ cells expressing IFN-gamma in both elderly and young people. In contrast, IL-2 secreting CD3+ cells were associated with TNF-alpha and IFN-gamma producing CD3+ cells in young but not elderly subjects providing further evidence for the remodelling of the cytokine network associated with old age.

Background It is unclear whether physical activity in later life is beneficial for maintenance of cognitive function. We performed a systematic review examining the effects of exercise on cognitive function in older individuals, and present possible mechanisms whereby physical activity may improve cognition. Methods Sources consisted of PubMed, Medline, CINAHL, the Cochrane Controlled Trials Register, and the University of Washington, School of Medicine Library Database, with a search conducted on August 15, 2012 for publications limited to the English language starting January 1, 2000. Randomized controlled trials including at least 30 participants and lasting at least 6 months, and all observational studies including a minimum of 100 participants for one year, were evaluated. All subjects included were at least 60 years of age. Results Twenty-seven studies met the inclusion criteria. Twenty-six studies reported a positive correlation between physical activity and maintenance or enhancement of cognitive function. Five studies reported a dose-response relationship between physical activity and cognition. One study showed a nonsignificant correlation. Conclusion The preponderance of evidence suggests that physical activity is beneficial for cognitive function in the elderly. However, the majority of the evidence is of medium quality with a moderate risk of bias. Larger randomized controlled trials are needed to clarify the association between exercise and cognitive function and to determine which types of exercise have the greatest benefit on specific cognitive domains. Despite these caveats, the current evidence suggests that physical activity may help to improve cognitive function and, consequently, delay the progression of cognitive impairment in the elderly.

The ApoE gene has three alleles coding for the proteins apoE2, apoE3 and apoE4. E4 has been reported to be associated with hypercholesteraemia, ischaemic heart disease, age-related cognitive decline and Alzheimer's disease. Conversely, the E2 allele has been associated with longevity in French centenarians and their siblings. In this study, we have assessed any shift in the ApoE genotypes in nonagenarian subjects from Belfast where there is a high intrinsic incidence of cardiovascular disease. ApoE phenotypes were determined by electrofocusing and immunoblotting in 114 Senieur-approximated subjects >90 years old and compared with 2071 subjects, 30–65 years of age, recruited from the same geographical area by the MONItoring of CArdiovascular trends study group in Belfast (MONICA). The E4 allele was reduced in the nonagenarian group (X2=11.1; P=0.0006), the E3 unchanged and E2 frequency was increased (X2=4.0; P=0.047). These results suggest that longevity is negatively associated with the E4 allele and may be associated with carriage of E2.

We have previously reported the presence of Hsp60 and Hsp70 in the peripheral circulation of normal individuals. Given that the capacity to generate stress proteins declines with age, this study measured Hsp60 and Hsp70 levels in the sera of 60 individuals aged between 20 and 96 years. Levels of anti-human Hsp60, anti-human Hsp70 and anti-mycobacterial Hsp65 antibody were also measured. Senieur-approximated elderly subjects were well and randomly selected from the Belfast Elderly Longitudinal Free-living Aging STudy (BELFAST). Samples from younger individuals were obtained from the Northern Ireland Blood Transfusion Service. Hsp60, anti-Hsp60, anti-Hsp70 and anti-mycobacterial Hsp65 antibodies were detected in all samples, whereas Hsp70 was detectable in only 46 of the samples analysed (77%). Regression analysis revealed a progressive decline in Hsp60 (759ng/ml40 years; 294ng/mlor = 90 years) and Hsp70 (400ng/ml40 years; 20ng/mlor = 90 years) levels with age whereas no relationship was apparent for anti-Hsp60 and Hsp65 antibody levels. Hsp70 antibody levels tended to increase with age (115U/ml40 years; 191U/mlor = 90 years). This study in Senieur-approximated subjects demonstrates an apparent decrease in Hsp60 and Hsp70 with increasing age that does not appear to be related to anti-heat shock protein antibody status. These findings support in vitro work that demonstrates an age-related reduced ability to respond to stress. Further studies are required to understand the basis for declining serum Hsp60 and Hsp70 levels in aging and to elucidate their origin and role in the maintenance of homeostasis and resistance to environmental challenges.

Enumeration of various lymphocyte subsets is used widely in the diagnosis and monitoring of various disease states. With the development of flow cytometric technology and whole blood analysis, methodologies have become more sensitive. It is therefore important to establish reference intervals in normal, healthy individuals using these techniques to give a better indication of the border between health and disease. Since some lymphocyte subpopulations are known to change with age, we have enumerated common subsets in healthy individuals from all decades of adult life, including nonagenarian subjects. We report reference intervals for these subsets in each age group, which will be of use in diagnosis and disease monitoring, particularly in elderly subjects, the most rapidly expanding group within the population today.

Northern Ireland remains close to the top of the world league for coronary heart disease [1]. Classical risk factors such as blood pressure, cholesterol and cigarette smoking do not explain country wide differences as shown by the WHO MONICA project [1]. Hyperhomocysteinaemia is a risk factor for vascular disease and accounts for approximately 10% of the population’s cardiovascular disease risk [2]. The homozygous thermolabile (tt) genotype of 5,10methylenetetrahydrofolate reductase (MTHFR) contributes significantly to hyperhomocysteinaemia [3] and is present in 5–15% of individuals in european and asian populations [4]. The tt genotype itself is associated with cardiovascular disease [5] and may be expected to account for a proportion of homocysteine associated mortality. Elderly people are survivors of their peer groups and are likely to have been protected from premature vascular disease and its associated mortality. Previous studies of genetic risk factors for vascular diseases found that the apolipoprotein E (apo E) ‘o4’ allele, which is associated with premature atherosclerosis, was found significantly less frequently in elderly individuals compared to young controls, whereas the ‘protective’ o2 allele was more frequently present [6]. We conducted a similar study to assess the importance of the tt genotype in determining early mortality. Subjects (male 106, female 217) aged 80 to 104 years (mean age 89) were enlisted from the Greater Belfast area General Practices. Ethical permission was obtained for all subjects, who were apparently well, mentally competent, ambulatory and living in the community. Controls (n=625) were a working male population aged 30–49 years from the same geographical area. The control genotype frequencies conformed to the Hardy-Weinberg predictions [3] indicating that no genotype specific losses had occurred in this age group. No studies to date have documented any differences between male and female genotype frequencies for control populations. MTHFR genotyping was carried out as described previously [3]. Statistical significance was assessed by x test. In the older age group the overall frequencies for the thermolabile homozygotes, the heterozygotes and the non thermolabile homozgyotes were 9.6, 48.3 and 42.1% respectively. The tt genotype frequency was 9.6% in the elderly group (male 10.4, female 9.2%), compared to 11.5% in the controls (not significant, P=0.37). The heterozygote frequency was slightly elevated in the elderly (48.3 versus 43.7% in controls, P=0.18). The elderly subjects showed a slight, non-significant departure from the Hardy-Weinberg genotype frequency predictions: 31 tt genotypes (36.8 expected) and 156 heterozygotes (144.4 expected) (P\0.10). The OR, * Corresponding author. Tel.: +44 1232 245133, ext. 2153; fax: +44 1232 325839: e-mail: ger.med@qub.ac.uk

Understanding how to 'Age Longer and Age Well' is a priority for people personally, for populations globally and for government policy. Nonagenarians are the oldest members of our societies and survivors of their generation. Approximately 10 % of nonagenarians reach 90 years and beyond in good condition and seem to have a combination of both age-span and health-span. But what are the factors which help people reach their ninetieth birthday and beyond in good condition? Are they genetics, as in 'nature', or do they depend on 'nurture' and are related to environment, or are both factors inextricably intertwined within the concept of behavioural genetics? Nonagenarians have rich life experiences that can teach us much about ageing well; they are reservoirs of genetic, life-style and behavioural information which can help dissect out how to live not only longer but better. Personal family history and narrative are powerful tools that help to determine familial traits, beliefs and social behaviours and when used in parallel with new biotechnology methods inform and elaborate causality. Here we present themes and insights from personal narrative enquiry from nonagenarian participants from the Belfast Elderly Longitudinal Free-living Ageing STudy (BELFAST) about factors they consider important for good quality ageing and relate these insights to the emerging genetics and life-style evidence associated with healthy longevity.

In this study, the changes in some of the cellular components of the immune system and the activity of the cytokine interleukin 2, important for immune activation and lymphocyte proliferation, were measured in a large cross-sectional study of all age groups including octogenarian and nonagenarian subjects. In 206 apparently well community-living subjects, the absolute lymphocyte count and T and B cell numbers fell a little in old and very old subjects. Within the T cell compartment, helper/inducer CD4+ T cells, together with their subsets identified as 'naive' (CD4+/CD45RA+) and 'memory' (CD4+/CD45RO+) cells, also showed a decline with increased age. The suppressor/cytotoxic CD8+ subset showed no age-related change. The levels of the cytokine interleukin 2 were very low in octogenarian and nonagenarian subjects, while the soluble interleukin 2 receptor levels increased with increasing age. The interleukin 2 levels were associated with number and percentage of the 'memory' (CD4+/CD45RO+) subset of T cells which mediates the host response to previously met antigens. Since the interleukin 2 values were very low in the oldest groups and were associated with a reduced 'memory' (CD4+/CD45RO+) compartment, this suggests a possible mechanism of why the very elderly subject is more susceptible to morbidity and mortality from infectious or other agents.

We report the case of a patient with severe hypothyroid coma in whom hypothyroid-related neurogenic oropharyngeal dysphagia was suspected, videoscopically confirmed, and successfully treated. This complication has not previously been described, and may have contributed to the historically high mortality associated with severe cases of hypothyroid coma. In the future, the early detection and aggressive treatment of this complication and its sequelae should ensure a further reduction in mortality from hypothyroid coma.