Centenarian Population Research Articles

N-Glycomic Changes in Serum Proteins During Human Aging

N-glycan profiling of the human serum glycoproteins including immunoglobulin fraction on different age groups of healthy persons shows substantial changes with increasing age in three major N-glycan structures. In individuals more than 40-50 years of age, there is an increase in under-galactosylated glycans and a decrease in the core alpha-1,6-fucosylated bi-galactosylated biantennary structure. These three glycan structures are also substantially changed in a Werner syndrome patient, to a level comparable or even more pronounced than those observed in a healthy Italian centenarian population. These data show that the glycosylation machineries in both liver cells and B-cells are affected in a similar way by the aging process despite their highly different nature. The observed changes in the glycan structures are indicative that biosynthetic processes are at the basis of the changes, possibly together with changes in serum clearing of glycan-altered proteins. Our data suggest that measurement of the N-glycan level changes could provide a noninvasive surrogate marker for general health or for age-related disease progression, and for monitoring the improvement of health after therapy.

Lack of replication of genetic associations with human longevity

The exceptional longevity of centenarians is due in part to inherited genetic factors, as deduced from data that show that first degree relatives of centenarians live longer and have reduced overall mortality. In recent years, a number of groups have performed genetic association studies on long-living individuals (LLI) and young controls to identify alleles that are either positively or negatively selected in the centenarian population as consequence of a demographic pressure. Many of the reported studies have shown genetic loci associated with longevity. Of these, with the exception of APOE, none have been convincingly reproduced. We validated our populations by typing the APOE locus. In addition, we used 749 American Caucasian LLI, organized in two independent tiers and 355 American Caucasian controls in the attempt to replicate previously published findings. We tested Klotho (KL)-VS variant (rs952706), Cholesteryl Ester Transfer Protein (CETP) I405V (rs5882), Paraoxonase 1 (PON1) Q192R (rs662), Apolipoprotein C-III (APOC3) -641C/A (rs2542052), Microsomal Transfer Protein (MTP) -493G/T (rs2866164) and apolipoprotein E (APOE) epsilon2 and epsilon4 isoforms, (rs7412 and rs429358) haplotypes respectively. Our results show that, at present, except for APOE, none of the selected genes show association with longevity if carefully tested in a large cohort of LLI and their controls, pointing to the need of larger populations for case-control studies in extreme longevity.

Echocardiographic Characteristics in Patients ≥100 Years of Age

The centenarian population is increasing, and patients > or =100 years old are encountered more frequently in clinical practice. Cardiovascular disease is the most common cause of death in this subset of patients. We report the echocardiographic characteristics of 63 hospitalized centenarians. Patients ranged in age from 100 to 112 years and were admitted to the hospital for a variety of diagnoses. The mean left ventricular end-diastolic dimension was 3.9 +/- 0.7 cm (2.8 to 5.8), the mean left ventricular end-systolic dimension was 1.8 +/- 0.7 cm (0.8 to 3.5), the mean ventricular septal thickness was 1.2 +/- 0.25 cm (0.8 to 1.9), the mean left ventricular posterior wall thickness was 1.1 +/- 0.14 cm (0.8 to 1.6), the mean left ventricular ejection fraction was 84% +/- 11% (49% to 97%), the mean aortic root diameter at the level of the sinuses was 3.3 +/- 0.4 cm (2.1 to 4.1), the mean left atrial dimension was 4.5 +/- 0.7 cm (3.1 to 7), the mean right ventricular end-diastolic dimension was 3.4 +/- 0.6 cm (2.0 to 4.8), and the mean pulmonary artery systolic pressure was 37 +/- 14 mm Hg. Moderate or severe valvular lesions were common, including aortic stenosis (27%), aortic regurgitation (17%), mitral regurgitation (22%), and tricuspid regurgitation (28%). In conclusion, centenarian hearts have important differences from younger hearts, including more hypertrophied left ventricle, higher ejection fraction, higher pulmonary artery systolic pressure, and more prevalent significant valvular heart disease.

Characteristics, Management, and Outcomes of 5,557 Patients Age ≥90 Years With Acute Coronary Syndromes: Results From the CRUSADE Initiative

The goal of this work was to explore the treatment and outcomes of patients with non-ST-segment elevation acute coronary syndromes (NSTE-ACS) age > or =90 years. The elderly are often excluded from clinical trials of NSTE-ACS and are underrepresented in clinical registries. We used data from the CRUSADE registry to study 5,557 patients with NSTE-ACS age > or =90 years and compared their baseline characteristics, treatment patterns, and in-hospital outcomes with a cohort age 75 to 89 years (n = 46,270). Although both groups had much in common, compared with the younger elderly, the older elderly were less likely to be diabetic, smokers, or obese. Among patients without contraindications, the older elderly were less likely to receive glycoprotein IIb/IIIa inhibitors and statins during the first 24 h and were less likely to undergo cardiac catheterization within 48 h. The older elderly were more likely to die (12.0% vs. 7.8%) and experienced more frequent adverse events (26.8% vs. 21.3%) during the hospitalization-differences that persisted after adjustment for baseline patient and hospital characteristics. Increasing adherence to guideline-recommended therapies was associated with both increased bleeding and a graded reduction in risk-adjusted in-hospital mortality across both age groups. In this large population of nonagenarians and centenarians with NSTE-ACS, increasing adherence to guideline-recommended therapies was associated with decreased mortality. These findings reinforce the importance of optimizing care patterns for even the oldest patients with NSTE-ACS, while examining novel approaches to reduce the risk of bleeding in this rapidly expanding patient population.

Psychological aspects of ageing

This paper examines the psychological aspects of ageing. In particular, it focuses on two experimental psychology phenomena – the speed of performance and intellectual performance – in order to understand how these two aspects of functioning interrelate and change with normal ageing. This helps to provide useful insights into psychological adaptation across the lifespan, and helps to identify opportunities for constructive intervention. The focus is on: slowing down with age, the trade-offs made in speed and accuracy, ageing and intellectual performance (particularly the use of the Wechsler Adult Intelligence Scale, WAIS), intellectual skills in relation to mortality and ‘terminal decline’ and factors associated with maintaining intellectual functioning in later life. Finally, since the centenarian population has increased at a rate of approximately 7% a year throughout the economically developed world since 1960, it briefly considers the need for a new generation of longitudinal studies in order to throw considerable light on the developments occurring in extreme old age.

Study of the Association with −330T/G IL-2 in a Population of Centenarians from Centre and South Italy

Immune response in elderly is characterised by a progressive loss of the ability to cope environmental stressors with a characteristic remodelling of cytokine network. One of the data constantly reported in literature is the decrease of IL-2 production. An IL-2 central role in the reconstitution of T cell function in vitro is largely documented. Studies on a T-->G polymorphism at -330 nt of IL-2 gene promoter region have demonstrated that T lymphocytes from 330GG homozygous subjects are able to produce in vitro higher amount of IL-2, than -330TG heterozygous or -330TT homozygous subjects. As a genetic background conditioning the maintaining of an efficient immune response would exert positive effects on healthy ageing, we have typed for 330T/G IL-2 single nucleotide polymorphism (SNP), 168 centenarians and 214 control subjects matched for age and ancestry from Centre and South Italy to check the 330GG genotype association to longevity. The statistical analysis doesn't show a significant difference of genotypic and allelic frequencies at -330 IL-2 T/G SNP among centenarians and controls. Comparing the two cohorts of subjects by extended Mantel Haenszel procedure a marginally significant trend for an increased -330TT genotype frequency was observed. Our data seem to be paradoxical considering the role attributed to a well-conserved T cell function in the successful ageing. On the other hand, in a recent study on a sample of Irish octogenarians a similar distribution of -330T/G genotype even was observed. These data suggest that a genetic background favouring an increased IL-2 production might be detrimental for longevity. On the other hand, an increase of IL-2 and other pro-inflammatory cytokine production characterise the Alzheimer's disease serum profile. All in all our data seem to suggest that reduction of -330G allele frequency might be protective for healthy ageing limiting cell mediated inflammation implied in age associated diseases.

Do Centenarians Die Healthy? An Autopsy Study

Our goal was to assess the prevalence of common causes of death and the demographic variables in a selected population of centenarians. The autopsy reports and medical histories of all individuals > or =100 years, dying unexpectedly out of hospital, were gathered from 42,398 consecutive autopsies, performed over a period of 18 years at the Institute of Forensic Medicine, Vienna. These records were evaluated with regard to age and sex, circumstances of death, season, time and the cause of death, as well as the presence of any other comorbidity. Forty centenarians (11 men, 29 women) were identified with a median age of 102 +/- 2.0 (range: 100-108) years. Sixty percent were described as having been healthy before death. However, an acute organic failure causing death was found in 100%, including cardiovascular diseases in 68%, respiratory illnesses in 25%, gastrointestinal disorders in 5%, and cerebrovascular disease in 2%. Additionally, centenarians suffered from several comorbidities (cardiac antecedents, neurologic disorders, liver diseases, cholecystolithiasis), which were not judged to be the cause of death. Centenarians, though perceived to have been healthy just prior to death, succumbed to diseases in 100% of the cases examined. They did not die merely "of old age." The 100% post mortem diagnosis of death as a result of acute organic failure justifies autopsy as a legal requirement for this clinically difficult age group.

Estado de salud de los muy ancianos: situación clínica y funcional de la población centenaria

We planned a prospective and descriptive analysis of the centenarian population in Lugo sanitary area, establishing their social, functional and medical status as well as its relationship with their basic hematological and biochemical parameters. During the study period between January 2001 and September 2003, participants were visited at home by a doctor and a nurse. The following variables were assessed: social status, past medical history, physical examination, functional status (Barthel index), blood analysis. 54 centenarians were interviewed, 16 men and 38 women. 75.9% were widows; 87% lived with their family and 57,4% in urban areas. 79.6% had followed studies. All of them had their own incomes. Regarding past medical history, 64.8% had some visual or auditive disturbances, 81.5% were taking medical drugs, 59.3% had some surgical intervention and 46.3% had been hospitalized for medical reasons. Their vaccination status was poor. Functional status, assessed by Barthel index, showed an average of 59 +/- 36.4, higher in men (82.7 +/- 28.7) than in women (49.6 +/- 35.1) (p<0.003). Blood samples were analyzed in 51 cases, there were not significant differences among them regarding sex or physical disability. The features of the centenarian population of Lugo are similar to other countries. It is an heterogeneous group. There are more women, but their clinical and functional status are significantly worse than in males. We have not founded a relationship between hematological and nutritional parameters and the degree of functional dependence in centenarians.

High prevalence of autoantibodies among Danish centenarians.

The aim of this study was to investigate the prevalence of organ and nonorgan specific autoantibodies in relation to disability and comorbidity in an unselected population of centenarians. A population-based survey of all persons living in Denmark who celebrated their 100th birthday during the period 1 April 1995 to 31 May 1996, a total of 276 persons, was undertaken. Participants underwent an interview, a physical examination and blood sampling. Organ specific autoantibodies (Tg-ab, TPO-ab, PCA-ab) and nonorgan specific autoantibodies (ANA, IgM RF, IgA RF, MPO-ab, c-ANCA, p-ANCA, oxLDL-ab, IgM ACA, IgG ACA, PR3-ANCA, histone-ab, SSA-ab, SSB-ab, Mit-ab) were measured, and comorbidity and disability (Katz Index of ADL) were registered. In all, 207 (75.0%) of 276 eligible subjects participated, and 148 agreed to blood tests. A large majority (79.3%) had at least one autoantibody detected. Organ specific autoantibodies were present in 32.1% of the centenarians. The high level of autoantibodies did not reflect an equally high level of overt autoimmune disease. While nonorgan specific autoantibodies were equally represented in less-disabled/disabled subjects as well as in subjects with low/high comorbidity, significantly fewer subjects with organ specific autoantibodies were found among less-disabled subjects or subjects with low comorbidity. Autoantibodies (both nonorgan and organ specific) are common in an unselected population of centenarians of today, but do not reflect an equally high level of overt autoimmune disease. Non-organ specific autoantibodies are evenly distributed irrespective of the level of disability or comorbidity, suggesting underlying, undiagnosed pathological processes which may be part of the processes involved in frailty.

Hip fractures in centenarians

The centenarian population is increasing yet there is little about their morbidity and mortality rates following hip fracture. The aim was to review centenarians treated for proximal femoral fractures in Edinburgh describing treatment outcomes in relation to mortality, walking ability and residential status comparing centenarians with a the more typical hip fracture population. In this retrospective review, 18 centenarians sustaining hip fractures in Edinburgh between 1998 and 2002 were compared to 18 randomly selected “normal” hip fracture patients aged 75–83 years. Centenarian in-hospital, 1 and 4 month mortality was 11.1, 33.3 and 50%, respectively, versus 0, 0 and 5.6% in the normal group. Centenarian 4 month mortality was significantly greater than that of the normal group (Fisher’s Exact Test, P=0.00723 ). A total of 22.2% of centenarians regained pre-fracture walking ability compared to 58.8% of the normal patients. A total 28.6% of centenarians could continue living independently post-fracture compared to 69.2% of the normal group.

Reaching for Utopia and slouching toward Gomorrah.

Reaching for Utopia and slouching toward Gomorrah.

A Sociological Assessment of Centenarians from Central Illinois Cemeteries, 1825–1985

Centenarians, the fastest growing age group in the United States, recently have become the focus of medical and social research. However, historically, little is known of centenarians beyond anecdotal narrative. This research identifies 60 centenarians from 55,914 burials between 1825 and 1985 in a single Midwest county. These centenarians are compared to a sample of burials from the same county and time span, and to patterns of current centenarians. The prevalence of centenarians, historically, compares more favorably with current prevalence rates than anticipated, suggesting regional concentrations of the oldest old. Racial crossover was found, as anticipated, but historically, centenarians were not as disproportionately female as is the contemporary centenarian population. Seasonal death patterns of centenarians are similar to, but more exaggerated than, the seasonal patterns of younger elderly. Finally, findings suggest that centenarians came from larger families than noncentenarians, and that these families experienced greater longevity.

Healthy centenarians do not exist, but autonomous centenarians do: a population-based study of morbidity among Danish centenarians.

To assess the prevalence of common illnesses in an unselected population of centenarians. A population-based survey. Denmark. All Danes who celebrated their 100th anniversary between April 1, 1995 and May 31, 1996: 276 persons. All participants (including proxies) were visited at their domicile for an interview (sociodemographic characteristics, activities of daily living, living conditions, need of assistance from other people, former health and current diseases, current medication) and a clinical examination (dementia screening test, heart and lung auscultation, neurological assessment, height and weight, electrocardiogram, arm and ankle blood pressure, assessment of hearing and vision capacity, a short physical performance test, bio-impedance, lung function test, blood test). Further health information was retrieved from medical files and national health registers. Seventy-five percent (207) of eligible subjects participated in the study. Cardiovascular disease was present in 149 (72%) subjects. Osteoarthritis (major joints) was present in 54%, hypertension (> or =140/ > or =90) in 52%, dementia in 51%, and ischemic heart disease in 28%. The mean number of illness was 4.3 (standard deviation (SD) 1.86). Only one subject was identified as being free from any chronic condition or illness. Sixty percent had been treated for illness with high mortality. In 25 autonomous (nondemented, functioning well physically, living at home) and 182 nonautonomous centenarians, comorbidities were equivalent. Because they have a high prevalence of several common diseases and chronic conditions, Danish centenarians are not healthy. However, a minor proportion was identified as being cognitively intact and functioning well.

New polymorphisms in the human poly(ADP-ribose) polymerase-1 coding sequence: lack of association with longevity or with increased cellular poly(ADP-ribosyl)ation capacity.

Poly(ADP-ribose) polymerase-1 (PARP-1) encoded by the PARP-1 gene, is a ubiquitous and abundant DNA-binding protein involved in the cellular response to various genotoxic agents. In a previous study we showed that maximal oligonucleotide-stimulated poly(ADP-ribosyl)ation was significantly higher in permeabilised lymphoblastoid cell lines from a French population of centenarians compared with controls aged 20-70 years, supporting the notion that longevity is associated with a genetically determined, high poly(ADP-ribosyl)ation capacity. Here, we describe four new genetic polymorphisms, three of which represent silent nucleotide variants (C402T, T1011C, G1215A), and one of which leads to a valine762-to-alanine exchange (T2444C). We undertook an association study between two of these polymorphisms and human longevity or poly(ADP-ribosyl)ation capacity in permeabilised lymphoblastoid cells. By analysing 648 DNA samples from a French population (324 centenarians and 324 controls) by fluorescent-allele-specific PCR, we showed the absence of any significant enrichment of any of the genotypes in the study of centenarians versus controls. Furthermore, we studied genotype distributions from individuals who had previously been tested for poly(ADP-ribosyl)ation capacity. None of the genotype combinations at any polymorphic site studied could be related to a high or low level of poly(ADP-ribosyl)ation capacity. Together, these results strongly suggest that the longevity-related differences in the poly(ADP-ribosyl)ation capacity of human lymphoblastoid cell lines cannot be explained by genetic polymorphisms in the PARP-1 coding sequence and that other mechanisms have to be considered as potential regulators of specific poly(ADP-ribosyl)ation capacity.

Thyroid function, morphology and prevalence of thyroid disease in a population-based study of Danish centenarians.

To investigate thyroid function, morphology, and autoimmunity in relation to physical function in an unselected population of centenarians. A population-based survey. Denmark. All persons living in Denmark who celebrated their 100th anniversary during the period April 1, 1995 to May 31, 1996, a total of 276 persons. Thyroid hormones (TSH, T4, FT4I, T3, FT3I, and T3RU), thyroid autoantibodies (TPOab and Tgab), thyroid volume, activities of daily living according to the Katz Index of ADL. In all, 207 (75%) of the 276 eligible subjects participated, and 148 agreed to blood tests. Among the participants, 2.9% had previously known hyperthyroidism, and the same proportion had previously known hypothyroidism. The blood tests did not reveal any undiagnosed cases of overt thyroid dysfunction. However 7.2% had a subnormal serum TSH, and 2.9% had an elevated serum TSH; all had normal serum T3 and serum T4 levels. Thyroid autoantibodies were detected in 26 (17.6%) centenarians (11.5% had Tgab and 9.5% had TPOab). Among relatively independent centenarians, low serum T3 was significantly associated with high comorbidity (P = .029), whereas both low serum T3 and thyroid autoantibodies were significantly associated with ADL-dependency (P < .001 and P = .030, respectively). Ultrasonography (n = 50) revealed a small gland with a median volume of 8.3 mL (range 3.2-27.9) compared with an expected volume of 20 mL (14-26) (P < .001). There was no significant relationship to body weight. When examined by ultrasound, only 26% had significant morphological alterations. Thyroid dysfunction does not seem to be more prevalent among centenarians than among younger old people. Low serum T3 is related to poor physical function and co-morbidity, whereas thyroid autoimmunity is related only to poor physical functioning. Despite atrophy of the thyroid gland, these findings suggest that thyroid function is well preserved in centenarians.

Polymorphisms at the Werner locus: I. Newly identified polymorphisms, ethnic variability of 1367Cy/Arg, and its stability in a population of Finnish centenarians

The Werner syndrome gene (WRN) encodes a novel helicase of 1,432 amino acids. Homozygous mutations, all of which result in the truncation of the protein, lead to Werner syndrome. However, little is known about the role of WRN in "normal" aging. We have identified four missense polymorphisms and four conservative polymorphsims in WRN gene. A single study showed that a polymorphism at amino acid 1367 Cys(TTG)/ Arg(CTG) is associated with a variation in risk of myocardial infarction among a Japanese population. The 1367 Cys/Arg polymorphism was examined during aging in three different populations: Finnish, Mexican, and North American. The frequencies of 1367 Cys were higher than those of 1367 Arg in all the populations examined, though the frequencies varied among populations. The frequency of the 1367 Arg allele, thought to be protective against myocardial infarction in a Japanese population, was approximately three times higher in the North American and Finnish adult populations. When newborns and centenarians were compared within the Finnish population, no differences were observed in the proportions of 1367 Cys/Arg across age groups. Within the Finnish population, we confirmed a significant decrease of the APOE epsilon2 allele and an increase in the epsilon4 allele in newborn infants compared with centenarians. Thus, unlike the APOE polymorphism, there is no evidence of an association of this WRN polymorphism with longevity.

Polymorphisms at the Werner locus: I. Newly identified polymorphisms, ethnic variability of 1367Cy/Arg, and its stability in a population of Finnish centenarians

Polymorphisms at the Werner locus: I. Newly identified polymorphisms, ethnic variability of 1367Cy/Arg, and its stability in a population of Finnish centenarians

A census-based comparison of centenarians in New Zealand with those in the United States.

To describe the characteristics of New Zealand's centenarians, as given in the 1991 census, and to compare these characteristics with those of centenarians from the United States. A census-based descriptive study. The complete national population as defined by the 1991 New Zealand census. In 1991, there were 246 female and 51 male centenarians in New Zealand. Fifty-one percent of the men and 29% of the women lived at home; 16% lived at home with someone else (55% with children). People who were widowed were more likely to be living in a residential institution (69%) than people who were married (40%). Forty-three percent of men and 39% of women earned less than NZ$10,000 per year. Most had no formal educational qualification. Fourteen percent of men and 35% of women living at home did housework in the previous week. Compared with the United States, there are fewer New Zealand centenarians per number of population. People of European race were overrepresented in the New Zealand centenarian population, whereas African Americans were overrepresented in the United States centenarian population. Our data have shown the heterogeneity associated with extreme ageing and can be used as a basis for comparison with other countries.

Elevated lipoprotein(a) levels and small apo(a) isoforms are compatible with longevity: Evidence from a large population of French centenarians

Epidemiological studies have shown lipoprotein(a) (Lp(a)) to be an independent risk factor for cardiovascular disease. Lp(a) is a cholesterol-rich, low-density lipoprotein (LDL)-like particle to which a large glycoprotein, apolipoprotein(a) (apo(a)) is attached. Plasma Lp(a) levels are highly genetically determined and influenced to a minor degree by environmental factors. In an effort to determine whether Lp(a) might be associated with longevity, we have evaluated Lp(a) levels and apo(a) isoform sizes in a population of French centenarians ( n=109) compared to a control group ( n=227). The mean age of centenarians was 101.5±2.4 years while the control group was 39.4±7.2 years. Plasma levels of total cholesterol and triglyceride were within the normal range in both centenarian and control subjects. Lp(a) levels were higher in centenarians (both male and female) than in the normolipidemic control group (mean Lp(a) level=0.33±0.42 and 0.22±0.27 mg/ml, respectively, P<0.005). The distribution of apo(a) isoforms was significantly shifted towards small isoform size in the centenarian population as compared to the controls (54.4 and 41.4% of isoforms≤27 kringles (kr), respectively, P=0.04). Nonetheless, the apo(a) size distribution in centenarians did not entirely explain the high Lp(a) levels observed in this population. Factors other than apo(a) size, and which may be either genetic or environmental in nature, appear to contribute to the elevated plasma Lp(a) levels of our centenarian population. We conclude therefore that high plasma Lp(a) levels are compatible with longevity.

Hormone levels in centenarians

The serum profiles of total triiodothyronine (T(3)), free thyroxin (fT(4)), thyroid stimulating hormone (TSH), cortisol, prolactin (HPRL), parathormone (PTH), osteocalcin and growth hormone (GH) were measured in a group of 12 centenarians and compared to the values of a control group of twenty-nine subjects, aged 67-98 years. The study was aimed at revealing whether there are appreciable differences or age-related modifications in the hormone status of healthy control elderly and the centenarian population. In this series, the modifications in hormone levels were unremarkable, and the serum levels of the studied hormones in centenarians often fell within a range considered to be normal for the younger age classes.