Healthy Centenarians Research Articles

Circulating miR-19a-3p and miR-19b-3p characterize the human aging process and their isomiRs associate with healthy status at extreme ages.

Blood circulating microRNAs (c‐miRs) are potential biomarkers to trace aging and longevity trajectories to identify molecular targets for anti‐aging therapies. Based on a cross‐sectional study, a discovery phase was performed on 12 donors divided into four groups: young, old, healthy, and unhealthy centenarians. The identification of healthy and unhealthy phenotype was based on cognitive performance and capabilities to perform daily activities. Small RNA sequencing identified 79 differentially expressed c‐miRs when comparing young, old, healthy centenarians, and unhealthy centenarians. Two miRs, that is, miR‐19a‐3p and miR‐19b‐3p, were found increased at old age but decreased at extreme age, as confirmed by RT‐qPCR in 49 donors of validation phase. The significant decrease of those miR levels in healthy compared to unhealthy centenarians appears to be due to the presence of isomiRs, not detectable with RT‐qPCR, but only with a high‐resolution technique such as deep sequencing. Bioinformatically, three main common targets of miR‐19a/b‐3p were identified, that is, SMAD4, PTEN, and BCL2L11, converging into the FoxO signaling pathway, known to have a significant role in aging mechanisms. For the first time, this study shows the age‐related increase of plasma miR‐19a/b‐3p in old subjects but a decrease in centenarians. This decrease is more pronounced in healthy centenarians and was confirmed by the modified pattern of isomiRs comparing healthy and unhealthy centenarians. Thus, our study paves the way for functional studies using c‐miRs and isomiRs as additional parameter to track the onset of aging and age‐related diseases using new potential biomarkers.

The Immunity Clock.

The immune system has been for long considered a marker of health. The age-related decline in its function results in a greater incidence of infections, autoimmune diseases, and cancer. Nevertheless, it is still not known if immune function can be used to accurately estimate the rate of aging of an individual. A set of 14 immune function variables were measured in 214 healthy individuals ranging from 19 to 88 years old. All immune variables were selected as independent variables for the prediction of age by multiple linear regression. The Immunity Clock was constructed including the following 5 immune variables: natural killer activity, phagocytosis and chemotaxis of neutrophils, and chemotaxis and proliferative capacity of lymphocytes, reaching an adjusted R2 of 80.3% and a standard error of the estimate of 4.74 years. The Immunity Clock was validated in a different group of healthy individuals (N = 106) obtaining a Pearson's correlation coefficient of .898 (p < .001) between chronological age and the age estimated by the Immunity Clock, the ImmunolAge. Moreover, we demonstrate that women with anxiety (N = 10) show a higher ImmunolAge than their chronological age, whereas healthy centenarians (N = 8) show a lower one. In addition, the Immunity Clock provided here proves to be useful for monitoring the effectiveness of a nutritional intervention lasting 1 month, by detecting a diminished ImmunolAge in the same individuals. Further research will be needed to ascertain if the Immunity Clock is a passive marker of the aging process or it plays an active role in it.

Rare genetic variants prioritize molecular pathways for semaphorin interactions in Alzheimer’s disease patients

Contemporary genetic methods have not yet solved the ‘missing heritability’ problem of complex diseases such as Alzheimer’s disease (AD). The impact of rare or less common variation on human complex diseases and traits remains to date barely investigated. In this study rare population variants detected using whole-exome sequencing were employed to examine how molecular pathways are prioritized in four groups: Alzheimer’s disease (AD) patients, Frontotemporal dementia (FTD) patients, young and healthy individuals and centenarians. The set of prioritized genes in AD patients associated with Semaphorin interactions pathways, contrasting with the results of the other groups. We identified rare pathogenic, likely pathogenic and variants of unknown significance in these prioritized genes in AD patients. The results of this study offer evidence that semaphorin pathways play a role in AD genetic etiology.

Immune response and endocytosis pathways are associated with the resilience against Alzheimer’s disease

AbstractBackgroundDeveloping Alzheimer’s disease (AD) is influenced by multiple genetic variants that are involved in five major AD‐pathways: immune response, β‐amyloid metabolism, endocytosis, cholesterol/lipid metabolism and angiogenesis. The extent to which these pathways are involved in the resilience against AD have thus far been poorly addressed. Here, we investigated the association of each molecular mechanism with (i) the increased risk of AD, and (ii) the resilience against AD until extreme old age, by comparing pathway‐specific polygenic risk scores (pathway‐PRS).MethodWe focused on 29 genetic variants identified in GWAS studies of AD to calculate a pathway‐PRS for the five major pathways involved in AD. For our pathway‐PRS, we developed an integrative framework that allows multiple genes to associate with a variant, and multiple pathways to associate with a gene. We studied the pathway‐PRSs in the Amsterdam Dementia Cohort of well‐phenotyped AD patients (N = 1,909), Dutch population controls from the Longitudinal Aging Study Amsterdam (N = 1,654), and our unique 100‐plus Study cohort of cognitively healthy centenarians who avoided AD (N = 293). Moreover, we estimated the contribution of each pathway to the genetic risk of AD in the general population.ResultAll pathway‐PRSs (except for angiogenesis) significantly associated with increased AD‐risk and, in the opposite direction, with resilience against AD (p &lt; 0.05). The pathway that contributed the most to the overall modulation of AD‐risk was β‐amyloid metabolism (29.6%), which was driven mainly by APOE‐variants. After excluding APOE variants, all pathway‐PRSs (except for angiogenesis) associated with increased AD‐risk (p &lt; 0.05), while specifically immune response (p = 0.003) and endocytosis (p = 2.2 × 10−4) significantly associated, in the opposite direction, with resilience against AD. Indeed, the variants in these pathways were the main contributors to the overall modulation of genetic risk of AD in the general population (45.5% and 19.2%, respectively).ConclusionThe genetic variants associated with the resilience against AD indicate which pathways are involved with maintained cognitive functioning until extreme ages. Our work suggests that a favorable immune response and a maintained endocytosis pathway might be involved in neuro‐protection mechanisms of AD, which highlight the need to investigate these pathways, next to β‐amyloid metabolism.

Dietary vitamin intake and risk of metabolic syndrome among centenarians in China.

The present study aimed to investigate dietary vitamin intake levels and their association with the prevalence of obesity, hypertension, dyslipidemia and hyperglycemia in centenarians in China. From June 2014 to December 2016, a total of 992 centenarians aged >99 years (177 males and 815 females; age range, 100-115 years) were enrolled through household visits in the cities and rural areas of Hainan province. Details regarding food intake were recorded by continuous collection of 7-day food frequency and 24-h dietary review, and dietary vitamin intake levels were calculated according to the Chinese Food Composition Table. The deficiency rates of vitamin A (VA), VE, VB1, VB2, niacin and VC among the centenarians were relatively high and the prevalence of metabolic syndrome (MS) was 53.67% (519/967). The dietary intake levels of VA, VE and PP were significantly higher among the healthy centenarians than among the centenarians with MS (P<0.05). Compared with the lowest quartiles (Q1) of dietary vitamin intake, higher dietary intake levels of VA (Q4) [odds ratio (OR)=0.72; 95% CI: 0.38, 0.99], VE (Q3) (OR=0.61; 95% CI=0.36, 0.88) and VB2 (Q4) (OR=0.51; 95% CI: 0.32, 0.81) were associated with a reduced risk of hypertension (P<0.05). However, higher dietary intake levels of VA, VE, VB2 and PP were associated with increased risks of central obesity, hyperglycemia and low high-density lipoprotein cholesterol levels. A high prevalence of MS and vitamin deficiency were detected among the centenarians and these two items were associated with each other. It was indicated that specific vitamins are necessary for certain centenarians.

A Prospective, Randomized, Double Blind, Two Arms, Parallel, Placebo Controlled, Clinical Study to Evaluate the Efficacy of OPTIMEALTH FOOD P Supplementation in Modulating Gut Microbiome in Healthy Adults

A structured and equilibrated gut microbiome is needed for optimal health status. Factors such as antibiotic use, caesarean-section deliveries, excessive hygiene, stress, and lack of exercise have a major impact on the microbiome which further leads to microbiota shift. This shift may trigger the development of several disorders, such as obesity, metabolic syndrome, cardiovascular diseases, colorectal cancer and Inflammatory Bowel Diseases (IBD). The present study was designed to evaluate the efficacy and safety of the formulation OPTIMEALTH® FOOD P (OF PB-LBF) on gut microbiota population. OPTIMEALTH® FOOD P® is composed of more than 300 metabolites produced by a selected complex of lactic acid bacteria strains through high tech Fermentation Technology. OPTIMEALTH® FOOD P was developed by studying the microbiota of healthy centenarians who have a particular microbiota profile. A total of 59 subjects compliant with inclusion criteria were randomly assigned to one of the two groups, OPTIMEALTH® FOOD P or placebo group using a simple randomization process. Consumption of OPTIMEALTH® FOOD P by healthy men and women with self-selected diets and unchanged physical activity patterns resulted in the group of OPTIMEALTH® FOOD P in an increased of Bifidobacterium longum by 27.5%, Lactobacillus acidophilus by 24.6%, Lactobacillus plantarum by 28.6%, Roseburia intestinalis by 14.5%, Faecalibacterium prausnitzii by 23.4% and an increase of Akkermansia muciniphila by 11.11%. In conclusion, supplementation with OPTIMEALTH® FOOD P resulted in significant gut microbiota modulation. The tolerance was good among subjects. No side effects or adverse events were reported during the study. Hence OPTIMEALTH® FOOD P at 100 mg/day could be recommended as a safe solution to modulate gut microbiota and improve diseases related to microbiota dysbiosis.

20-Year trend of high prevalence of zero coronary artery calcium in beach cities of Southern California: A blue zone?

BackgroundBlue zones are longevity hotspots around the world characterized by highest concentrations of healthy centenarians. Certified blue zone communities are designed by implementation of environmental and policy changes that promote healthy behaviors. ObjectiveTo examine the trends of prevalence of zero CAC, a marker of ideal cardiovascular and overall health status and burden of cardiovascular risk factors in Beach Cities/certified blue zones of Southern California and rest of California. MethodsThis is a population-based cohort study of persons aged 50 years or older in California, who underwent CAC screening between 2000 and 2019. A total of 3864 participants from Beach Cities of Southern California were identified by Zip Codes and compared with 35,537 participants from rest of California. We compared trends of prevalence of zero CAC and cardiovascular risk factors between the two groups, in 5-year intervals. ResultsAmong 39,401 participants (mean age, 58.1 years; 36% women), 13,374 (34%) had zero CAC. The prevalence of CAC ​= ​0 was significantly higher in Beach Cities compared to the rest of California (p ​< ​0.001). Across the study period, the prevalence of cardiac risk factors including obesity, smoking, diabetes and hypertension remain significantly lower in Beach Cities. (p ​< ​0.001) ConclusionsThis study, shows for the first time, that higher prevalence of zero CAC in Beach Cities of California, adds validity to excellent prognosis and longevity in these areas. The impact of policy implementation and environmental changes on lifestyle patterns, cardiovascular health and healthy ageing needs to be evaluated.

Immune response and endocytosis pathways are associated with the resilience against Alzheimer\u2019s disease

Developing Alzheimer’s disease (AD) is influenced by multiple genetic variants that are involved in five major AD-pathways. Per individual, these pathways may differentially contribute to the modification of the AD-risk. The pathways involved in the resilience against AD have thus far been poorly addressed. Here, we investigated to what extent each molecular mechanism associates with (i) the increased risk of AD and (ii) the resilience against AD until extreme old age, by comparing pathway-specific polygenic risk scores (pathway-PRS). We used 29 genetic variants associated with AD to develop pathway-PRS for five major pathways involved in AD. We developed an integrative framework that allows multiple genes to associate with a variant, and multiple pathways to associate with a gene. We studied pathway-PRS in the Amsterdam Dementia Cohort of well-phenotyped AD patients (N = 1895), Dutch population controls from the Longitudinal Aging Study Amsterdam (N = 1654) and our unique 100-plus Study cohort of cognitively healthy centenarians who avoided AD (N = 293). Last, we estimated the contribution of each pathway to the genetic risk of AD in the general population. All pathway-PRS significantly associated with increased AD-risk and (in the opposite direction) with resilience against AD (except for angiogenesis, p < 0.05). The pathway that contributed most to the overall modulation of AD-risk was β-amyloid metabolism (29.6%), which was driven mainly by APOE-variants. After excluding APOE variants, all pathway-PRS associated with increased AD-risk (except for angiogenesis, p < 0.05), while specifically immune response (p = 0.003) and endocytosis (p = 0.0003) associated with resilience against AD. Indeed, the variants in these latter two pathways became the main contributors to the overall modulation of genetic risk of AD (45.5% and 19.2%, respectively). The genetic variants associated with the resilience against AD indicate which pathways are involved with maintained cognitive functioning until extreme ages. Our work suggests that a favorable immune response and a maintained endocytosis pathway might be involved in general neuro-protection, which highlight the need to investigate these pathways, next to β-amyloid metabolism.

Nutritional Aspects of Spermidine.

Natural polyamines (spermidine and spermine) are small, positively charged molecules that are ubiquitously found within organisms and cells. They exert numerous (intra)cellular functions and have been implicated to protect against several age-related diseases. Although polyamine levels decline in a complex age-dependent, tissue-, and cell type-specific manner, they are maintained in healthy nonagenarians and centenarians. Increased polyamine levels, including through enhanced dietary intake, have been consistently linked to improved health and reduced overall mortality. In preclinical models, dietary supplementation with spermidine prolongs life span and health span. In this review, we highlight salient aspects of nutritional polyamine intake and summarize the current knowledge of organismal and cellular uptake and distribution of dietary (and gastrointestinal) polyamines and their impact on human health. We further summarize clinical and epidemiological studies of dietary polyamines.

Metagenomics Study Reveals Changes in Gut Microbiota in Centenarians: A Cohort Study of Hainan Centenarians.

Several studies based on 16SrDNA analysis have revealed certain unique characteristics of gut microbiome in centenarians. We established a prospective cohort of fecal microbiota and conducted the first metagenomics-based study among centenarians. The objective was to explore the dynamic changes of gut microbiota in healthy centenarians and centenarians approaching end of life and to unravel the characteristics of aging-associated microbiome. Seventy-five healthy centenarians residing in three regions of Hainan participated in follow-up surveys and collection of fecal samples at intervals of 3 months. Data pertaining to dietary status, health status scores, cause of disease and death, and fecal specimens were collected for 15 months. Twenty participants died within 20 months during the follow-up period. The median survival time was 8–9 months (range, 1–17) and the mortality rate was 14.7% per year. The health status scores before death were significantly lower than those at 3 months before the end of the follow-up period [median score: 3 (range, 1–5), P < 0.05]. At this time, the participants mainly exhibited symptoms of anorexia and reduced dietary intake and physical activity. Metagenomics sequencing and analysis were carried out to characterize the gut microbiota changes in the centenarians during their transition from healthy status to death. Anosim analysis showed a significant change in gut microbiota from 7 months prior to death (R = 0.10, P = 0.02). All participants were grouped with 7 months before death as cut-off; no significant difference in α diversity was found between the two groups (P = 0.45). Semi-supervised monitoring and log rank sum analysis revealed significant changes in the abundance of ten bacterial species before death; of these, eight species were significantly reduced (Akkermansia muciniphila, Alistipes finegoldii, Alistipes shahii, Bacteroides faecis, Bacteroides intestinalis, Butyrivibrio crossotus, Bacteroides stercoris, and Prevotella stercorea) while two were significantly increased before death (Bifidobacterium longum and Ruminococcus bromii). Compared to centenarians in northern Italy, Hainan centenarians exhibited unique characteristics of gut microbiome. The abundance of ten bacterial species showed significant changes starting from 7 months before death. We speculate that these changes might occur before the clinical symptoms of deterioration in health status.

Successful aging: insights from proteome analyses of healthy centenarians.

Healthy aging depends on a complex gene-environment network that is ultimately reflected in the expression of different proteins. We aimed to perform a comparative analysis of the plasma proteome of healthy centenarians (n=9, 5 women, age range 100–103 years) with a notably preserved ambulatory capacity (as a paradigm of ‘successful’ aging), and control individuals who died from a major age-related disease before the expected life expectancy (n=9, 5 women, age range: 67–81 years), and while having impaired ambulatory capacity (as a paradigm of ‘unsuccessful’ aging). We found that the expression of 49 proteins and 86 pathways differed between the two groups. Overall, healthy centenarians presented with distinct expression of proteins/pathways that reflect a healthy immune function, including a lower pro-inflammatory status (less ‘inflammaging’ and autoimmunity) and a preserved humoral immune response (increased B cell-mediated immune response). Compared with controls, healthy centenarians also presented with a higher expression of proteins involved in angiogenesis and related to enhanced intercellular junctions, as well as a lower expression of proteins involved in cardiovascular abnormalities. The identification of these proteins/pathways might provide new insights into the biological mechanisms underlying the paradigm of healthy aging.

Self-reported oral health in the Dutch 100-plus Study of cognitively healthy centenarians: an observational cohort study

BackgroundDue to improved healthcare, more people reach extreme ages. Oral health in the oldest-old has thus far been poorly described. Here, we investigated self-reported oral health factors, use of professional oral health care, and associations with clinical measures in centenarians considered cognitively healthy.MethodsIn this observational cohort study, we included 162 (74% female) centenarians from the Dutch 100-plus Study cohort who self-reported to be cognitively healthy, as confirmed by a proxy. Centenarians were questioned about their physical well-being including medication use and their cognitive functioning was evaluated using the Mini-Mental State Examination. Questions regarding oral health included preservation of teeth, oral pain or discomfort, chewing ability, xerostomia, and time since last visit to an oral health care provider. Associations between oral health and clinical measures were investigated with ordinal logistic or linear regression analyses, adjusted for gender, age, and education.ResultsThe majority of the centenarians indicated to have good oral health: 76% felt no oral pain/discomfort, 65% indicated to chew well; while only 18% had symptoms of xerostomia. Of all centenarians, 83% were edentulous and were wearing removable complete maxillary and mandibular dental prostheses, 1% was edentulous with no dental prosthesis, while 16% was dentate with or without removable partial dental prostheses (10 and 6% respectively). Dentate and edentulous centenarians experienced similar levels of oral pain and/or discomfort, chewing ability, xerostomia, and their cognitive functioning was similar. No relationship between cognitive functioning and chewing ability was found. Xerostomia was associated with medication use (p = .001), which mostly regarded medications for cardiovascular diseases, diuretics, anti-coagulants, and antacids. Only 18% of the centenarians visited an oral health care provider during the year prior to the interview, of whom 48% were dentate centenarians. Notably, 49% of the centenarians had not visited an oral health care provider for ≥10 years.ConclusionsMost centenarians were edentulous and did not report oral complaints. Less than one-fifth of the centenarians continued to seek regular professional oral health care. Since the proportion of dentates in the oldest-old will increase in the near future, a proactive attitude toward this group is necessary.

Distribution Characteristics of Rare Earth Elements and Selenium in Hair of Centenarians Living in China Longevity Region.

In order to explore the characteristics of the rare earth elements (REEs) and selenium (Se) among the Chinese centenarians, the concentrations of REE and Se were detected in the hair of healthy centenarians living in typical Chinese longevity region, and the influences of physiological conditions and behavior on the concentrations of REE and Se were assessed. The average values of light RE (LRE) and heavy RE (HRE) are 31.87 and 11.12ng/g. Female centenarians had higher concentrations of lanthanum (La), praseodymium (Pr), gadolinium (Gd), terbium (Tb), erbium (Er), thulium (Tm), yttrium (Y), and Se but lower levels of cerium (Ce), neodymium (Nd), samarium (Sm), europium (Eu), dysprosium (Dy), holmium (Ho), ytterbium (Yb), and lutetium (Lu). Except for Ce, the higher the age, the lower the REE and Se content were. Smoking was positively associated with Dy, Er, and Yb levels, whereas drinking habits showed no significant effect on all the elements. Elderly individuals who ate smoked and pickled food and who consumed high amounts of salt had higher levels of REE and Se in their hair, and centenarians who consumed egg and milk had higher Se and REE in the hair than did the non-eaters. This comprehensive study on the REE and Se concentrations among the healthy centenarians can provide scientific support for shaping a healthy aging society.

Immune Function, Oxidative, and Inflammatory Markers in Centenarians as Potential Predictors of Survival and Indicators of Recovery After Hospital Admission.

Several parameters of immune function, oxidative, and inflammatory stresses have been proposed as markers of health and predictors of longevity and mortality. However, it is unknown if any of these parameters can be used as predictors of survival in centenarians. Therefore, in a group of 27 centenarians, at the time of admission to the Clinical Hospital of Madrid, a series of immune function, antioxidant, oxidant, and inflammatory parameters were studied. Some centenarians survived and others did not, thus establishing two groups, "survivors" (n = 9) and "nonsurvivors" (n = 18). The results show that surviving centenarians display higher neutrophil chemotaxis and microbicidal capacity, natural killer activity, lymphoproliferation, glutathione reductase activity, and basal interleukin-10 release. Moreover, lower neutrophil and lymphocyte adherence, superoxide anion and malondialdehyde concentrations, and basal release of tumor necrosis factor α are also reported. The odds ratios for survival for these parameters were also calculated, with the highest odds ratios being the lymphoproliferative capacity and the ex vivo basal and stimulated release of interleukin-6 from mononuclear cells (odds ratio = 136.00). Therefore, these parameters have the potential to be used in the clinical setting as predictors of survival in centenarians. In the survivors group, the same parameters were also analyzed after 3 months. Because survivors showed an increase in neutrophil and lymphocyte chemotaxis capacity during the recovery period, reaching similar values to those observed in healthy centenarians, these parameters could be proposed as indicators of recovery.

Allele-Specific Transcript Abundance: A Pilot Study in Healthy Centenarians.

The genetic basis of healthy aging and longevity remains largely unexplained. One hypothesis as to why long-lived individuals do not appear to have a lower number of common-complex disease variants, is that despite carrying risk variants, they express disease-linked alleles at a lower level than the wild-type alleles. Allele-specific abundance (ASA) is the different transcript abundance of the two haplotypes of a diploid individual. We sequenced the transcriptomes of four healthy centenarians and four mid-life controls. CIBERSORT was used to estimate blood cell fractions: neutrophils were the most abundant source of RNA, followed by CD8+ T cells, resting NK cells, and monocytes. ASA variants were more common in noncoding than coding regions. Centenarians and controls had a comparable distribution of ASA variants by predicted effect, and we did not observe an overall bias in expression toward major or minor alleles. Immune pathways were most highly represented among the gene set that showed ASA. Although we found evidence of ASA in disease-associated genes and transcription factors, we did not observe any differences in the pattern of expression between centenarians and controls in this small pilot study.

The complete genome sequence of Bifidobacterium longum LTBL16, a potential probiotic strain from healthy centenarians with strong antioxidant activity

B. longum LTBL16 is a potential probiotic strain that was isolated from healthy centenarians in Bama, China. In vitro experiments show that B. longum LTBL16 has a strong antioxidant activity and the complete genome of B. longum LTBL16 was sequenced in this work. The genome consists of one 2,430,682 bp circular chromosome that is plasmid free. The circular chromosome has a GC content of 61.23% and contains 2071 coding sequences (CDSs), 4 rRNA manipulators and 55 tRNA coding genes. Genetic analysis showed that at least five protein-coding genes were associated with antioxidant activity, and the abundance of these genes may be related to free radical scavenging rates and oxygen tolerance. In addition, the safety of B. longum LTBL16 was evaluated using a virulence factor database and antibiotic resistance gene database. The results indicate that B. longum LTBL16 has the good potential for the development and utilization as a probiotic.

Meta-analysis of genomic variants and gene expression data in schizophrenia suggests the potential need for adjunctive therapeutic interventions for neuropsychiatric disorders

Schizophrenia (SZ) is a debilitating mental illness with a multigenic aetiology and significant heritability. Despite extensive genetic studies, the molecular aetiology has remained enigmatic. A recent systems biology study suggested a protein-protein interaction network for SZ with 504 novel interactions. The onset of psychiatric disorders is predominant during adolescence, often accompanied by subtle structural abnormalities in multiple regions of the brain. The availability of BrainSpan Atlas data allowed us to re-examine the genes present in the SZ interactome as a function of space and time. The availability of genomes of healthy centenarians and nonpsychiatric Exome Aggregation Consortium database allowed us to identify the variants of criticality. The expression of the SZ candidate genes responsible for cognition and disease onset was studied in different brain regions during particular developmental stages. A subset of novel interactors detected in the network was further validated using gene expression data of post-mortem brains of patients with psychiatric illness. We have narrowed down the list of drug targets proposed by theprevious interactome study to 10 proteins. These proteins belonging to 81 biological pathways are targeted by 34 known Food and Drug Administration-approved drugs that have distinct potential for the treatment of neuropsychiatric disorders. We also report the possibility of targeting key genes belonging to celecoxib pharmacodynamics, Gα signalling and cGMP-PKG signalling pathwaysthat are not known to be specific to SZ aetiology.

Neuropsychological Test Performance of Cognitively Healthy Centenarians: Normative Data From the Dutch 100-Plus Study.

ObjectivesThe fraction of the population that reaches the age of 100 years is growing. At this age, dementia incidence is high and cognitive functioning is highly variable across individuals. Normative data for neuropsychological tests are lacking in centenarians, which hampers the ability to evaluate their cognitive functioning for both research and clinical practice. Here, we generated norms for neuropsychological tests in a sample of cognitively healthy centenarians while taking sensory impairments into account.DesignCross‐sectional cohort study.SettingCentenarians who participate in the prospective 100‐plus Study.ParticipantsA total of 235 centenarians (71.5% female), who self‐reported to be cognitively healthy, which was confirmed by an informant and a trained researcher.MeasurementsWe generated normative data for 15 cognitive tests, measuring global cognition (Mini‐Mental State Examination [MMSE]), premorbid intelligence, attention, language, memory, executive function, and visuospatial function by multiple linear regressions and/or by reporting percentiles.ResultsNormative data for global cognition resulted in a mean MMSE score of 25.6 ± 3.1 (range = 17‐30; interquartile range = 24‐28). Vision problems and fatigue often complicated the ability to complete tests, and these problems explained 41% and 22% of the missing test scores, respectively. In contrast, hearing problems (4%) and task incomprehension (6%) rarely complicated test performance. While educational level was associated with performance on the majority of the tests, sex and age were only weakly associated with test performance.ConclusionsWe generated normative data for 15 common neuropsychological tests in a large sample of cognitively healthy centenarians, while taking age‐related sensory impairments into consideration. These normative data allow the detection of deficits across a wide range of cognitive domains. Our results suggest that, next to education level, vision ability and the level of fatigue should be taken into account when evaluating cognitive functioning in centenarians. J Am Geriatr Soc 67:759–767, 2019.

The 100-plus Study of cognitively healthy centenarians: rationale, design and cohort description

Although the incidence of dementia increases exponentially with age, some individuals reach more than 100 years with fully retained cognitive abilities. To identify the characteristics associated with the escape or delay of cognitive decline, we initiated the 100-plus Study (www.100plus.nl). The 100-plus Study is an on-going prospective cohort study of Dutch centenarians who self-reported to be cognitively healthy, their first-degree family members and their respective partners. We collect demographics, life history, medical history, genealogy, neuropsychological data and blood samples. Centenarians are followed annually until death. PET–MRI scans and feces donation are optional. Almost 30% of the centenarians agreed to post-mortem brain donation. To date (September 2018), 332 centenarians were included in the study. We analyzed demographic statistics of the first 300 centenarians (25% males) included in the cohort. Centenarians came from higher socio-economic classes and had higher levels of education compared to their birth cohort; alcohol consumption of centenarians was similar, and most males smoked during their lifetime. At baseline, the centenarians had a median MMSE score of 25 points (IQR 22.0–27.5); most centenarians lived independently, retained hearing and vision abilities and were independently mobile. Mortality was associated with cognitive functioning: centenarians with a baseline MMSE score ≥ 26 points had a mortality percentage of 17% per annual year in the second year after baseline, while centenarians with a baseline MMSE score < 26 points had a mortality of 42% per annual year (p = 0.003). The cohort was 2.1-fold enriched with the neuroprotective APOE-ε2 allele relative to 60–80 year-old population controls (p = 4.8 × 10−7), APOE-ε3 was unchanged and the APOE-ε4 allele was 2.3-fold depleted (p = 6.3 × 10−7). Comprehensive characterization of the 100-plus cohort of cognitively healthy centenarians might reveal protective factors that explain the physiology of long-term preserved cognitive health.

Centenarian controls increase variant effect sizes by an average twofold in an extreme case\u2013extreme control analysis of Alzheimer\u2019s disease

The detection of genetic loci associated with Alzheimer’s disease (AD) requires large numbers of cases and controls because variant effect sizes are mostly small. We hypothesized that variant effect sizes should increase when individuals who represent the extreme ends of a disease spectrum are considered, as their genomes are assumed to be maximally enriched or depleted with disease-associated genetic variants. We used 1,073 extensively phenotyped AD cases with relatively young age at onset as extreme cases (66.3 ± 7.9 years), 1,664 age-matched controls (66.0 ± 6.5 years) and 255 cognitively healthy centenarians as extreme controls (101.4 ± 1.3 years). We estimated the effect size of 29 variants that were previously associated with AD in genome-wide association studies. Comparing extreme AD cases with centenarian controls increased the variant effect size relative to published effect sizes by on average 1.90-fold (SE = 0.29, p = 9.0 × 10−4). The effect size increase was largest for the rare high-impact TREM2 (R74H) variant (6.5-fold), and significant for variants in/near ECHDC3 (4.6-fold), SLC24A4-RIN3 (4.5-fold), NME8 (3.8-fold), PLCG2 (3.3-fold), APOE-ε2 (2.2-fold), and APOE-ε4 (twofold). Comparing extreme phenotypes enabled us to replicate the AD association for 10 variants (p < 0.05) in relatively small samples. The increase in effect sizes depended mainly on using centenarians as extreme controls: the average variant effect size was not increased in a comparison of extreme AD cases and age-matched controls (0.94-fold, p = 6.8 × 10−1), suggesting that on average the tested genetic variants did not explain the extremity of the AD cases. Concluding, using centenarians as extreme controls in AD case–control studies boosts the variant effect size by on average twofold, allowing the replication of disease-association in relatively small samples.