Protein signatures of centenarians and their offspring suggest centenarians age slower than other humans

Using samples from the New England Centenarian Study (NECS), we sought to characterize the serum proteome of 77 centenarians, 82 centenarians'' offspring, and 65 age‐matched controls of the offspring (mean ages: 105, 80, and 79 years). We identified 1312 proteins that significantly differ between centenarians and their offspring and controls (FDR < 1%), and two different protein signatures that predict longer survival in centenarians and in younger people. By comparing the centenarian signature with 2 independent proteomic studies of aging, we replicated the association of 484 proteins of aging and we identified two serum protein signatures that are specific of extreme old age. The data suggest that centenarians acquire similar aging signatures as seen in younger cohorts that have short survival periods, suggesting that they do not escape normal aging markers, but rather acquire them much later than usual. For example, centenarian signatures are significantly enriched for senescence‐associated secretory phenotypes, consistent with those seen with younger aged individuals, and from this finding, we provide a new list of serum proteins that can be used to measure cellular senescence. Protein co‐expression network analysis suggests that a small number of biological drivers may regulate aging and extreme longevity, and that changes in gene regulation may be important to reach extreme old age. This centenarian study thus provides additional signatures that can be used to measure aging and provides specific circulating biomarkers of healthy aging and longevity, suggesting potential mechanisms that could help prolong health and support longevity.     

A serum protein signature of APOE genotypes in centenarians

The discovery of treatments to prevent or delay dementia and Alzheimer's disease is a priority. The gene APOE is associated with cognitive change and late‐onset Alzheimer's disease, and epidemiological studies have provided strong evidence that the e₂ allele of APOE has a neuroprotective effect, it is associated with increased longevity and an extended healthy lifespan in centenarians. In this study, we correlated APOE genotype data of 222 participants of the New England Centenarian Study, including 75 centenarians, 82 centenarian offspring, and 65 controls, comprising 55 carriers of APOE e₂, with aptamer‐based serum proteomics (SomaLogic technology) of 4,785 human proteins corresponding to 4,137 genes. We discovered a signature of 16 proteins that associated with different APOE genotypes and replicated the signature in three independent studies. We also show that the protein signature tracks with gene expression profiles in brains of late‐onset Alzheimer's disease versus healthy controls. Finally, we show that seven of these proteins correlate with cognitive function patterns in longitudinally collected data. This analysis in particular suggests that Baculoviral IAP repeat containing two (BIRC2) is a novel biomarker of neuroprotection that associates with the neuroprotective allele of APOE. Therefore, targeting APOE e₂ molecularly may preserve cognitive function.     

Scale matters: Indicators of ecological health along the urban–rural interface near Columbus,Georgia

Ecological data obtained from field plots can provide detailed information about ecosystem structure and function. However, this information typically reflects processes that occur over small spatial areas. Accordingly, it is difficult to extrapolate these data to patterns and processes that take place at regional scales. Satellite imagery can provide a means to explore environmental variables over a larger area. Therefore, our main objective was to examine the utility of a regional ecological assessment tool using landscape indicators of ecosystem health in a rapidly developing area of West Georgia near the city of Columbus. Indicator variables included in the assessment were: population density and change, road density, percent forest land-cover, forest patch density, landscape Shannon's Diversity Index, proportion of all streams with roads within 30 m, proportion of area that has agriculture on slopes >3%, proportion of all streams with adjacent agriculture, and proportion of all streams with adjacent forest cover. Cluster analysis was used to combine these variables into different groups, and resulting cluster means were used to rank regional areas according to degree of environmental impact. To assess the spatial accuracy of this tool results were compared to those obtained from a separate plot-level field-based forest condition study. Results derived using the landscape ecological assessment tool suggest that rural areas were the least environmentally impacted (or most healthy) of all areas in West Georgia, and support the findings from the field study. Results for developing areas were mixed between the two different studies and may be attributed to differences in scale. Overall, it appears that this tool is useful for broad generalizations about a given landscape, but is not detailed enough for site-specific management goals due to its inherent coarse spatial resolution (30 m × 30 m). However, these site-specific goals may be achieved using higher resolution (1 m × 1 m) satellite imagery and warrants further research. In any case, this tool is a useful asset for anyone needing a rapid diagnosis of ecosystem health in an inexpensive and timely manner.     

Comparison of abundance and habitat usage for common bottlenose dolphins between sites exposed to differential anthropogenic stressors within the estuaries of southern Georgia,U.S.A

The health of common bottlenose dolphins (Tursiops truncatus) within southern Georgia estuaries is of particular concern due to high levels of anthropogenic contaminants in their tissues. Dolphins in this region have the highest polychlorinated biphenyl (PCB) concentrations recorded for any marine mammal and these concentrations correlate to distance from a Superfund point‐source in the Turtle/Brunswick River Estuary (TBRE). Currently, little is known about the population structure of dolphins in this region. This study identifies and compares baseline data on abundance, habitat use, site‐fidelity, and ranging patterns of dolphins across two adjacent field sites; Brunswick, including the TBRE, and Sapelo, including the Sapelo Island National Estuarine Research Reserve. Sapelo is relatively undeveloped and was selected for comparison to the more contaminated TBRE. Dolphin densities increased with tributary size in both sites but dolphin density and total abundance were significantly higher in Sapelo than in Brunswick. Anthropogenic stressors within the TBRE may be an important factor contributing to the differences in abundance, density, and habitat use observed in this study.     

Relationship between Concentrations of Lutein and StARD3 among Pediatric and Geriatric Human Brain Tissue

Lutein, a dietary carotenoid, selectively accumulates in human retina and brain. While many epidemiological studies show evidence of a relationship between lutein status and cognitive health, lutein’s selective uptake in human brain tissue and its potential function in early neural development and cognitive health have been poorly evaluated at a molecular level. The objective of this study was to evaluate the cross-sectional relationship between concentrations of brain lutein and StARD3 (identified as its binding protein in retinal tissue) among three age groups: infants (1–4 months, n = 10), older adults (55–86 years, n = 8), and centenarians (98–105 years, n = 10). Brain lutein concentrations were analyzed by high-performance liquid chromatography and StARD3 levels were analyzed by Western Blot analysis. The strong relationship in infant brains (r = 0.75, P < 0.001) suggests that lutein has a role in neural development. The relationship remained significant but weaker in older adults (r = 0.51, P < 0.05) and insignificant in centenarians (r = 0.08, P > 0.05), seven of whom had mild cognitive impairment (MCI) or dementia. These exploratory findings suggest an age-related decrease or abnormality of StARD3 activity in human brain. Given that StARD3 is also involved in cholesterol transportation, a process that is aberrant in neurodegenerative diseases, the potential protective function of lutein against these diseases remains to be explored.     

Genetics of longevity. data from the studies on Sicilian centenarians

ABSTRACT: The demographic and social changes of the past decades have determined improvements in public health and longevity. So, the number of centenarians is increasing as a worldwide phenomenon. Scientists have focused their attention on centenarians as optimal model to address the biological mechanisms of "successful and unsuccessful ageing". They are equipped to reach the extreme limits of human life span and, most importantly, to show relatively good health, being able to perform their routine daily life and to escape fatal age-related diseases, such as cardiovascular diseases and cancer. Thus, particular attention has been centered on their genetic background and immune system. In this review, we report our data gathered for over 10 years in Sicilian centenarians. Based on results obtained, we suggest longevity as the result of an optimal performance of immune system and an over-expression of anti-inflammatory sequence variants of immune/inflammatory genes. However, as well known, genetic, epigenetic, stochastic and environmental factors seem to have a crucial role in ageing and longevity. Epigenetics is associated with ageing, as demonstrated in many studies. In particular, ageing is associated with a global loss of methylation state. Thus, the aim of future studies will be to analyze the weight of epigenetic changes in ageing and longevity.     

Nutrient intakes in women and risks of anophthalmia and microphthalmia in their offspring

BACKGROUND: There is a paucity of information about risk factors for the human eye anomalies anophthalmia and microphthalmia. In this population-based case-control study we investigated whether periconceptional intakes of supplemental folic acid, dietary folate, vitamin A, and several other nutrients were associated with these eye defects. METHODS: This study included data on deliveries that had estimated due dates from 1997-2002 and were part of the National Birth Defects Prevention Study (the National Birth Defects Prevention Study is a population-based case-control study of a wide spectrum of birth defects, incorporating data from 10 birth defects surveillance systems in the United States [Arkansas, California, Georgia/Centers for Disease Control and Prevention, Iowa, Massachusetts, New Jersey, New York, North Carolina, Texas, and Utah]). Cases were those infants or fetuses born with either anophthalmia or microphthalmia. Liveborn infants without major malformations were eligible as controls. Maternal interviews were conducted, primarily by telephone, in English or Spanish. Participation in the interview was 71% among case mothers and 68% among control mothers. Interviews were completed with 89 case mothers and 4,143 control mothers. A shortened version of the food frequency questionnaire from the Nurse's Health Study was used to assess frequency of intake of 58 food items during the year before pregnancy. RESULTS: Our results did not indicate reduced risks for these eye malformations associated with maternal intake of vitamin supplements containing folic acid. The data did not show an association between malformation risk and higher or lower intakes of vitamin A. We also did not observe strong evidence that an abundance or a lack of dietary intake of any other nutrient was associated with increased risk of the studied eye malformations. CONCLUSIONS: Our observations contribute to a limited body of findings on these rare eye defects.     

Centenarians – a useful model for healthy aging? A 29‐year follow‐up of hospitalizations among 40 000 Danes born in 1905

Centenarians surpass the current human life expectancy with about 20–25 years. However, whether centenarians represent healthy aging still remains an open question. Previous studies have been hampered by a number of methodological shortcomings such as a cross-sectional design and lack of an appropriate control group. In a longitudinal population-based cohort, it was examined whether the centenarian phenotype may be a useful model for healthy aging. The study was based on a complete follow up of 39 945 individuals alive in the Danish 1905 birth cohort on January 1, 1977 identified through the Danish Civil Registration System (DCRS). Data from the Danish Demographic Database and The Danish National Patient Register (in existence since 1977) were used. The 1905 cohort was followed up from 1977 through 2004 with respect to hospitalizations and number of hospital days. Survival status was available until December 2006. Danish centenarians from the 1905 cohort were hospitalized substantially less than their shorter-lived contemporaries at the same point in time during the years 1977 through 2004. For example, at age 71–74, the proportion of nonhospitalized centenarians was 80.5% compared with 68.4% among individuals who died in their early 80s. This trend was evident in both sexes. As a result of their lower hospitalization rates and length of stay in hospital compared with their contemporaries, who died at younger ages, Danish centenarians represent healthy agers. Centenarians constitute a useful study population in the search for fixed traits associated with exceptional longevity, such as genotype.     

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.     

Differential Item Functioning in the SF-36 Physical Functioning and Mental Health Sub-Scales: A Population-Based Investigation in the Canadian Multicentre Osteoporosis Study

Background

Self-reported health status measures, like the Short Form 36-item Health Survey (SF-36), can provide rich information about the overall health of a population and its components, such as physical, mental, and social health. However, differential item functioning (DIF), which arises when population sub-groups with the same underlying (i.e., latent) level of health have different measured item response probabilities, may compromise the comparability of these measures. The purpose of this study was to test for DIF on the SF-36 physical functioning (PF) and mental health (MH) sub-scale items in a Canadian population-based sample.

Methods

Study data were from the prospective Canadian Multicentre Osteoporosis Study (CaMos), which collected baseline data in 1996–1997. DIF was tested using a multiple indicators multiple causes (MIMIC) method. Confirmatory factor analysis defined the latent variable measurement model for the item responses and latent variable regression with demographic and health status covariates (i.e., sex, age group, body weight, self-perceived general health) produced estimates of the magnitude of DIF effects.

Results

The CaMos cohort consisted of 9423 respondents; 69.4% were female and 51.7% were less than 65 years. Eight of 10 items on the PF sub-scale and four of five items on the MH sub-scale exhibited DIF. Large DIF effects were observed on PF sub-scale items about vigorous and moderate activities, lifting and carrying groceries, walking one block, and bathing or dressing. On the MH sub-scale items, all DIF effects were small or moderate in size.

Conclusions

SF-36 PF and MH sub-scale scores were not comparable across population sub-groups defined by demographic and health status variables due to the effects of DIF, although the magnitude of this bias was not large for most items. We recommend testing and adjusting for DIF to ensure comparability of the SF-36 in population-based investigations.     

Negotiating “The Social” and Managing Tuberculosis in Georgia

In this paper I utilize anthropological insights to illuminate how health professionals and patients navigate and negotiate what for them is social about tuberculosis in order to improve treatment outcomes and support patients as human beings. I draw on ethnographic research about the implementation of the DOTS (Directly Observed Therapy, Short Course) approach in Georgia’s National Tuberculosis Program in the wake of the Soviet healthcare system. Georgia is a particularly unique context for exploring these issues given the country’s rich history of medical professionalism and the insistence that the practice of medicine is a moral commitment to society. I argue for critical attention to the ways in which treatment recipients and providers navigate what, for them, is “social” about therapeutic practices and their significance for avoiding biological and social reductionism.     

Genetic polymorphisms of Fas (CD95) and FasL (CD178) in human longevity: studies on centenarians

Apoptosis plays a crucial role in immunosenescence, as also evidenced by the increased expression of Fas in lymphocytes from aged people. However, little is known about the genetic regulation of Fas and its ligand, FasL. We have studied their polymorphisms in 50 centenarians and 86 young donors living in Northern Italy. The first Fas polymorphism, at position -670, has in Caucasian a heterozigosity of 51%; the second, at -1377 position, has the wild type allele (G) with a very high frequency (83%) respect to the mutant allele. Genotype and allele distribution for both polymorphisms were similar in controls and centenarians. Similar results were found as far as two FasL polymorphisms (IVS2nt-124 and IVS3nt169) are concerned. On the whole, our data suggest that Fas and FasL polymorphisms, as well as their haplotypes, are unlikely to be associated with successful human longevity.     

The Georgia Cardiovascular Twin Study.

The Georgia Cardiovascular Twin Study is a longitudinal study of biobehavioral antecedents of cardiovascular disease in youth. It includes roughly equal numbers of African Americans and European Americans, with a total of > 500 twin pairs. Focus of the study is the change in relative influence of genetic and environmental factors on development of risk factors for cardiovascular disease. Future work will explore the influence of polymorphic variation in candidate genes and their potential interaction with the environment on these risk factors.     

Genetic signatures of exceptional longevity in humans

Like most complex phenotypes, exceptional longevity is thought to reflect a combined influence of environmental (e.g., lifestyle choices, where we live) and genetic factors. To explore the genetic contribution, we undertook a genome-wide association study of exceptional longevity in 801 centenarians (median age at death 104 years) and 914 genetically matched healthy controls. Using these data, we built a genetic model that includes 281 single nucleotide polymorphisms (SNPs) and discriminated between cases and controls of the discovery set with 89% sensitivity and specificity, and with 58% specificity and 60% sensitivity in an independent cohort of 341 controls and 253 genetically matched nonagenarians and centenarians (median age 100 years). Consistent with the hypothesis that the genetic contribution is largest with the oldest ages, the sensitivity of the model increased in the independent cohort with older and older ages (71% to classify subjects with an age at death>102 and 85% to classify subjects with an age at death>105). For further validation, we applied the model to an additional, unmatched 60 centenarians (median age 107 years) resulting in 78% sensitivity, and 2863 unmatched controls with 61% specificity. The 281 SNPs include the SNP rs2075650 in TOMM40/APOE that reached irrefutable genome wide significance (posterior probability of association = 1) and replicated in the independent cohort. Removal of this SNP from the model reduced the accuracy by only 1%. Further in-silico analysis suggests that 90% of centenarians can be grouped into clusters characterized by different “genetic signatures” of varying predictive values for exceptional longevity. The correlation between 3 signatures and 3 different life spans was replicated in the combined replication sets. The different signatures may help dissect this complex phenotype into sub-phenotypes of exceptional longevity.     

Ashkenazi Jewish centenarians do not demonstrate enrichment in mitochondrial haplogroup J

Background

Association of mitochondrial haplogroup J with longevity has been reported in several population subgroups. While studies from northern Italy and Finland, have described a higher frequency of haplogroup J among centenarians in comparison to non-centenarian, several other studies could not replicate these results and suggested various explanations for the discrepancy.

Methodology/Principal Findings

We have evaluated haplogroup frequencies among Ashkenazi Jewish centenarians using two different sets of matched controls. No difference was observed in the haplogroup J frequencies between the centenarians or either matched control group, despite adequate statistical power to detect such a difference. Furthermore, the lack of association was robust to population substructure in the Ashkenazi Jewish population. Given this discrepancy with the previous reported associations in the northern Italian and the Finnish populations, we conducted re-analysis of these previously published data, which supported one of several possible explanations: i) inadequate matching of cases and controls; ii) inadequate adjustment for multiple comparison testing; iii) cryptic population stratification.

Conclusions/Significance

There does not exist a universal association of mitochondrial haplogroup J with longevity across all population groups. Reported associations in specialized populations may reflect genetic or other interactions specific to those populations or else cryptic confounding influences, such as inadequate matching attributable to population substructure, which are of general relevance to all studies of the possible association of mitochondrial DNA haplogroups with common complex phenotypes.     

Identificación de polimorfismos de nucleótido simple en centenarios

IntroductionLongevity is determined by genetic and external factors, such as nutritional, environmental, social, etc. Nevertheless, when living conditions are optimal, longevity is determined by genetic variations between individuals. In a same population, with relative genotypic homogeneity, subtle changes in the DNA sequence affecting a single nucleotide can be observed. These changes, called single nucleotide polymorphisms (SNP) are present in 1-5% of the population.Material and methodsA total of 92 subjects were recruited, including 28 centenarians and 64 controls, in order to find SNP that maybe implicated in the extreme longevity, as in the centenarians. Blood samples were collected to isolate and amplify the DNA in order to perform the analysis of SPN by Axiom™ Genotyping of Affymetrix technology. Statistical analyses were performed using the Plink program and libraries SNPassoc and skatMeta.ResultsOur results show 12 mutations with a p<.001, where 5 of these (DACH1, LOC91948, BTB16, NFIL3 y HDAC4) have regulatory functions of the expressions of others genes.ConclusionsTherefore, these results suggest that the genetic variation between centenarians and controls occurs in five genes that are involved in the regulation of gene expression to adapt to environmental changes better than controls.     

Trace Elements in Fingernails of Healthy Chinese Centenarians

Trace element concentrations in body tissues of healthy centenarians have not been widely analyzed, yet they can be used as reference data leading to improved assessment of the aging process and monitoring of the micronutrient status of this age group. The present study sought to assess trace element concentrations and behaviors in the fingernails of healthy Chinese centenarians. The effects of gender on element concentrations, which also play an important role in determining the lifespan, were also investigated. Trace elements (Ba, Cd, Co, Cr, Cu, Fe, Li, Mn, Mo, Ni, Pb, Se, Sr, and Zn) in the fingernails of 78 healthy Chinese centenarians were determined by inductively coupled plasma mass spectrometry. The overall reference values obtained in milligram per kilogram are as follows: Ba, 5.10; Cd, 0.031; Co, 0.101; Cr, 0.82; Cu, 3.71; Fe, 154.35; Li, 0.31; Mn, 3.09; Mo, 0.040; Ni, 0.95; Pb, 1.86; Se, 0.44; Sr, 6.20; and Zn, 147.96. Data analysis showed that only Cr and Se concentrations show a normal distribution, and no significant difference between male and female groups was found for any element except Cr. Result also revealed that sufficient Se, Co, and Zn as well as lower or lack of exposure to Cr contribute positively to the lifespan of centenarians. The results suggest that regulating in vivo contents of trace elements, especially Se, Co, and Zn, is reasonable to intervene with geriatric diseases.     

Impact of hormone therapy for women aged 35 to 65 years,from contraception to hormone replacement

Background: Midlife women (aged 35–65 years) present a complex combination of clinical challenges and health care opportunities. To meet these issues effectively, recognition of the various phases of the entire menopausal transition is necessary, because each possesses unique biological properties underlying phase-specific clinical presentations.Objective: The aim of this article is to inform health care decisions by defining the endocrine, metabolic, and clinical consequences of therapeutic inaction or intervention at each stage of the midlife experience.Methods: Using PubMed, MEDLINE was searched for age- and phase-specific publications about ovarian function and corresponding clinical manifestations in women aged 35 to 65 years. Large, long-term longitudinal prospective, case-control, and observational studies were selected for inclusion. Results of the Framingham Heart Study, Study of Women's Health Across the Nation, Nurses' Health Study (NHS), and Women's Health Initiative (WHI), as well as materials from the World Health Organization and American College of Obstetricians and Gynecologists, were obtained from the relevant groups' Web sites in 2008.Results: Synthesis of the data acquired, particularly the confirmatory and contrasting elements displayed in the WHI and NHS publications, leads to a set of guiding principles whereby individualized phase-specific management strategies may be safely employed. These include the value of weight control and exercise; use of specific nonhormonal therapies for defined indications; definition of strict inclusion/exclusion criteria; and individualization of timing, regimen, dosage, and portal of entry for possible hormone therapy.Conclusion: An evidence-based, restrictive inclusion/exclusion strategy can be used to maximize benefits and minimize risks for this large, growing, and health-conscious but increasingly vulnerable population.     

Risk factors for birth defects: data from the Atlanta Birth Defects Case-Control Study

The Atlanta Birth Defects Case-Control Study data comprises information obtained from interviews with parents of 4,900 babies born with major birth defects and with the parents of 3,000 babies born without defects. The source of cases is the Centers for Disease Control's Metropolitan Atlanta Congenital Defects program; the case-control study is population-based. Birth defects are classified into 92 groups and cross-tabulated by 105 exposure/risk factor variables; data from selected cross-tabulations are presented. The associations of each of the 105 exposure variables with all types of defects combined are presented, as are the associations of each of the 92 defect groups with the specific exposure variable, maternal diabetes. These data can be used to evaluate hypotheses arising from other sources, and for the purpose of "generating" hypotheses. The data describing all 92 x 105 cross-tabulations are available to other investigators on floppy disk; write to Chief, Birth Defects and Genetic Diseases Branch, Centers for Disease Control, Atlanta, Georgia 30333.