Ageing Abstracts 6, Biomarkers


Women who maintain optimal cognitive function into old age.
            (Barnes et al., 2007) Download
OBJECTIVES: To determine whether older women who maintain optimal cognitive function into old age differ from those who experience minor cognitive decline typically associated with normal aging. DESIGN: Prospective cohort study. SETTING: The Study of Osteoporotic Fractures. PARTICIPANTS: Nine thousand seven hundred four older women. MEASUREMENTS: A modified Mini-Mental State Examination (mMMSE) was performed at baseline and Years 6, 8, 10, and 15. Random-effects regression was used to classify subjects as cognitive maintainers (slope>/=0), minor decliners (slope < 0 but > lowest tertile), or major decliners (slope <or= lowest tertile). Stepwise logistic regression was used to identify factors most predictive of being a cognitive maintainer versus a minor decliner (excluding major decliners). RESULTS: Women had a mean age of 72 at baseline and 85 at follow-up. Nine percent maintained optimal cognitive function, 58% experienced minor decline, and 33% experienced major decline. Most factors differed progressively over the three cognitive groups. After adjustment for key confounders, odds ratios for factors most predictive of being a cognitive maintainer as opposed to minor decliner were 1.9 (95% confidence interval (CI)=1.2-2.9) for lack of diabetes mellitus, 1.2 (95% CI=1.0-1.4) for lack of hypertension, 1.7 (95% CI=1.3-2.3) for lack of smoking, 1.2 (95% CI=1.1-1.5) for moderate alcohol consumption, 1.4 (95% CI=1.1-1.7) for lack of difficulty with instrumental activities of daily living, and 1.2 (95% CI=1.0-1.4) for lack of low social network. CONCLUSION: Almost 10% of older women maintained optimal cognitive function into old age. Cognitive maintainers were less likely to have comorbid medical conditions, less likely to have difficulty with daily activities or poor social networks, and more likely to engage in healthy behaviors than minor cognitive decliners.

Epigenetic predictor of age.
            (Bocklandt et al., 2011) Download
From the moment of conception, we begin to age. A decay of cellular structures, gene regulation, and DNA sequence ages cells and organisms. DNA methylation patterns change with increasing age and contribute to age related disease. Here we identify 88 sites in or near 80 genes for which the degree of cytosine methylation is significantly correlated with age in saliva of 34 male identical twin pairs between 21 and 55 years of age. Furthermore, we validated sites in the promoters of three genes and replicated our results in a general population sample of 31 males and 29 females between 18 and 70 years of age. The methylation of three sites--in the promoters of the EDARADD, TOM1L1, and NPTX2 genes--is linear with age over a range of five decades. Using just two cytosines from these loci, we built a regression model that explained 73% of the variance in age, and is able to predict the age of an individual with an average accuracy of 5.2 years. In forensic science, such a model could estimate the age of a person, based on a biological sample alone. Furthermore, a measurement of relevant sites in the genome could be a tool in routine medical screening to predict the risk of age-related diseases and to tailor interventions based on the epigenetic bio-age instead of the chronological age.

MARK-AGE biomarkers of ageing.
            (Burkle et al., 2015) Download
Many candidate biomarkers of human ageing have been proposed in the scientific literature but in all cases their variability in cross-sectional studies is considerable, and therefore no single measurement has proven to serve a useful marker to determine, on its own, biological age. A plausible reason for this is the intrinsic multi-causal and multi-system nature of the ageing process. The recently completed MARK-AGE study was a large-scale integrated project supported by the European Commission. The major aim of this project was to conduct a population study comprising about 3200 subjects in order to identify a set of biomarkers of ageing which, as a combination of parameters with appropriate weighting, would measure biological age better than any marker in isolation.

Development of a serum profile for healthy aging.
            (Byerley et al., 2010) Download
Increasing numbers of Americans are reaching 85 years of age or older, yet there are no reliable biomarkers to predict who will live this long. The goal of this pilot study therefore was: (1) to identify a potential serum pattern that could identify proteins involved in longevity and (2) to determine if this pattern was a marker of longevity in an independent sample of individuals. Serum samples were analyzed in three cohorts of individuals (n = 12 in each) aged 20-34, 60-74, and >/= 90 years who participated in The Louisiana Healthy Aging Study. The 12 most abundant proteins were removed and the remaining proteins separated by two-dimensional gel electrophoresis. Gels were matched and the intensity of each spot quantified. Multivariate discriminant analysis was used to identify a serum pattern that could separate these three age cohorts. Seven protein spots were found that correctly distinguished the subjects into the three groups. However, these spots were not as successful in discriminating the ages in a second set of 15 individuals as only eight of these subjects were placed into their correct group. These preliminary results show that the proteomics approach can be used to identify potential proteins or markers that may be involved in the aging process and/or be important determinants of longevity.

Is telomere length a biomarker for aging: cross-sectional evidence from the west of Scotland?
            (Der et al., 2012) Download
BACKGROUND: The search for biomarkers of aging (BoAs) has been largely unsuccessful to-date and there is widespread skepticism about the prospects of finding any that satisfy the criteria developed by the American Federation of Aging Research. This may be because the criteria are too strict or because a composite measure might be more appropriate. Telomere length has attracted a great deal of attention as a candidate BoA. We investigate whether it meets the criteria to be considered as a single biomarker of aging, and whether it makes a useful contribution to a composite measure. METHODOLOGY/PRINCIPAL FINDINGS: Using data from a large population based study, we show that telomere length is associated with age, with several measures of physical and cognitive functioning that are related to normal aging, and with three measures of overall health. In the majority of cases, telomere length adds predictive power to that of age, although it was not nearly as good a predictor overall. We used principal components analysis to form two composites from the measures of functioning, one including telomere length and the other not including it. These composite BoAs were better predictors of the health outcomes than chronological age. There was little difference between the two composites. CONCLUSIONS: Telomere length does not satisfy the strict criteria for a BoA, but does add predictive power to that of chronological age. Equivocal results from previous studies might be due to lack of power or the choice of measures examined together with a focus on single biomarkers. Composite biomarkers of aging have the potential to outperform age and should be considered for future research in this area.

ApoE gene and exceptional longevity: Insights from three independent cohorts.
            (Garatachea et al., 2014) Download
The ApoE gene is associated with the risk of Alzheimer or cardiovascular disease but its influence on exceptional longevity (EL) is uncertain. Our primary purpose was to determine, using a case-control design, if the ApoE gene is associated with EL. We compared ApoE allele/genotype frequencies among the following cohorts: cases (centenarians, most with 1+ major disease condition; n=163, 100-111years) and healthy controls (n=1039, 20-85years) from Spain; disease-free cases (centenarians; n=79, 100-104years) and healthy controls (n=597, age 27-81years) from Italy; and cases (centenarians and semi-supercentenarians, most with 1+ major disease condition; n=729, 100-116years) and healthy controls (n=498, 23-59years) from Japan. Our main findings were twofold. First, the epsilon4-allele was negatively associated with EL in the three cohorts, with the following odds ratio (OR) values (adjusted by sex) having been found: 0.55 (95% confidence interval (CI): 0.33, 0.94), P=0.030 (Spain); 0.41 (95%CI: 0.18, 0.99), P=0.05 (Italy); and 0.35 (95%CI: 0.26, 0.57), P<0.001 (Japan). Second, although no association was found in the Spanish cohort (OR=1.42 (95%CI: 0.89, 2.26), P=0.145), the epsilon2-allele was positively associated with EL in the Italian (OR=2.14 (95%CI: 1.18, 3.45), P=0.01) and Japanese subjects (OR=1.81 (95%CI: 1.25, 2.63), P=0.002). Notwithstanding the limitations of case-control designs, our data suggest that the ApoE might be a candidate to influence EL. The epsilon4-allele appears to decrease the likelihood of reaching EL among individuals of different ethnic/geographic origins. An additional, novel finding of our study was that the epsilon2-allele might favor EL, at least in the Italian and Japanese cohorts.

Biomarkers and ageing: The clock-watcher.
            (Gibbs, 2014) Download

DNA methylation age of human tissues and cell types.
            (Horvath, 2013) Download
BACKGROUND: It is not yet known whether DNA methylation levels can be used to accurately predict age across a broad spectrum of human tissues and cell types, nor whether the resulting age prediction is a biologically meaningful measure. RESULTS: I developed a multi-tissue predictor of age that allows one to estimate the DNA methylation age of most tissues and cell types. The predictor, which is freely available, was developed using 8,000 samples from 82 Illumina DNA methylation array datasets, encompassing 51 healthy tissues and cell types. I found that DNA methylation age has the following properties: first, it is close to zero for embryonic and induced pluripotent stem cells; second, it correlates with cell passage number; third, it gives rise to a highly heritable measure of age acceleration; and, fourth, it is applicable to chimpanzee tissues. Analysis of 6,000 cancer samples from 32 datasets showed that all of the considered 20 cancer types exhibit significant age acceleration, with an average of 36 years. Low age-acceleration of cancer tissue is associated with a high number of somatic mutations and TP53 mutations, while mutations in steroid receptors greatly accelerate DNA methylation age in breast cancer. Finally, I characterize the 353 CpG sites that together form an aging clock in terms of chromatin states and tissue variance. CONCLUSIONS: I propose that DNA methylation age measures the cumulative effect of an epigenetic maintenance system. This novel epigenetic clock can be used to address a host of questions in developmental biology, cancer and aging research.

Markers of oxidant stress that are clinically relevant in aging and age-related disease.
            (Jacob et al., 2013) Download
Despite the long held hypothesis that oxidant stress results in accumulated oxidative damage to cellular macromolecules and subsequently to aging and age-related chronic disease, it has been difficult to consistently define and specifically identify markers of oxidant stress that are consistently and directly linked to age and disease status. Inflammation because it is also linked to oxidant stress, aging, and chronic disease also plays an important role in understanding the clinical implications of oxidant stress and relevant markers. Much attention has focused on identifying specific markers of oxidative stress and inflammation that could be measured in easily accessible tissues and fluids (lymphocytes, plasma, serum). The purpose of this review is to discuss markers of oxidant stress used in the field as biomarkers of aging and age-related diseases, highlighting differences observed by race when data is available. We highlight DNA, RNA, protein, and lipid oxidation as measures of oxidative stress, as well as other well-characterized markers of oxidative damage and inflammation and discuss their strengths and limitations. We present the current state of the literature reporting use of these markers in studies of human cohorts in relation to age and age-related disease and also with a special emphasis on differences observed by race when relevant.

The GH/IGF-1 axis in ageing and longevity.
            (Junnila et al., 2013) Download
Secretion of growth hormone (GH), and consequently that of insulin-like growth factor 1 (IGF-1), declines over time until only low levels can be detected in individuals aged >/=60 years. This phenomenon, which is known as the 'somatopause', has led to recombinant human GH being widely promoted and abused as an antiageing drug, despite lack of evidence of efficacy. By contrast, several mutations that decrease the tone of the GH/IGF-1 axis are associated with extended longevity in mice. In humans, corresponding or similar mutations have been identified, but whether these mutations alter longevity has yet to be established. The powerful effect of reduced GH activity on lifespan extension in mice has generated the hypothesis that pharmaceutically inhibiting, rather than increasing, GH action might delay ageing. Moreover, mice as well as humans with reduced activity of the GH/IGF-1 axis are protected from cancer and diabetes mellitus, two major ageing-related morbidities. Here, we review data on mouse strains with alterations in the GH/IGF-1 axis and their effects on lifespan. The outcome of corresponding or similar mutations in humans is described, as well as the potential mechanisms underlying increased longevity and the therapeutic benefits and risks of medical disruption of the GH/IGF-1 axis in humans.

Glycans are a novel biomarker of chronological and biological ages.
            (Kristic et al., 2014) Download
Fine structural details of glycans attached to the conserved N-glycosylation site significantly not only affect function of individual immunoglobulin G (IgG) molecules but also mediate inflammation at the systemic level. By analyzing IgG glycosylation in 5,117 individuals from four European populations, we have revealed very complex patterns of changes in IgG glycosylation with age. Several IgG glycans (including FA2B, FA2G2, and FA2BG2) changed considerably with age and the combination of these three glycans can explain up to 58% of variance in chronological age, significantly more than other markers of biological age like telomere lengths. The remaining variance in these glycans strongly correlated with physiological parameters associated with biological age. Thus, IgG glycosylation appears to be closely linked with both chronological and biological ages. Considering the important role of IgG glycans in inflammation, and because the observed changes with age promote inflammation, changes in IgG glycosylation also seem to represent a factor contributing to aging. SIGNIFICANCE STATEMENT: Glycosylation is the key posttranslational mechanism that regulates function of immunoglobulins, with multiple systemic repercussions to the immune system. Our study of IgG glycosylation in 5,117 individuals from four European populations has revealed very extensive and complex changes in IgG glycosylation with age. The combined index composed of only three glycans explained up to 58% of variance in age, considerably more than other biomarkers of age like telomere lengths. The remaining variance in these glycans strongly correlated with physiological parameters associated with biological age; thus, IgG glycosylation appears to be closely linked with both chronological and biological ages. The ability to measure human biological aging using molecular profiling has practical applications for diverse fields such as disease prevention and treatment, or forensics.

The hallmarks of aging.
            (Lopez-Otin et al., 2013) Download
Aging is characterized by a progressive loss of physiological integrity, leading to impaired function and increased vulnerability to death. This deterioration is the primary risk factor for major human pathologies, including cancer, diabetes, cardiovascular disorders, and neurodegenerative diseases. Aging research has experienced an unprecedented advance over recent years, particularly with the discovery that the rate of aging is controlled, at least to some extent, by genetic pathways and biochemical processes conserved in evolution. This Review enumerates nine tentative hallmarks that represent common denominators of aging in different organisms, with special emphasis on mammalian aging. These hallmarks are: genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication. A major challenge is to dissect the interconnectedness between the candidate hallmarks and their relative contributions to aging, with the final goal of identifying pharmaceutical targets to improve human health during aging, with minimal side effects.

Increased cerebrospinal fluid F2-isoprostanes are associated with aging and latent Alzheimer's disease as identified by biomarkers.
            (Montine et al., 2011) Download
Alzheimer's disease (AD) is a common age-related chronic illness with latent, prodrome, and fully symptomatic dementia stages. Increased free radical injury to regions of brain is one feature of prodrome and dementia stages of AD; however, it also is associated with advancing age. This raises the possibility that age-related free radical injury to brain might be caused in part or in full by latent AD. We quantified free radical injury in the central nervous system with cerebrospinal fluid (CSF) F(2)-isoprostanes (IsoPs) in 421 clinically normal individuals and observed a significant increase over the adult human lifespan (P < 0.001). Using CSF amyloid (A) beta(42) and tau, we defined normality using results from 28 clinically normal individuals <50 years old, and then stratified 74 clinically normal subjects >/=60 years into those with CSF that had normal CSF Abeta(42) and tau (n = 37); abnormal CSF Abeta(42) and tau, the biomarker signature of AD (n = 24); decreased Abeta(42) only (n = 4); or increased tau only (n = 9). Increased CSF F(2)-IsoPs were present in clinically normal subjects with the biomarker signature of AD (P < 0.05) and those subjects with increased CSF tau (P < 0.001). Finally, we analyzed the relationship between age and CSF F(2)-IsoPs for those clinically normal adults with normal CSF (n = 37) and those with abnormal CSF Abeta(42) and/or tau (n = 37); only those with normal CSF demonstrated a significant increase with age (P < 0.01). These results show that CSF F(2)-IsoPs increased across the human lifespan and that this age-related increase in free radical injury to brain persisted after culling those with laboratory evidence of latent AD.

Molecular insights into the pathogenesis of Alzheimer's disease and its relationship to normal aging.
            (Podtelezhnikov et al., 2011) Download
Alzheimer's disease (AD) is a complex neurodegenerative disorder that diverges from the process of normal brain aging by unknown mechanisms. We analyzed the global structure of age- and disease-dependent gene expression patterns in three regions from more than 600 brains. Gene expression variation could be almost completely explained by four transcriptional biomarkers that we named BioAge (biological age), Alz (Alzheimer), Inflame (inflammation), and NdStress (neurodegenerative stress). BioAge captures the first principal component of variation and includes genes statistically associated with neuronal loss, glial activation, and lipid metabolism. Normally BioAge increases with chronological age, but in AD it is prematurely expressed as if some of the subjects were 140 years old. A component of BioAge, Lipa, contains the AD risk factor APOE and reflects an apparent early disturbance in lipid metabolism. The rate of biological aging in AD patients, which cannot be explained by BioAge, is associated instead with NdStress, which includes genes related to protein folding and metabolism. Inflame, comprised of inflammatory cytokines and microglial genes, is broadly activated and appears early in the disease process. In contrast, the disease-specific biomarker Alz was selectively present only in the affected areas of the AD brain, appears later in pathogenesis, and is enriched in genes associated with the signaling and cell adhesion changes during the epithelial to mesenchymal (EMT) transition. Together these biomarkers provide detailed description of the aging process and its contribution to Alzheimer's disease progression.

Lifestyle factors of people with exceptional longevity.
            (Rajpathak et al., 2011) Download
OBJECTIVES: To assess lifestyle factors including physical activity, smoking, alcohol consumption, and dietary habits in men and women with exceptional longevity. DESIGN: Retrospective cohort study. SETTING: A cohort of community-dwelling Ashkenazi Jewish individuals with exceptional longevity defined as survival and living independently at age 95 and older. PARTICIPANTS: Four hundred seventy-seven individuals (mean 97.3 +/- 2.8, range 95-109; 74.6% women) and a subset of participants of the National Health and Nutrition Examination Survey (NHANES) I (n = 3,164) representing the same birth cohort as a comparison group. MEASUREMENTS: A trained interviewer administrated study questionnaires to collect information on lifestyle factors and collected data on anthropometry. RESULTS: People with exceptional longevity had similar mean body mass index (men, 25.4 +/- 2.8 kg/m(2) vs 25.6 +/- 4.0 kg/m(2) , P=.63; women, 25.0 +/- 3.5 kg/m(2) vs 24.9 +/- 5.4 kg/m(2) ; P = .90) and a similar proportion of daily alcohol consumption (men, 23.9 vs 22.4, P = .77; women, 12.1 vs 11.3, P = .80), of regular physical activity (men: 43.1 vs 57.2; P = .07; women: 47.0 vs 44.1, P = .76), and of a low-calorie diet (men: 20.8 vs 21.1, P=.32; women: 27.3 vs 27.1, P=.14) as the NHANES I population. CONCLUSION: People with exceptional longevity are not distinct in terms of lifestyle factors from the general population, suggesting that people with exceptional longevity may interact with environmental factors differently than others. This requires further investigation.

Aging is not a disease: implications for intervention.
            (Rattan, 2014) Download
Aging of biological systems occurs in spite of numerous complex pathways of maintenance, repair and defense. There are no gerontogenes which have the specific evolutionary function to cause aging. Although aging is the common cause of all age-related diseases, aging in itself cannot be considered a disease. This understanding of aging as a process should transform our approach towards interventions from developing illusory anti-aging treatments to developing realistic and practical methods for maintaining health throughout the lifespan. The concept of homeodynamic space can be a useful one in order to identify a set of measurable, evidence-based and demonstratable parameters of health, robustness and resilience. Age-induced health problems, for which there are no other clear-cut causative agents, may be better tackled by focusing on health mechanisms and their maintenance, rather than only disease management and treatment. Continuing the disease-oriented research and treatment approaches, as opposed to health-oriented and preventive strategies, are economically, socially and psychologically unsustainable.

Growth hormone in the aging male.
            (Sattler, 2013) Download
Secretion of growth hormone (GH) and IGF-1 levels decline during advancing years-of-life. These changes (somatopause) are associated with loss of vitality, muscle mass, physical function, together with the occurrence of frailty, central adiposity, cardiovascular complications, and deterioration of mental function. For GH treatment to be considered for anti-aging, improved longevity, organ-specific function, or quality of life should be demonstrable. A limited number of controlled studies suggest that GH supplementation in older men increases lean mass by approximately 2 kg with similar reductions in fat mass. There is little evidence that GH treatment improves muscle strength and performance (e.g. walking speed or ability to climb stairs) or quality of life. The GHRH agonist (tesamorelin) restores normal GH pulsatility and amplitude, selectively reduces visceral fat, intima media thickness and triglycerides, and improves cognitive function in older persons. This report critically reviews the potential for GH augmentation during aging with emphasis on men since women appear more resistant to treatment.

Potential biomarkers of ageing.
            (Simm et al., 2008) Download
Life span in individual humans is very heterogeneous.Thus, the ageing rate, measured as the decline of functional capacity and stress resistance, is different in every individual. There have been attempts made to analyse this individual age, the so-called biological age, in comparison to chronological age. Biomarkers of ageing should help to characterise this biological age and, as age is a major risk factor in many degenerative diseases,could be subsequently used to identify individuals at high risk of developing age-associated diseases or disabilities. Markers based on oxidative stress, protein glycation,inflammation, cellular senescence and hormonal deregulation are discussed.

Inflammatory markers in population studies of aging.
            (Singh and Newman, 2011) Download
PURPOSE: To review findings from major epidemiologic studies regarding risk factors for and consequences of elevated markers of inflammation in older adults. RESULTS: Most large, current epidemiologic studies of older adults have measured serum interleukin-6 (IL-6), C-reactive protein (CRP) and tumor necrosis factor alpha (TNF-alpha) and some studies also include more extensive batteries of measures including soluble receptors. There are few defined risk factors for the modest elevations in inflammatory markers seen with aging. These include visceral adiposity, lower sex steroid hormones, smoking, depression and periodontal disease. Of the markers assessed, IL-6 is most robustly associated with incident disease, disability and mortality. CONCLUSION: Though correlated with age, the etiology of elevated inflammatory markers remains incompletely defined. Inflammation, especially IL-6 may be a common cause of multiple age-related diseases or a final common pathway by which disease leads to disability and adverse outcomes in older adults. Future research targeting inflammation should examine these pathways.

Indicators of "healthy aging" in older women (65-69 years of age). A data-mining approach based on prediction of long-term survival.
            (Swindell et al., 2010) Download
BACKGROUND: Prediction of long-term survival in healthy adults requires recognition of features that serve as early indicators of successful aging. The aims of this study were to identify predictors of long-term survival in older women and to develop a multivariable model based upon longitudinal data from the Study of Osteoporotic Fractures (SOF). METHODS: We considered only the youngest subjects (n = 4,097) enrolled in the SOF cohort (65 to 69 years of age) and excluded older SOF subjects more likely to exhibit a "frail" phenotype. A total of 377 phenotypic measures were screened to determine which were of most value for prediction of long-term (19-year) survival. Prognostic capacity of individual predictors, and combinations of predictors, was evaluated using a cross-validation criterion with prediction accuracy assessed according to time-specific AUC statistics. RESULTS: Visual contrast sensitivity score was among the top 5 individual predictors relative to all 377 variables evaluated (mean AUC = 0.570). A 13-variable model with strong predictive performance was generated using a forward search strategy (mean AUC = 0.673). Variables within this model included a measure of physical function, smoking and diabetes status, self-reported health, contrast sensitivity, and functional status indices reflecting cumulative number of daily living impairments (HR >or= 0.879 or RH <or= 1.131; P < 0.001). We evaluated this model and show that it predicts long-term survival among subjects assigned differing causes of death (e.g., cancer, cardiovascular disease; P < 0.01). For an average follow-up time of 20 years, output from the model was associated with multiple outcomes among survivors, such as tests of cognitive function, geriatric depression, number of daily living impairments and grip strength (P < 0.03). CONCLUSIONS: The multivariate model we developed characterizes a "healthy aging" phenotype based upon an integration of measures that together reflect multiple dimensions of an aging adult (65-69 years of age). Age-sensitive components of this model may be of value as biomarkers in human studies that evaluate anti-aging interventions. Our methodology could be applied to data from other longitudinal cohorts to generalize these findings, identify additional predictors of long-term survival, and to further develop the "healthy aging" concept.

Red blood cell omega-3 fatty acid levels and markers of accelerated brain aging.
            (Tan et al., 2012) Download
OBJECTIVE: Higher dietary intake and circulating levels of docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) have been related to a reduced risk for dementia, but the pathways underlying this association remain unclear. We examined the cross-sectional relation of red blood cell (RBC) fatty acid levels to subclinical imaging and cognitive markers of dementia risk in a middle-aged to elderly community-based cohort. METHODS: We related RBC DHA and EPA levels in dementia-free Framingham Study participants (n = 1575; 854 women, age 67 +/- 9 years) to performance on cognitive tests and to volumetric brain MRI, with serial adjustments for age, sex, and education (model A, primary model), additionally for APOE epsilon4 and plasma homocysteine (model B), and also for physical activity and body mass index (model C), or for traditional vascular risk factors (model D). RESULTS: Participants with RBC DHA levels in the lowest quartile (Q1) when compared to others (Q2-4) had lower total brain and greater white matter hyperintensity volumes (for model A: beta +/- SE = -0.49 +/- 0.19; p = 0.009, and 0.12 +/- 0.06; p = 0.049, respectively) with persistence of the association with total brain volume in multivariable analyses. Participants with lower DHA and omega-3 index (RBC DHA+EPA) levels (Q1 vs. Q2-4) also had lower scores on tests of visual memory (beta +/- SE = -0.47 +/- 0.18; p = 0.008), executive function (beta +/- SE = -0.07 +/- 0.03; p = 0.004), and abstract thinking (beta +/- SE = -0.52 +/- 0.18; p = 0.004) in model A, the results remaining significant in all models. CONCLUSION: Lower RBC DHA levels are associated with smaller brain volumes and a "vascular" pattern of cognitive impairment even in persons free of clinical dementia.

Age-associated epigenetic drift: implications, and a case of epigenetic thrift?
            (Teschendorff et al., 2013) Download
It is now well established that the genomic landscape of DNA methylation (DNAm) gets altered as a function of age, a process we here call 'epigenetic drift'. The biological, functional, clinical and evolutionary significance of this epigenetic drift, however, remains unclear. We here provide a brief review of epigenetic drift, focusing on the potential implications for ageing, stem cell biology and disease risk prediction. It has been demonstrated that epigenetic drift affects most of the genome, suggesting a global deregulation of DNAm patterns with age. A component of this drift is tissue-specific, allowing remarkably accurate age-predictive models to be constructed. Another component is tissue-independent, targeting stem cell differentiation pathways and affecting stem cells, which may explain the observed decline of stem cell function with age. Age-associated increases in DNAm target developmental genes, overlapping those associated with environmental disease risk factors and with disease itself, notably cancer. In particular, cancers and precursor cancer lesions exhibit aggravated age DNAm signatures. Epigenetic drift is also influenced by genetic factors. Thus, drift emerges as a promising biomarker for premature or biological ageing, and could potentially be used in geriatrics for disease risk prediction. Finally, we propose, in the context of human evolution, that epigenetic drift may represent a case of epigenetic thrift, or bet-hedging. In summary, this review demonstrates the growing importance of the 'ageing epigenome', with potentially far-reaching implications for understanding the effect of age on stem cell function and differentiation, as well as for disease prevention.

Health-and disease-related biomarkers in aging research.
            (Thompson and Voss, 2009) Download
This article focuses on a synthesis of knowledge about healthy aging research in human beings and then synthesized nurse-led research in gerontology and geriatrics that use biomarkers. Healthy aging research has attracted considerable attention in the biomedical and basic sciences within the context of four major areas: (a) genetic variations as an expression of successful or unsuccessful aging; (b) caloric restriction as an intervention to slow the progression of aging; (c) immunological aging; (d) neurobiology of the aging brain. A systematic review of the literature was performed to identify nurse-led geriatric-related biomarker research. Nurse researchers who have chosen to integrate biomarkers as part of their research studies have been working in six focal areas, which are reviewed: health promotion within risk populations, cancer, vascular disease, Alzheimer's disease, caregiving, and complementary therapies. The article provides a discussion of contributions to date, identifying existing gaps and future research opportunities.

The molecular chaperone apolipoprotein J/clusterin as a sensor of oxidative stress: implications in therapeutic approaches - a mini-review.
            (Trougakos, 2013) Download
BACKGROUND: Organisms are constantly exposed to physiological and environmental stresses and therefore require an efficient surveillance of genome and proteome quality in order to prevent disruption of homeostasis. Central to the intra- and extracellular proteome surveillance system are the molecular chaperones that contribute to both proteome maintenance and clearance. The conventional protein product of the apolipoprotein J/clusterin (CLU) gene is a heterodimeric secreted glycoprotein (also termed as sCLU) with a ubiquitous expression in human tissues. CLU exerts a small heat shock protein-like stress-induced chaperone activity and has been functionally implicated in numerous physiological processes as well as in ageing and most age-related diseases including tumorigenesis, neurodegeneration, and cardiovascular and metabolic syndromes. OBJECTIVE: The CLU gene is differentially regulated by a wide variety of stimuli due to the combined presence of many distinct regulatory elements in its promoter that make it an extremely sensitive cellular biosensor of environmental and/or oxidative stress. Downstream to CLU gene induction, the CLU protein seems to actively intervene in pathological states of increased oxidative injury due to its chaperone-related property to inhibit protein aggregation and precipitation (a main feature of oxidant injury), as well as due to its reported distribution in both extra- and, most likely, intracellular compartments. CONCLUSION: On the basis of these findings, CLU has emerged as a unique regulator of cellular proteostasis. Nevertheless, it seemingly exerts a dual function in pathology. For instance, in normal cells and during early phases of carcinogenesis, CLU may inhibit tumor progression as it contributes to suppression of proteotoxic stress. In advanced neoplasia, however, it may offer a significant survival advantage in the tumor by suppressing many therapeutic stressors and enhancing metastasis. This review will critically present a synopsis of recent novel findings that relate to the function of this amazing molecule and support the notion that CLU is a biosensor of oxidative injury; a common link between ageing and all pathologies where CLU has been implicated. Potential future perspectives, implications and opportunities for translational research and the development of new therapies will be discussed.

Dynamic determinants of longevity and exceptional health.
            (Yashin et al., 2010) Download
It is well known from epidemiology that values of indices describing physiological state in a given age may influence human morbidity and mortality risks. Studies of connection between aging and life span suggest a possibility that dynamic properties of age trajectories of the physiological indices could also be important contributors to morbidity and mortality risks. In this paper we use data on longitudinal changes in body mass index, diastolic blood pressure, pulse pressure, pulse rate, blood glucose, hematocrit, and serum cholesterol in the Framingham Heart Study participants, to investigate this possibility in depth. We found that some of the variables describing individual dynamics of the age-associated changes in physiological indices influence human longevity and exceptional health more substantially than the variables describing physiological state. These newly identified variables are promising targets for prevention aiming to postpone onsets of common elderly diseases and increase longevity.


Select aging biomarkers based on telomere length and chronological age to build a biological age equation.
            (Zhang et al., 2014) Download
The purpose of this study is to build a biological age (BA) equation combining telomere length with chronological age (CA) and associated aging biomarkers. In total, 139 healthy volunteers were recruited from a Chinese Han cohort in Beijing. A genetic index, renal function indices, cardiovascular function indices, brain function indices, and oxidative stress and inflammation indices (C-reactive protein [CRP]) were measured and analyzed. A BA equation was proposed based on selected parameters, with terminal telomere restriction fragment (TRF) and CA as the two principal components. The selected aging markers included mitral annulus peak E anterior wall (MVEA), intima-media thickness (IMT), cystatin C (CYSC), D-dimer (DD), and digital symbol test (DST). The BA equation was: BA = -2.281TRF + 26.321CYSC + 0.025DD - 104.419MVEA + 34.863IMT - 0.265DST + 0.305CA + 26.346. To conclude, telomere length and CA as double benchmarks may be a new method to build a BA.



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