Unsuccessful Aging Research Articles

Role of prothrombotic polymorphisms in successful or unsuccessful aging

The study of the genetic profile of centenarians aims to identify the genes and allelic variants which may influence a greater life expectancy and that can be considered as predisposing factors associated to the aging diseases, such as Alzheimer. Centenarians, that represent a cohort of selected survivors, show an hypercoagulability state characterised by striking signs of high coagulation enzyme activity, as directly assessed by the tested higher plasma level of some important factors involved in the haemostasis balance. Anyway, these individuals seem to have a reduced susceptibility to dementia, as well as to cardiovascular events. In this study we analyze the frequencies of Leiden Factor V polymorphism (G1691A), and G20210A of prothrombin (FII) in three cohorts of subjects: patients with Alzheimer's disease (unsuccessful aging), nonagenarians (successful aging) and young healthy controls, to assess whether allelic variants associated to the modification of haemostatic system function, may play a role in the protection or susceptibility to Alzheimer disease, as well as to reach a successful aging. No significant differences were observed in the frequencies of the three groups studied. These results indicate that the presence or absence of the gene variants examined did not influence the achievement of advanced age and are not risk factors for Alzheimer's disease. The state of hypercoagulability and the possession of these risk alleles appear to be compatible with the achievement of longevity and are not implied as risk factors in Alzheimer disease development.

Discourse of successful aging in The Globe & Mail: Insights from critical gerontology

While the determinants of successful aging receive much attention from researchers, few studies have considered media portrayals of successful aging. Yet the mass media shape the agenda for discussing and understanding aging and transmit the meanings and various experiences of aging between generations. Through thematic analysis of 146 articles featuring older adults in various contexts including family, work, civic engagement, social policy, health care, consumer market, and leisure published in The Globe & Mail in 2004–2006, this paper explores stereotypes of successful aging. Drawing on the insights from critical gerontology and critical discourse analysis, this study suggests that the three themes in the media discourse of successful aging (successful aging as an individual choice, individual responsibility for unsuccessful aging, and how to age successfully by staying engaged) embody the neo-liberal principles of containing the costs of eldercare and maximizing individual effort and responsibility for managing risks of disease and decline in later life.

Cardiac Index as a Correlate of Brain Volume

The importance of vascular risk factors in the development and progression of cognitive disorders is gaining appreciation; the term “vascular cognitive disorders” refers to the common situation in which vascular damage plays a role, either alone or in combination with a neurodegenerative or other process, in the development of cognitive impairment or dementia. Numerous vascular risk factors have been implicated in vascular cognitive disorders, and many of these have been linked to cognitive decline through white matter damage and brain atrophy.1–8 As the American Heart Association launches its new strategic plan to improve the cardiovascular health of all Americans by 20%, a greater focus on ideal cardiovascular health will likely lead to improved brain health and therefore cognitive health. To address the health needs of our aging population, a better understanding of the links between cardiovascular disease and brain structure and function will be required. In addition, it will be important to identify early markers of unsuccessful aging to test interventions that can improve outcomes. Article see p 690 Various quantitative measures are now available to help us understand the relationships between vascular disease and brain health. These include neuropsychological testing, structural and functional magnetic resonance imaging, and metabolic imaging with magnetic resonance imaging and positron emission tomography. These tools have helped us better quantify changes in brain structure and metabolism and relate them to associations between aging, neurovascular risk factors, and cognitive function. In this issue of Circulation , Jefferson et al9 report an association between cardiac index and brain volume and relate these to cognitive function in a subsample of the well-characterized Framingham Study (participants were healthier than the overall cohort, being well enough to undergo magnetic resonance imaging). The brain volumes of participants were smaller among those with lower cardiac index values, even after adjustment …

Impact of the genetic background on immune system

The aim of this study was to compare some immune parameters between healthy centenarian offspring (CO), healthy age‐matched old (O) and young (Y) controls to evaluate whether any difference exists in the naïve/memory compartments that might explain the familiar increased lifespan expectancy of centenarian offspring (CO). In fact it is now supposed that longevity is based on genetic background and it has been demonstrated that centenarian siblings have an increased probability to reach long life as well.MethodsPeripheral blood mononuclear cells (PBMC) were collected from CO, O and Y donors. Lymphocyte subsets were evaluated by cytofluorimetric analysis. We have studied the naïve/memory compartment in T and B cells evaluating the expression of CD45R0, CD27, CD28 (on CD4 and CD8 T cells) and IgD and CD27 (on CD19 B cells).ResultsOur results show that O show the most differentiated phenotype, Y display the less differentiated phenotype and CO show an intermediate profile between the other two control groups.ConclusionThese data support the hypothesis of a “familiar youth” of the immune system that can be a big advantage both to fight the main age‐related diseases, and to properly respond to vaccinations. So, T and B cell subset changes could represent an hallmark of successful or unsuccessful ageing and could be used as a biomarker of human life span.This work was supported by the Italian Ministry of Education, University and Research grant (Does parental longevity impact on the health ageing of their offspring? An immunological and genetic study) to C. Caruso.

B Cells Compartment in Centenarian Offspring and Old People

Immunosenescence is considered a major contributory factor to the increased frequency of morbidity and mortality among elderly. On the other hand centenarians are considered the best example of successful ageing. To gain insight into mechanisms of immunosenescence and its clinical relevance, a possible model is represented by centenarians and/or their offspring. Nowadays centenarians are not more a curiosity, but in Europe are 1/8000 inhabitants and it has been demonstrated that the centenarian offspring, who are typically in their 70s and 80s, have a survival advantage when compared with age-matched controls whose parents died at an average life expectancy. Then again, studies on immunosenescence focus mainly on T cell impairment, although B cells are also affected. So, in the present preliminary report, we have studied B cell compartment in two classes of individuals, old people and centenarian offspring. B cell compartment was analysed using IgD and CD27 antibodies which characterize naïve B cells (IgD(+) CD27(-)), memory unswitched B cells (IgD(+)CD27(+)), memory switched B cells(IgD(-)CD27(+)) and double negative B cells (DN) (IgD(-)CD27(-)), i.e. exhausted memory cells. As expected, in both cohorts we observed a decreased B cell count. However, in centenarian offspring, naïve B cells are more abundant whereas exhausted memory cells (DN B cells, IgD(-)CD27(-)) do not show the increase that we have previously demonstrated in healthy elderly donors. These data are similar to that found in previously experiments on young subjects. So, our preliminary results show that centenarian offspring do not have the typical trend of memory/naive B cell subsets observed in elderly people and this is in agreement with the higher levels of IgM in the serum of centenarian offspring in comparison with data obtained in age-matched controls. This reservoir of naive B cell might be one of the causes that make centenarian offspring able to keep fighting off new infections, hence prolonging their life. So, B cell subset changes could represent a hallmark of successful or unsuccessful ageing and could be used as a biomarker of human life span, potentially useful for the evaluation of anti-ageing treatment.

T Cell Homeostasis in Centenarians: From the Thymus to the Periphery

The immune system undergoes a process of profound remodelling during aging, referred to as immunosenescence, and characterized by complex modifications of several components. In this review, we discuss recent developments and observations regarding the generation of T cells in the thymus during aging and longevity, and the regulation and maintenance of peripheral blood lymphocytes. The generation of new T cells is indeed crucial to maintain a functional immune system, and is a fundamental step to avoid unsuccessful aging, thus reaching longevity in good health. Mechanisms will be described that are related to the production and maintenance of those lymphocytes defined "recent thymic emigrants", and to the detection of the so called "T cell receptor rearrangement excision circles (TREC)", along with the presence in the periphery of naïve and memory T cells, that can be influenced and regulated by several different mechanisms. Several strategies aimed at improving thymic functionality are currently receiving a growing interest, and some of them are based on molecules that are produced by, and/or act on immune cells. Data on the possible use of these molecules, including cytokines like interleukin (IL)-7, IL-15 and keratinocyte growth factor, to restore thymic function are reviewed and discussed.

Evidence Regarding the Benefits of Physical Exercise

Evidence Regarding the Benefits of Physical Exercise

The Intersection of Geriatrics and Chronic Kidney Disease: Frailty and Disability Among Older Adults With Kidney Disease

Older adults (aged >or=65 years) comprise the largest segment of the CKD population, and impaired kidney function is linked with unsuccessful aging. Individuals across the spectrum of kidney disease have clinical features of the frailty phenotype, suggesting that frailty is not confined to old age among vulnerable populations. This manifests as a high prevalence of impaired physical performance, emergent geriatric syndromes, disability, and risk of death. Considering the multiple system involvement underlying the symptoms and deficits seen in CKD, especially in the more severe stages, the concept of frailty is a highly useful tool to identify older adults with kidney disease who are on the trajectory of vulnerability leading to decline and death. Further work is needed to characterize the relationship between kidney disease and frailty and to identify opportunities to intervene.

TLR4 Polymorphisms and Ageing: Implications for the Pathophysiology of Age-Related Diseases

Innate immunity provides a first line of host defense against infection by recognizing and killing microbes while simultaneously activating an instructive immune response. Toll-like receptors (TLRs) are principal mediators of rapid microbial recognition and function mainly by detection of pathogen-associated molecular patterns that do not exist in the host. Recognition of their ligands leads to a series of signaling events resulting in acute host responses, involved in killing pathogens. We describe the involvement of TLR4 polymorphisms in ageing, and in particular in age-related diseases, suggesting the crucial role of molecules of innate immunity in pathophysiology of these diseases. Hence, we observed that pro-inflammatory alleles may be related to unsuccessful ageing, such as Alzheimer's disease, prostate cancer, and atherosclerosis; in contrast, the control of inflammation by anti-inflammatory alleles may result in increased longevity and successful ageing. Finally, a possible therapeutic approach to delay age-related diseases is outlined.

Health- and Disease-Related Biomarkers in Aging Research

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.

Cystatin C and Aging Success

To our knowledge, the effect of kidney function on successful aging has not been examined. We evaluated the relationship between cystatin C and aging success during a 6-year follow-up in the Cardiovascular Health Study, a community-based cohort of older adults (aged >or= 65 years). Successful aging was defined as remaining free of cardiovascular disease, cancer, and chronic obstructive pulmonary disease and having intact physical and cognitive functioning. In adjusted analysis, an accelerated failure time model was used to evaluate the percentage reduction in successful years by level of cystatin C. A separate Cox proportional hazards model evaluated whether cystatin C was related to incident physical and cognitive disability. A total of 2140 participants had cystatin C measured and were free of the previously mentioned conditions at baseline. Their mean age was 74 years. The mean cystatin C level, creatinine level, and estimated glomerular filtration rate were 1.06 mg/L, 0.93 mg/dL, and 78 mL/min/1.73 m(2), respectively (to convert cystatin C to nanomoles per liter, multiply by 75; and to convert creatinine to micromoles per liter, multiply by 88.4). A total of 873 participants reached a first event in follow-up, 138 because of cognitive disability, 238 because of physical disability, 34 because of chronic obstructive pulmonary disease, 146 because of cancer, and 317 because of cardiovascular disease. The adjusted percentage reduction in successful life years in the highest vs the lowest quartile of cystatin C was 27% (95% confidence interval, 11%-39%). The highest vs lowest quartile of cystatin C also was independently associated with incident cognitive or physical disability (hazard ratio, 1.39; 95% confidence interval, 1.00-1.98). A higher cystatin C level, even within a range of relatively normal kidney function, was associated with unsuccessful aging.

Role of TLR4 Polymorphisms in Inflammatory Responses

The total burden of infection at various sites may affect the progression of atherosclerosis and Alzheimer's disease (AD), the risk being modulated by host genotype. The role of lipopolysaccharide (LPS) receptor TLR4 is paradigmatic. It initiates the innate immune response against gram-negative bacteria, and TLR4 single nucleotide polymorphisms (SNPs), such as +896A/G, known to attenuate receptor signaling, have been described. This SNP shows a significantly lower frequency in patients affected by myocardial infarction or AD. Thus, people genetically predisposed to developing lower inflammatory activity seem to have less chance of developing cardiovascular disease (CVD) or AD. In the present report, to validate this hypothesis, the levels of the eicosanoids, leukotriene B4 (LTB4) and prostaglandin E2 (PGE2), known to be involved as mediators in age-related diseases, were determined by an enzyme-linked immunosorbent assay in supernatants from a whole blood assay, after stimulation with subliminal doses of LPS from Escherichia coli. The samples, genotyped for the +896A/G SNP, were challenged with LPS for 4, 24, and 48 h. Both LTB4 and PGE2 values were significantly lower in carriers bearing the TLR4 mutation. Therefore, the pathogen burden, by interacting with the host genotype, determines the type and intensity of the inflammatory responses accountable for proinflammatory status, CVD, AD, and unsuccessful aging (i.e., age-related inflammatory diseases).

Apolipoprotein E Genotypic Frequencies Among Down Syndrome Patients Imply Early Unsuccessful Aging for ApoE4 Carriers

Down syndrome (DS) might be considered a model for unsuccessful and early aging, possibly accelerated for those who carry the APOE4 allele associated with common age-related diseases, e.g., Alzheimer's disease and a poor prognosis after acute myocardial infarction, causing lower ApoE4 frequencies among the very old in general populations. We compared ApoE genotypic frequencies found for healthy adults (n = 211, age < 40; n = 79, ages 70-79; n = 71, ages > 90) to those found for DS patients (n = 106, mean age 9 years), all living in western Sicily. We found that the frequency of the ApoE23 genotype increased with age among the healthy adults (8.5%, 6.4%, 19.7%; p = 0.024) while ApoE34 frequency decreased (16.1%, 12.6%, 4.1%; p = 0.012). DS patients had APOE34 genotypic frequencies very similar to those found in septuagenarians (9%; p = 0.005). Analyzing results according to surviving rate of persons with DS, an age-related reduction of ApoE3/4 genotype frequency was found comparing =5 years old to >5 years old DS subjects. These results highlight DS as a model to understand the role of APOE4 allele in unsuccessful ageing considering that a number of proinflammatory supernumerary genes (Cu/Zn superoxide dismutase, Ets-2 transcription factors, Down syndrome critical region 1, stress-inducible factor, interferon-alpha receptor and the amyloid precursor protein) are located on chromosome 21 and are implied in the pathologic processes of DS.

ESTUDO DA OCORRÊNCIA DE “DOR CRÔNICA” EM IDOSOS DE UMA COMUNIDADE ATENDIDA PELO PROGRAMA SAÚDE DA FAMÍLIA EM GOIÂNIA

The aim of this descriptive research was to analyze the chronicle pain (NANDA, 2002) in old people of a community in Goiânia (GO). A group of 40 old people from 102 registered ones in a Family Health Program composed the sample. The data were collect from January to June of 2004, at the old people residences. The procedures of data collect consisted by an interview, a physical examination, both pain and depression valuation scales. It was identified chronicle pain in 62.5% of the old people. The pain intensity related was predominantly unsupportable (36%) and slight (28%), followed by the moderated (20%) and intense (16%). The pain place was mainly in the dorsal region (48%), and, then, in the inferior members (24%). The biologic injurious agents were the most frequent related factor. The defining characteristics present in more 50% of the sample were: verbal report or codified (100%); modified capacity of continuing previous activities (68%); changes on the sleeping pattern (48%) and tiredness (52%). The chronicle pain is a frequent diagnosis in old people with multiple defining characteristics that maintain the affirmation steady. The relation factors generally refer to the unsuccessful aging process or to the pathologies characteristic of this age range. KEY-WORDS: diagnosis; pain, nursing, aged; family health program.

Inflammatory networks in ageing, age-related diseases and longevity

Inflammation is considered a response set by the tissues in response to injury elicited by trauma or infection. It is a complex network of molecular and cellular interactions that facilitates a return to physiological homeostasis and tissue repair. The individual response against infection and trauma is also determined by gene variability. Ageing is accompanied by chronic low-grade inflammation state clearly showed by 2–4-fold increase in serum levels of inflammatory mediators. A wide range of factors has been claimed to contribute to this state; however, the most important role seems to be played by the chronic antigenic stress, which affects immune system thorough out life with a progressive activation of macrophages and related cells. This pro-inflammatory status, interacting with the genetic background, potentially triggers the onset of age-related inflammatory diseases as atherosclerosis. Thus, the analysis of polymorphisms of the genes that are key nodes of the natural immunity response might clarify the patho-physiology of age-related inflammatory diseases as atherosclerosis. On the other hand, centenarians are characterized by marked delay or escape from age-associated diseases that, on average, cause mortality at earlier ages. In addition, centenarian offspring have increased likelihood of surviving to 100 years and show a reduced prevalence of age-associated diseases, as cardiovascular disease (CVD) and less prevalence of cardiovascular risk factors. So, genes involved in CVD may play an opposite role in human longevity. Thus, the model of centenarians can be used to understand the role of these genes in successful and unsuccessful ageing. Accordingly, we report the results of several studies in which the frequencies of pro-inflammatory alleles were significantly higher in patients affected by infarction and lower in centenarians whereas age-related controls displayed intermediate values. These findings point to a strong relationship between the genetics of inflammation, successful ageing and the control of cardiovascular disease at least in men, in which these studies were performed. These data are also briefly discussed in the light of antagonistic pleiotropy theory and in order to pursuit a pharmacogenomics approach.

Inflammation, Longevity, and Cardiovascular Diseases

The total burden of infection at various sites may affect the progression of atherosclerosis, the risk being modulated by host genotype. The role of lipopolysaccaride receptor TLR4 is paradigmatic. It initiates the innate immune response against gram-negative bacteria; and TLR4 polymorphisms, as ASP299GLY, suggested to attenuate receptor signaling, have been described. We demonstrated that TLR4 ASP299GLY polymorphism shows a significantly lower frequency in patients affected by myocardial infarction compared to controls, whereas centenarians show a higher frequency. Thus, people genetically predisposed to developing weak inflammatory activity, seem to have fewer chances of developing cardiovascular diseases (CVD) and, subsequently, live longer if they do not become affected by serious infectious diseases. These results are in agreement with our other data demonstrating how genetic background may exert the opposite effect with respect to inflammatory components in CVD and longevity. In the present report, to validate this hypothesis, the levels of interleukin (IL)-6, a pro-inflammatory cytokine involved in atherosclerosis and longevity, were determined by an enzyme-linked immuno-sorbent assay (ELISA) in supernatants from a whole blood assay after stimulation with subliminal doses of lipopolysaccaride (LPS) from Escherichia coli (E. coli). The samples, genotyped for the ASP299GLY polymorphism, were challenged with LPS for 4, 24, and 48 h. What we found was that Il-6 values were significantly lower in carriers bearing TLR4 mutation. Therefore, the pathogen burden, by interacting with host genotype, determines the type and intensity of the immune-inflammatory responses accountable for pro-inflammatory status, CVD, and unsuccessful aging. On the other hand, our present data seem to explain the inconclusive results obtained in case-control studies taking into account the role of functional IL-6 polymorphisms in successful and unsuccessful aging. In fact, IL6 levels seem to depend, in addition, on IL-6 polymorphisms and on innate immunity gene polymorphisms as well.

Association between +1059G/C CRP Polymorphism and Acute Myocardial Infarction in a Cohort of Patients from Sicily

Inflammation plays a role in all the phases of atherosclerosis, and increased production of the acute-phase reactant, C-reactive protein (CRP), predicts future cardiovascular events. Furthermore, CRP has been claimed to play a role in the pathogenesis of atherosclerosis; therefore, CRP polymorphisms might be associated with acute myocardial infarction (AMI). We have analyzed male patients affected by AMI and healthy age-related male controls from Sicily for +1059G/C CRP single-nucleotide polymorphism (SNP). There was a significantly higher frequency of +1059C SNP (P = 0.0008; OR 3.86) in patients compared to controls. CRP serum levels were significantly higher in C+ healthy subjects rather than in C- subjects (P = 0.0075). The results of the present pilot case-control study performed in a homogeneous caucasoid population suggest that +1059C CRP gene SNP is associated with AMI. In any case, the results of the present study should add to the growing body of evidence on the role of pro-inflammatory genotypes in unsuccessful aging, determining susceptibility to immune-inflammatory diseases such as coronary heart disease.

The Genetics of Human Longevity

Aging is due to a complex interaction of genetic, epigenetic, and environmental factors, but a strong genetic component appears to have an impact on survival to extreme ages. In order to identify "longevity genes" in humans, different strategies are now available. In our laboratory, we performed association studies on a variety of "candidate" polymorphisms in Italian centenarians. Many genes/polymorphisms gave negative results, while others showed a positive association with human longevity and a sometimes-positive association with unsuccessful aging (myocardial infarction, Alzheimer's disease, and type 2 diabetes). Results regarding genes involved in inflammation (IL-1 cluster, IL-6, IL-10, TNF-alpha, TGF-beta, TLR-4, PPARgamma), insulin/IGF-1 signaling pathway and lipid metabolism (apolipoproteins, CETP, PON1), and oxidative stress (p53, p66(shc)) will be described. In addition, a strong role of the interaction between nuclear and mitochondrial genomes (mtDNA haplogroups and the C150T mutation) emerged from our findings. Thus, the genetics of human longevity appears to be quite peculiar in a context where antagonistic pleiotropy can play a major role and genes can have a different biological role at different ages.

Commentary on “The NIH Cognitive and Emotional Health Project: Report of the Critical Evaluation Study Committee.”

m t p o s s i t s t u g m a a a a e The National Institutes of Health (NIH) Cognitive and motional Health Project recently published their “Report f the Critical Evaluation Study Committee.” The Commitee chose to evaluate factors that preserve cognitive and motional health, instead of factors associated with disorers or other negative outcomes. However, as the authors oint out, the majority of studies are concerned with disases or bad outcomes, such as cognitive decline or depresive symptoms. Therefore, the results of this review are ased mainly on the assumption that if a factor is associated ith impaired cognitive or emotional health, its absence ould be related to preserved or improved cognitive funcion (and factors that are associated with less impairment hould be related to improved function). However, as the ommittee also notes, even if these assumptions are true, uccessful aging should be distinguished from normal aging nd unsuccessful aging. Preserved or even improved cogitive and emotional health might thus be related to other actors than what is found for deteriorating emotional and ognitive function and, even more so, for defined disorders. When evaluating factors associated with these outcomes, he Study Committee chose to evaluate only results from a umber of preselected large epidemiologic studies (more han 500 participants, age greater than 65 years, longitudinal esign, and including measurements of at least memory and ne more cognitive domain and measurement of depression nd one more emotional domain). The report is, thus, not a omprehensive meta-analysis of all studies published in the rea. In this way, the Committee hoped to circumvent the roblem of publication bias; specifically the studies were arge enough for meaningful interpretations of negative ndings. However, the report is based on published articles. o effort seems to have been made to elucidate possible

Analysis of Candidate Genes in Celiac Disease: A Tool to Identify Life-Threatening Associated Genes?

The authors have recently reported that celiac patients show a proinflammatory cytokine genetic profile characterized by the contemporaneous presence of both the tumour necrosis factor-alpha-308A and the interferon-gamma +874T allele-positive genotypes. The same alleles are considered risk factors for aging associated disease, whereas an anti-inflammatory cytokine genotype profile might be associated with an extended life expectancy. This paper reports data on the 1249-1250InsACAA/Non-Ins transforming growth factor (TGF)-beta2, a multifunctional anti-inflammatory cytokine, polymorphism distribution in 88 celiac disease (CD) patients, 99 age- and sex-matched controls, and 28 >95-year-old healthy subjects living in western Sicily. These data demonstrate that genotype frequencies of CD patients are not different from that of age-matched and >95-year-old healthy control subjects. These data might suggest that TGF-beta2 polymorphism is not involved in the complex genotypes associated with successful or unsuccessful aging. In addition, one can speculate that the genotype profile associated with CD susceptibility might be detrimental for longevity, and studies of this CD genetic asset might point to a candidate gene for antiaging strategies.