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The presence of circulating microbiome in blood has been reported in both physiological and pathological conditions, although its origins, identities and function remain to be elucidated. This study aimed to investigate the presence of blood microbiome by quantitative real-time PCRs targeting the 16S rRNA gene. To our knowledge, this is the first study in which the circulating microbiome has been analyzed in such a large sample of individuals since the study was carried out on 1285 Randomly recruited Age-Stratified Individuals from the General population (RASIG). The samples came from several different European countries recruited within the EU Project MARK-AGE in which a series of clinical biochemical parameters were determined. The results obtained reveal an association between microbial DNA copy number and geographic origin. By contrast, no gender and age-related difference emerged, thus demonstrating the role of the environment in influencing the above levels independent of age and gender at least until the age of 75. In addition, a significant positive association was found with Free Fatty Acids (FFA) levels, leukocyte count, insulin, and glucose levels. Since these factors play an essential role in both health and disease conditions, their association with the extent of the blood microbiome leads us to consider the blood microbiome as a potential biomarker of human health. publishedVersion

Upstream transcription factor 1 (USF1) regulates the transcription of many genes related to cell and organism survival processes such as stress and immune response, regulation of cellular senesce, and carcinogenesis. In this study, our aim was to investigate the effect of USF1 single nucleotide variations (SNVs) on longevity in the Vitality 90+ study, a population-based study of nonagenarians (90 ±1 years of age) living in the area of Tampere municipality, Finland. Altogether 509 voluntary nonagenarians (115 males, 394 females) were genotyped using the 5'-nuclease assay for rs2774279G A, rs2516839T C, and rs2073658C T SNVs. During the 4 years of follow-up, the total mortality rate was 64.2%. In the study, we found that the frequency of C-allele of rs2516839 among nonsurviving nonagenarians (52.5%) was higher than those who survived (41.2%; P = 0.0006, odds ratio = 1.575, 95% confidence interval [CI]: 1.215-2.041). Furthermore, carriage of this variation and its haplotypes had a significant gender by genotype interaction (P 0.05) on mortality. Kaplan-Meier log-rank test during 4-years of follow-up showed significantly higher mortality rate in the case of CC genotype carriage than other genotype carriages in nonagenarian women (P 0.0001). In addition, after adjusting for age in Cox regression analysis, cardiovascular disease, diabetes, infectious disease, dementia, and living place (nursing home or home), CC genotype of rs2516839T C was found to be associated with shorter life expectancy in nonagenarian women (hazard ratio = 2.27; 95% CI, 1.34-3.85 P = 0.002). In conclusion, rs2516839 variation and related haplotypes of the USF1 gene are strongly related to all-cause mortality in Finnish nonagenarians, especially among women.

Ageing of the human immune system, or immunosenescence, is characterised by distinct changes in the proportion of the various cell types, e.g., increase of the CD14+ monocytic cells, decrease of CD19+ B lymphocytes, and changes in T cell subpopulations, namely increase of CD4+ and CD8+ cells which have lost the costimulatory CD28 antigen. Currently, it is believed that the lifelong antigenic burden may be one of the inducers of immunosenescence. Thus far, only one exogenous stimulus, cytomegalovirus infection, has shown to be a major factor in this respect. To find other possible candidates, we evaluated the role of the evolutionary youngest group of human endogenous retroviruses, namely HERV-K(HML-2), on immunosenescence. HERVs exist in the genome as proviruses, but their activation has been detected in several immunopathologic conditions. The expression of HERV-K(HML-2) env was observed to be lower in the peripheral blood mononuclear cells of nonagenarians (n=61) than in those of young controls (n=37). These mRNA levels did not correlate with the age-associated differences in the proportions of CD14+, CD4+CD28- and CD8+CD28- cells, but in the case of CD19+ B cells a strong positive correlation was observed in the nonagenarians. Thus, these data suggest that HERVs do not function as antigenic drivers of immunosenescence. On the contrary, expression of HERV-K(HML-2) env is associated with more youthful levels of B cells.

Oxidative stress and antioxidants play a role in age-related diseases and in the aging process. We here present data on protein carbonyls, 3-nitrotyrosine, malondialdehyde, and cellular and plasma antioxidants (glutathione, cysteine, ascorbic acid, uric acid,α-tocopherol, and lycopene) and their relation with age in the European multicenter study MARK-AGE. To avoid confounding, only data from countries which recruited subjects from all three study groups (five of eight centers) and only participants aged ≥55 years were selected resulting in data from 1559 participants. These included subjects from (1) the general population, (2) members from long-living families, and (3) their spouses. In addition, 683 middle-aged reference participants (35–54 years) served as a control. After adjustment for age, BMI, smoking status, gender, and country, there were differences in protein carbonyls, malondialdehyde, 3-nitrotyrosine,α-tocopherol, cysteine, and glutathione between the 3 study groups. Protein carbonyls and 3-nitrotyrosine as well as cysteine, uric acid, and lycopene were identified as independent biomarkers with the highest correlation with age. Interestingly, from all antioxidants measured, only lycopene was lower in all aged groups and from the oxidative stress biomarkers, only 3-nitrotyrosine was increased in the descendants from long-living families compared to the middle-aged control group. We conclude that both lifestyle and genetics may be important contributors to redox biomarkers in an aging population.

BACKGROUND Low socioeconomic status is associated both with poorer functioning and elevated levels of inflammatory and cardiometabolic biomarkers; however, knowledge of such relations for the oldest old is limited. Our aim was to study whether education is associated with cardiometabolic (cholesterol levels, body mass index, and leptin) and inflammatory (C-reactive protein, interleukin-6, interleukin-1Ra) biomarkers for the 90-year-olds who participated in the Vitality 90+ study. In addition, we investigated whether these biomarkers explain educational inequalities in functioning. METHODS All persons in Tampere, Finland, who were born in 1909 or 1910, were invited to participate, irrespective of their health status or dwelling place. The sample consisted of 262 participants who went through the home interview and blood tests. The socioeconomic status indicator used was the highest education, and physical functioning was assessed using the Barthel index. The association of education with individual and combined biomarker scores, and with functioning, was analyzed cross-sectionally applying generalized linear models. RESULTS The low- and mid-level-educated participants had greater odds of belonging to the high risk group in cardiometabolic biomarkers than did the high-educated. Differences were statistically significant in three individual biomarkers (high-density lipoprotein-cholesterol, leptin, and body mass index) and in a cardiometabolic score. There were no educational differences in inflammatory biomarkers. When all biomarkers were combined, they mediated educational differences in functioning on an average of 23%. After controlling for smoking, alcohol use and diseases, biomarkers mediated part of the differences between the mid-level- and high-educated. CONCLUSIONS High education was associated with better cardiometabolic biomarkers and functioning among the 90-year-olds. In part, educational inequalities in functioning were explained by cardiometabolic biomarkers.

Objective: To discover whether successful aging, understood as a multidimensional concept, predicts further survival in very old people. Method: The population sample consisted of 1,370 persons aged 90 or over in the Vitality 90+ study. Four alternative models of successful aging were constructed, each of them consisting of physical, psychological, and social dimensions. Mortality was followed up after 4 and 7 years. Results: Three out of four models significantly predicted survival at both follow-ups for the whole group. Separately, “success” in the physical, psychological, and social components was also associated with higher survival. The associations were stronger in women than in men. Discussion: Successful aging, measured using physical, psychological, and social dimensions, predicts the length of future life in nonagenarians.

Epigenetic mechanisms such as DNA methylation (DNAm) have a central role in the regulation of gene expression and thereby in cellular differentiation and tissue homeostasis. It has recently been shown that aging is associated with profound changes in DNAm. Several of these methylation changes take place in a clock-like fashion, i.e. correlating with the calendar age of an individual. Thus, the epigenetic clock based on these kind of DNAm changes could provide a new biomarker for human aging process, i.e. being able to separate the calendar and biological age. Information about the correlation of the time indicated by this clock to the various aspects of immunosenescence is still missing. As chronic cytomegalovirus (CMV) infection is probably one of the major driving forces of immunosenescence, we now have analyzed the correlation of CMV seropositivity with the epigenetic age in the Vitality 90+cohort 1920 (122 nonagenarians and 21 young controls, CMV seropositivity rates 95% and 57%, respectively). The data showed that CMV seropositivity was associated with a higher epigenetic age in both of these age groups (median 26.5 vs. 24.0 (p < 0.02,Mann–Whitney U-test) in the young controls and 76.0 vs. 70.0 (p < 0.01) in the nonagenarians). Thus, these data provide a new aspect to the CMV associated pathological processes.

Background Ageing is characteristically accompanied by changes in vascular endothelial markers and growth factor as well as increased cellular death. We analysed the associations of the plasma levels of vascular cell adhesion molecule-1 (VCAM-1), hepatocyte growth factor (HGF) and soluble Fas (sFAS), and their combinations, with 4-year mortality to identify new biomarkers. Methods A total of 238 individuals, both community-dwelling and institutionalised, aged 89‒91 years and participating in the Vitality 90 + study were included. Biomarkers of endothelial function (VCAM-1), growth factor (HGF) and a marker of apoptosis (sFAS) were determined from plasma using Luminex® technology. This newly-determined data was combined with earlier data, e.g., 4-year mortality and medical history. Results Subjects who died during the follow-up had higher baseline plasma levels of VCAM-1, sFas, and HGF. When other known risk factors were adjusted for, subjects in the highest concentration tertile for VCAM-1 (HR 1.85; 95% CI, 1.12–3.05) and HGF (HR 2.22; 95% CI, 1.33–3.71) had higher mortality compared to those in the lowest tertile. In the adjusted analyses, when compared to subjects with none of the biomarkers in the highest concentration tertile, mortality was also higher when sFas and VCAM-1 were simultaneously (HR 2.03; 95% CI, 1.13–3.64) or all three were simultaneously (HR 3.63; 95% CI, 1.65–7.97) in the highest concentration tertile. Conclusions Our results suggest that increased concentrations of these biomarkers, separately and in combination, associate with mortality among the aged and are prognostic markers of death.

Plasma cell-free DNA (cf-DNA) has recently emerged as a potential biomarker of aging, reflecting systemic inflammation, and cell death. In addition, it has been suggested that cf-DNA could promote autoinflammation. Because the total cf-DNA pool comprises different cf-DNA species, we quantified the plasma levels of gene-coding cf-DNA, Alu repeat cf-DNA, mitochondrial DNA (mtDNA) copy number, and the amounts of unmethylated and total cf-DNAs. We identified the relationships between these cf-DNA species and age-associated inflammation, immunosenescence, and frailty. Additionally, we determined the cf-DNA species-specific transcriptomic signatures in blood mononuclear cells to elucidate the age-linked leukocyte responses to cf-DNA. The study population consisted of n = 144 nonagenarian participants of the Vitality 90+ Study and n = 30 young controls. In the nonagenarians, higher levels of total and unmethylated cf-DNAs were associated with systemic inflammation and increased frailty. The mtDNA copy number was also directly correlated with increased frailty but not with inflammation. None of the cf-DNA species were associated with immunosenescence. The transcriptomic pathway analysis revealed that higher levels of total and unmethylated cf-DNAs were associated with immunoinflammatory activation in the nonagenarians but not in the young controls. The plasma mtDNA appeared to be inert in terms of inflammatory activation in both the nonagenarians and young controls. These data demonstrate that the plasma levels of total and unmethylated cf-DNA and the mtDNA copy number could serve as biomarkers of frailty. In addition, we suggest that circulating self-DNA, assessed as total or unmethylated cf-DNA, might aggravate immunoinflammatory reactivity in very old individuals.

Background: information about the predictors of mortality among the oldest-old is limited. Also possible gender differences are poorly known. Objective: to examine the predictors of mortality among individuals aged 90 and older, focusing on differences between men and women. We also analysed gender differences in survival at different levels of mobility and activities in daily living (ADL). Design: this 9-year follow-up study is part of the Vitality 90+ study, a population-based study of people aged 90 and older. Subjects: all inhabitants aged 90 and older in the area of Tampere, Finland were contacted, irrespective of health or dwelling place. The study population consisted of 171 men and 717 women. Methods: data were collected with a mailed questionnaire asking questions concerning ADL and mobility, self-rated health, chronic conditions and socio-economic factors. The participation rate was 79%. Cox regression enter models were used for the analysis. Results: older age, male gender, disability in ADL and mobility, poor self-rated health and institutionalisation increased the risk of mortality in the total study group. In age-adjusted Cox regression models, ADL and mobility were stronger predictors in men than in women (gender interactions, P< 0.001). Among those who were partly but not totally dependent in ADL or mobility women survived longer than men. Conclusion: the same health indicators that are important at younger old age also predict mortality in the oldest-old. Disability increases the likelihood of death more in men than women. At a very old age, women survive longer with moderate disability than do men.

The epigenetic clock, defined as the DNA methylome age (DNAmAge), is a candidate biomarker of ageing. In this study, we aimed to characterize the behaviour of this marker during the human lifespan in more detail using two follow-up cohorts (the Young Finns study, calendar age i.e. cAge range at baseline 15-24 years, 25-year-follow-up, N = 183; The Vitality 90+ study, cAge range at baseline 19-90 years, 4-year-follow-up, N = 48). We also aimed to assess the relationship between DNAmAge estimate and the blood cell distributions, as both of these measures are known to change as a function of age. The subjects' DNAmAges were determined using Horvath's calculator of epigenetic cAge. The estimate of the DNA methylome age acceleration (Δ-cAge-DNAmAge) demonstrated remarkable stability in both cohorts: the individual rank orders of the DNAmAges remained largely unchanged during the follow-ups. The blood cell distributions also demonstrated significant intra-individual correlation between the baseline and follow-up time points. Interestingly, the immunosenescence-associated features (CD8+CD28- and CD4+CD28- cell proportions and the CD4/CD8 cell ratio) were tightly associated with the estimate of the DNA methylome age. In summary, our data demonstrate that the general level of Δ-cAge-DNAmAge is fixed before adulthood and appears to be quite stationary thereafter, even in the oldest-old ages. Moreover, the blood DNAmAge estimate seems to be tightly associated with ageing-associated shifts in blood cell composition, especially with those that are the hallmarks of immunosenescence. Overall, these observations contribute to the understanding of the longitudinal aspects of the DNAmAge estimate.

Background Only scarce data exist on the association between obesity and disability in the oldest old. The purpose of this prospective study is to examine if body mass index and waist circumference (WC) are associated with incident mobility and activities of daily living (ADL) disability in nonagenarians. Methods We used longitudinal data from the Vitality 90+ Study, which is a population-based study conducted at the area of Tampere, Finland. Altogether 291 women and 134 men, aged 90-91 years, had measured data on body mass index and/or WC and did not have self-reported mobility or ADL disability at baseline. Incident mobility and ADL disability was followed-up on median 3.6 years (range 0.6-7.8 years). Mortality was also followed-up. Multinomial logistic regression models were used for the analyses, as death was treated as an alternative outcome. The follow-up time was taken into account in the analyses. Results Neither low or high body mass index, nor low or high WC, were associated with incident mobility disability. In women, the lowest WC tertile (

Increased proinflammatory status is associated with both increased adiposity and higher mortality risk. Thus, it is paradoxical that mild obesity does not predict increased mortality in older adults. We investigated the association of inflammatory markers with body mass index (BMI), waist circumference (WC), and waist-to-hip ratio (WHR) in nonagenarians, and the combined effects of BMI, WC, WHR, and inflammatory status on mortality.This study was based on a prospective population-based study, Vitality 90+, carried out in Tampere, Finland. Altogether, 157 women and 53 men aged 90 years were subjected to anthropometric measurements, blood samples, and a 4-year mortality follow-up. Inflammatory status was based on sex-specific median levels of interleukin-1 receptor antagonist (IL-1RA), interleukin-6 (IL-6), C-reactive protein (CRP), and tumor necrosis factor-α (TNF-α).In the unadjusted linear regression analyses, IL-1RA, CRP, and TNF-α were positively associated with BMI and WC in women, whereas in men IL-1RA was positively associated with BMI and IL-6 positively with WC. In the models adjusted for diseases, functional status, and smoking, IL-1RA and CRP were positively associated with BMI and WC in women. Low WC and WHR combined with low inflammation protected from mortality in women and high BMI and WC regardless of inflammation protected from mortality in men in the adjusted Cox regression analysis.In the oldest old, the effect of adiposity in combination with inflammatory status on mortality differs between men and women. More research is needed to disentangle the role of adiposity among the oldest old.

Aging is characteristically accompanied by a low-grade inflammatory state and increased cellular death. In this study, we analyzed the associations between the plasma cell-free DNA (cf-DNA) level and immunoinflammatory factors and 4-year mortality. The distribution of qualitative cf-DNA patterns in relation to the total cf-DNA concentration and the antinuclear antibody (ANA) serostatus was also evaluated. The study population consisted of n=258 nonagenarians who were participants in the Vitality 90+ Study. Cf-DNA levels were positively correlated with the C-reactive protein (CRP) level, the interleukin-1 receptor antagonist (IL-1ra) level, the serum amyloid A (SAA) level and the indoleamine 2,3-dioxygenase enzyme activity (IDO), weight and chair-stand test time and inversely correlated with the HDL cholesterol level. The total cf-DNA concentration also remained as an independent predictor of 4-year all-cause mortality. A predominance of low-molecular-weight cf-DNA was observed in ANA-seropositive subjects but this cf-DNA pattern was not associated with mortality. The cf-DNA concentration could thus represent a novel biomarker for systemic inflammation and mortality in the elderly.

Background. The associations of body mass index (BMI) and abdominal obesity with mortality among very old people are poorly known. The purpose of this study was to investigate the association of BMI, waist circumference (WC), and waist-to-hip ratio with mortality in nonagenarians. Methods. This study is part of a prospective population-based study, Vitality 90+, including both community-dwelling and institutionalized persons from Tampere, Finland. Altogether 192 women and 65 men aged 90 years were subjected to anthropometric measurements, a baseline interview, and a 4-year mortality follow-up. Cox proportional hazards models were used in the statistical analyses. Results. In men, normal weight indicated a three times higher mortality risk (hazard ratio [HR] 3.09, 95% confidence interval [CI] 1.35–7.06) compared with overweight, and WC was inversely associated with mortality (HR 0.96, 95% CI 0.93–1.00) after adjustment for covariates. In women, the univariate waist-to-hip ratio (HR 1.43, 95% CI 1.06–1.92) and BMI-adjusted waist-to-hip ratio (HR 1.45, 95% CI 1.07–1.97) were positively associated with mortality. Also, overweight women whose WC was

As a marker of cellular death, cell-free DNA (cf-DNA) has a utility in diagnosis and prognosis of various disorders. Since aging accompanies increased cellular senescence and death, we aimed to characterize potential age-related alterations in cf-DNA. The study population consisted of 12 nonagenarian women (participants in the Vitality 90+ Study) and 11 healthy control women (aged 22-37 years). Some of the nonagenarians (n=8) were also recruited for follow-up after one year. cf-DNA was extracted using two different methods. Total cf-DNA was quantified directly in plasma and the amplifiable cf-DNA was assessed using quantitative PCR. Quality of cf-DNA was analysed with a DNA Chip assay. For all the quantification methods, the concentration of cf-DNA was significantly higher (p

Background Inflammation plays a major role in both aging and chronic disease. Longitudinal studies in very old people can improve our understanding of these processes. We investigated blood levels of C-reactive protein (CRP), interleukin-6 (IL-6), interleukin-1 receptor antagonist (IL-1ra), and their combinations as predictors of mortality in nonagenarians. Methods This is a prospective population-based study including both community-dwelling and institutionalized nonagenarians enrolled in the Vitality 90+ Study. Altogether 285 persons participated in the baseline interview and gave blood. Information on chronic disease was drawn from health center registers. Data on mortality over 4 years were obtained from the Population Register Center. In Cox proportional hazards models, chronic disease and major risk factors were adjusted for. Results Plasma levels of IL-1ra, IL-6, and CRP were higher in persons who died during the follow-up than in those who survived. When sex, education, cardiovascular disease, diabetes, cancer, history of infections, high density lipoprotein cholesterol, Mini-Mental State Examination, body mass index, smoking status, and exercise were adjusted for, only IL-1ra was a significant predictor of mortality (hazard ratio [HR] 2.12; 95% confidence interval [CI], 1.24-3.62). Persons in the upper tertiles of both CRP and IL-1ra (HR 2.72; 95% CI, 1.25-6.00), or in the upper tertile of all three markers (HR 2.34; 95% CI, 1.23-4.61), had higher mortality than those who were not in the upper tertile in any of the markers. Conclusions IL-1ra is a powerful prognostic marker in very old people. Our results implicate its role in the complex interaction between inflammatory markers in aging and disease.

Background and aims: Taking medical history from a very old patient for either clinical or research purposes raises the question of the reliability of the information obtained. We ascertained whether the self-reported medical history and self-rated health of 90-year-olds would be in agreement with their medical records. Methods: Information on chronic diseases and self-rated health was collected using medical records and a mailed questionnaire in a population sample of community-living 90-year-old subjects in Tampere, Finland. The results were compared with earlier studies on self-reported medical history. Results: The inter-source agreement of the reported diseases was relatively good. As expected, many of the diseases diagnosed were under-reported in the mailed questionnaire. However, dementia, depression and arthritis were reported more often than doctors had recorded them. Of the respondents, 78% reported their current health as good or average. Subjects with heart disease, stroke, rheumatoid arthritis, Parkinson’s disease or depression reported poor health more often than those not having these diseases. Conclusions: The agreement between medical records and self-reported medical history obtained by questionnaire showed a similar pattern to earlier studies in younger old populations, but in the 90-year olds, the differences became larger. In future studies, special attention should be paid to the oldest old who under-report certain diagnosed medical conditions.

Background Several studies have focused on predictors of mobility limitations and disabilities. Yet little is known about the pace and patterns of mobility changes among very old people. This study examined changes in functional mobility among individuals aged 90 years and older during a 2-9-year follow-up. In addition, we were interested in the patterns of mobility changes. Methods Data were collected through a mailed questionnaire in the years 2001, 2003, 2007 and 2010. The study population (n = 948) consisted of individuals from three cohorts (2001, 2003, 2007) who participated in at least two survey rounds and answered the mobility questions. The length of the follow-up varied from 2–9 years between individuals as well as according to how many times an individual took part in the survey. Multilevel ordinal logistic regression analysis was used to evaluate the effects of time, age, gender, cohort and chronic conditions on changes in mobility. Results At the baseline, “younger” old people, men and individuals in the cohorts for 2003 and 2007 had significantly better mobility compared with women, older individuals and individuals in the 2001 cohort. In addition, individuals with fewer chronic conditions had better mobility than those with more diseases. Mobility declined for most of the participants during the follow-up. The difference in the change in mobility over time for gender, age or chronic conditions was not statistically significant. The analyses were performed with a subgroup of participants aged 90–91 years at the baseline, and results did not differ substantially from the results for the entire study sample. However, the effect of chronic conditions on the change in mobility was statistically significant among participants aged 90-91years. Conclusions No differences were observed in the rate of mobility decline over time between age or gender. The effect of chronic conditions on the change in mobility was significant only among individuals aged 90–91 years. The prevention efforts are important and should focus even more, also among the oldest-old, on additional modifiable risk factors such as maintaining muscle strength. BioMed Central open access

// Saara Marttila 1,2 , Laura Kananen 1,2 , Juulia Jylhava 1,2 , Tapio Nevalainen 1,2 , Antti Hervonen 2,3 , Marja Jylha 2,3,4 and Mikko Hurme 1,2,5 1 Department of Microbiology and Immunology, School of Medicine, University of Tampere, Tampere, Finland 2 Gerontology Research Center, Tampere, Finland 3 School of Health Sciences, University of Tampere, Tampere, Finland 4 Institute for Advanced Social Research, University of Tampere, Tampere, Finland 5 Fimlab Laboratories, Tampere, Finland Correspondence to: Saara Marttila, email: // Keywords : lifespan, longevity, DNA methylation, methylome, intergenerational inheritance, Gerotarget Received : August 17, 2015 Accepted : August 27, 2015 Published : September 30, 2015 Abstract The heritability of lifespan is 20-30%, but only a few genes associated with longevity have been identified. To explain this discrepancy, the inheritance of epigenetic features, such as DNA methylation, have been proposed to contribute to the heritability of lifespan. We investigated whether parental lifespan is associated with DNA methylation profile in nonagenarians. A regression model, adjusted for differences in blood cell proportions, identified 659 CpG sites where the level of methylation was associated with paternal lifespan. However, no association was observed between maternal lifespan and DNA methylation. The 659 CpG sites associated with paternal lifespan were enriched outside of CpG islands and were located in genes associated with development and morphogenesis, as well as cell signaling. The largest difference in the level of methylation between the progeny of the shortest-lived and longest-lived fathers was identified for CpG sites mapping to CXXC5 . In addition, the level of methylation in three Notch-genes ( NOTCH1 , NOTCH3 and NOTCH4 ) was also associated with paternal lifespan. There are implications for the inheritance of acquired traits via epigenetic mechanisms in mammals. Here we describe DNA methylation features that are associated with paternal lifespan, and we speculate that the identified CpG sites may represent intergenerational epigenetic inheritance.

OBJECTIVES: To establish whether the relationship between interleukin-6 (IL-6) and plasma lipid and C-reactive protein (CRP) concentrations is different in Finnish nonagenarians than in middle-aged subjects with lower inflammatory status. DESIGN: Cross-sectional. SETTING: Observational cohort study concentrating on the oldest old. PARTICIPANTS: Nonagenarians (n = 291, mean age ± standard deviation 90 ± 1; 68 men, 223 women) who lived in the Tampere municipality in southern Finland and a middle-aged control population from the same area (n = 227, aged 44 ± 8). MEASUREMENTS: Plasma high sensitive CRP and lipid concentrations were analyzed using an automatic analyzer and IL-6 levels using enzyme-linked immunosorbent assay. RESULTS: Plasma concentrations of IL-6 (4.39 ± 5.25 vs 1.88 ± 1.98 pg/mL) and CRP (3.54 ± 4.98 vs 1.53 ± 1.91 mg/L) were significantly higher in nonagenarians than in middle-aged subjects (P

Data on how body mass index (BMI), waist circumference (WC) and waist-to-hip ratio (WHR) are associated with body fat in the oldest-old people are scarce. The purpose of this study was to examine if BMI, WC or WHR are associated with leptin, a biological surrogate measure of body fat in 90-year-old people. The data comes from the Vitality 90+ Study, a prospective population-based study of people living in Tampere, Finland. BMI, WC, WHR and plasma concentration of leptin were available for 160 women and 54 men aged 90 years. BMI and WC had a strong significant positive association with leptin both in women and in men, but WHR was associated with leptin only in men. In conclusion, based on the circulating level of leptin, BMI and WC, and WHR in men, reflect body fat in 90-year-old people, but WHR seems to be a poor indicator of body fat in 90-year-old women.

Mitochondrial DNA (mtDNA) coding region polymorphisms, as well as the 150T polymorphism in the noncoding region, have been associated with longevity. We have studied here the association of 150T with longevity further and assessed differences in this association between various mtDNA haplogroups. We analysed a sample of 321 very old subjects and 489 middle-aged controls from Finland and Japan. 150T was more frequent among the very old than among the controls in both the Finnish and Japanese subjects. Interestingly, the association was not similar in all haplogroups, and a stratified analysis revealed that two additional common polymorphisms, 489C and 10398G, modified the association between 150T and longevity. These findings suggest that longevity is partly determined by epistatic interactions involving these three mtDNA loci.

Polymorphisms affecting the expression of matrix metalloproteinases (MMPs), i.e. proteolytic enzymes that degrade intercellular material, have been found at position -1607 (1G/2G) in MMP1 and at -1171 (5A/6A) in MMP3. Interestingly, elevated levels of MMP1 and MMP3 have been observed in the brains of Alzheimer's disease (AD) patients and those of tissue inhibitors of MMPs in the cerebrospinal fluid of AD and Parkinson's disease (PD) patients, suggesting a role for MMPs in these disorders. The aim was to investigate a possible association between the afore-mentioned MMP1 and MMP3 polymorphisms and the risk of developing AD or PD. The polymorphisms were genotyped in 97 AD, 52 PD and 101 control patients. We found an interaction between MMP3*5A and APOE 4 alleles (P < 0.0001) which increases the risk of AD (OR: 23.7, 95% CI: 5.8-144.9, P < 0.0001) compared to those who possess neither MMP3*5A nor APOE 4. In conclusion, our finding suggests that the MMP3 gene, especially together with APOE 4, may contribute to the development of AD.

People live longer than ever before, and the rapidly growing population of the oldest-old are increasingly frequent users of health care services. To determine the extent and causes of hospital care in the population aged 90, we examined the hospital discharge registers for the annual cohorts of Tampere residents born in 1907–1910 at age 90. The basic population consisted of 1077 people, 20.6% of who were men and 79.4% women. Close on one-fifth or 18.7% of this group died during the year under review. During this year, 43.2% of men and 50.3% of women had been admitted to hospital. Men spent significantly fewer days in hospital than women: the mean length of stay for men was 19 days, for women 46 days. Of the 90-year olds, 6.7% were permanently staying in hospitals. The most common diagnoses at discharge were cardiovascular diseases, infections, psychiatric diseases including dementia, and trauma. Of those who had been admitted to hospital once or more within the year, 31.7% died during the follow-up time, while the figure for those not admitted was only 6.2%. People aged 90 are an important group of hospital users. In the future, hospitals need to be prepared to provide adequate care for the most common diseases affecting the growing population of the oldest-old.

Based on an analysis of extracts from 11 free-form written texts and 13 focused interviews with Finnish husbands who had given care to their demented wives, this study was aimed at finding out how husbands signify their action as spousal caregivers. The data were approached qualitatively from a social constructionistic point of view. Husbands’ written material described their action of caregiving mainly in a passive voice that echoed duty and responsive agency. Analysis of the interview talk revealed a wider spectrum of voices and more agentive talk about caregiving. The results of the study challenge interpretations of men as either ineffective or capable caregivers and highlight, instead, the contextual nature of the way that men construct their agencies, depending upon the purposes and audiences of their narration.

Background: Study of the long-term effects of chronic alcohol consumption in human populations is confounded by genetic and environmental factors. Methods: The study was intended to investigate the effects on morbidity and survival of lifetime forced ethanol consumption in male and female AA (Alko, Alcohol) and ANA (Alko, Non-Alcohol) rats. The ethanol-exposed rats had 12% ethanol as the only available fluid from 3 to 24 months of age. The control groups had water. Rats that died during the experiment and those that were killed at 24 months of age were all autopsied, and the pathologic findings were recorded. Results: Lifelong ethanol consumption did not change the survival rate of the rats, and had no significant effect on the rates of any of the pathologic measures in either the AA or ANA line of rats, suggesting that this may not be a good animal model for studying the detrimental effects of chronic alcohol. An unexpected, highly significant finding was observed: the AA rats, bred for high voluntary ethanol drinking, lived much longer than the ANA rats, bred for ethanol avoidance. The death rate by 24 months in the AA line was less than one-third of that in the ANA line. This difference was found regardless of whether the animals were maintained on alcohol or water, and in both genders. The AA rats had significantly lower rates of kidney disease, benign tumors, and cardiovascular disease than the ANA animals. Conclusions: Lifelong ethanol consumption increased neither the mortality nor the morbidity of AA and ANA line of rats. Genes selected in the development of the high drinking AA line have additional effects producing rats that are healthier and living longer than the ANA rats possessing genes resulting in alcohol avoidance.

Background and aims: The oldest-old population is expanding rapidly. There is a new need for clinical information about this group, which is actively using social and health care. We studied the population of people born in 1907–1910 and living in the city of Tampere (Finland) at the age 90 (N=916, 79.4% women, 20.6% men); 71.7% of the population lived in the community and 28.3% in institutions. Methods: Medical records of 832 (90.8%) nonagenarians were obtained. We registered diagnoses of chronic diseases or diseases that required hospitalization at any time of their lives, as well as physicians’ notes on their memory and mobility. Diseases were coded and grouped according to ICD-10. Results: The most common diagnosis groups were cardiovascular diseases (78.3%), gastrointestinal diseases (58.6%), infections (53.6%) and trauma (49.6%). There was an average of 8 chronic or severe diseases mentioned in patient records. The diagnosis of dementia was mentioned in 26.7% of cases, most of them living in institutions; a problem with memory — from for-getfulness to dementia — was mentioned in 35.9% of cases; 37.5% were able to move using no or a light support, 8.3% were bedridden. Conclusions: We conclude that this age group suffers from numerous chronic diseases influencing mobility and cognition. Dementia seems to be the most important symptom leading to institutionalization.

Sequence variation in mitochondrial DNA (mtDNA) may cause slight differences both in the functioning of the respiratory chain and in free radical production, and an association between certain mtDNA haplogroups and longevity has been suggested. In order to determine further the role of mtDNA in longevity, we studied the frequencies of mtDNA haplogroups and haplogroup clusters among elderly subjects and controls in a Finnish population. Samples were obtained from 225 persons aged 90-91 years (Vitality 90+) and from 400 middle-aged controls and 257 infants. MtDNA haplogroups were determined by restriction fragment length polymorphism. The haplogroup frequencies of the Vitality 90+ group differed from both those of the middle-aged controls ( P=0.01) and the infants ( P=0.00005), haplogroup H being less frequent than among the middle-aged subjects ( P=0.001) and infants ( P=0.00001), whereas haplogroups U and J were more frequent. Haplogroup clusters also differed between Vitality 90+ and both the middle-aged subjects ( P=0.002) and infants ( P=0.00001), the frequency of haplogroup cluster HV being lower in the former and that of UK and WIX being higher. These data suggest an association between certain mtDNA haplogroups or haplogroup clusters and longevity. Furthermore, our data appear to favour the presence of advantageous polymorphisms and support a role for mitochondria and mtDNA in the degenerative processes involved in ageing.

Within the MARK-AGE project, a population study (3337 subjects) was conducted to identify a set of biomarkers of ageing which, as a combination of parameters with appropriate weighting, would measure biological age better than any single marker. The MARK-AGE project involves 14 European countries and a total of 26 research centres. In such a study, standard operating procedures (SOPs) are an essential task, which are binding for all MARK-AGE Beneficiaries. The SOPs cover all aspects of subject's recruitment, collection, shipment and distribution of biological samples (blood and its components, buccal mucosa cells or BMC and urine) as well as the anthropometric measurements and questionnaires. published

The rate of inflammation increases in elderly individuals, a phenomenon called inflammaging and is associated with degenerative diseases. However, the causes of inflammaging and the origin of the associated inflammatory mediators have remained enigmatic. We show herein that there is a positive correlation between the number of sons born and C-reactive protein concentrations in 90-year-old women. This association is influenced by HLA genetics known to regulate the immune response against HY antigens.

There has been increasing interest in research on genetic basis of longevity. Aging is accompanied by immune deterioration and dysregulation of cytokines. Increased IL-6 concentration in vivo and enhanced IL-6, IL-1beta, and TNF-alpha production in vitro have been reported in healthy elderly people. Cytokine gene polymorphisms have been demonstrated to be associated with cytokine production both in vivo and in vitro, and with some diseases. Thus, gene polymorphisms of cytokine may play a role in longevity by modulating an individual's responses to life-threatening disorders. Cytokine gene polymorphisms at IL1A-889, IL1B+3953, IL1B-511, IL1RN VNTR, IL6-174, IL10-1082, and TNFA-308 were genotyped in 250 Finnish nonagenarians (52 men and 198 women) and in 400 healthy blood donors (18-60 years) as controls. No statistically significant differences were found in the genotype distributions, allelic frequencies and A2+ carrier status of IL-1alpha, IL-1beta, IL-1RA, IL-6, IL-10, and TNF-alpha genes between nonagenarians and younger controls within Finnish population, nor between male and female nonagenarians. No differences emerged between nonagenarians and younger controls by comparing different IL-1 gene cluster haplotypes. Thus, there is no evidence of an association of IL-1 complex, IL-6, IL-10, and TNF-alpha gene polymorphisms with longevity, alone or in combination.

The effects of aging and lifelong ethanol consumption on astrocytic morphology and glial fibrillary acidic protein-immunoreactivity (GFAP-IR) in the cerebellar vermis obtained from ethanol-preferring Alko, Alcohol (AA) rats were analyzed by using computer-assisted image analysis. The ethanol-consuming animals (both male and female) were given ethanol (10%–12%, vol./vol.) as the only available fluid for 21 months (3–24 months), whereas the young (3 months) and the old (24 months) controls received water. In the male rats, but not in the female rats, an age-related decrease in GFAP-IR was found in folia II, VII, and X of the molecular layer, and in turn, an age-related increase was found in folium X of the granular layer, indicating opposite changes in GFAP-IR for male rats due to aging in adjacent brain regions. In the female rats, 21 months of daily average ethanol consumption of 6.6 g/kg resulted in decreased GFAP-IR in folium VII of the molecular layer, and the decrease in cerebellar GFAP-IR correlated with the average daily ethanol intake ( r =−.886, P =.019) when folia II, IV, VII, and X were analyzed together. No effect of ethanol on GFAP-IR was detected in the granular layer or in the central white matter of the female rats. There was no change in GFAP-IR in any of the three cerebellar layers of the male rats with average daily ethanol consumption of 3.2 g/kg. These results indicate that the Bergmann glial fibers are the GFAP-expressing structures of the cerebellum most sensitive to moderate-to-heavy chronic ethanol exposure and that this effect is dose dependent.

This article applies the method of discourse analysis to look at how older people talk about age and getting old. The data come from biographical interviews with people aged 90 years or over. The picture that emerges from these interviewees is one of ambivalence: old age is constructed through two contrasting repertoires that are described as the choice repertoire and the necessity repertoire. Talk about old age as a necessity produces it as a self-evident fact that the essence of old age is deterioration. Talk about old age as a choice is used to undermine the necessity repertoire and to argue for various and more positive definitions of old age among which one can make a choice. It is important to note that the contrast is not between cultural views and individual experience, but the ambivalence is rooted in people's minds. Both repertoires are reasonable and justifiable, which turns old age into a dilemma. Our thinking about old age is dilemmatic by nature

The use of medical drugs is not founded on medical knowledge alone, but it is also dependent on lay logic and reasoning. This study set out to explore the views of the oldest-old on their medication. The data for the study came from narrative interviews with people aged 90 or over. Our aim was to look for different culturally shared interpretative repertoires used by the interviewees as they gave descriptions and accounts of their drug use and presented themselves as users of medical drugs. Three interpretative repertoires were identified. The moral repertoire stressed lay people's moral norms and presented them as morally acceptable and responsible users of drugs by explaining and minimizing. The patient repertoire was used by the respondents to show they had accepted the role of patient. The self-help repertoire was used by the respondents to emphasize that they had made their own choices in medical care despite the biomedical facts. These repertoires showed that not only the biomedical logic, but also other logics are valid in the everyday world where most medical drugs are used. A better understanding of cultural ideas of drug use would help to improve the care of older people.

In our discourse analytic study on 15 stories written by Finnish husbands who were giving or who had given care to their demented wives, we identified articulations of four different ways to speak about one's actions and experiences as a family caregiver. We called these four modes of speech the factual, familistic, agency, and destiny speech repertoires. Using different speech repertoires in their narration, the husbands adopted the respective identities of an observer and reporter, a responsible caregiver, an independent actor, and a victim or a drifter. The speech repertoires and identity constructions varied according to the contexts of the writers' speech and bore different functions for the writers' narration. The main finding of the study was the diversity of husbands' experiences of caregiving and the contexuality of the ways in which these experiences were talked about.

Background: Binge ethanol exposure is known to induce degeneration of central nervous system (CNS) neurons. Sympathetic hyperactivity has been related to ethanol withdrawal symptoms, but the effects of repeated withdrawals on peripheral sympathetic neurons have not been studied previously. Methods: The effects of continuous versus intermittent ethanol consumption on sympathetic neurons of the superior cervical ganglion (SCG) were studied in male Wistar rats. Two-month-old rats were divided into three groups: one group with ethanol (10% v/v) as the drinking fluid throughout the 5½-month experiment (continuous, n=9), one group drinking ethanol on 4 days/week and water on 3 days/week (intermittent, n=9), and a control group (n=9) with water as the only available fluid. All groups had food ad libitum. SCG volume, neuron density, and total number of neurons were measured by using unbiased morphometric methods. Results: As the mean daily ethanol consumption did not differ between the two ethanol-exposed groups (continuous 5.7 g/kg/day versus intermittent 5.8 g/kg/day), the total dose of ethanol consumed was 42% smaller in the intermittent group. The total number of SCG neurons decreased by 28%, and neuron density by 23%, in the intermittent group compared with the control group, whereas no significant neuron loss was observed in the continuous group. The volume of the SCG was similar in all study groups. The results suggest that repeated ethanol withdrawals, rather than ethanol exposure per se, are deleterious to sympathetic neurons. Conclusions: Ethanol-induced degeneration of neurons is not only related to the amount of ethanol consumed, but also to the patterns of drinking.

In the present study, the neuroprotective effects of dexmedetomidine on rat locus coeruleus were studied during a 5-week intermittent ethanol exposure. Male Wistar rats (3 to 4 months old) were given ethanol or isocaloric sucrose by intragastric intubations three times a day for 4 days, which was followed by a 3-day withdrawal period. This 7-day cycle of ethanol exposure and withdrawal was repeated five times. Dexmedetomidine (at a dose decreasing from 30 microg/kg to 10 microg/kg, s.c.) was given to the treatment group during the withdrawal phase. The results showed that, during the 5-week experiment, dexmedetomidine significantly relieved the ethanol withdrawal syndrome, measured as the sum of the three most specific symptoms (rigidity, tremor, and irritability). The total neuron number of locus coeruleus (LC) decreased in the ethanol-treated group by 24%, compared with the nontreated control group and by 11%, compared with the sucrose-treated control group. Interestingly, the LC neuron numbers were found to decrease in the sucrose-intubated rats as well, compared with the nontreated control group. Dexmedetomidine was found to relieve ethanol-induced neuronal loss in the LC. Dexmedetomidine might be a new interesting alternative in the treatment of ethanol withdrawal syndrome, particularly due to its possible neuroprotective effects in the central nervous system.

The aim of this work was to evaluate the effects of long-term ethanol consumption on arterial responses in vitro in young and aged rats. Therefore, Wistar rats (ages 3 and 29 mo, respectively) were allocated to six groups: control-young, sucrose-young, ethanol-young, control-aged, sucrose-aged, and ethanol-aged. The ethanol-fed groups were given 25% ethanol by intragastric gavage three times a day 4 days a week. Responses of mesenteric arterial rings were examined in standard organ chambers after 5 treatment weeks. In norepinephrine-precontracted arterial rings, endothelium-dependent relaxations to acetylcholine, as well as endothelium-independent relaxations to isoproterenol, were attenuated in aged rats when compared with young controls. Relaxation responses to isoproterenol, but not to acetylcholine and nitroprusside, were clearly improved by ethanol treatment in both young and aged rats. The cyclooxygenase inhibitor diclofenac, which reduces the synthesis of dilating and constricting prostanoids, enhanced the relaxation to acetylcholine in all three aged rat groups but was without significant effect in the young rats. In the presence of the nitric oxide synthase inhibitor N G-nitro-l-arginine methyl ester the relaxation to acetylcholine in control and sucrose-fed aged rats was markedly reduced compared with control rats, whereas in the young controls and in both young and aged ethanol-exposed groups, distinct relaxations to higher concentrations of acetylcholine were still present. The endothelium-independent relaxations to cromakalim, a hyperpolarizing vasodilator acting via ATP-sensitive potassium channels, were also markedly augmented by ethanol feeding in both young and aged rats. In conclusion, ethanol consumption in both young and aged rats was associated with markedly improved arterial relaxations to isoproterenol and cromakalim, as well as clearly augmented relaxation to acetylcholine during inhibition of cyclooxygenase and nitric oxide synthase. These findings suggest that especially the potassium channel-related component of arterial relaxation was augmented by long-term ethanol exposure.

Chronic low-grade inflammation is involved in the pathogenesis of many disease conditions in humans and it is frequently quantified by measuring the blood concentration of C-reactive protein (CRP). Here we show that the CRP concentration in old people (nonagenarians) is, at least partially, genetically determined, and that the high producer genotype is associated with a shorter life expectancy during follow-up. Thus, the data imply that the CRP gene may be a longevity gene in humans.

Many studies have suggested that parenteral administration of coenzyme Q 10 (Q 10 ) protects the myocardium of young experimental animals from post-ischemic reperfusion injury. Although parenteral administration, in contrast to per os supplementation, seems to elevate coenzyme Q concentrations in heart tissue, it is not suitable for prophylactic use. In addition, the incidence of ischemic events is greatest in older age. We studied the effect of Q 10 supplementation on myocardial postischemic recovery in 18-month-old Wistar rats. The treated group (n = 9) received 10 mg/kg day of Q 10 for 8 weeks in their chow while the normal chow of the control group (n = 9) contained less than 0.5 mg/kg day of Q 10 . The treatment clearly elevated plasma Q 10 concentration (286 ± 25 μmol l and 48 ± 30 μmol l , treated and controls, respectively, p 9 nor Q 10 concentrations in heart tissue were affected by the supplementation. The isolated perfused hearts were subjected to 20 minutes of ischemia and 30 minutes of reperfusion. The preischemic values of developed pressure (DP) but not contractility ( +DP Δt ) and relaxation ( −DP Δt ) were improved by Q 10 supplementation (p = 0.034, p = 0.057 and p = 0.13, respectively) while in postischemic recovery no differences were observed between the groups (p > 0.05 at all time points). Also, in myocardial flow, myocardial oxygen consumption (MVO 2 ) and myocardial aerobic efficiency (DP/MVO 2 ) the groups did not differ at any time points. Although dietary Q 10 supplementation clearly elevated plasma Q 10 concentrations in senescent rats, the coenzyme Q contents in heart tissue and myocardial recovery from ischemia were not affected. However, it is possible that the site of action for the reported beneficial effects of Q 10 is in the coronary endothelium rather than myocardium itself.

1. Age-associated deterioration of arterial function may result from long-lasting oxidative stress. Since coenzyme Q (Q10) has been suggested to protect the vascular endothelium from free radical-induced damage, we investigated the effects of long-term dietary Q10 supplementation on arterial function in senescent Wistar rats. 2. At 16 months of age, 18 rats were divided into two groups. The control group was kept on a standard diet while the other group was supplemented with Q10 (10 mg kg(-1) day(-1)). In addition, nine rats (age 2 months) also ingesting a standard diet were used as the young control group. After 8 study weeks the responses of the mesenteric arterial rings in vitro were examined. 3. Endothelium-independent arterial relaxations to isoprenaline and nitroprusside (SNP) were attenuated in aged rats. Increased dietary Q10 clearly enhanced the relaxation to isoprenaline, but did not affect the response to SNP. In addition, vasodilation of noradrenaline-precontracted rings to acetylcholine (ACh), which was also impaired in aged vessels, was improved after Q10 supplementation. Cyclooxygenase inhibition with diclofenac enhanced the relaxation to ACh only in young rats, while it abolished the difference between the old controls and Q10 supplemented rats, suggesting that the improved endothelium-dependent vasodilation observed in Q10 supplemented rats was largely mediated by prostacyclin (PGI2). 4. In conclusion, long-term Q10 supplementation improved endothelium-dependent vasodilation and enhanced beta-adrenoceptor-mediated arterial relaxation in senescent Wistar rats. The mechanisms underlying the improvement of endothelial function may have included augmented endothelial production of PGI2, increased sensitivity of smooth muscle to PGI2, or both.

Infection with human cytomegalovirus (CMV) affects the function and composition of the immune system during ageing. In addition to the presence of the pathogen, the strength of the immune response, as measured by the anti-CMV IgG titre, has a significant effect on age-related pathogenesis. High anti-CMV IgG titres have been associated with increased mortality and functional impairment in the elderly. In this study, we were interested in identifying the molecular mechanisms that are associated with the strength of the anti-CMV response by examining the gene expression profiles that are associated with the level of the anti-CMV IgG titre. Results The level of the anti-CMV IgG titre is associated with the expression level of 663 transcripts in nonagenarians. These transcripts and their corresponding pathways are, for the most part, associated with metabolic functions, cell development and proliferation and other basic cellular functions. However, no prominent associations with the immune system were found, and no associated transcripts were found in young controls. Conclusions The lack of defence pathways associated with the strength of the anti-CMV response can indicate that the compromised immune system can no longer defend itself against the CMV infection. Our data imply that the association between high anti-CMV IgG titres and increased mortality and frailty is mediated by basic cellular processes. BioMed Central open access

The effect of dexmedetomidine, a selective alpha 2-adrenoceptor agonist, on ethanol withdrawal symptoms was studied in chronically ethanol-fed rats. After a 4-day ethanol intoxication period the rats were given s.c. injections of dexmedetomidine (3, 10, or 30 micrograms/kg) or saline (control group) at 10, 16, 22, and 39 h after the last dose of ethanol. The severity of ethanol withdrawal symptoms (rigidity, tremor, irritability, hypoactivity) was rated up to 58 h, blind to the treatments. The results showed that dexmedetomidine at doses 10 and 30 micrograms/kg significantly diminished the severity of the ethanol withdrawal reaction as measured by the sum score of the three most specific withdrawal signs (rigidity, tremor, and irritability). Dexmedetomidine at 10 micrograms/kg was the most effective dose, especially in the latter half of the withdrawal period (23-58 h after last dose of ethanol). The results suggest that dexmedetomidine in the treatment of ethanol withdrawal symptoms should be further studied.

Aging and the diseases that typically follow with increasing age, notably atherosclerosis and cancer, are often proposed to be involved in increased oxidative stress. Animal studies, on the other hand, show no clear-cut pattern of age-related changes in enzymatic antioxidant defences. In this study we have demonstrated that total peroxyl radical scavenging antioxidant capacity (TRAP) in human plasma changes with age. We also found that among the antioxidants in human plasma there exists a major fraction of so far unidentified antioxidant(s). A chemiluminescent TRAP assay was used to determine the presence of peroxyl radical scavenging antioxidants in human plasma. The material consisted of 87 healthy volunteers, aged 20-96 years, who used no regular medication, vitamins, or trace elements. In females, total antioxidant capacity increased significantly during the life span. The increase in TRAP was mainly due to unidentified antioxidants. In males, TRAP increased until age 51-74, and then significantly decreased. The decrease observed among males was also due to the sharp decline in the concentration of unidentified antioxidants.

Plasma total peroxyl radical scavenging capacity was studied in terminal patients who were chronically immobilized because of an acute (stroke) or chronic neurodegenerative disease (Alzheimer's disease). A luminometric assay was used to measure total antioxidant capacity (TRAP). The immobilized patients showed significant decrease in TRAP primarily because of a decrease in the concentration of unknown antioxidants. Our results suggest that human plasma may contain unknown antioxidants, the regulation of which could be related to the basic metabolic rate.

It has been demonstrated that in obviously healthy, very old people increased levels of inflammatory markers as well as some defects in T lymphocyte populations are strong predictors of mortality. Very little is known about the role of possible functional defects in antibody formation. To examine this, we now measured IgM, IgG and IgA concentrations in a cohort of 285 nonagenarians (67 males, 218 females). IgG and IgA levels were significantly higher than those of healthy middle-aged controls. The analyzed serum samples were taken at the age of 90-91 years. After 4 years, 20 males and 94 females had survived. To analyze the role in predicting mortality, the immunoglobulin data (as well as the measured CRP and IL-6 concentrations) were stratified according to this survival data. IgA levels (and CRP and IL-6 levels) were clearly higher in the nonsurvivors than in the survivors. These data imply that elevated serum IgA level, i.e. indicator of intestinal inflammation and/or defect in mucosal defence, is a strong mortality predicting factor.

Selegiline is a selective and irreversible monoamine B inhibitor with the capacity to increase the level of several antioxidative enzymes in rat brain. It can protect adrenergic neurons against injury induced by neurotoxins such as MPTP, DSP-4 and AF64A in animal studies. In addition, the protective action is not limited to catecholaminergic cells, as selegiline can also minimize the loss of developing motoneurons after axotomy. The aim of this study was to determine whether selegiline can protect peripheral catecholaminergic neurons against the neurotoxic effect of 6-OHDA. This kind of protective effect against 6-OHDA neurotoxicity has not been reported before. Wistar albino male rats aged 4 or 24 months were treated with selegiline or saline solution 1 h before 6-OHDA injection. At 2 weeks after the 6-OHDA injection, the superior cervical ganglia (SCG) and submandibular glands (SMG) were studied using catecholamine histofluorescence and immunohistochemistry for tyrosine hydroxylase (TH). The number of TH-positive cells in the SCG and the length and number of adrenergic nerve fibers in the SMG were quantified. Our findings showed that 6-OHDA caused a reduction of TH immunoreactivity and catecholamine histofluorescence in neuronal somata, as well as a decrease in the number and length of adrenergic nerve fibers in the submandibular gland. Selegiline pretreatment protected SCG neurons and their postganglionic nerve fibers in SMG against these changes in a dose-dependent manner. The mechanism through which selegiline exerts its neuroprotective effect is as yet unknown.

The increased paternal age at conception (PAC) has been associated with autism spectrum disorder (ASD), schizophrenia and other neurodevelopmental disorders, thus raising questions that imply, potential health concerns in the offspring. As opposed to female oogonia, the male germ cells undergo hundreds of cell divisions during the fertile years. Thus, the advanced paternal age is associated with increase of point mutations in the male spermatogonia DNA, implying that this could be the major driving mechanism behind the paternal age effect observed in the offspring. In addition to replication errors, DNA replication fidelity and inefficient DNA repair machinery in the spermatogonia also contribute to the mutagenic load. Our study population consisted of 38 nonagenarians, participants in the Vitality 90+ Study, born in the year 1920 (women n = 25, men n = 13), for whom the parental birth dates were available. The gene expression profile of the study subjects was determined with HumanHT-12 v4 Expression BeadChip from peripheral blood mononuclear cells. We used Spearman's rank correlation to look for the associations of gene expression with paternal age at conception. Associated transcripts were further analyzed with GOrilla and IPA to determine enriched cellular processes and pathways. PAC was associated with the expression levels of 648 transcripts in nonagenarian subjects. These transcripts belonged to the process of mitochondrial translational termination and the canonical pathway of Mitochondrial dysfunction, more specifically of Oxidative phosphorylation. The observed systematic down-regulation of several mitochondrial respiratory chain components implies compromised function in oxidative phosphorylation and thus in the production of chemical energy. Public Library of Science open access