Self-rated health in individuals with and without disease is associated with multiple biomarkers representing multiple biological domains.

Self-rated health (SRH) is one of the most frequently used indicators in health and social research. Its robust association with mortality in very different populations implies that it is a comprehensive measure of health status and may even reflect the condition of the human organism beyond clinical diagnoses. Yet the biological basis of SRH is poorly understood. We used data from three independent European population samples (N approx. 15,000) to investigate the associations of SRH with 150 biomolecules in blood or urine (biomarkers). Altogether 57 biomarkers representing different organ systems were associated with SRH. In almost half of the cases the association was independent of disease and physical functioning. Biomarkers weakened but did not remove the association between SRH and mortality. We propose three potential pathways through which biomarkers may be incorporated into an individual's subjective health assessment, including (1) their role in clinical diseases; (2) their association with health-related lifestyles; and (3) their potential to stimulate physical sensations through interoceptive mechanisms. Our findings indicate that SRH has a solid biological basis and it is a valid but non-specific indicator of the biological condition of the human organism.

Circulating cell-free DNA level predicts all-cause mortality independent of other predictors in the Health 2000 survey.

Increased levels of circulating cell-free DNA (cf-DNA) are associated with and predict poor health outcomes. However, its predictive ability for mortality in population-based samples remains understudied. We analysed the capability of cf-DNA to predict all-cause mortality and assessed whether it adds predictive value on top of the other risk factors in the Health 2000 survey (n = 1,257, 46-76 years of age, 15-years-follow-up, 18% deceased). When analysed in a multivariate model with the other factors that independently predicted mortality in the sample (age, gender, self-rated health, smoking and plasma levels of glucose and adiponectin), increases in cf-DNA levels were associated with increased risk of mortality (hazard ratio [HR] for 0.1 µg increase in cf-DNA: 1.017, 95% confidence interval [CI] 1.008-1.026, p = 0.0003). Inclusion of cf-DNA in the model improved the model fit and discrimination. Stratifying the analysis by cardiovascular disease (CVD) status indicated that cf-DNA predicted mortality equally well in individuals with (HR 1.018, 95% CI 1.008-1.026, p = 0.002) and without (HR 1.018, 95% CI 1.001-1.035, p = 0.033) CVD. In conclusion, our study indicates that cf-DNA level predicts mortality in middle-aged and older individuals, also among those with established CVD, and adds significant value to mortality prediction. Our results thus underscore the role of cf-DNA as a viable marker of health.

A case study on the re-establishment of the cyanolichen symbiosis: where do the compatible photobionts come from?

BACKGROUND AND AIMS: In order to re-establish lichen symbiosis, fungal spores must first germinate and then associate with a compatible photobiont. To detect possible establishment limitations in a sexually reproducing cyanolichen species, we studied ascospore germination, photobiont growth and photobiont association patterns in Pectenia plumbea. METHODS: Germination tests were made with ascospores from 500 apothecia under different treatments, and photobiont growth was analysed in 192 isolates obtained from 24 thalli. We determined the genotype identity [tRNALeu (UAA) intron] of the Nostoc cyanobionts from 30 P. plumbea thalli from one population. We also sequenced cyanobionts of 41 specimens of other cyanolichen species and 58 Nostoc free-living colonies cultured from the bark substrate. KEY RESULTS: Not a single fungal ascospore germinated and none of the photobiont isolates produced motile hormogonia. Genetic analyses revealed that P. plumbea shares Nostoc genotypes with two other cyanolichen species of the same habitat, but these photobionts were hardly present in the bark substrate. CONCLUSIONS: Due to the inability of both symbionts to thrive independently, the establishment of P. plumbea seems to depend on Dendriscocaulon umhausense, the only cyanolichen species in the same habitat that reproduces asexually and acts as a source of appropriate cyanobionts. This provides support to the hypothesis about facilitation among lichens.

The rs2516839 variation of USF1 gene is associated with 4-year mortality of nonagenarian women: The Vitality 90+ study.

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.

The trajectory of the blood DNA methylome ageing rate is largely set before adulthood: evidence from two longitudinal studies.

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.

Transcriptomic and epigenetic analyses reveal a gender difference in aging-associated inflammation: the Vitality 90+ study.

Aging is associated with a pro-inflammatory state, often referred to as inflammaging. The origin of the pro-inflammatory mediators and their role in the pathogenesis of the aging-associated diseases remain poorly understood. As aging is also associated with profound changes in the transcriptomic and epigenetic (e.g., DNA methylation) profiles of cells in the peripheral blood, we analyzed the correlation of these profiles with inflammaging using the "classical" marker interleukin-6 as an indicator. The analysis of the whole-genome peripheral blood mononuclear cell (PBMC) gene expression revealed 62 transcripts with expression levels that significantly correlated with the plasma interleukin-6 (IL-6) levels in men, whereas no correlations were observed in women. The Gene Ontology analysis of plasma IL-6-associated transcripts in men revealed processes that were linked to the inflammatory response. Additionally, an Ingenuity Pathway Analysis (IPA) pathway analysis identified Tec kinase signaling as an affected pathway and upstream regulator analysis predicted the activation of IL-10 transcript. DNA methylation was assessed using a HumanMethylation450 array. Seven genes with expression profiles that were associated with the plasma IL-6 levels in men were found to harbor CpG sites with methylation levels that were also associated with the IL-6 levels. Among these genes were IL1RN, CREB5, and FAIM3, which mapped to a network of inflammatory response genes. According to our results, inflammaging is manifested differently at the genomic level in nonagenarian men and women. Part of this difference seems to be of epigenetic origin. These differences point to the genomic regulation of inflammatory response and suggest that the gender-specific immune system dimorphism in older individuals could be accounted for, in part, by DNA methylation.

Are body mass index, waist circumference and waist-to-hip ratio associated with leptin in 90-year-old people?

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.

Design, recruitment, logistics, and data management of the GEHA (Genetics of Healthy Ageing) project.

In 2004, the integrated European project GEHA (Genetics of Healthy Ageing) was initiated with the aim of identifying genes involved in healthy ageing and longevity. The first step in the project was the recruitment of more than 2500 pairs of siblings aged 90 years or more together with one younger control person from 15 areas in 11 European countries through a coordinated and standardised effort. A biological sample, preferably a blood sample, was collected from each participant, and basic physical and cognitive measures were obtained together with information about health, life style, and family composition. From 2004 to 2008 a total of 2535 families comprising 5319 nonagenarian siblings were identified and included in the project. In addition, 2548 younger control persons aged 50-75 years were recruited. A total of 2249 complete trios with blood samples from at least two old siblings and the younger control were formed and are available for genetic analyses (e.g. linkage studies and genome-wide association studies). Mortality follow-up improves the possibility of identifying families with the most extreme longevity phenotypes. With a mean follow-up time of 3.7 years the number of families with all participating siblings aged 95 years or more has increased by a factor of 5 to 750 families compared to when interviews were conducted. Thus, the GEHA project represents a unique source in the search for genes related to healthy ageing and longevity.

CRP gene is involved in the regulation of human longevity: a follow-up study in Finnish nonagenarians.

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.

Autoimmunity and longevity: presence of antinuclear antibodies is not associated with the rate of inflammation or mortality in nonagenarians.

There are reports demonstrating elevated levels of autoantibodies in elderly people. We now analyzed whether the strong inflammatory response associated with aging is interrelated with the production of autoantibodies, antinuclear antibodies (ANA). In a cohort of 284 nonagenarians the rate of ANA positivity was 12.3%, which is significantly (p<0.001) higher than that in the middle-aged controls (2.8%). The mortality data of this cohort was collected after a 4-year follow-up. The ANA positivity at the age of 90 did not have any effect on the rate of survival, or on the levels of serum markers of inflammation.

Improvement in depressive symptoms and changes in self-rated health among community-dwelling disabled older adults.

This study investigated the association between improvement in depressive symptoms and changes in self-rated health among community-dwelling disabled older adults over time. Multivariate logistic regression models were applied using the 1993 and 1995 Assets and Health Dynamics among the Oldest-Old Survey data. Changes in depressive symptoms and changes in self-rated health clearly coincide. Among participants with functional disability in 1993 and 1995, a decrease in depressive symptoms was associated with decreased odds of having decline in self-rated health (odds ratio [OR], 0.85; 95% confidence interval [CI], 0.78-0.93) and was associated with increased odds of having improvement in self-rated health (OR, 1.15; 95% CI, 1.04-1.27). Similar results were also found among participants with no functional disability in 1993 and with functional disability in 1995. Among community-dwelling older adults who remained disabled at follow-up or who experienced disability only at follow-up, even just a small decrease in depressive symptoms was associated with increased odds of having improvement in self-rated health and with decreased risks of having decline in self-rated health. Reducing the number of symptoms of depression among these disabled older adults would be beneficial in improving their self-rated health as well as maintaining and promoting their quality of life.

Indoleamine 2,3-dioxygenase activity in nonagenarians is markedly increased and predicts mortality.

Indoleamine 2,3-dioxygenase (IDO), an enzyme degrading tryptophan (trp) to kynurenine (kyn), suppresses T cell activity. Ageing of the immune system, immunosenescence, includes a decline in T cell function. We therefore sought to establish whether IDO activity is involved in immunosenescence and whether it predicts mortality in aged subjects. We measured kyn/trp, reflecting IDO activity, in 284 nonagenarians and 309 blood donor controls. IDO activity was significantly higher in nonagenarians compared with controls and IDO activity at study entry predicted subsequent mortality in nonagenarians. Thus, increased IDO activity might be a mechanism involved in the decline of T cell responses in immunosenescence.

A harmonized measure of activities of daily living was a reliable and valid instrument for comparing disability in older people across countries.

BACKGROUND AND OBJECTIVES: Our aim was to construct a harmonized measure of activities of daily living (ADL) across six countries, and to evaluate the reliability and validity of this measure. METHODS: A population of 9,297 persons, aged 65-89 years, was drawn from the Comparison of Longitudinal European Studies on Aging (CLESA) study, which includes data from five European countries and Israel. Because the number, type, and response format of the ADL items differed across the six studies, a four-item scale was constructed to harmonize the data, using items common to most countries. A procedure was devised to substitute or construct items that were not available in two of the countries. RESULTS: Cronbach's alpha for the four-item ADL measure varied from 0.81 in Spain to 0.92 in Finland, and was similar to the alpha of scales including five or six items. Kappa scores between substituted or constructed items and the actual items varied from 0.50 to 0.78. In all countries, the percentage of persons with ADL disability differed significantly across age and was associated with chronic diseases, poor self-rated health, global disability, and home help utilization. CONCLUSION: The harmonized four-item ADL measure seems a reliable and valid instrument for comparing ADL disability in older people across countries.

Interleukin-6 -174G/C polymorphism and longevity: a follow-up study.

Increased rate of inflammation has been observed to be associated with aging. This is manifested, e.g. as increased blood levels of proinflammatory cytokines, such as interleukin-6 (IL-6). The production of IL-6 is, at least partially, genetically determined the single nucleotide polymorphism (SNP) at the promoter (-174G/C) being decisive. Consequently, some studies have demonstrated that the -174G/C genotype frequencies are different in very old persons as compared to younger ones. However, the results published this far have been conflicting. One of the main confounding factors in these kind of case/control association studies is the undetected difference in the population structure. To avoid this, we now have collected the mortality data of our cohort of 285 nonagenarians (representing mortality between 90 and 95 years of age) and correlated these to the IL-6 genotype. The frequency of -174 allele G was clearly higher in the survivors (n = 114) than in the non-survivors (n = 171).

Disability and social ties: comparative findings of the CLESA study.

The associations between prevalence, incidence and recovery from activities of daily living (ADL) disability and social ties among community-dwelling persons over 65 in Finland, The Netherlands and Spain are examined. Data were harmonized in the CLESA study. The baseline sample was composed of 3,648 subjects between 65 and 85 years old, living in Finland, The Netherlands and Spain. Disability in four activities of daily living was determined at baseline and at follow-up. Social participation, number of family ties and presence of friends were added to obtain a social ties index. Logistic regressions were fitted to the prevalence, incidence and recovery data to estimate the associations between disability and social ties, adjusting for education, co-morbidity and self-rated health. The modifying effects of country, age and sex were tested in all models. For every country, the social ties index, having friends and social participation were negatively associated with ADL disability prevalence. ADL incidence was negatively related to the number of family ties, with a stronger relationship in Spain than in The Netherlands or Finland. ADL recovery was associated with the social ties index. No age or gender differences in these associations were found. Social ties appear to generate a beneficial effect on the maintenance and restoration of ADL function. While social ties play an important role in maintaining and restoring function in all three countries, family ties appear to generate a stronger effect on protection from disability incidence than does social participation, and the strength of this effect varies by culture.

Disability-free life expectancy: a cross-national comparison of six longitudinal studies on aging. The CLESA project.

Disability-free life expectancy (DFLE) was compared in six countries taking part in the Cross-national Determinants of Quality of Life and Health Services for the Elderly (CLESA) project. Data from six existing longitudinal studies were used: TamELSA (Tampere, Finland), CALAS (Israel), ILSA (Italy), LASA (The Netherlands), Aging in Leganés (Leganés, Spain) and SATSA (Sweden). A harmonised four-item disability measure (bathing, dressing, transferring, toileting) was used to calculate DFLE; the harmonised measure was dichotomised into 'independent in all four activities' vs. 'dependent in at least one'. Calculations of DFLE were made using the multistate life table approach and the IMaCh program (INED/EuroREVES, http://eurorevesinedfr/imach/) for subjects aged 65-89 years. Prevalence ratios of disability varied significantly across countries, with Italy and Leganés having the highest percentages among men and among women, respectively, while The Netherlands presented the lowest for both sexes. At 75 years of age the estimated total life expectancy among men ranged from 7.8 years in Tampere and Sweden to 9.0 years in Israel; among women it ranged from 9.5 years in Israel to 11.6 years in Italy. For both sexes Italy showed the lowest total life expectancy without disability (72% among men, 61% among women) and Sweden the highest (89% among men and 71% among women). The results yielded a north/south gradient, with residents in Tampere, The Netherlands and Sweden expected to spend a higher percentage of their lives without disability than those in Italy, Israel and Leganés.

Urgency, urge incontinence and voiding symptoms in men and women aged 70 years and over.

OBJECTIVE: To evaluate the prevalence of urgency, urge incontinence and voiding symptoms, and their associations in older men and women. SUBJECTS AND METHODS: A population-based cross-sectional survey was conducted involving 171 men and 227 women aged > or = 70 years. The data were collected by interview, with a response rate of 92.8%. Voiding symptoms were defined as weakened and/or intermittent stream. The prevalence of urgency, urge incontinence and voiding symptoms were calculated for men and women aged 70-79 and > or = 80 years. Logistic regression models were used to examine the association of voiding symptoms with urgency, with or without incontinence, adjusted in the separate models for age and in the combined model also for gender. RESULTS: The prevalence of urge incontinence was higher than urgency alone in both men and women (23.9% vs. 9.8% and 36.4% vs. 8.6%, respectively); 71.9% of the men and 48.3% of the women reported voiding symptoms (P < 0.001). Men and women with voiding symptoms were both significantly more likely to report urgency with or without incontinence than those with no voiding symptoms (odds ratio 3.49, 95% confidence interval 1.42-8.57, and 2.34, 1.31-4.17, respectively). Age had no independent effect in men, and in women the effect was marginal. In the combined model female gender (1.98, 1.25-3.16) increased the risk of urgency with or without incontinence. CONCLUSION: Urgency, urge incontinence and voiding symptoms are common and associated with each other in older men and women; the association is stronger in men. Women are at greater risk of having urgency with or without incontinence. Because the study was cross-sectional a causal relationship cannot be confirmed.

Lack of association between human longevity and polymorphisms of IL-1 cluster, IL-6, IL-10 and TNF-alpha genes in Finnish nonagenarians.

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.

Walking difficulty, walking speed, and age as predictors of self-rated health: the women's health and aging study.

BACKGROUND: Older persons reporting disability are more likely to report poor self-rated health, but little work has been done to assess the independent relationships of reported walking difficulty and measured walking performance with self-rated health. This study examines the associations of walking difficulty, walking speed, and age with self-rated health in older women. METHODS: The data are from the baseline of the Women's Health and Aging Study. Difficulty walking one quarter mile was used as a measure of mobility in the representative population aged 65 and older screened for the study (n = 3841) and in the one third most disabled study group (n = 1002). Maximal walking speed was measured in the study sample. RESULTS: Increasing severity of walking difficulty (in the screened population and in the disabled study group), slower walking speed (in the study group), and younger age were all associated with fair or poor self-rated health, after simultaneous adjustment for these and other objective measures of physical performance and health. The associations of both measures of walking with self-rated health weakened with age. CONCLUSIONS: Both walking difficulty and walking speed are independent determinants of self-rated health. Adjusted for health and functioning, self-rated health tends to improve with age.

Association of smoking with urgency in older people.

OBJECTIVE: To evaluate the association of smoking with urgency in older people. METHODS: A population-based survey involving 1,059 people aged 60-89 years. A stratified sampling method was used and data were collected by interviews. The response rate was 82%. The indicators were urgency, former and current smoking, alcohol and coffee drinking. Prevalences of urgency were calculated for 15-year age groups of the two genders. Logistic regression models were used to analyse the age-adjusted association of urgency with smoking, use of alcohol and coffee drinking in the whole study population and separately in the two gender groups. RESULTS: The prevalence of urgency was lowest among younger men (6.6%) and highest among older women (19.5%). In the whole study population including both genders the current smokers were at greater risk of suffering from urgency [OR (odds ratio) 2.76; 95% CI (confidence interval) 1.43-5.32] than the never-smokers while the OR of urgency for former smokers was 1.63 (95% CI 0.97-2.74). In the separate models for the two genders the current male smokers (OR 2.55; 95% CI 1.13-5.73) and the former female smokers (OR 2.62; 95% CI 1.14-6.0) were at greater risk. The OR for current female smokers was 2.54 (95% CI 0.79-8.22), but the group was very small. Alcohol use and coffee drinking were not associated with urgency. CONCLUSION: Smoking is associated with urgency in older people. Especially current smokers are at greater risk than never-smokers. The prevalence of urgency is higher among women and is increased in both genders with advancing age. The study material being cross-sectional the causal relationship cannot be confirmed.