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.

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.

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.

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.

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.

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.

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.

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).

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.

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.

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.

Ten-year change in the use of medical drugs among the elderly--a longitudinal study and cohort comparison.

Longitudinal changes and cohort differences from 1979 to 1989 in the use of prescribed and non-prescribed medical drugs were examined and the connections of drug use to various background variables were analysed in the framework of the Tampere Longitudinal Study of Ageing. In the longitudinal study random samples of men and women born in 1900-09 and 1910-19 (738 persons) were interviewed in 1979 and the survivors (62%) were interviewed again in 1989. In the cohort comparison the 60-69-year-olds studied in 1979 (364 persons) were compared with the 60-69-year-olds in 1989 (395 persons). In the longitudinal setting the number of prescribed drugs increased. In 1989 2 or 3 in 10 persons used at least five prescribed drugs simultaneously. In the cohort comparison there were no differences in the number of prescribed drugs between the two groups of 60-69-year-olds. Use was connected with multimorbidity and poor self-rated health. Both the longitudinal comparison in the group born in 1910-19 and the cohort comparison revealed a significant increase in the use of non-prescribed drugs. The use of analgesics was connected with sex, occupational class, self-rated health and feelings of loneliness. In the use of vitamins, no connection was found with health variables, but they were mostly used by white-collar employees and women. However, when all these variables were controlled for, both analgesics and, in particular, vitamins were used more in 1989 than in 1979. The results suggest that the increase in the use of non-prescribed drugs is mainly due to social and historical factors, by changes both in drug policies, health culture and health behaviour of elderly persons.

Social ties and survival among the elderly in Tampere, Finland.

The association between social ties and survival was assessed using a stratified sample of 1060 elderly aged 60-89 years in the city of Tampere, Finland. During the 6.5-year follow-up, 240 men and 153 women died. Compared with married men, the death rate ratio among unmarried men was 1.7 and among widowers 1.2. The respective ratios for women were 1.2 and 1.2. Vicinity of children, living alone, loneliness, social contacts, and social participation were used as indicators of social ties. Men and women were analysed separately. None of the indicators were significant predictors of survival in proportional hazard analyses, after adjusting for age, perceived health, functional ability and occurrence of a disabling disease at baseline. The relative hazards ranged between 0.85 and 1.38, and all 95% confidence intervals included unity. However, when social participation was entered into the models as a continuous variable, it was strongly associated with increased survival in both sexes. Social participation is probably not protective as such, but it may rather reflect way-of-life, which is characterized by social competence or 'control of destiny'.

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.

Self-rated health revisited: exploring survey interview episodes with elderly respondents.

Analysing transcripts of survey interview episodes where self-rated health was discussed, the paper aims (1) to throw light on the interview situation and the way in which talk is structured in this situation, and (2) to uncover the elements out of which the interviewees construct their 'health'. The excerpts analysed show that the survey interview is an interactional situation produced by the interpretations and actions of the people involved. As a rule, the interviewees did not simply opt for one of the preset alternative answers but inserted their own descriptions and explanations. In this talk, 'health' appears as a multidimensional, context-bound phenomenon that can be constructed out of different, even contradictory elements.

Predictors of decline in self-assessments of health among older people--a 5-year longitudinal study.

Within the framework of the Evergreen project we examined how changes in several indicators of health and functioning and physical activity predicted a decline in self-assessments of health evaluated over a 5-year period in older people by two different measurements: self-rated health (SRH) and self-assessed change in health (SACH). The study group comprised all 75-year-old persons born in 1914 (N = 382) and living in Jyväskylä, a town in central Finland. At baseline in 1989, 91.6%, and at follow-up 5 years later in 1994, 87.3% of those eligible participated in the interview and 77.2 and 71.3%, respectively, in the examinations in the study centre, focusing on different domains of health and functional capacity. One-fifth of the subjects reported a deterioration in and one-fifth an improvement in SRH over the 5 years. The rest gave identical self-assessments of their health at baseline and at follow-up in response to the same question. Decline in SRH was associated with a decrease in physical activity and cognitive capacity. When asked directly about changes in their health (SACH), however, half the subjects said their health had declined. Negative SACH over the 5-year period was related to an increased number of chronic conditions, deterioration in functional performance and physical activity, and to the number of chronic conditions at baseline. We suggest that ageing people adapt to changes in their objective health and functional performance: the majority tend to assess their health as similar to or even better with increasing age despite an increase in chronic diseases and decline in functional performance. However, a negative SACH indicates that older people are realistic about these negative changes. These results support the assumption that the two subjective measurements of change in health are based on different criteria: assessment of current general health status tends to be based on inter-individual comparison, whereas assessment of change in health over a given time period may be based on intra-individual comparison. Physical activity seems to be an important factor when older people assess their health.

Self-rated health and self-assessed change in health in elderly men and women--a five-year longitudinal study.

The purpose of the present investigation was two fold: (1) to examine how men and women self-rate their health as they age from 75 to 80 yr and how they assess the change in their health over the five year period; and (2) to ascertain how self-assessed change in health over the follow-up period corresponded to the difference in self-ratings of health between the assessments performed at baseline and at follow-up. The study was part of the Evergreen-project with the study group comprising all inhabitants born in 1914 (N = 388) living in Jyväskylä, central Finland. At baseline, 93.4%, and at follow-up, 93.3%, of those who were eligible participated in the interview. Self-rated health, when asked using the same questions, did not change at follow-up compared to baseline. However, nearly half of the follow-up group reported that their health had become worse over the five year period. Gender differences in self-rated health were not found, although women reported more often than men that their health had become worse and some of the men said their health had become better. It is concluded that self-rated health seems to be age-adjusted; elderly people who say their health has become worse as they age actually self-rate their health as the same or better than before.

Interpretative repertoires of medication among the oldest-old.

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.

Constant hierarchic patterns of physical functioning across seven populations in five countries.

This research was aimed at identifying critical steps in the decline in physical function that often parallels aging. Six basic and nine instrumental activities of daily living (ADLs) were classified into four domains of disability characterized by specific underlying physical impairment. The hierarchical order of this classification was verified in two random samples representative of the older home-dwelling population. The concordance level of disability and results of performance-based measures of physical function were also tested. Finally, the cross-cultural reliability of the model was verified in seven population-based samples of older persons living in five European countries. In older persons the disabling process follows a general pattern of progression based on a typical sequence of impairments.