Risk factors of post-COVID-19 conditions attributed to COVID-19 disease in people aged ≥50 years in Europe and Israel.

OBJECTIVES: High age, male sex and pre-existing comorbidities are risk factors for a more severe development of COVID-19, and individuals surviving COVID-19 may experience persistent symptoms afterwards referred to as 'post-COVID-19 condition', which represents a range of symptoms after recovering from COVID-19. This study aims at identifying risk factors of post-COVID-19 conditions among people aged ≥50 years. STUDY DESIGN: We conducted a cross-sectional study based on data from the Survey of Health, Ageing and Retirement in Europe. METHODS: A multiple logistic regression model was used to investigate age, sex, education, comorbidities, smoking, body mass index, and COVID-19 hospitalisation as risk factors of post-COVID-19 condition. RESULTS: Participants aged ≥70 years (odds ratio [OR] 1.61) with medium (OR 2.38) and lower (OR 2.14) educational levels have a higher risk of post-COVID-19 conditions. In addition, when considering the severity of the COVID-19 disease, those who were hospitalised due to COVID-19 had a 26 times higher risk of post-COVID-19 conditions compared with those who were only tested positive (OR 25.9). CONCLUSIONS: This study supports that health inequalities exist across educational levels with respect to post-COVID-19 conditions, although misclassification may be more common among lower educated participants. The results suggest that policy makers should increase educational interventions towards increasing health literacy.

Building Bridges for Innovation in Ageing: Synergies between Action Groups of the EIP on AHA.

The Strategic Implementation Plan of the European Innovation Partnership on Active and Healthy Ageing (EIP on AHA) proposed six Action Groups. After almost three years of activity, many achievements have been obtained through commitments or collaborative work of the Action Groups. However, they have often worked in silos and, consequently, synergies between Action Groups have been proposed to strengthen the triple win of the EIP on AHA. The paper presents the methodology and current status of the Task Force on EIP on AHA synergies. Synergies are in line with the Action Groups' new Renovated Action Plan (2016-2018) to ensure that their future objectives are coherent and fully connected. The outcomes and impact of synergies are using the Monitoring and Assessment Framework for the EIP on AHA (MAFEIP). Eight proposals for synergies have been approved by the Task Force: Five cross-cutting synergies which can be used for all current and future synergies as they consider overarching domains (appropriate polypharmacy, citizen empowerment, teaching and coaching on AHA, deployment of synergies to EU regions, Responsible Research and Innovation), and three cross-cutting synergies focussing on current Action Group activities (falls, frailty, integrated care and chronic respiratory diseases).

Operational Definition of Active and Healthy Ageing (AHA): A Conceptual Framework.

Health is a multi-dimensional concept, capturing how people feel and function. The broad concept of Active and Healthy Ageing was proposed by the World Health Organisation (WHO) as the process of optimizing opportunities for health to enhance quality of life as people age. It applies to both individuals and population groups. A universal Active and Healthy Ageing definition is not available and it may differ depending on the purpose of the definition and/or the questions raised. While the European Innovation Partnership on Active and Healthy Ageing (EIP on AHA) has had a major impact, a definition of Active and Healthy Ageing is urgently needed. A meeting was organised in Montpellier, France, October 20-21, 2014 as the annual conference of the EIP on AHA Reference Site MACVIA-LR (Contre les Maladies Chroniques pour un Vieillissement Actif en Languedoc Roussillon) to propose an operational definition of Active and Healthy Ageing including tools that may be used for this. The current paper describes the rationale and the process by which the aims of the meeting will be reached.

Does socio-economic status predict grip strength in older Europeans? Results from the SHARE study in non-institutionalised men and women aged 50+.

BACKGROUND: Reduced hand-grip strength predicts disability, morbidity and mortality, but whether it is shaped by socio-economic experiences is yet unknown. The authors examined the association of education, occupation, income and wealth with grip strength in older Europeans. METHODS: Data came from the Survey of Health, Ageing and Retirement in Europe comprising 27 351 participants ages 50+ in 11 countries. Grip strength was objectively measured using a handheld dynamometer. Estimates were obtained based on multivariate linear regression controlling for a wide set of confounders, demographics, health and disability measures, and behavioural risk factors. RESULTS: In the total sample, education, occupational class, income and wealth predicted grip strength among men, whereas only education and wealth predicted grip strength among women. While education and income effects were inconsistent in most countries, wealth consistently predicted grip strength in each country. A one-point increase in the log of wealth was associated with 0.38 kg (95% CI 0.31 to 0.45) higher grip strength in men and 0.18 kg (95% CI 0.15 to 0.21) higher grip strength in women. While education, income and occupation effects disappeared after adjustment for health measures, log of wealth effects remained significant in both men (0.22, 95% CI 0.15 to 0.29) and women (0.08, 95% CI 0.05 to 0.11). Wealth effects were particularly evident in the two lowest quintiles. CONCLUSION: Old-age socio-economic and financial circumstances as measured by wealth are associated with grip strength, particularly among the least wealthy, while circumstances defined earlier in life as measured by education, income and occupation do not consistently predict grip strength.

High prevalence of autoantibodies among Danish centenarians.

The aim of this study was to investigate the prevalence of organ and nonorgan specific autoantibodies in relation to disability and comorbidity in an unselected population of centenarians. A population-based survey of all persons living in Denmark who celebrated their 100th birthday during the period 1 April 1995 to 31 May 1996, a total of 276 persons, was undertaken. Participants underwent an interview, a physical examination and blood sampling. Organ specific autoantibodies (Tg-ab, TPO-ab, PCA-ab) and nonorgan specific autoantibodies (ANA, IgM RF, IgA RF, MPO-ab, c-ANCA, p-ANCA, oxLDL-ab, IgM ACA, IgG ACA, PR3-ANCA, histone-ab, SSA-ab, SSB-ab, Mit-ab) were measured, and comorbidity and disability (Katz Index of ADL) were registered. In all, 207 (75.0%) of 276 eligible subjects participated, and 148 agreed to blood tests. A large majority (79.3%) had at least one autoantibody detected. Organ specific autoantibodies were present in 32.1% of the centenarians. The high level of autoantibodies did not reflect an equally high level of overt autoimmune disease. While nonorgan specific autoantibodies were equally represented in less-disabled/disabled subjects as well as in subjects with low/high comorbidity, significantly fewer subjects with organ specific autoantibodies were found among less-disabled subjects or subjects with low comorbidity. Autoantibodies (both nonorgan and organ specific) are common in an unselected population of centenarians of today, but do not reflect an equally high level of overt autoimmune disease. Non-organ specific autoantibodies are evenly distributed irrespective of the level of disability or comorbidity, suggesting underlying, undiagnosed pathological processes which may be part of the processes involved in frailty.

Modest implication of interleukin-6 promoter polymorphisms in longevity.

The multifunctional interleukin-6 has been suggested to contribute to a chronic low-grade inflammatory status, thereby conferring susceptibility to age-related pathological conditions as well as functional decline and increased mortality. Several polymorphisms have been identified in the interleukin-6 promoter, but investigation of the effect of these on interleukin-6 levels and disease susceptibility have led to contradictory results. This study investigates the significance of the three single-point polymorphisms (-597G/A, -572G/C and -174G/C) and the AT-stretch polymorphism (-373(A)n(T)m) in ageing, by comparison of the frequency of each single polymorphism separately as well as the entire promoter haplotype in a total of 1710 Danish subjects ranging in age from 47 to 100 years. We found a modest, but significant, increase in the frequency of interleukin-6 -174GG homozygotes with age suggesting that this genotype is advantageous for longevity.

Is ageing associated with a shift in the balance between Type 1 and Type 2 cytokines in humans?

The balance between Type 1 and Type 2 cytokines is important for the outcome of several infectious diseases. As elderly humans show increased morbidity and mortality from infectious diseases, this study tests if ageing is associated with a change towards Type 2 dominance in T cells. Expression of IFN-gamma, and IL-4 was measured in CD4+ and CD8+ T cells by flow cytometry in three groups: young controls (n=28), 81-year-olds (n=22), and centenarians (n=25). The major findings were that the percentage of IFN-gamma+ as well as IL-4+ T cells was increased in aged subjects. Furthermore, after adjusting for decreased lymphocyte counts in the elderly, the concentration in the blood of IFN-gamma+ and IL-4+ CD8+ T cells was still increased in the 81-year-olds. In centenarians, a shift towards a relative dominance of Type 2 cytokine expression was found within CD8+ T cells. Furthermore, the percentage of T cells with cytokine expression was closely correlated to the in vivo expression of CD95 and CD45RO. In conclusion, we found some evidence for an age-related shift towards a Type 2 cytokine profile.

Replication studies in longevity: puzzling findings in Danish centenarians at the 3'APOB-VNTR locus.

In Danes we replicated the 3'APOB-VNTR gene/longevity association study previously carried out in Italians, by which the Small alleles (less than 35 repeats) had been identified as frailty alleles for longevity. In Danes, neither genotype nor allele frequencies differed between centenarians and 20-64-year-old subjects. However, when Danish and Italian data were compared, a significant difference (p = 0.0004) was found between the frequencies of Small alleles in youths, which disappeared in centenarians (p = 0.290). Furthermore, the demographic-genetic approach revealed in Danes a significant gene-sex interaction relevant to Long alleles (more than 37 repeats). The different findings in Denmark and Italy suggest that gene/longevity associations are population-specific, and heavily affected by the population-specific genetic and environmental history.

Variations of cardiovascular disease associated genes exhibit sex-dependent influence on human longevity.

This article investigates the relationship between the polymorphic variations in genes associated with cardiovascular disease and longevity in the Danish population. A new procedure that combines both demographic and the individual genetic information in determining the relative risks of the observed genetic variations is applied. The sex-dependent influences can be found by introducing sex-specific population survival and incorporating the risk of gene-sex interaction. Three genetic polymorphisms, angiotensinogen M/T235, blood coagulation factor VII (FVII) R/Q353 and FVII-323ins10, manifest significant influences on survival in males, with reduced hazards of death for carriers of the angiotensinogen M235 allele, the F VII Q353 allele, and the FVII-323P10 allele. The results show that some of these genotypes associated with lower risk of CVD could also reduce the carrier's death rate and contribute to longevity. However, the presence of sex-dependent effects and the fact that major CVD-associated genes failed to impose detrimental influence on longevity lead us to concur that the aging process is highly complicated.

Healthy centenarians do not exist, but autonomous centenarians do: a population-based study of morbidity among Danish centenarians.

OBJECTIVE: To assess the prevalence of common illnesses in an unselected population of centenarians. DESIGN: A population-based survey. SETTING: Denmark. PARTICIPANTS: All Danes who celebrated their 100th anniversary between April 1, 1995 and May 31, 1996: 276 persons. MEASUREMENTS: All participants (including proxies) were visited at their domicile for an interview (sociodemographic characteristics, activities of daily living, living conditions, need of assistance from other people, former health and current diseases, current medication) and a clinical examination (dementia screening test, heart and lung auscultation, neurological assessment, height and weight, electrocardiogram, arm and ankle blood pressure, assessment of hearing and vision capacity, a short physical performance test, bio-impedance, lung function test, blood test). Further health information was retrieved from medical files and national health registers. RESULTS: Seventy-five percent (207) of eligible subjects participated in the study. Cardiovascular disease was present in 149 (72%) subjects. Osteoarthritis (major joints) was present in 54%, hypertension (> or =140/ > or =90) in 52%, dementia in 51%, and ischemic heart disease in 28%. The mean number of illness was 4.3 (standard deviation (SD) 1.86). Only one subject was identified as being free from any chronic condition or illness. Sixty percent had been treated for illness with high mortality. In 25 autonomous (nondemented, functioning well physically, living at home) and 182 nonautonomous centenarians, comorbidities were equivalent. CONCLUSION: Because they have a high prevalence of several common diseases and chronic conditions, Danish centenarians are not healthy. However, a minor proportion was identified as being cognitively intact and functioning well.

[Thyroid dysfunction in the elderly]. / Thyreoideadysfunktion hos aeldre.

In the elderly, thyroid dysfunction usually develops insidiously and is dominated by non-specific symptoms and clinical findings, typically related to normal aging or to age-associated disease. Case finding, in combination with a low threshold for biochemical control, is recommended. In Denmark, hyperthyroidism is more frequent than hypothyroidism. Subclinical hyperthyroidism is generally temporary. In subclinical hypothyroidism the annual progression rate to manifest hypothyroidism is 2-3%, but higher (5-10%) in the presence of thyroid autoantibodies. Treatment recommendation is related to the serum level of thyroid stimulating hormone and the presence of thyroid peroxidase autoantibodies. Hypothyroidism should be treated with lower doses of thyroxine, and the titration phase is longer. An antithyroid drug is the initial treatment in hyperthyroidism, often followed by radioiodine therapy. In Denmark, radioiodine therapy of nontoxic goitre has become more common.

Dementia is not inevitable: a population-based study of Danish centenarians.

The authors evaluated the prevalence of dementia in centenarians. In this population-based survey, persons living in Denmark who turned 100 during the period April 1, 1995--May 31, 1996 (N = 276) were interviewed and examined at their residences. Additional health information was retrieved from medical files, including the National Discharge Registry. A participation rate was 75%, and no differences were found between participants and nonparticipants regarding sex and type of housing. The prevalence of mild to severe dementia in centenarians was 51%; 37% had no signs of dementia. Among the 105 demented centenarians, 13 (12%) had diseases (vitamin B12 and folic acid deficiencies, hypothyroidism, Parkinson's disease) that could contribute to a dementia diagnosis. Of the remaining 92 demented participants, 46 (50%) had 1 one or more cerebro- or cardiovascular diseases known to be risk factors in the development of dementia. The prevalence of these risk factors was the same in demented and nondemented participants, whereas hypertension was significantly more frequent in nondemented than demented participants. Dementia is common but not inevitable in centenarians. Cerebro- and cardiovascular diseases are equally common in demented and nondemented persons.

X-linked genetic factors regulate hematopoietic stem-cell kinetics in females.

X inactivation makes females mosaics for 2 cell populations, usually with an approximate 1:1 distribution. Skewing of this distribution in peripheral blood cells is more common among elderly women. The depletion of hematopoietic stem cells followed by random differentiation may explain the acquired skewing with age. However, an animal model suggests that selection processes based on X-linked genetic factors are involved. We studied peripheral blood cells from 71 monozygotic twin pairs aged 73 to 93 years and from 33 centenarians, and we found that with age, 1 of the cell populations becomes predominant for most women. We also observed a strong tendency for the same cell line to become predominant in 2 co-twins. This suggests that X-linked genetic factors influence human hematopoietic stem cell kinetics. The fact that females have 2 cell lines with different potentials could be one of the reasons women live longer than men.

Thyroid function, morphology and prevalence of thyroid disease in a population-based study of Danish centenarians.

OBJECTIVES: To investigate thyroid function, morphology, and autoimmunity in relation to physical function in an unselected population of centenarians. DESIGN: A population-based survey. SETTING: Denmark. PARTICIPANTS: All persons living in Denmark who celebrated their 100th anniversary during the period April 1, 1995 to May 31, 1996, a total of 276 persons. MAIN OUTCOME MEASUREMENTS: Thyroid hormones (TSH, T4, FT4I, T3, FT3I, and T3RU), thyroid autoantibodies (TPOab and Tgab), thyroid volume, activities of daily living according to the Katz Index of ADL. RESULTS: In all, 207 (75%) of the 276 eligible subjects participated, and 148 agreed to blood tests. Among the participants, 2.9% had previously known hyperthyroidism, and the same proportion had previously known hypothyroidism. The blood tests did not reveal any undiagnosed cases of overt thyroid dysfunction. However 7.2% had a subnormal serum TSH, and 2.9% had an elevated serum TSH; all had normal serum T3 and serum T4 levels. Thyroid autoantibodies were detected in 26 (17.6%) centenarians (11.5% had Tgab and 9.5% had TPOab). Among relatively independent centenarians, low serum T3 was significantly associated with high comorbidity (P = .029), whereas both low serum T3 and thyroid autoantibodies were significantly associated with ADL-dependency (P < .001 and P = .030, respectively). Ultrasonography (n = 50) revealed a small gland with a median volume of 8.3 mL (range 3.2-27.9) compared with an expected volume of 20 mL (14-26) (P < .001). There was no significant relationship to body weight. When examined by ultrasound, only 26% had significant morphological alterations. CONCLUSIONS: Thyroid dysfunction does not seem to be more prevalent among centenarians than among younger old people. Low serum T3 is related to poor physical function and co-morbidity, whereas thyroid autoimmunity is related only to poor physical functioning. Despite atrophy of the thyroid gland, these findings suggest that thyroid function is well preserved in centenarians.

Longevity is independent of common variations in genes associated with cardiovascular risk.

Do extremely old persons have a genetically favourable profile which has protected them from cardiovascular death? We have tried to answer this question by measuring DNA polymorphisms of selected cardiovascular risk indicators [factor VII, FVII (R/Q353, intron 7 (37bp)n, and -323ins10), beta fibrinogen (-455G/A), plasminogen activator inhibitor type 1, PAI-1 (-675(4G/5G)), tissue plasminogen activator, t-PA (intron 8 ins311), platelet receptor glycoprotein IIb/IIIa, GPIIb/IIIa (L/P33), prothrombin (20210G/A), methylene tetrahydrofolate reductase, MTHFR (A/V114), angiotensin converting enzyme, ACE (intron 16 ins287), and angiotensinogen (M/T235)]. Blood was collected from 187 unselected Danish centenarians, and 201 healthy Danish blood donors, aged 20-64 years (mean age 42 years). Genomic DNA was amplified using PCR and the genotype was determined by RFLP methods or allele-specific amplification followed by agarose gel electrophoresis. The frequencies of the high-risk alleles in centenarians were: for FVII R/Q353 0.91; for FVII intron 7 (37bp)n 0.67; for FVII-323 ins10 0.90; for fibrinogen 0.16; for PAI-1 0.52; for t-PA 0.59; for GPIIb/IIIa 0.16; for prothrombin 0.008; for MTHFR 0.33; for ACE 0.52; and for angiotensinogen 0.36. Comparable frequencies were observed in the blood donors. Subgroup analysis of men and women separately gave similar results. The genotype frequencies in the centenarians and the blood donors were similar for all polymorphisms, and this study suggests that common variations in genes associated with cardiovascular risk do not contribute significantly to longevity.

A high plasma concentration of TNF-alpha is associated with dementia in centenarians.

BACKGROUND: Inflammatory mechanisms and immune activation have been hypothesized to play a role in the pathogenesis of age-associated diseases such as dementia and atherosclerosis. The purpose of this study was to evaluate the plasma concentration of tumor necrosis factor (TNF)-alpha in a large cohort of centenarians and to look for its possible associations with cognitive function, atherosclerosis, and general health status. Furthermore, we investigated whether the concentration of TNF-alpha was correlated with the blood concentration of leucocyte subsets or the plasma concentrations of interleukin (IL)-6, soluble TNF receptor 11 (sTNFR-H) (75 kDa) and C-reactive protein (CRP). METHODS: Plasma TNF-alpha was measured by ELISA in 126 centenarians, 45 subjects aged 81 years, 23 subjects aged 55-65 years, and 38 subjects aged 18-30 years. Atherosclerosis was evaluated by the ankle-brachial blood pressure index, and general health status was evaluated by the body mass index and the number of diagnoses present. RESULTS: The concentration of TNF-alpha was significantly increased in 126 centenarians compared to younger control groups, and a high concentration of TNF-alpha was associated with both Alzheimer's disease and generalized atherosclerosis in the centenarians. The concentration of TNF-alpha was positively correlated with the concentrations of plasma IL-6, sTNFR-II, and CRP. No associations were found with increased leucocyte subsets or the body mass index. CONCLUSION: This study demonstrates that, even in apparently healthy subjects, age-associated immune activation indicated by raised levels of pro-inflammatory cytokines may reflect age-associated pathological processes that develop over decades.

Declining physical abilities with age: a cross-sectional study of older twins and centenarians in Denmark.

OBJECTIVE: To evaluate whether physical disability reaches a plateau in the oldest age groups. DESIGN: Cross-sectional survey. PARTICIPANTS: A total of 3351 individuals, which included all those living in Denmark who celebrated their 100th anniversary during the period from 1 April 1995 to 31 May 1996 (276 subjects) and all Danish twins aged 75-94 registered in the Danish Twin Register (3075 subjects). MAIN OUTCOME MEASURES: The ability to perform selected items of basic activities of daily living independently. RESULTS: The prevalence of independence in each of six selected activities of daily living was significantly lower in both men and women centenarians compared with octo- and septuagenarians. The sex difference in independence in all six selected activities of daily living was larger for each advancing age group, with women being most disabled (P < 0.001). In centenarians 20% of women and 44% of men were able to perform all selected activities of daily living independently. CONCLUSION: Compared with individuals aged 75-79 years, physical abilities of men and women gradually diminished in age groups 80-84, 85-90 and 90-94, with the lowest levels among 100-year-olds. Although women have lower mortality, they are more disabled than men, and this difference is more marked with advancing age.

Genotypes for the cytochrome P450 enzymes CYP2D6 and CYP2C19 in human longevitY. Role of CYP2D6 and CYP2C19 in longevity.

OBJECTIVE: To test whether some genotypes for CYP2D6 or CYP2C19 could contribute to longevity, we genotyped 241 Danish nonagenarians and centenarians for CYP2D6 and CYP2C19. METHODS: For CYP2D6 we identified the alleles CYP2D6*1, CYP2D6*3 and CYP2D6*4 with allele-specific polymerase chain reaction (PCR). The CYP2D6*5 alleles were identified with a long PCR method. For CYP2C19 we identified the alleles CYP2C19*1, CYP2C19*2 and CYP2C19*3 with an oligonucleotide ligation assay. RESULTS: The four alleles for CYP2D6 did not occur in Hardy-Weinberg proportions. The frequency of poor metabolism was slightly higher (10.2%) than expected [7.7%; odds ratio (OR) = 1.36 (0.75-2.40)]. The genotypes for CYP2C19 occur in Hardy-Weinberg proportions. The frequency of poor metabolism (3.8%) was not significantly different from a young control group [3.1%; OR = 1.21 (0.26-5.75)]. CONCLUSION: CYP2D6 could play a role in human longevity due to the lack of Hardy-Weinberg proportions. If CYP2D6 only plays a role in longevity by protecting the poor metabolizers from cancer, we should expect a rise in the frequency in these genotypes in Denmark from 7.7% among young adults to 10-11% among very old people. We found a frequency of poor metabolism of 10.2% in the very old group. CYP2C19 is - due to the occurrence of Hardy-Weinberg proportions and the expected number of poor metabolizers unlikely to contribute to human longevity.