Search

Abstract 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.

Biomarkers of ageing (BA) can predict health risks beyond chronological age, but little is known about how marital/living status affects longitudinal changes in BA. We examined the association between marital/living status and BA over time using the-Swedish-Adoption/Twin-Study-of-Aging (SATSA) cohort. Four BAs were analyzed: telomere length (TL) (638 individuals; 1603 measurements), DNAmAge (535 individuals; 1392 measurements), cognition (823 individuals; 3218 measurements), and frailty index (FI) (1828 individuals; 9502 measurements). Individuals were born between 1900 and 1948, and data on marital/living status, BAs, and covariates were collected through nine waves of questionnaires and in-person testing from 1986 to 2014. Mixed linear regression with random effects at twin-pair and individual levels were used to assess BA changes for constant marital/living status. Conditional generalized estimating equation assessed within-individual BA changes for varying marital/living status. Results showed that individuals who were consistently unmarried/non-cohabiting (β = 0.291, 95%CI = 0.189-0.393) or living alone (β = 0.203, 95%CI = 0.090-0.316) were more frail, and experienced accelerated frailty (p-for-interaction with age < 0.001 for marital status; p-for-interaction = 0.002 for living status) and cognitive decline (p-for-interaction < 0.001), compared to those married/cohabiting or living with someone Among individuals whose marital/living status changed, frailty was higher when living alone (β = 0.089, 95%CI = 0.017-0.162) and frailty accelerated when they became unmarried/non-cohabiting or were living alone (p-for-interaction < 0.001). Cognitive decline also accelerated when living alone (p-for-interaction = 0.020). No associations were observed for TL and DNAmAge. In conclusion, being unmarried/non-cohabiting or living alone from mid-to-old age is linked to accelerated cognitive decline and frailty. These findings highlight the potential importance of social support networks and living arrangements for healthy ageing., Competing Interests: Declarations. Conflict of interest: We declare no competing interests and confirm the independence of researchers from funders. Ethical approval: All participants provided informed consent. This study has received ethical approval from the Regional Ethics Review Vetting Board, Stockholm (Dnr 2015/1729-31/5)., (© 2025. The Author(s).)

Aims: About 10%-30% of individuals with obesity are metabolically healthy, but the specific characteristics of the metabolically healthy obesity (MHO) phenotype remain unclear. We aimed to examine how physical activity, education, depressive symptoms and genetic predisposition to obesity differ between individuals with MHO and those with metabolically unhealthy obesity (MUO), and whether these factors predict stability in MHO or conversion to a metabolically unhealthy state., Materials and Methods: We retrieved data on 9809 individuals with obesity from the Health and Retirement Study collected between 2006 and 2016. We compared how physical activity, education, depressive symptoms and a polygenic score for higher body mass index (BMI) (PGS BMI ) differed cross-sectionally between MHO and MUO using logistic regression. We then examined if the same factors predict conversion to a metabolically unhealthy state over 4 years in individuals with MHO., Results: Individuals with MHO had higher physical activity (odds ratio [OR] = 0.81), higher education (OR = 0.83) and lower depressive symptoms (OR = 1.14) compared to those with MUO but did not differ in the PGS BMI . The associations were slightly attenuated in mutually adjusted models. None of the factors were associated with conversion from MHO to a metabolically unhealthy state. However, a higher PGS BMI indicated 24% lower risk of conversion to a metabolically unhealthy state (p = 0.07)., Conclusions: Physical activity, education and depressive symptoms differed between MHO and MUO, even when mutually adjusted for, but did not predict conversion from a metabolically healthy to unhealthy state. Although not statistically significant, the results indicated that those with genetically predicted high BMI are more likely to maintain MHO and not convert to a metabolically unhealthy state., (© 2024 The Author(s). Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Introduction: Celiac disease (CeD) is increasingly diagnosed in older adults, though few studies have explored complications in this group. As frailty confers increased risk for adverse events, we aimed to explore frailty in older adults with CeD., Methods: In a nationwide Swedish cohort, we identified adults ≥60 years with incident CeD between 2004 and 2017 which we matched to population-based controls without CeD by age, sex, county, and calendar-period. Baseline frailty within 3 years before CeD diagnosis or index date was assessed using the Hospital Frailty Risk Score. Among those without baseline frailty, we used conditional logistic regression to estimate odds ratios and 95% confidence intervals of future frailty at 5 years comparing CeD with controls. Logistic regression was used to evaluate the association between persistent villous atrophy vs mucosal healing and frailty in patients with CeD., Results: A total of 4,646 older adults with CeD were matched to 21,944 non-CeD individuals. Baseline frailty was increased in patients with CeD (54.4%) compared with controls (29.7%, P < 0.001), which existed across all frailty categories: low-risk (43.4% vs 23.8%), intermediate-risk (10.3% vs 5.4%), and high-risk (0.8% vs 0.6%). Among those without baseline frailty, patients with CeD had a 61% increased risk of overall frailty at 5 years (95% confidence interval 1.46-1.78). Mucosal healing in CeD individuals on follow-up biopsy did not protect against future frailty., Discussion: Older adults with CeD were significantly more likely to become frail than matched comparators. This analysis reveals the increased vulnerability that older patients with CeD are likely to experience., (Copyright © 2024 by The American College of Gastroenterology.)

Background: Although age is an important risk factor for both cancer and frailty, it is unclear whether cancer itself increases the risk of frailty. We aimed to assess the association between cancer and frailty in a longitudinal cohort of older Danish twins, taking familial effect into account., Methods: Using the Danish Cancer Registry, cancer cases were identified among participants aged 70 and over in the Longitudinal Study of Aging Danish Twins (LSADT). Frailty was evaluated over 10 years of follow-up using the frailty index (FI) and defined as FI > 0.21. Stratified Cox regressions were performed on discordant twin pairs (pairs where one twin had incident cancer and the other was cancer-free) and on all LSADT individual twins (twin pairs and singletons) with no history of cancer., Results: Among the 72 discordant pairs (n = 144, median age at inclusion = 75) included in the study, the median FI at inclusion was 0.08 for both cancer twins and cancer-free co-twins. From the stratified Cox regression, twins with cancer had an increased hazard of developing frailty (hazard ratio [HR] = 3.67, 95% confidence interval [CI] = 1.02-13.14) compared with their cancer-free co-twins. The analyses on individual twins (n = 4 027) provided similar results, showing an increased hazard of frailty in individuals with cancer (HR = 2.57, 95% CI = 1.77-3.74) compared with those without cancer., Conclusions: We showed a higher risk of becoming frail following a cancer diagnosis in both discordant twin pairs and individual twins. These findings support the importance of monitoring frailty in older adults with cancer through geriatric assessments and the implementation of frailty interventions., (© The Author(s) 2024. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: DNA methylation-derived epigenetic clocks and frailty are well-established biological age measures capturing different aging processes. However, whether they are dynamically linked to each other across chronological age remains poorly understood., Methods: This analysis included 1 309 repeated measurements in 524 individuals aged 50-90 years from the Swedish Adoption/Twin Study of Aging. Frailty was measured using a validated 42-item frailty index (FI). Five epigenetic clocks were calculated, including 4 principal component (PC)-based clocks trained on chronological age (PCHorvathAge and PCHannumAge) and aging-related physiological conditions (PCPhenoAge and PCGrimAge), and a pace of aging clock (DunedinPACE). Using dual change score models, we examined the dynamic, bidirectional associations between each of the epigenetic clocks and the FI over age to test for potential causal associations., Results: The FI exhibited a nonlinear, accelerated increase across the older adulthood, whereas the epigenetic clocks mostly increased linearly with age. For PCHorvathAge, PCHannumAge, PCPhenoAge, and PCGrimAge, their associations with the FI were primarily due to correlated levels at age 50 but with no evidence of a dynamic longitudinal association. In contrast, we observed a unidirectional association between DunedinPACE and the FI, where a higher DunedinPACE predicted a subsequent increase in the FI, but not vice versa., Conclusions: Our results highlight a temporal order between epigenetic aging and frailty such that changes in DunedinPACE precede changes in the FI. This potentially suggests that the pace of aging clock can be used as an early marker of the overall physiological decline at system level., (© The Author(s) 2023. Published by Oxford University Press on behalf of The Gerontological Society of America.)

Background: Around the world, individuals are living longer, but an increased average lifespan does not always equate to an increased healthspan. With advancing age, the increased prevalence of ageing-related diseases can have a significant impact on health status, functional capacity, and quality of life. It is therefore vital to develop comprehensive classification and staging systems for ageing-related pathologies, diseases and syndromes. This will allow societies to better identify, quantify, understand, and meet the healthcare, workforce, wellbeing, and socioeconomic needs of ageing populations, while supporting the development and utilisation of interventions to prevent or to slow, halt or reverse the progression of ageing-related pathologies., Methods: The foundation for developing such classification and staging systems is to define the scope of what constitutes an ageing-related pathology, disease or syndrome. To this end, a consensus meeting was hosted by the International Consortium to Classify Ageing-Related Pathologies (ICCARP), on February 19 th , 2024, in Cardiff, UK, and was attended by 150 recognised experts. Discussions and voting were centred on provisional criteria that had been distributed prior to the meeting. The participants debated and voted on these. Each criterion required a consensus agreement of ≥70% for approval., Results: The accepted criteria for an ageing-related pathology, disease or syndrome were: Develops and/or progresses with increasing chronological age.Should be associated with, or contribute to, functional decline, or an increased susceptibility to functional decline.Evidenced by studies in humans., Conclusions: Criteria for an ageing-related pathology, disease or syndrome have been agreed by an international consortium of subject experts. These criteria will now be used by the ICCARP for the classification and ultimately staging of ageing-related pathologies, diseases and syndromes.

Epigenetics plays an important role in the aging process, but it is unclear whether epigenetic factors also influence frailty, an age-related state of physiological decline. In this study, we performed a meta-analysis of epigenome-wide association studies in four samples drawn from the Swedish Adoption/Twin Study of Aging (SATSA) and the Longitudinal Study of Aging Danish Twins (LSADT) to explore the association between DNA methylation and frailty. Frailty was defined using the frailty index (FI), and DNA methylation levels were measured in whole blood using Illumina's Infinium HumanMethylation450K and MethylationEPIC arrays. In the meta-analysis consisting of a total of 829 participants, we identified 589 CpG sites that were statistically significantly associated with either the continuous or categorical FI (false discovery rate <0.05). Many of these CpGs have previously been associated with age and age-related diseases. The identified sites were also largely directionally consistent in a longitudinal analysis using mixed-effects models in SATSA, where the participants were followed up to a maximum of 20 years. Moreover, we identified three differentially methylated regions within the MGRN1, MIR596, and TAPBP genes that have been linked to neuronal aging, tumor growth, and immune functions. Furthermore, our meta-analysis results replicated 34 of the 77 previously reported frailty-associated CpGs at p < 0.05. In conclusion, our findings demonstrate robust associations between frailty and DNA methylation levels in 589 novel CpGs, previously unidentified for frailty, and strengthen the role of neuronal/brain pathways in frailty., (© 2024 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)

Antihypertensive, lipid-lowering, and blood glucose-lowering drugs have slowed down the aging process in animal models. In humans, studies are limited, have short follow-up times, and show mixed results. Therefore, this study aimed to estimate the effects of commonly used medications on functional aging, cognitive function, and frailty. We included information on individuals from three Swedish longitudinal population-based studies collected between 1986 and 2014. Our exposures were the 21 most used groups of medications among individuals aged 65 years and older in the Swedish population in 2022. Functional aging index (n = 1191), cognitive function (n = 1094), and frailty index (n = 1361) were the outcomes of interest. To estimate the medication effects, we used a self-controlled analysis, where each individual is his/her own control, thereby adjusting for all time-stable confounders. The analysis was additionally adjusted for time-varying confounders (chronological age, Charlson Comorbidity Index, smoking, body mass index, and the number of drugs). The participants were 65.5-82.8 years at the first in-person assessment. Adrenergics/inhalants (effect size = 0.089) and lipid-modifying agents/plain (effect size = 0.082) were associated with higher values of cognitive function (improvement), and selective calcium channel blockers with mainly vascular effects (effect size = -0.129) were associated with lower values of the functional aging index (improvement). No beneficial effects were found on the frailty index. Adrenergics/inhalants, lipid-modifying agents/plain, and selective calcium channel blockers with mainly vascular effects may benefit functional biomarkers of aging. More research is needed to investigate their clinical value in preventing adverse aging outcomes., (© 2024 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)

Introduction: There is evidence that older adults with cancer have a higher risk of functional decline than cancer-free older adults. However, few studies are longitudinal, and none are twin studies. Thus, we aimed to investigate the relationship between cancer and functional decline in older adult (aged 70+ years) twins., Materials and Methods: Cancer cases in the Longitudinal Study of Aging Danish Twins were identified through the Danish Cancer Registry. Functional status was assessed using hand grip strength (6 years follow-up), and self-reported questions on mobility (10 years follow-up), and cut-offs were defined to assess functional decline. Cox regression models were performed for all the individual twins. In addition, we extended the analysis to discordant twin pairs (twin pairs with one having cancer and the other being cancer-free), to control to a certain extent for (unmeasured) shared confounders (genetic and environmental factors)., Results: The analysis based on individual twins showed that individual twins with cancer are at increased hazard of worsening hand grip strength (hazard ratio (HR) 1.37, 95% confidence interval (CI) 1.04, 1.80) than cancer-free twins. Among the discordant twin pairs, twins with cancer had a higher hazard of worsening hand grip strength (HR 3.50, 95% CI 1.15, 10.63) than cancer-free cotwins. In contrast, there was no evidence of a difference between the hazard of experiencing mobility decline for twins with cancer compared with cancer-free twins, in both individual twins and discordant twin pairs analyses., Discussion: Cancer was associated with hand grip strength functional decline in old individual twins and discordant pairs. Our results strengthen the importance of comprehensive geriatric assessment in older adults with cancer, as well as the importance of routine assessment of functional status. Promoting physical activity through exercise training programmes could enable the prevention of functional decline in older adults with cancer., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Few studies have examined longitudinal changes in lifestyle-related factors and frailty., Methods: We examined the association between individual lifestyle factors (exercise, diet, sleep, alcohol, smoking and body composition), their sum at baseline, their change over the 17-year follow-up and the rate of change in frailty index values using linear mixed models in a cohort of 2,000 participants aged 57-69 years at baseline., Results: A higher number of healthy lifestyle-related factors at baseline was associated with lower levels of frailty but not with its rate of change from late midlife into old age. Participants who stopped exercising regularly (adjusted β × Time = 0.19, 95%CI = 0.10, 0.27) and who began experiencing sleeping difficulties (adjusted β × Time = 0.20, 95%CI = 0.10, 0.31) experienced more rapid increases in frailty from late midlife into old age. Conversely, those whose sleep improved (adjusted β × Time = -0.10, 95%CI = -0.23, -0.01) showed a slower increase in frailty from late midlife onwards. Participants letting go of lifestyle-related factors (decline by 3+ factors vs. no change) became more frail faster from late midlife into old age (adjusted β × Time = 0.16, 95% CI = 0.01, 0.30)., Conclusions: Lifestyle-related differences in frailty were already evident in late midlife and persisted into old age. Adopting one new healthy lifestyle-related factor had a small impact on a slightly less steeply increasing level of frailty. Maintaining regular exercise and sleeping habits may help prevent more rapid increases in frailty., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Geriatrics Society.)

Obesity and metabolic syndrome (MetS) share common pathophysiological characteristics with aging. To better understand their interplay, we examined how body mass index (BMI) and MetS jointly associate with physiological age, and if the associations changed from midlife to late-life. We used longitudinal data from 1,825 Swedish twins. Physiological age was measured as frailty index (FI) and functional aging index (FAI) and modeled independently in linear mixed-effects models adjusted for chronological age, sex, education, and smoking. We assessed curvilinear associations of BMI and chronological age with physiological age, and interactions between BMI, MetS, and chronological age. We found a significant three-way interaction between BMI, MetS, and chronological age on FI (p-interaction = 0·006), not FAI. Consequently, we stratified FI analyses by age: < 65, 65-85, and ≥ 85 years, and modeled FAI across ages. Except for FI at ages ≥ 85, BMI had U-shaped associations with FI and FAI, where BMI around 26-28 kg/m 2 was associated with the lowest physiological age. MetS was associated with higher FI and FAI, except for FI at ages < 65, and modified the BMI-FI association at ages 65-85 (p-interaction = 0·02), whereby the association between higher BMI levels and FI was stronger in individuals with MetS. Age modified the MetS-FI association in ages ≥ 85, such that it was stronger at higher ages (p-interaction = 0·01). Low BMI, high BMI, and metabolic syndrome were associated with higher physiological age, contributing to overall health status among older individuals and potentially accelerating aging., (© 2023. The Author(s).)

Introduction: Few studies have investigated the association between frailty and subsequent body composition., Methods: We performed separate linear mixed model analyses to study the associations between changes in the participant frailty status assessed by a frailty index (FI) and subsequent body mass index (BMI), lean mass index (LMI), fat mass index (FMI), and FMI to LMI ratio values assessed on three occasions over 17 years. The analyses were carried out among 996 participants spanning from age 57 to 84 years., Results: With advancing age, LMI and BMI decreased, whereas FMI and FMI to LMI ratio increased. Participants with "stable frailty," followed by those with "increasing frailty" experienced faster decreases in LMI and faster increases in FMI and FMI to LMI ratio values from midlife into old age relative to those in the group "stable not frail." Contrastingly, those in the highest third of absolute annual increase in FMI and FMI to LMI ratio became more frail faster from midlife into old age relative to those in the lowest third., Conclusions: We found evidence of an adverse health outcome of frailty where lean indices declined faster and fat indices and fat-to-lean ratios increased faster from midlife into old age. The changes resembled those that occurred with aging, but at a faster pace. The relationship between body composition and frailty is likely bidirectional, where high or increasing levels of fat are associated with the risk of becoming more frail earlier, but where a longer duration of frailty may increase the risk of faster age-related changes to body composition., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

Electronic medical records (EMRs) have many benefits in clinical research in gerontology, enabling data analysis, development of prognostic tools and disease risk prediction. EMRs also offer a range of advantages in clinical practice, such as comprehensive medical records, streamlined communication with healthcare providers, remote data access, and rapid retrieval of test results, ultimately leading to increased efficiency, enhanced patient safety, and improved quality of care in gerontology, which includes benefits like reduced medication use and better patient history taking and physical examination assessments. The use of artificial intelligence (AI) and machine learning (ML) approaches on EMRs can further improve disease diagnosis, symptom classification, and support clinical decision-making. However, there are also challenges related to data quality, data entry errors, as well as the ethics and safety of using AI in healthcare. This article discusses the future of EMRs in gerontology and the application of AI and ML in clinical research. Ethical and legal issues surrounding data sharing and the need for healthcare professionals to critically evaluate and integrate these technologies are also emphasized. The article concludes by discussing the challenges related to the use of EMRs in research as well as in their primary intended use, the daily clinical practice., Competing Interests: The authors report no conflicts of interest in this work., (© 2023 Bednorz et al.)

Background: C-reactive protein (CRP) is a sensitive biomarker of inflammation with moderate heritability. The role of rare functional genetic variants in relation to serum CRP is understudied. We aimed to examine gene mutation burden of protein-altering (PA) and loss-of-function (LOF) variants in association with serum CRP, and to further explore the clinical relevance., Methods: We included 161,430 unrelated participants of European ancestry from the UK Biobank. Of the rare (minor allele frequency <0.1%) and functional variants, 1,776,249 PA and 266,226 LOF variants were identified. Gene-based burden tests, linear regressions, and logistic regressions were performed to identify the candidate mutations at the gene and variant levels, to estimate the potential interaction effect between the identified PA mutation and obesity, and to evaluate the relative risk of 16 CRP-associated diseases., Results: At the gene level, PA mutation burdens of the CRP (β = -0.685, p = 2.87e-28) and G6PC genes (β = 0.203, p = 1.50e-06) were associated with reduced and increased serum CRP concentration, respectively. At the variant level, seven PA alleles in the CRP gene decreased serum CRP, of which the per-allele effects were approximately three to seven times greater than that of a common variant in the same locus. The effects of obesity and central obesity on serum CRP concentration were smaller among the PA mutation carriers in the CRP (p interaction  = 0.008) and G6PC gene (p interaction  = 0.034) compared to the corresponding non-carriers., Conclusion: PA mutation burdens in the CRP and G6PC genes are strongly associated with decreased serum CRP concentrations. As serum CRP and obesity are important predictors of cardiovascular risks in clinics, our observations suggest taking rare genetic factors into consideration might improve the delivery of precision medicine., (© 2023 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.)

Background: Anticoagulants (AC) were introduced in March 2020 as standard of care in nursing home (NH) residents affected with COVID-19 in the Stockholm region, Sweden. ACs are proven to reduce the risk of complications and mortality from COVID-19 among patients of other ages and settings, but there is limited scientific evidence underpinning this practice in the NH setting., Methods: This matched cohort study included 182 NH residents in the Stockholm Region diagnosed with COVID-19 in March-May 2020. The main exposure was any AC treatment. Exposed ( n  = 91), 49% prevalent (pre-COVID-19 diagnosis) AC and 51% incident AC were compared with unexposed controls ( n  = 91). The outcome was 28-days all-cause mortality after COVID-19 infection. The mortality odds ratios (OR) were assessed using logistic regression, adjusted for age, sex, multimorbidity, and mobility, also stratified by incident or prevalent AC-type, age group, and sex., Results: Of the 182 individuals diagnosed with COVID-19 (median age 88 years, 68% women), 39% died within 28 days after diagnosis. Use of either incident or prevalent AC was associated with a reduced, adjusted 28-day mortality (OR[95% CI]: 0.31[0.16-0.62]). In stratified analyses, the association was significant in both age groups: 70-89 (OR: 0.37 [0.15-0.89]) and 90-99 years of age (OR: 0.22 [0.07-0.65]. In sex-stratified analysis, the AC-lowering effect was significant in women only (OR: 0.28[0.11-0.67]). In the analyses stratified by AC type, the mortality-lowering effect was observed for both prevalent AC (OR: 0.35[0.12-0.99]) and incident AC (OR: 0.29[0.11-0.76])., Conclusions: Both prevalent and incident use of ACs in prophylactic dosing was associated with reduced 28-day mortality among older individuals with COVID-19 in a NH setting. The effect was seen across age-strata and in women. The findings present new insight in best practice for individuals diagnosed with COVID-19 in the NH setting., Competing Interests: The authors declare no conflict of interest., (© 2023 The Authors. Health Science Reports published by Wiley Periodicals LLC.)

Frailty is an age-related clinical condition characterised by an increased susceptibility to stressors and an elevated risk of adverse outcomes such as mortality. In the light of global population ageing, the prevalence of frailty is expected to soar in coming decades. This narrative review provides critical insights into recent developments and emerging practices in frailty research regarding identification, management, risk factors, and prevention. We searched journals in the top two quartiles of geriatrics and gerontology (from Clarivate Journal Citation Reports) for articles published between 01 January 2018 and 20 December 2022. Several recent developments were identified, including new biomarkers and biomarker panels for frailty screening and diagnosis, using artificial intelligence to identify frailty, and investigating the altered response to medications by older adults with frailty. Other areas with novel developments included exercise (including technology-based exercise), multidimensional interventions, person-centred and integrated care, assistive technologies, analysis of frailty transitions, risk-factors, clinical guidelines, COVID-19, and potential future treatments. This review identified a strong need for the implementation and evaluation of cost-effective, community-based interventions to manage and prevent frailty. Our findings highlight the need to better identify and support older adults with frailty and involve those with frailty in shared decision-making regarding their care., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Identifying metabolic biomarkers of frailty, an age-related state of physiological decline, is important for understanding its metabolic underpinnings and developing preventive strategies. Here, we systematically examined 168 nuclear magnetic resonance-based metabolomic biomarkers and 32 clinical biomarkers for their associations with frailty. In up to 90,573 UK Biobank participants, we identified 59 biomarkers robustly and independently associated with the frailty index (FI). Of these, 34 associations were replicated in the Swedish TwinGene study (n = 11,025) and the Finnish Health 2000 Survey (n = 6073). Using two-sample Mendelian randomization, we showed that the genetically predicted level of glycoprotein acetyls, an inflammatory marker, was statistically significantly associated with an increased FI (β per SD increase = 0.37%, 95% confidence interval: 0.12-0.61). Creatinine and several lipoprotein lipids were also associated with increased FI, yet their effects were mostly driven by kidney and cardiometabolic diseases, respectively. Our findings provide new insights into the causal effects of metabolites on frailty and highlight the role of chronic inflammation underlying frailty development., (© 2023 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)

Background: Despite a clear link between aging and cancer, there has been inconclusive evidence on how biological age (BA) may be associated with cancer incidence., Methods: We studied 308,156 UK Biobank participants with no history of cancer at enrolment. Using 18 age-associated clinical biomarkers, we computed three BA measures (Klemera-Doubal method [KDM], PhenoAge, homeostatic dysregulation [HD]) and assessed their associations with incidence of any cancer and five common cancers (breast, prostate, lung, colorectal, and melanoma) using Cox proportional-hazards models., Results: A total of 35,426 incident cancers were documented during a median follow-up of 10.9 years. Adjusting for common cancer risk factors, 1-standard deviation (SD) increment in the age-adjusted KDM (hazard ratio = 1.04, 95% confidence interval = 1.03-1.05), age-adjusted PhenoAge (1.09, 1.07-1.10), and HD (1.02, 1.01-1.03) was significantly associated with a higher risk of any cancer. All BA measures were also associated with increased risks of lung and colorectal cancers, but only PhenoAge was associated with breast cancer risk. Furthermore, we observed an inverse association between BA measures and prostate cancer, although it was attenuated after removing glycated hemoglobin and serum glucose from the BA algorithms., Conclusions: Advanced BA quantified by clinical biomarkers is associated with increased risks of any cancer, lung cancer, and colorectal cancer., (© 2023. The Author(s).)

Aging is a major risk factor for many chronic diseases. This study aimed to examine the effects of antihypertensive, lipid-lowering, and antidiabetic drugs on biological aging. We included 672 participants and 2746 repeated measurements from the Swedish Adoption/Twin Study of Aging. Self-reported medicine uses were categorized into antidiabetic, antihypertensive, and lipid-lowering drugs. A total of 12 biomarkers for biological aging (BA biomarkers) were included as outcomes. Conditional generalized estimating equations were applied conditioning on individuals to estimate the drug effect on BA biomarker level within the same person when using or not using the drug. Chronological age, body mass index, smoking status, number of multiple medication uses, blood pressure, blood glucose level, and apoB/apoA ratio were adjusted for as covariates in the model. Overall, using antihypertensive drugs was associated with a decrease in one DNA-methylation age (PCGrimAge: beta = - 0.39, 95%CI = - 0.67 to - 0.12). When looking into drug subcategories, calcium channel blockers (CCBs) were associated with a decrease in several DNA-methylation ages (PCHorvathAge beta = - 1.28, 95%CI = - 2.34 to - 0.21; PCSkin&bloodAge beta = - 1.34, 95%CI = - 2.61 to - 0.07; PCPhenoAge beta = - 1.74, 95%CI = - 2.58 to - 0.89; PCGrimAge beta = - 0.57, 95%CI = - 0.96 to - 0.17) and in functional biological ages (functional age index beta = - 2.18, 95%CI = - 3.65 to - 0.71; frailty index beta = - 1.31, 95%CI = - 2.43 to - 0.18). However, the results within other drug subcategories were inconsistent. Calcium channel blockers may decrease biological aging captured by the BA biomarkers measured at epigenetic and functional level. Future studies are warranted to confirm these effects and understand the underlying biological mechanisms., (© 2023. The Author(s).)

While chronological age is the single biggest risk factor for cancer, it is less clear whether frailty, an age-related state of physiological decline, may also predict cancer incidence. We assessed the associations of frailty index (FI) and frailty phenotype (FP) scores with the incidence of any cancer and five common cancers (breast, prostate, lung, colorectal, melanoma) in 453,144 UK Biobank (UKB) and 36,888 Screening Across the Lifespan Twin study (SALT) participants, who aged 38-73 years and had no cancer diagnosis at baseline. During a median follow-up of 10.9 and 10.7 years, 53,049 (11.7%) and 4,362 (11.8%) incident cancers were documented in UKB and SALT, respectively. Using multivariable-adjusted Cox models, we found a higher risk of any cancer in frail vs. non-frail UKB participants, when defined by both FI (hazard ratio [HR] = 1.22; 95% confidence interval [CI] = 1.17-1.28) and FP (HR = 1.16; 95% CI = 1.11-1.21). The FI in SALT similarly predicted risk of any cancer (HR = 1.31; 95% CI = 1.15-1.49). Moreover, frailty was predictive of lung cancer in UKB, although this association was not observed in SALT. Adding frailty scores to models including age, sex, and traditional cancer risk factors resulted in little improvement in C-statistics for most cancers. In a within-twin-pair analysis in SALT, the association between FI and any cancer was attenuated within monozygotic but not dizygotic twins, indicating that it may partly be explained by genetic factors. Our findings suggest that frailty scores are associated with the incidence of any cancer and lung cancer, although their clinical utility for predicting cancers may be limited., (© 2023. The Author(s).)

Aims: Although up to 25% of older adults are frail, assessing frailty can be difficult, especially in registry data. This study evaluated the utility of a code-based frailty score in registry data by comparing it to a gold-standard frailty score to understand how frailty can be quantified in population data and perhaps better addressed in healthcare., Methods: We compared the Hospital Frailty Risk Score (HFRS), a frailty measure based on 109 ICD codes, to a modified version of the Frailty Index (FI) Frailty Index (FI), a self-report frailty measure, and their associations with all-cause mortality both cross-sectionally and longitudinally (follow-up = 36 years) in a Swedish cohort study ( n = 1368)., Results: The FI and HFRS were weakly correlated (rho = 0.11, p  < 0.001). Twenty-two percent ( n = 297) of participants were considered frail based on published cut-offs of either measure. Only 3% ( n = 35) of participants were classified as frail by both measures; 4% ( n = 60) of participants were considered frail by only the HFRS; and 15% ( n = 202) of participants were considered frail based only on the FI. Frailty as measured by the HFRS showed greater variance and no clear increase or decrease with age, while frailty as measured by the FI increased steadily with age. In adjusted Cox proportional hazard models, baseline HFRS frailty (HR = 1.17, 95% CI 0.92, 1.49) was not statistically significantly associated with mortality, while FI frailty was (HR = 2.89, 95% CI 1.61, 2.23). These associations were modified by age and sex., Conclusions: The HFRS may not capture the full spectrum of frailty among community-dwelling individuals, particularly at younger ages, in Swedish registry data.

Background: Body mass index (BMI) may not be an optimal predictor of frailty as its constituents, lean and fat mass, may have opposite associations with frailty., Methods: A linear mixed model analysis was performed in the Helsinki Birth Cohort Study (n = 2 000) spanning from 57 to 84 years. A 39-item frailty index (FI) was calculated on three occasions over 17 years. Body composition in late midlife included BMI, percent body fat (%BF), waist-to-hip ratio (WHR), lean mass index (LMI), and fat mass index (FMI)., Results: Mean FI levels increased by 0.28%/year among men and by 0.34%/year among women. Among women, per each kg/m2 higher BMI and each unit higher %BF the increases in FI levels per year were 0.013 percentage points (PP) steeper (95% CI = 0.004, 0.023) and 0.009 PP steeper (95% CI = 0.002, 0.016) from late midlife into old age. Among men, per each 0.1-unit greater WHR the increase in FI levels was 0.074 PP steeper per year (95% CI = -0.0004, 0.148). Cross-sectionally, greater FMI and LMI in late midlife were associated with higher FI levels but the direction of the association regarding LMI changed after adjustment for FMI. The categories "high FMI and high LMI" and "high FMI and low LMI" showed the highest FI levels relative to the category "low FMI and low LMI"., Conclusions: In late midlife, greater adiposity (%BF) among women and abdominal obesity (WHR) among men may predispose to higher levels of frailty from late midlife into old age. Greater lean mass alone may be protective of frailty, but not in the presence of high fat mass., (© The Author(s) 2022. Published by Oxford University Press on behalf of The Gerontological Society of America.)

Background: Evidence indicates that the adverse health effects of obesity differ between genetically and environmentally influenced obesity. We examined differences in the association between obesity and cardiovascular disease (CVD) between individuals with a genetically predicted low, medium, or high body mass index (BMI)., Methods: We used cohort data from Swedish twins born before 1959 who had BMI measured between the ages of 40-64 years (midlife) or at the age of 65 years or later (late-life), or both, and prospective CVD information from nationwide register linkage through 2016. A polygenic score for BMI (PGS BMI ) was used to define genetically predicted BMI. Individuals missing BMI or covariate data, or diagnosed with CVD at first BMI measure, were excluded, leaving an analysis sample of 17,988 individuals. We applied Cox proportional hazard models to examine the association between BMI category and incident CVD, stratified by the PGS BMI . Co-twin control models were applied to adjust for genetic influences not captured by the PGS BMI ., Findings: Between 1984 and 2010, the 17,988 participants were enrolled in sub-studies of the Swedish Twin Registry. Midlife obesity was associated with a higher risk of CVD across all PGS BMI categories, but the association was stronger with genetically predicted lower BMI (hazard ratio from 1.55 to 2.08 for those with high and low PGS BMI , respectively). Within monozygotic twin pairs, the association did not differ by genetically predicted BMI, indicating genetic confounding not captured by the PGS BMI . Results were similar when obesity was measured in late-life, but suffered from low power., Interpretation: Obesity was associated with CVD regardless of PGS BMI category, but obesity influenced by genetic predisposition (genetically predicted high BMI) was less harmful than obesity influenced by environmental factors (obesity despite genetically predicted low BMI). However, additional genetic factors, not captured by the PGS BMI , still influence the associations., Funding: The Strategic Research Program in Epidemiology at Karolinska Institutet; Loo and Hans Osterman's Foundation; Foundation for Geriatric Diseases at Karolinska Institutet; the Swedish Research Council for Health, Working Life and Welfare; the Swedish Research Council; and the National Institutes of Health., Competing Interests: JJ reports grant funding paid to their institution from the 10.13039/501100004359Swedish Research Council (grant 2018-02077), 10.13039/501100002341Academy of Finland (grant 349335), 10.13039/501100006306Sigrid Jusélius Foundation, 10.13039/100010114Yrjö Jahnsson Foundation, and 10.13039/501100008413Instrumentarium Science Foundation. CAR reports honorarium from the National Institute on Aging and grant funding from the 10.13039/100000002National Institutes of Health (grants NIH 1R01 DA054087, NIH 2R01 AG046938, NIH 2R01 AG050595, NIH 1R01 AG059329, NIH 1RF1 AG058068, NIH 1R01 AG077742, and NIH 1R01 AG053217). IKK reports payments to their institution from the Karolinska Institutet Research Foundation (grant 2022-01718) and Eurolife (mobility grant). IKK also reports payment via a Promising Researcher Award from The Nordic Gerontological Federation. All other authors declare no competing interests., (© 2023 The Author(s).)

Objective: To analyse if the health progression of geriatric Covid-19 survivors three months after an acute Covid-19 infection was worse than in other geriatric patients. Specifically, we wanted to see if we could see distinct health profiles in the flow of re-admitted Covid-19 patients compared to re-admitted non-Covid-19 controls., Design: Matched cohort study., Setting and Participants: Electronic medical records of geriatric patients hospitalised in geriatric clinics in Stockholm, Sweden, between March 2020 and January 2022. Patients readmitted three months after initial admission were selected for the analysis and Covid-19 survivors (n = 895) were compared to age-sex-Charlson comorbidity index (CCI)-matched non-Covid-19 controls (n = 2685)., Methods: We assessed using binary logistic and Cox regression if a previous Covid-19 infection could be a risk factor for worse health progression indicated by the CCI, hospital frailty risk score (HFRS), mortality and specific comorbidities., Results: The patients were mostly older than 75 years and, already at baseline, had typically multiple comorbidities. The Covid-19 patients with readmission had mostly had their acute-phase infection in the 1st or 2nd pandemic waves before the vaccinations. The Covid-19 patients did not have worse health after three months compared to the matched controls according to the CCI (odds ratio, OR[95% confidence interval, CI] = 1.12[0.94-1.34]), HFRS (OR[95%CI] = 1.05[0.87-1.26]), 6-months (hazard ratio, HR[95%CI] = 1.04[0.70-1.52]) and 1-year-mortality risk (HR[95%CI] = 0.89[0.71-1.10]), adjusted for age, sex and health at baseline (the CCI and HFRS)., Conclusions and Implications: The overall health progression of re-hospitalized geriatric Covid-19 survivors did not differ dramatically from other re-hospitalized geriatric patients with similar age, sex and health at baseline. Our results emphasize that Covid-19 was especially detrimental for geriatric patients in the acute-phase, but not in the later phase. Further studies including post-vaccination samples are needed., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Kananen et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Frailty is a complex, dynamic geriatric condition, but limited evidence has shown how genes and environment may contribute to its longitudinal changes. We sought to investigate sources of individual differences in the longitudinal trajectories of frailty, considering potential selection bias when including a sample of oldest-old twins., Methods: Data were from 2 Swedish twin cohort studies: a younger cohort comprising 1 842 adults aged 29-96 years followed up to 15 waves, and an older cohort comprising 654 adults aged ≥79 years followed up to 5 waves. Frailty was measured using the frailty index (FI). Age-based latent growth curve models were used to examine longitudinal trajectories, and extended to a biometric analysis to decompose variability into genetic and environmental etiologies., Results: A bilinear model with an inflection point at age 75 best described the data, indicating a fourfold to fivefold faster FI increase after 75 years. Twins from the older cohort had significantly higher mean FI at baseline but slower rate of increase afterward. FI level at age 75 was moderately heritable in both men (42%) and women (55%). Genetic influences were relatively stable across age for men and increasing for women, although the most salient amplification in FI variability after age 75 was due to individual-specific environmental influences for both men and women; conclusions were largely consistent when excluding the older cohort., Conclusion: Increased heterogeneity of frailty in late life is mainly attributable to environmental influences, highlighting the importance of targeting environmental risk factors to mitigate frailty in older adults., (© The Author(s) 2022. Published by Oxford University Press on behalf of The Gerontological Society of America.)

Circulating cell-free DNA (cf-DNA) has emerged as a promising biomarker of ageing, tissue damage and cellular stress. However, less is known about health behaviours, ageing phenotypes and metabolic processes that lead to elevated cf-DNA levels. We sought to analyse the relationship of circulating cf-DNA level to age, sex, smoking, physical activity, vegetable consumption, ageing phenotypes (physical functioning, the number of diseases, frailty) and an extensive panel of biomarkers including blood and urine metabolites and inflammatory markers in three human cohorts (N = 5385; 17-82 years). The relationships were assessed using correlation statistics, and linear and penalised regressions (the Lasso), also stratified by sex.cf-DNA levels were significantly higher in men than in women, and especially in middle-aged men and women who smoke, and in older more frail individuals. Correlation statistics of biomarker data showed that cf-DNA level was higher with elevated inflammation (C-reactive protein, interleukin-6), and higher levels of homocysteine, and proportion of red blood cells and lower levels of ascorbic acid. Inflammation (C-reactive protein, glycoprotein acetylation), amino acids (isoleucine, leucine, tyrosine), and ketogenesis (3-hydroxybutyrate) were included in the cf-DNA level-related biomarker profiles in at least two of the cohorts.In conclusion, circulating cf-DNA level is different by sex, and related to health behaviour, health decline and metabolic processes common in health and disease. These results can inform future studies where epidemiological and biological pathways of cf-DNA are to be analysed in details, and for studies evaluating cf-DNA as a potential clinical marker., (© 2022. The Author(s).)

Introduction: Although frailty is commonly considered as a syndrome of old individuals, recent studies show that it can affect younger adults, too. Whether and how frailty differs in younger adults compared to old is however unknown. To this end, we analyzed the prevalence, characteristics, and risk factors of early-life (aged &lt;65) and late-life (aged ≥65) frailty., Methods: We analyzed individuals in the UK Biobank (N = 405,123) and Swedish Screening Across the Lifespan Twin (SALT; N = 43,641) study. Frailty index (FI) scores ≥0.21 were used to demarcate frailty. Characteristics of early-life versus late-life frailty were analyzed by collating the FI items (deficits) into domains and comparing the domain scores between younger and older frail individuals. Logistic regression was used to assess the risk factors of frailty., Results: The pooled prevalence rates of frailty were 10.3% (95% confidence interval [CI]: 2.7-32.7), 14.4% (95% CI: 4.5-37.2), 19.2% (95% CI: 2.5-68.5) in individuals aged ≤55, 55-64, 65-74, respectively. Younger frail adults (aged &lt;65) had higher scores in immunological, mental wellbeing, and pain-related domains, whereas older frail adults (aged ≥65) had higher scores in cardiometabolic, cancer, musculoskeletal, and sensory-related domains. Higher age, female sex, smoking, lower alcohol consumption, lower education, obesity, overweight, low income, and maternal smoking were similarly associated with the risk of early-life and late-life frailty., Conclusion: Frailty is prevalent also in younger age groups (aged &lt;65) but differs in some of its characteristics from the old. The risk factors of frailty are nevertheless largely similar for early-life and late-life frailty., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

Introduction: Frailty, a measure of biological aging, has been linked to worse COVID-19 outcomes. However, as the mortality differs across the COVID-19 waves, it is less clear whether a medical record-based electronic frailty index (eFI) that we have previously developed for older adults could be used for risk stratification in hospitalized COVID-19 patients., Objectives: The aim of the study was to examine the association of frailty with mortality, readmission, and length of stay in older COVID-19 patients and to compare the predictive accuracy of the eFI to other frailty and comorbidity measures., Methods: This was a retrospective cohort study using electronic health records (EHRs) from nine geriatric clinics in Stockholm, Sweden, comprising 3,980 COVID-19 patients (mean age 81.6 years) admitted between March 2020 and March 2022. Frailty was assessed using a 48-item eFI developed for Swedish geriatric patients, the Clinical Frailty Scale, and the Hospital Frailty Risk Score. Comorbidity was measured using the Charlson Comorbidity Index. We analyzed in-hospital mortality and 30-day readmission using logistic regression, 30-day and 6-month mortality using Cox regression, and the length of stay using linear regression. Predictive accuracy of the logistic regression and Cox models was evaluated by area under the receiver operating characteristic curve (AUC) and Harrell's C-statistic, respectively., Results: Across the study period, the in-hospital mortality rate decreased from 13.9% in the first wave to 3.6% in the latest (Omicron) wave. Controlling for age and sex, a 10% increment in the eFI was significantly associated with higher risks of in-hospital mortality (odds ratio = 2.95; 95% confidence interval = 2.42-3.62), 30-day mortality (hazard ratio [HR] = 2.39; 2.08-2.74), 6-month mortality (HR = 2.29; 2.04-2.56), and a longer length of stay (β-coefficient = 2.00; 1.65-2.34) but not with 30-day readmission. The association between the eFI and in-hospital mortality remained robust across the waves, even after the vaccination rollout. Among all measures, the eFI had the best discrimination for in-hospital (AUC = 0.780), 30-day (Harrell's C = 0.733), and 6-month mortality (Harrell's C = 0.719)., Conclusion: An eFI based on routinely collected EHRs can be applied in identifying high-risk older COVID-19 patients during the continuing pandemic., (© 2022 The Author(s). Published by S. Karger AG, Basel.)

Background & Aims: Overweight and obesity have been consistently reported to carry an increased risk for poorer outcomes in coronavirus disease 2019 (COVID-19) in adults. Existing reports mainly focus on in-hospital and intensive care unit mortality in patient cohorts usually not representative of the population with the highest mortality, i.e. the very old and frail patients. Accordingly, little is known about the risk patterns related to body mass and nutrition in very old patients. Our aim was to assess the relationship between body mass index (BMI), nutritional status and in-geriatric hospital mortality among geriatric patients treated for COVID-19. As a reference, the analyses were performed also in patients treated for other diagnoses than COVID-19., Methods: We analyzed up to 10,031 geriatric patients with a median age of 83 years of which 1409 (14%) were hospitalized for COVID-19 and 8622 (86%) for other diagnoses in seven geriatric hospitals in the Stockholm region, Sweden during March 2020-January 2021. Data were available in electronic hospital records. The associations between 1) BMI and 2) nutritional status, assessed using the Mini-Nutritional Assessment - Short Form (MNA-SF) scale, and short-term in-geriatric hospital mortality were analyzed using logistic regression., Results: After adjusting for age, sex, comorbidity, polypharmacy, frailty and the wave of the pandemic (first vs. second), underweight defined as BMI<18.5 increased the risk of in-hospital mortality in COVID-19 patients (odds ratio [OR] = 2.30; confidence interval [CI] = 1.17-4.31). Overweight and obesity were not associated with in-hospital mortality. Malnutrition; i.e. MNA-SF 0-7 points, increased the risk of in-hospital mortality in patients treated for COVID-19 (OR = 2.03; CI = 1.16-3.68) and other causes (OR = 6.01; CI = 2.73-15.91)., Conclusions: Our results indicate that obesity is not a risk factor for very old patients with COVID-19, but emphasize the role of underweight and malnutrition for in-hospital mortality in geriatric patients with COVID-19., Competing Interests: Conflict of interest The authors declare no conflicts of interest., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

While midlife adiposity is a risk factor for dementia, adiposity in late-life appears to be associated with lower risk. What drives the associations is poorly understood, especially the inverse association in late-life. Using results from genome-wide association studies, we identified inflammation and lipid metabolism as biological pathways involved in both adiposity and dementia. To test if these factors mediate the effect of midlife and/or late-life adiposity on dementia, we then used cohort data from the Swedish Twin Registry, with measures of adiposity and potential mediators taken in midlife (age 40-64, n = 5999) or late-life (age 65-90, n = 7257). Associations between body-mass index (BMI), waist-hip ratio (WHR), C-reactive protein (CRP), lipid levels, and dementia were tested in survival and mediation analyses. Age was used as the underlying time scale, and sex and education included as covariates in all models. Fasting status was included as a covariate in models of lipids. One standard deviation (SD) higher WHR in midlife was associated with 25% (95% CI 2-52%) higher dementia risk, with slight attenuation when adjusting for BMI. No evidence of mediation through CRP or lipid levels was present. After age 65, one SD higher BMI, but not WHR, was associated with 8% (95% CI 1-14%) lower dementia risk. The association was partly mediated by higher CRP, and suppressed when high-density lipoprotein levels were low. In conclusion, the negative effects of midlife adiposity on dementia risk were driven directly by factors associated with body fat distribution, with no evidence of mediation through inflammation or lipid levels. There was an inverse association between late-life adiposity and dementia risk, especially where the body's inflammatory response and lipid homeostasis is intact., (© 2022. The Author(s).)

Background: Frailty assessment in the Swedish health system relies on the Clinical Frailty Scale (CFS), but it requires training, in-person evaluation, and is often missing in medical records. We aimed to develop an electronic frailty index (eFI) from routinely collected electronic health records (EHRs) and assess its association with adverse outcomes in hospitalized older adults., Methods: EHRs were extracted for 18 225 patients with unplanned admissions between 1 March 2020 and 17 June 2021 from 9 geriatric clinics in Stockholm, Sweden. A 48-item eFI was constructed using diagnostic codes, functioning and other health indicators, and laboratory data. The CFS, Hospital Frailty Risk Score, and Charlson Comorbidity Index were used for comparative assessment of the eFI. We modeled in-hospital mortality and 30-day readmission using logistic regression; 30-day and 6-month mortality using Cox regression; and length of stay using linear regression., Results: Thirteen thousand one hundred and eighty-eight patients were included in analyses (mean age 83.1 years). A 0.03 increment in the eFI was associated with higher risks of in-hospital (odds ratio: 1.65; 95% confidence interval: 1.54-1.78), 30-day (hazard ratio [HR]: 1.43; 1.38-1.48), and 6-month mortality (HR: 1.34; 1.31-1.37) adjusted for age and sex. Of the frailty and comorbidity measures, the eFI had the highest area under receiver operating characteristic curve for in-hospital mortality of 0.813. Higher eFI was associated with longer length of stay, but had a rather poor discrimination for 30-day readmission., Conclusions: An EHR-based eFI has robust associations with adverse outcomes, suggesting that it can be used in risk stratification in hospitalized older adults., (© The Author(s) 2022. Published by Oxford University Press on behalf of The Gerontological Society of America.)

Background: Early-life exposures have been associated with the risk of frailty in old age. We investigated whether early-life exposures predict the level and rate of change in a frailty index (FI) from midlife into old age., Methods: A linear mixed model analysis was performed using data from 3 measurement occasions over 17 years in participants from the Helsinki Birth Cohort Study (n = 2 000) aged 57-84 years. A 41-item FI was calculated on each occasion. Information on birth size, maternal body mass index (BMI), growth in infancy and childhood, childhood socioeconomic status (SES), and early-life stress (wartime separation from both parents) was obtained from registers and health care records., Results: At age 57 years the mean FI level was 0.186 and the FI levels increased by 0.34%/year from midlife into old age. Larger body size at birth associated with a slower increase in FI levels from midlife into old age. Per 1 kg greater birth weight the increase in FI levels per year was -0.087 percentage points slower (95% confidence interval = -0.163, -0.011; p = 0.026). Higher maternal BMI was associated with a higher offspring FI level in midlife and a slower increase in FI levels into old age. Larger size, faster growth from infancy to childhood, and low SES in childhood were all associated with a lower FI level in midlife but not with its rate of change., Conclusions: Early-life factors seem to contribute to disparities in frailty from midlife into old age. Early-life factors may identify groups that could benefit from frailty prevention, optimally initiated early in life., (© The Author(s) 2022. Published by Oxford University Press on behalf of The Gerontological Society of America.)

Background and Aims: We aimed to compare the risk of frailty in older adults with incident inflammatory bowel disease (IBD) and matched non-IBD comparators and assess the association between frailty and future hospitalizations and mortality., Methods: In a cohort of patients with incident IBD ≥60 years of age from 2007 to 2016 in Sweden identified using nationwide registers, we defined frailty using Hospital Frailty Risk Score. We compared prevalence of frailty in patients with IBD with age, sex, place of residency- and calendar year-matched population comparators. In the IBD cohort, we used Cox proportional hazards modeling to examine the associations between frailty risk and hospitalizations or mortality., Results: We identified 10,590 patients with IBD, 52% female with a mean age of 71 years of age, matched to 103,398 population-based comparators. Among patients with IBD, 39% had no risk for frailty, 49% had low risk for frailty, and 12% had higher risk for frailty. Mean Hospital Frailty Risk Score was 1.9 in IBD and 0.9 in matched comparators (P &lt; .01). Older adults with IBD at higher risk for frailty had a 20% greater risk for mortality at 3 years compared with those who were not frail. Compared with nonfrail older patients with IBD, patients at higher risk for frailty had increased mortality (hazard ratio [HR], 3.22, 95% confidence interval [CI], 2.86-3.61), all-cause hospitalization (HR, 2.42; 95% CI, 2.24-2.61), and IBD-related hospitalization (HR, 1.50; 95% CI, 1.35-1.66). These associations were not attenuated after adjusting for comorbidities., Conclusions: Frailty is more prevalent in older adults with IBD than in matched comparators. Among older patients with IBD, frailty is associated with increased risk for hospitalizations and mortality., (Copyright © 2022 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Aims & methods: The aim of this study was to characterize the methylation level of a polymorphically imprinted gene, VTRNA2-1 / nc886 , in human populations and somatic tissues.48 datasets, consisting of more than 30 tissues and >30,000 individuals, were used. Results: nc886 methylation status is associated with twin status and ethnic background, but the variation between populations is limited. Monozygotic twin pairs present concordant methylation, whereas ∼30% of dizygotic twin pairs present discordant methylation in the nc886 locus. The methylation levels of nc886 are uniform across somatic tissues, except in cerebellum and skeletal muscle. Conclusion: The nc886 imprint may be established in the oocyte, and, after implantation, the methylation status is stable, excluding a few specific tissues.

This essay considers the factors that have contributed to very high COVID-19 mortality in longer-term care facilities (LTCFs). We compare the demographic characteristics of LTCF residents with those of community-dwelling older adults, and then we review the evidence regarding prevalence and infection fatality rates (IFRs), including links to frailty and some comorbidities. Finally, we discuss policy measures that could foster the physical and mental health and well-being of LTCF residents in the present context and in potential future pandemics., (© 2022. The Author(s).)

Background: Observational studies have suggested that better protein nutritional status may contribute to prevention of frailty., Objective: We sought to examine this hypothesis using a Mendelian randomization (MR) analysis., Methods: We conducted a two-sample MR study using GWAS summary statistics data of the UK Biobank. We applied genetically predicted serum albumin as a primary exposure measure and serum total protein as a secondary exposure measure. The outcome measure was the Rockwood frailty index (FI) based on 49 deficits from 356,432 individuals (53.3% of them were women, with a mean ± SD age of 56.7 ± 8.0 y. The association between serum protein measures and FI was mainly analyzed by use of the inverse variance weighted method., Results: A genetically predicted serum albumin concentration was not statistically significantly associated with FI in the full sample. However, in women, we observed a preventive association between genetically predicted serum albumin and FI (β = -0.172 per g/L; 95% CI: -0.336, -0.007; P = 0.041). In the full sample, genetically predicted serum total protein was inversely associated with FI (β: -0.153 per g/L; 95% CI: -0.251, -0.056; P = 0.002). In both women and men, higher serum total protein was significantly inversely associated with FI; regression coefficients were -0.148 per g/L (95% CI: -0.287, -0.009; P = 0.037) for women, -0.154 per g/L (95% CI: -0.290, -0.018; P = 0.027) for men., Conclusions: The present MR study implies that better protein nutritional status modestly contributes to reducing the risk of frailty., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Society for Nutrition.)

Background: frailty shows an upward trajectory with age, and higher levels increase the risk of mortality. However, it is less known whether the shape of frailty trajectories differs by age at death or whether the rate of change in frailty is associated with mortality., Objectives: to assess population frailty trajectories by age at death and to analyse whether the current level of the frailty index (FI) i.e. the most recent measurement or the person-specific rate of change is more predictive of mortality., Methods: 3,689 individuals from three population-based cohorts with up to 15 repeated measurements of the Rockwood frailty index were analysed. The FI trajectories were assessed by stratifying the sample into four age-at-death groups: <70, 70-80, 80-90 and >90 years. Generalised survival models were used in the survival analysis., Results: the FI trajectories by age at death showed that those who died at <70 years had a steadily increasing trajectory throughout the 40 years before death, whereas those who died at the oldest ages only accrued deficits from age ~75 onwards. Higher level of FI was independently associated with increased risk of mortality (hazard ratio 1.68, 95% confidence interval 1.47-1.91), whereas the rate of change was no longer significant after accounting for the current FI level. The effect of the FI level did not weaken with time elapsed since the last measurement., Conclusions: Frailty trajectories differ as a function of age-at-death category. The current level of FI is a stronger marker for risk stratification than the rate of change., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Geriatrics Society. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Frailty has been identified as a risk factor for cognitive impairment and dementia. However, it is not known whether familial factors, such as genetics and shared environmental factors, underlie this association. We analyzed the association between frailty and the risk of dementia in a large twin cohort and examined the role of familial factors in the association., Methods: The Rockwood frailty index (FI) based on 44 health deficits was used to assess frailty. The population-level association between FI and the risk of all-cause dementia was analyzed in 41,550 participants of the Screening Across the Lifespan Twin (SALT) study (full sample, aged 41-97 years at baseline), using Cox and competing risk models. A subsample of 10,487 SALT participants aged 65 and older who received a cognitive assessment (cognitive sample) was used in a sensitivity analysis to assess the effect of baseline cognitive level on the FI-dementia association. To analyze the influence of familial effects on the FI-dementia association, a within-pair analysis was performed. The within-pair model was also used to assess whether the risk conferred by frailty varies by age at FI assessment., Results: A total of 3183 individuals were diagnosed with dementia during the 19-year follow-up. A 10% increase in FI was associated with an increased risk of dementia (hazard ratio [HR] 1.17 (95% confidence interval [CI] 1.07, 1.18)) in the full sample adjusted for age, sex, education, and tobacco use. A significant association was likewise found in the cognitive sample, with an HR of 1.13 (95% CI 1.09, 1.20), adjusted for age, sex, and cognitive level at baseline. The associations were not attenuated when adjusted for APOE ɛ4 carrier status or considering the competing risk of death. After adjusting for familial effects, we found no evidence for statistically significant attenuation of the effect. The risk conferred by higher FI on dementia was constant after age 50 until very old age., Conclusions: A higher level of frailty predicts the risk of dementia and the association appears independent of familial factors. Targeting frailty might thus contribute to preventing or delaying dementia., (© 2021. The Author(s).)

Background: Observational studies have suggested that fatty acids such as higher levels of n-3 polyunsaturated fatty acids (PUFAs) may prevent frailty. By using Mendelian randomization analysis, we examined the relationship between fatty acids and frailty., Methods: We used summary statistics data for single-nucleotide polymorphisms associated with plasma levels of saturated fatty acids (palmitic acid, stearic acid), mono-unsaturated fatty acids (MUFAs) (palmitoleic acid, oleic acid), n-6 PUFAs (linoleic acid, arachidonic acid), and n-3 PUFAs (alpha-linolenic acid, eicosapentaenoic acid, docosapentaenoic acid, docosahexaenoic acid), and the corresponding data for frailty index (FI) in 356,432 individuals in the UK Biobank., Results: Although there were no robust associations on the MUFAs or the PUFAs, genetically predicted higher plasma stearic acid level (one of saturated fatty acids) was statistically significantly associated with higher FI (β = 0.178; 95% confidence interval = -0.050 to 0.307; p = 0.007). Such a relationship was also observed in a multivariate MR (β = 0.361; 95% confidence interval = 0.155 to 0.567; p = 0.001). Genetically predicted higher palmitic acid was also significantly associated with higher FI (β = 0.288; 95% confidence interval = 0.128 to 0.447; p < 0.001) in the multivariate MR analysis., Conclusions: The present MR study implies that saturated fatty acids, especially stearic acid, is a risk factor of frailty.

Frailty is a common geriatric syndrome and strongly associated with disability, mortality and hospitalization. Frailty is commonly measured using the frailty index (FI), based on the accumulation of a number of health deficits during the life course. The mechanisms underlying FI are multifactorial and not well understood, but a genetic basis has been suggested with heritability estimates between 30 and 45%. Understanding the genetic determinants and biological mechanisms underpinning FI may help to delay or even prevent frailty. We performed a genome-wide association study (GWAS) meta-analysis of a frailty index in European descent UK Biobank participants (n = 164,610, 60-70 years) and Swedish TwinGene participants (n = 10,616, 41-87 years). FI calculation was based on 49 or 44 self-reported items on symptoms, disabilities and diagnosed diseases for UK Biobank and TwinGene, respectively. 14 loci were associated with the FI (p < 5*10 -8 ). Many FI-associated loci have established associations with traits such as body mass index, cardiovascular disease, smoking, HLA proteins, depression and neuroticism; however, one appears to be novel. The estimated single nucleotide polymorphism (SNP) heritability of the FI was 11% (0.11, SE 0.005). In enrichment analysis, genes expressed in the frontal cortex and hippocampus were significantly downregulated (adjusted p < 0.05). We also used Mendelian randomization to identify modifiable traits and exposures that may affect frailty risk, with a higher educational attainment genetic risk score being associated with a lower degree of frailty. Risk of frailty is influenced by many genetic factors, including well-known disease risk factors and mental health, with particular emphasis on pathways in the brain., (© 2021 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.)

Frailty is influenced by numerous genetic and environmental factors. However, sex differences in how these factors affect frailty, and the gene-environment interplay among frailty and two of its well-established risk factors, unhealthy body mass index (BMI) and low education, are less clear. In a large sample of 42,994 Swedish twins, we used structural equation models to estimate the genetic (heritability) and environmental sources of variance in frailty, defined as the frailty index (FI), separately in men and women. Genetic and individual-specific environmental factors contributed approximately equally to the FI variance. The heritability of FI was slightly, but significantly, higher in women (52%) than in men (45%), yet we found only weak-to-no indication of different sources of genetic variance influencing frailty across sexes. We observed a small-to-moderate genetic overlap between FI and BMI, and that the correlation between FI and education was largely explained by environmental factors common to twins in a pair. Additionally, genetic factors accounted for more of FI variation at both low and high BMI levels, with similar patterns in both sexes. In conclusion, the twin-based heritability of frailty is higher in women than in men, and different mechanisms may underlie the associations of frailty with BMI and education.

Mitochondrial (MT) dysfunction is a hallmark of aging and has been associated with most aging-related diseases as well as immunological processes. However, little is known about aging, lifestyle and genetic factors influencing mitochondrial DNA (mtDNA) abundance. In this study, mtDNA abundance was estimated from the weighted intensities of probes mapping to the MT genome in 295,150 participants from the UK Biobank. We found that the abundance of mtDNA was significantly elevated in women compared to men, was negatively correlated with advanced age, higher smoking exposure, greater body-mass index, higher frailty index as well as elevated red and white blood cell count and lower mortality. In addition, several biochemistry markers in blood-related to cholesterol metabolism, ion homeostasis and kidney function were found to be significantly associated with mtDNA abundance. By performing a genome-wide association study, we identified 50 independent regions genome-wide significantly associated with mtDNA abundance which harbour multiple genes involved in the immune system, cancer as well as mitochondrial function. Using mixed effects models, we estimated the SNP-heritability of mtDNA abundance to be around 8%. To investigate the consequence of altered mtDNA abundance, we performed a phenome-wide association study and found that mtDNA abundance is involved in risk for leukaemia, hematologic diseases as well as hypertension. Thus, estimating mtDNA abundance from genotyping arrays has the potential to provide novel insights into age- and disease-relevant processes, particularly those related to immunity and established mitochondrial functions.

DNA methylation profiles of aggressive behavior may capture lifetime cumulative effects of genetic, stochastic, and environmental influences associated with aggression. Here, we report the first large meta-analysis of epigenome-wide association studies (EWAS) of aggressive behavior (N = 15,324 participants). In peripheral blood samples of 14,434 participants from 18 cohorts with mean ages ranging from 7 to 68 years, 13 methylation sites were significantly associated with aggression (alpha = 1.2 × 10 -7 ; Bonferroni correction). In cord blood samples of 2425 children from five cohorts with aggression assessed at mean ages ranging from 4 to 7 years, 83% of these sites showed the same direction of association with childhood aggression (r = 0.74, p = 0.006) but no epigenome-wide significant sites were found. Top-sites (48 at a false discovery rate of 5% in the peripheral blood meta-analysis or in a combined meta-analysis of peripheral blood and cord blood) have been associated with chemical exposures, smoking, cognition, metabolic traits, and genetic variation (mQTLs). Three genes whose expression levels were associated with top-sites were previously linked to schizophrenia and general risk tolerance. At six CpGs, DNA methylation variation in blood mirrors variation in the brain. On average 44% (range = 3-82%) of the aggression-methylation association was explained by current and former smoking and BMI. These findings point at loci that are sensitive to chemical exposures with potential implications for neuronal functions. We hope these results to be a starting point for studies leading to applications as peripheral biomarkers and to reveal causal relationships with aggression and related traits., (© 2021. The Author(s).)

Aging is a complex biological process characterized by hallmark features accumulating over the life course, shaping the individual's aging trajectory and subsequent disease risks. There is substantial individual variability in the aging process between men and women. In general, women live longer than men, consistent with lower biological ages as assessed by molecular biomarkers, but there is a paradox. Women are frailer and have worse health at the end of life, while men still perform better in physical function examinations. Moreover, many age-related diseases show sex-specific patterns. In this review, we aim to summarize the current knowledge on sexual dimorphism in human studies, with support from animal research, on biological aging and illnesses. We also attempt to place it in the context of the theories of aging, as well as discuss the explanations for the sex differences, for example, the sex-chromosome linked mechanisms and hormonally driven differences., Competing Interests: SH, JJ No competing interests declared, (© 2021, Hägg and Jylhävä.)

Background/objectives: Frailty has been linked to increased risk of COVID-19 mortality, but evidence is mainly limited to hospitalized older individuals. This study aimed to assess and compare predictive abilities of different frailty and comorbidity measures for COVID-19 mortality in a community sample and COVID-19 inpatients., Design: Population-based cohort study., Setting: Community., Participants: We analyzed (i) the full sample of 410,199 U.K. Biobank participants in England, aged 49-86 years, and (ii) a subsample of 2812 COVID-19 inpatients with COVID-19 data from March 1 to November 30, 2020., Measurements: Frailty was defined using the physical frailty phenotype (PFP), frailty index (FI), and Hospital Frailty Risk Score (HFRS), and comorbidity using the Charlson Comorbidity Index (CCI). PFP and FI were available at baseline, whereas HFRS and CCI were assessed both at baseline and concurrently with the start of the pandemic. Inpatient COVID-19 cases were confirmed by PCR and/or hospital records. COVID-19 mortality was ascertained from death registers., Results: Overall, 514 individuals died of COVID-19. In the full sample, all frailty and comorbidity measures were associated with higher COVID-19 mortality risk after adjusting for age and sex. However, the associations were stronger for the concurrent versus baseline HFRS and CCI, with odds ratios of 20.40 (95% confidence interval = 16.24-25.63) comparing high (>15) to low (<5) concurrent HFRS risk category and 1.53 (1.48-1.59) per point increase in concurrent CCI. Moreover, only the concurrent HFRS or CCI significantly improved predictive ability of a model including age and sex, yielding areas under the receiver operating characteristic curve (AUC) >0.8. When restricting analyses to COVID-19 inpatients, similar improvement in AUC was not observed., Conclusion: HFRS and CCI constructed from medical records concurrent with the start of the pandemic can be used in COVID-19 mortality risk stratification at the population level, but they show limited added value in COVID-19 inpatients., (© 2021 The Authors. Journal of the American Geriatrics Society published by Wiley Periodicals LLC on behalf of The American Geriatrics Society.)