Deciphering the genetic and epidemiological landscape of mitochondrial DNA abundance

Acknowledgements: The computations and data handling were enabled by resources provided by the Swedish National Infrastructure for Computing (SNIC) at UPPMAX, Uppsala University, partially funded by the Swedish Research Council through grant agreement no. 2018-05973. This research has been conducted using the UK Biobank Resource under Application Number 22224. Funding: Open Access funding provided by Karolinska Institute. Open Access funding provided by Karolinska Institute. This work was financed by the Swedish Research Council (Grant 2018-02547, 2015-03255, 2019-01272, 2018-02077), the Swedish Cancer Society (Grants CAN 2016/684), the Stockholm County Council (Grant no. 20170088), the Karolinska Institutet’s Research Foundation (Grant 2018-02146), Karolinska Institutet’s Strategic Research Program in Epidemiology, King Gustaf V:s and Queen Victoria's Foundation of Freemasons, and the Åke Wibergs Foundation (M19-0294). FG was a Leopoldina Postdoctoral Fellow (Grant no. LPDS 2018-06) funded by the Academy of Sciences Leopoldina. Correction to: Deciphering the genetic and epidemiological landscape of mitochondrial DNA abundance (Human Genetics, (2020), 10.1007/s00439-020-02249-w) The data were exclusively retrieved from the UK Biobank and can be accessed upon request from the UK Biobank. The mitochondrial DNA abundance as computed in this manuscript will be reported back to the UK Biobank upon publication. The scripts to compute the weights and the weighted mtDNA abundance in the UKB dataset will be published at https://github.com/GrassmannLab/MT_UKB.Peer reviewedPublisher PD

Aging-associated increase in indoleamine 2,3-dioxygenase (IDO) activity appears to be unrelated to the transcription of the IDO1 or IDO2 genes in peripheral blood mononuclear cells

<p>Abstract</p> <p>Background</p> <p>Old age is associated with increased levels of circulating pro-inflammatory cytokines, a phenomenon termed inflamm-aging. Elevated levels of pro-inflammatory cytokines have been associated with several age-associated diseases and with a shortened lifespan. Indoleamine 2,3-dioxygenase (IDO) has immunomodulatory properties and its activity is elevated in inflammation, autoimmune disorders and malignancies. We have previously shown that IDO activity is increased in nonagenarians compared to young individuals and that high IDO activity is associated with mortality at old age.</p> <p>Findings</p> <p>In this study our aim was to assess whether this difference in IDO activity in the plasma was due to the differential expression of either the IDO1 or IDO2 gene in peripheral blood mononuclear cells. Our results show that IDO1 and IDO2 are not differently expressed in nonagenarians compared to controls and that the expression of IDO genes is not associated with the level of IDO activity in the plasma.</p> <p>Conclusion</p> <p>The level of IDO activity in the plasma is not regulated through the expression of IDO1 or IDO2 in the peripheral blood mononuclear cells.</p

Automated frailty scores : towards clinical implementation

Non peer reviewe

Identification of a prognostic signature for old-age mortality by integrating genome-wide transcriptomic data with the conventional predictors: the Vitality 90+ Study

Background Prediction models for old-age mortality have generally relied upon conventional markers such as plasma-based factors and biophysiological characteristics. However, it is unknown whether the existing markers are able to provide the most relevant information in terms of old-age survival or whether predictions could be improved through the integration of whole-genome expression profiles. Methods We assessed the predictive abilities of survival models containing only conventional markers, only gene expression data or both types of data together in a Vitality 90+ study cohort consisting of n = 151 nonagenarians. The all-cause death rate was 32.5% (49 of 151 individuals), and the median follow-up time was 2.55 years. Results Three different feature selection models, the penalized Lasso and Ridge regressions and the C-index boosting algorithm, were used to test the genomic data. The Ridge regression model incorporating both the conventional markers and transcripts outperformed the other models. The multivariate Cox regression model was used to adjust for the conventional mortality prediction markers, i.e., the body mass index, frailty index and cell-free DNA level, revealing that 331 transcripts were independently associated with survival. The final mortality-predicting transcriptomic signature derived from the Ridge regression model was mapped to a network that identified nuclear factor kappa beta (NF-κB) as a central node. Conclusions Together with the loss of physiological reserves, the transcriptomic predictors centered around NF-κB underscored the role of immunoinflammatory signaling, the control of the DNA damage response and cell cycle, and mitochondrial functions as the key determinants of old-age mortality.BioMed Central open acces

COVID-19 prevalence and mortality in longer-term care facilities

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.publishedVersionPeer reviewe

Use of Electronic Medical Records (EMR) in Gerontology : Benefits, Considerations and a Promising Future

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.Peer reviewe

Can frailty scores predict the incidence of cancer? : Results from two large population-based studies

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.publishedVersionPeer reviewe

Molecular mechanisms associated with the strength of the anti-CMV response in nonagenarians

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

Is Frailty Different in Younger Adults Compared to Old? Prevalence, Characteristics, and Risk Factors of Early-Life and Late-Life Frailty in Samples from Sweden and UK

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 <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 <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 <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.Peer reviewe

Internalization of novel non-viral vector TAT-streptavidin into human cells

BACKGROUND: The cell-penetrating peptide derived from the Human immunodeficiency virus-1 transactivator protein Tat possesses the capacity to promote the effective uptake of various cargo molecules across the plasma membrane in vitro and in vivo. The objective of this study was to characterize the uptake and delivery mechanisms of a novel streptavidin fusion construct, TAT(47–57)-streptavidin (TAT-SA, 60 kD). SA represents a potentially useful TAT-fusion partner due to its ability to perform as a versatile intracellular delivery vector for a wide array of biotinylated molecules or cargoes. RESULTS: By confocal and immunoelectron microscopy the majority of internalized TAT-SA was shown to accumulate in perinuclear vesicles in both cancer and non-cancer cell lines. The uptake studies in living cells with various fluorescent endocytic markers and inhibiting agents suggested that TAT-SA is internalized into cells efficiently, using both clathrin-mediated endocytosis and lipid-raft-mediated macropinocytosis. When endosomal release of TAT-SA was enhanced through the incorporation of a biotinylated, pH-responsive polymer poly(propylacrylic acid) (PPAA), nuclear localization of TAT-SA and TAT-SA bound to biotin was markedly improved. Additionally, no significant cytotoxicity was detected in the TAT-SA constructs. CONCLUSION: This study demonstrates that TAT-SA-PPAA is a potential non-viral vector to be utilized in protein therapeutics to deliver biotinylated molecules both into cytoplasm and nucleus of human cells