Age-related Chronic Diseases Research Articles

Lifestyle, Genetic Susceptibility, and the Risk of Idiopathic Pulmonary Fibrosis: A Large Prospective Cohort Study

Lifestyle is thought to be an important contributor of age-related chronic disease, but the association between lifestyle and the risk of idiopathic pulmonary fibrosis (IPF) remains unknown. Also, the extent to which genetic susceptibility modifies the effects of lifestyle on IPF remains unclear. Whether there is joint effect or interaction of lifestyle and genetic susceptibility on the risk of developing IPF? Our study included 407615 participants from the UK Biobank. We constructed a lifestyle score and a polygenic risk score (PRS) for each participant, separately. Participants were then classified into 3 lifestyle categories and 3 genetic risk categories based on the corresponding score. Cox models were fitted to assess the association of lifestyle and genetic risk with the risk of incident IPF. With favorable lifestyle as the reference group, intermediate lifestyle (hazard ratio (HR): 1.384, 95% confidence interval (CI): 1.218-1.574) and unfavorable lifestyle (HR: 2.271, 95% CI: 1.852-2.785) were significantly associated with increased risk of IPF. For the combined effect of lifestyle and PRS, participants with unfavorable lifestyle and high genetic risk had the highest risk of IPF (HR: 7.796, 95% CI: 5.482-11.086) compared to those with favorable lifestyle and low genetic risk. Moreover, approximately 32.7% (11.3%, 54.1%) of IPF risk could be attributed to the interaction of an unfavorable lifestyle and high genetic risk. Exposure to unfavorable lifestyle significantly increased the risk of IPF, particularly in those with high genetic risk.

Religious and Spiritual Coping Elements in Dealing with Chronic Diseases: A Qualitative Exploration of the Perspectives of Older Iranian Zoroastrians.

Religiosity is a desirable alternative coping strategy for many people when facing negative life events including age-related infirmities and stressors. Religious coping mechanisms (RCMs) have beeninvestigated meagerly with regard toreligious minorities aroundthe world and, to the best of current knowledge, no study has beenconducted on Iranian Zorostrians to explore their religious coping mechanisms in dealing with age-related chronic diseases. This qualitative research, therefore, was aimed to canvas perceptions about RCMs that are utilizedby Iranian Zoroastrian older adults to deal with chronic diseases in the city of Yazd, Iran. Semi-structured interviews were conducted with purposefully selected fourteen Zoroastrian older patients and four Zoroastrian priests in 2019. The main extracted themes included performing certain religious behaviors and having sincere religion-based beliefs as employed mechanisms for better coping with their chronic diseases. Prevalent dilemmas/barriers with mitigating impact on the coping capacities in dealing with a persistent illness was another predominant identified theme. Identification of RCMs that religious and ethnic minorities are using to better confront diverse life events, such as chronic diseases, could pave the path to expand new approaches in planing sustainable disease management and proactive quality of life improvement initiatives.

Aging Hallmarks and the Role of Oxidative Stress

Aging is a complex biological process accompanied by a progressive decline in the physical function of the organism and an increased risk of age-related chronic diseases such as cardiovascular diseases, cancer, and neurodegenerative diseases. Studies have established that there exist nine hallmarks of the aging process, including (i) telomere shortening, (ii) genomic instability, (iii) epigenetic modifications, (iv) mitochondrial dysfunction, (v) loss of proteostasis, (vi) dysregulated nutrient sensing, (vii) stem cell exhaustion, (viii) cellular senescence, and (ix) altered cellular communication. All these alterations have been linked to sustained systemic inflammation, and these mechanisms contribute to the aging process in timing not clearly determined yet. Nevertheless, mitochondrial dysfunction is one of the most important mechanisms contributing to the aging process. Mitochondria is the primary endogenous source of reactive oxygen species (ROS). During the aging process, there is a decline in ATP production and elevated ROS production together with a decline in the antioxidant defense. Elevated ROS levels can cause oxidative stress and severe damage to the cell, organelle membranes, DNA, lipids, and proteins. This damage contributes to the aging phenotype. In this review, we summarize recent advances in the mechanisms of aging with an emphasis on mitochondrial dysfunction and ROS production.

Assessment of Frailty Index at 66 Years of Age and Association With Age-Related Diseases, Disability, and Death Over 10 Years in Korea

A frailty index has been proposed as a measure of aging among older individuals. However, few studies have examined whether a frailty index measured at the same chronologic age at younger ages could forecast the development of new age-related conditions. To examine the association of the frailty index at 66 years of age with incident age-related diseases, disability, and death over 10 years. This retrospective nationwide cohort study used the Korean National Health Insurance database to identify 968 885 Korean individuals who attended the National Screening Program for Transitional Ages at 66 years of age between January 1, 2007, and December 31, 2017. Data were analyzed from October 1, 2020, to January 2022. Frailty was defined using a 39-item frailty index ranging from 0 to 1.00 as robust (<0.15), prefrail (0.15-0.24), mildly frail (0.25-0.34), and moderately to severely frail (≥0.35). The primary outcome was all-cause death. Secondary outcomes were 8 age-related chronic diseases (congestive heart failure, coronary artery disease, stroke, type 2 diabetes, cancer, dementia, fall, and fracture) and disability qualifying for long-term care services. Cox proportional hazards regression and cause-specific and subdistribution hazards regression were used to examine hazard ratios (HRs) and 95% CIs for the outcomes until the earliest of date of death, the occurrence of relevant age-related conditions, 10 years from the screening examination, or December 31, 2019. Among the 968 885 participants included in the analysis (517 052 women [53.4%]), the majority were classified as robust (65.2%) or prefrail (28.2%); only a small fraction were classified as mildly frail (5.7%) or moderately to severely frail (1.0%). The mean frailty index was 0.13 (SD, 0.07), and 64 415 (6.6%) were frail. Compared with the robust group, those in the moderately to severely frail group were more likely to be women (47.8% vs 61.7%), receiving medical aid insurance for low income (2.1% vs 18.9%), and less active (median, 657 [IQR, 219-1133] vs 319 [IQR, 0-693] metabolic equivalent task [min/wk]). After adjusting for sociodemographic and lifestyle characteristics, moderate to severe frailty was associated with increased rates of death (HR, 4.43 [95% CI, 4.24-4.64]) and new diagnosis of all chronic diseases, including congestive heart failure (adjusted cause-specific HR, 2.90 [95% CI, 2.67-3.15]), coronary artery disease (adjusted cause-specific HR, 1.98 [95% CI, 1.85-2.12]), stroke (adjusted cause-specific HR, 2.22 [95% CI, 2.10-2.34]), diabetes (adjusted cause-specific HR, 2.34 [95% CI, 2.21-2.47]), cancer (adjusted cause-specific HR, 1.10 [95% CI, 1.03-1.18]), dementia (adjusted cause-specific HR, 3.59 [95% CI, 3.42-3.77]), fall (adjusted cause-specific HR, 2.76 [95% CI, 2.29-3.32]), fracture (adjusted cause-specific HR, 1.54 [95% CI, 1.48-1.62]), and disability (adjusted cause-specific HR, 10.85 [95% CI, 10.00-11.70]). Frailty was associated with increased 10-year incidence of all the outcomes, except for cancer (moderate to severe frailty adjusted subdistribution HR, 0.99 [95% CI, 0.92-1.06]). Frailty at 66 years of age was associated with greater acquisition of age-related conditions (mean [SD] conditions per year for the robust group, 0.14 [0.32]; for the moderately to severely frail group, 0.45 [0.87]) in the next 10 years. The findings of this cohort study suggest that a frailty index measured at 66 years of age was associated with accelerated acquisition of age-related conditions, disability, and death over the next 10 years. Measuring frailty at this age may offer opportunities to prevent age-related health decline.

How can physical activity facilitate a sustainable future? Reducing obesity and chronic disease.

This review examines the ways in which physical activity can contribute to a sustainable future by addressing significant public health issues. The review begins by identifying obesity and ageing as two major challenges facing societies around the world due to the association of both with the risk of chronic disease. Recent developments in the understanding and treatment of obesity are examined followed by an appraisal of the role of exercise alone and in combination with other therapies in preventing and managing obesity. The review then addresses the interaction between exercise and appetite due to the central role appetite plays in the development of overweight and obesity. The final section of the review examines the potential of physical activity to combat age-related chronic disease risk including CVD, cancer and dementia. It is concluded that while bariatric surgery and pharmacotherapy are the most effective treatments for severe obesity, physical activity has a role to play facilitating and enhancing weight loss in combination with other methods. Where weight/fat reduction via exercise is less than expected this is likely due to metabolic adaptation induced by physiological changes facilitating increased energy intake and decreased energy expenditure. Physical activity has many health benefits independent of weight control including reducing the risk of developing CVD, cancer and dementia and enhancing cognitive function in older adults. Physical activity may also provide resilience for future generations by protecting against the more severe effects of global pandemics and reducing greenhouse gas emissions via active commuting.

Home-Based Pilot Intervention to Improve Quality of Life and Related Outcomes among Unpaid Caregivers and Their Care-Recipients with Visual Impairments

The increasing lifespan of the United States population has led to a rise in the prevalence of age-related chronic diseases, increasing the need for unpaid caregivers. Currently, little research is known about this specific population beyond the limited formal training unpaid caregivers receive on the caregiving process. Acquiring visual impairments (VI) later in life places a large emotional toll on both the loved one and their caregivers. The objectives of this pilot study were: (1) to implement a multimodal intervention targeted towards improving the quality of life of unpaid caregivers and their care recipients with visual impairments; (2) to evaluate the efficacy of the multimodal intervention in improving the quality of life of unpaid caregivers and their care recipients with visual impairments. A 10-week virtual intervention (e.g., tai chi, yoga, music) was implemented with 12 caregivers and 8 older adults with VI. The targeted outcomes of interest included: QoL, health, stress, burden, problem-solving, and barriers. In addition to surveys to inform the choice of the intervention, focus group interviews were conducted to obtain participants' perspectives on the effectiveness of the intervention. Results revealed many positive outcomes in the quality of life and well-being of the participants following the 10-week intervention. Overall, these results represent a promising program for unpaid caregivers of older adults with VI.

Anti-Neuroinflammatory Potential of Natural Products in the Treatment of Alzheimer's Disease.

Alzheimer's disease (AD) is an age-related chronic progressive neurodegenerative disease, which is the main cause of dementia in the elderly. Much evidence shows that the onset and late symptoms of AD are caused by multiple factors. Among them, aging is the main factor in the pathogenesis of AD, and the most important risk factor for AD is neuroinflammation. So far, there is no cure for AD, but the relationship between neuroinflammation and AD may provide a new strategy for the treatment of AD. We herein discussed the main etiology hypothesis of AD and the role of neuroinflammation in AD, as well as anti-inflammatory natural products with the potential to prevent and alleviate AD symptoms, including alkaloids, steroids, terpenoids, flavonoids and polyphenols, which are available with great potential for the development of anti-AD drugs.

The Central Role of the NAD+ Molecule in the Development of Aging and the Prevention of Chronic Age-Related Diseases: Strategies for NAD+ Modulation.

The molecule NAD+ is a coenzyme for enzymes catalyzing cellular redox reactions in several metabolic pathways, encompassing glycolysis, TCA cycle, and oxidative phosphorylation, and is a substrate for NAD+-dependent enzymes. In addition to a hydride and electron transfer in redox reactions, NAD+ is a substrate for sirtuins and poly(adenosine diphosphate-ribose) polymerases and even moderate decreases in its cellular concentrations modify signaling of NAD+-consuming enzymes. Age-related reduction in cellular NAD+ concentrations results in metabolic and aging-associated disorders, while the consequences of increased NAD+ production or decreased degradation seem beneficial. This article reviews the NAD+ molecule in the development of aging and the prevention of chronic age-related diseases and discusses the strategies of NAD+ modulation for healthy aging and longevity.

Mitochondrial stress and mitokines in aging.

Mitokines are signaling molecules that enable communication of local mitochondrial stress to other mitochondria in distant cells and tissues. Among those molecules are FGF21, GDF15 (both expressed in the nucleus) and several mitochondrial-derived peptides, including humanin. Their responsiveness to mitochondrial stress induces mitokine-signaling in response for example to exercise, following mitochondrial challenges in skeletal muscle. Such signaling is emerging as an important mediator of exercise-derived and dietary strategy-related molecular and systemic health benefits, including healthy aging. A compensatory increase in mitokine synthesis and secretion could preserve mitochondrial function and overall cellular vitality. Conversely, resistance against mitokine actions may also develop. Alterations of mitokine-levels, and therefore of mitokine-related inter-tissue cross talk, are associated with general aging processes and could influence the development of age-related chronic metabolic, cardiovascular and neurological diseases; whether these changes contribute to aging or represent "rescue factors" remains to be conclusively shown. The aim of the present review is to summarize the expanding knowledge on mitokines, the potential to modulate them by lifestyle and their involvement in aging and age-related diseases. We highlight the importance of well-balanced mitokine-levels, the preventive and therapeutic properties of maintaining mitokine homeostasis and sensitivity of mitokine signaling but also the risks arising from the dysregulation of mitokines. While reduced mitokine levels may impair inter-organ crosstalk, also excessive mitokine concentrations can have deleterious consequences and are associated with conditions such as cancer and heart failure. Preservation of healthy mitokine signaling levels can be achieved by regular exercise and is associated with an increased lifespan.

A computational approach based on weighted gene co-expression network analysis for biomarkers analysis of Parkinson's disease and construction of diagnostic model.

Parkinson's disease (PD) is a common age-related chronic neurodegenerative disease. There is currently no affordable, effective, and less invasive test for PD diagnosis. Metabolite profiling in blood and blood-based gene transcripts is thought to be an ideal method for diagnosing PD. In this study, the objective is to identify the potential diagnostic biomarkers of PD by analyzing microarray gene expression data of samples from PD patients. A computational approach, namely, Weighted Gene Co-expression Network Analysis (WGCNA) was used to construct co-expression gene networks and identify the key modules that were highly correlated with PD from the GSE99039 dataset. The Least Absolute Shrinkage and Selection Operator (LASSO) regression analysis was performed to identify the hub genes in the key modules with strong association with PD. The selected hub genes were then used to construct a diagnostic model based on logistic regression analysis, and the Receiver Operating Characteristic (ROC) curves were used to evaluate the efficacy of the model using the GSE99039 dataset. Finally, Reverse Transcription-Polymerase Chain Reaction (RT-PCR) was used to validate the hub genes. WGCNA identified two key modules associated with inflammation and immune response. Seven hub genes, LILRB1, LSP1, SIPA1, SLC15A3, MBOAT7, RNF24, and TLE3 were identified from the two modules and used to construct diagnostic models. ROC analysis showed that the diagnostic model had a good diagnostic performance for PD in the training and testing datasets. Results of the RT-PCR experiments showed that there were significant differences in the mRNA expression of LILRB1, LSP1, and MBOAT7 among the seven hub genes. The 7-gene panel (LILRB1, LSP1, SIPA1, SLC15A3, MBOAT7, RNF24, and TLE3) will serve as a potential diagnostic signature for PD.

HIV Infection, Chromosome Instability, and Micronucleus Formation.

Genome integrity is critical for proper cell functioning, and chromosome instability can lead to age-related diseases, including cancer and neurodegenerative disorders. Chromosome instability is caused by multiple factors, including replication stress, chromosome missegregation, exposure to pollutants, and viral infections. Although many studies have investigated the effects of environmental or lifestyle genotoxins on chromosomal integrity, information on the effects of viral infections on micronucleus formation and other chromosomal aberrations is still limited. Currently, HIV infection is considered a chronic disease treatable by antiretroviral therapy (ART). However, HIV-infected individuals still face important health problems, such as chronic inflammation and age-related diseases. In this context, this article reviews studies that have evaluated genomic instability using micronucleus assays in the context of HIV infection. In brief, HIV can induce chromosome instability directly through the interaction of HIV proteins with host DNA and indirectly through chronic inflammation or as a result of ART use. Connections between HIV infection, immunosenescence and age-related disease are discussed in this article. The monitoring of HIV-infected individuals should consider the increased risk of chromosome instability, and lifestyle interventions, such as reduced exposure to genotoxins and an antioxidant-rich diet, should be considered. Therapies to reduce chronic inflammation in HIV infection are needed.

Nintedanib and pirfenidone for idiopathic pulmonary fibrosis in King Abdulaziz Medical City, Riyadh: Real-life data.

Idiopathic pulmonary fibrosis (IPF) is a chronic progressive age-related lung disease causing relentless fibrosis of the lung parenchyma. Currently, pirfenidone and nintedanib are the two antifibrotic drugs, approved for the treatment of IPF. Both are shown to slow progression by preserving lung functions from rapid decline compared to a placebo. We are reporting a real-life patient experience using these two antifibrotic medications (AFMs) in our tertiary care hospital. A retrospective cohort study was conducted for all IPF cases diagnosed in multidisciplinary meetings between 2015 and 2020 at KAMC, Riyadh (Saudi Arabia). We are reporting patients' demographics, lung function, survival, tolerance, side effects, or death in patients taking AFMs. A total of 81 cases were identified. The majority of patients aged 67 years (68%) were men with a median age of 68 years. Late presentation, severe disease, and definite usual interstitial pneumonia patterns were reported in 60% of our patients. The average number of hospital admissions before starting treatment was 1 (range: 0-3) in the nintedanib group and 1.4 (range: 1.2-5) in the pirfenidone group. There was an increase in the number of hospital admissions in the group started on pirfenidone 1.7 (range: 1.9-8) compared to nintedanib 0.5 (range: 0-3), P = 0.001. The observed mortality outcome in this cohort was 4 (11%) and 12 (27%) for nintedanib and pirfenidone, respectively. The predominant side effects were gastrointestinal symptoms for both the groups 18 (22%). Pirfenidone and nintedanib are the available approved antifibrotic agents used for many years to treat IPF patients. Real-life data showed better tolerability than reported in the West, good compliance, and a manageable side effect profile in this group of elderly and severe IPF patients.

Microbially-Induced Exosomes from Dendritic Cells Promote Paracrine Immune Senescence: Novel Mechanism of Bone Degenerative Disease in Mice.

As the aging population grows, chronic age-related bone degenerative diseases become more prevalent and severe. One such disease, periodontitis (PD), rises to 70.1% prevalence in Americans 65 years and older. PD has been linked to increased risk of other age-related diseases with more serious mortality and morbidity profiles such as Alzheimer's disease and cardiovascular disease, but the cellular and biological mechanisms remain unclear. Recent in vitro studies from our group indicate that murine dendritic cells (DCs) and T cells are vulnerable to immune senescence. This occurs through a distinct process involving invasion of DCs by dysbiotic pathogen Porphyromonas gingivalis (Pg) activating the senescence associated secretory phenotype (SASP). Exosomes of the Pg-induced SASP transmit senescence to normal bystander DC and T cells, ablating antigen presentation. The biological significance of these findings in vivo and the mechanisms involved were examined in the present study using young (4-5mo) or old (22-24mo) mice subjected to ligature-induced PD, with or without dysbiotic oral pathogen and injection of Pg-induced DC exosomes. Senescence profiling of gingiva and draining lymph nodes (LN) corroborates role of advanced age and PD in elevation of senescence biomarkers beta galactosidase (SA-β-Gal), p16 INK4A p21Waf1/Clip1, IL6, TNFα, and IL1β, with attendant increase in alveolar bone loss, reversed by senolytic agent rapamycin. Immunophenotyping of gingiva and LN revealed that myeloid CD11c+ DCs and T cells are particularly vulnerable to senescence in vivo under these conditions. Moreover, Pg-induced DC exosomes were the most potent inducers of alveolar bone loss and immune senescence, and capable of overcoming senescence resistance of LN T cells in young mice. We conclude that immune senescence, compounded by advanced age, and accelerated by oral dysbiosis and its induced SASP exosomes, plays a pivotal role in the pathophysiology of experimental periodontitis.

Middle-age high normal serum sodium as a risk factor for accelerated biological aging, chronic diseases, and premature mortality.

It is known that some people age faster than others, some people live into old age disease-free, while others develop age-related chronic diseases. With a rapidly aging population and an emerging chronic diseases epidemic, finding mechanisms and implementing preventive measures that could slow down the aging process has become a new challenge for biomedical research and public health. In mice, lifelong water restriction shortens the lifespan and promotes degenerative changes. Here, we test the hypothesis that optimal hydration may slow down the aging process in humans. We performed a cohort analysis of data from the Atherosclerosis Risk in Communities study with middle-age enrollment (45-66 years, n=15,752) and 25 years follow-up. We used serum sodium, as a proxy for hydration habits. To estimate the relative speed of aging, we calculated the biological age (BA) from age-dependent biomarkers and assessed risks of chronic diseases and premature mortality. The analysis showed that middle age serum sodium >142mmol/l is associated with a 39% increased risk to develop chronic diseases (hazard ratio [HR]=1.39, 95% confidence interval [CI]:1.18-1.63) and >144mmol/l with 21% elevated risk of premature mortality (HR=1.21, 95% CI:1.02-1.45). People with serum sodium >142mmol/l had up to 50% higher odds to be older than their chronological age (OR=1.50, 95% CI:1.14-1.96). A higher BA was associated with an increased risk of chronic diseases (HR=1.70, 95% CI:1.50-1.93) and premature mortality (HR=1.59, 95% CI 1.39-1.83). People whose middle-age serum sodium exceeds 142mmol/l have increased risk to be biologically older, develop chronic diseases and die at younger age. Intervention studies are needed to confirm the link between hydration and aging. This work was funded by Intramural Research program of the National Heart, Lung, and Blood Institute (NHLBI). The ARIC study has been funded in whole or in part with federal funds from the NHLBI; the National Institutes of Health (NIH); and the Department of Health and Human Services.

Toxicology of pharmaceutical and nutritional longevity compounds.

Aging is the most prominent risk factor for many diseases, which is considered to be a complicated biological process. The rate of aging depends on the effectiveness of important mechanisms such as the protection of DNA from free radicals, which protects the structural and functional integrity of cells and tissues. In any organism, not all organs may age at the same rate. Slowing down primary aging and reaching maximum lifespan is the most basic necessity. In this process, it may be possible to slow down or stabilise some diseases by using the compounds for both dietary and pharmacological purposes. Natural compounds with antioxidant and anti-inflammatory effects, mostly plant-based nutraceuticals, are preferred in the treatment of age-related chronic diseases and can also be used for other diseases. An increasing number of long-term studies on synthetic and natural compounds aim to elucidate preclinically and clinically the mechanisms underlying being healthy and prolongation of life. To delay age-related diseases and prolong the lifespan, it is necessary to take these compounds with diet or pharmaceuticals, along with detailed toxicological results. In this review, the most promising and utilised compounds will be highlighted and it will be discussed whether they have toxic effects in short/long-term use, although they are thought to be used safely.

Association between a Mediterranean lifestyle and growth differentiation factor 15: The seniors ENRICA-2 cohort

BackgroundGrowth Differentiation Factor 15 (GDF-15) is a marker of inflammation and oxidative stress that has been associated with multiple age-related chronic diseases. Since lifestyle is key for preventing these adverse health outcomes, we examined the association between a Mediterranean lifestyle and GDF-15 serum concentrations in Spanish older adults. MethodsWe used cross-sectional data from 2502 older adults participating in the Seniors ENRICA-2 cohort. Adherence to the Mediterranean lifestyle was assessed with the 27-item MEDLIFE index, divided into three blocks: 1) “Mediterranean food consumption, 2) Mediterranean dietary habits, 3) Physical activity, rest, social habits, and conviviality”. Analyses of the association between the MEFLIFE index and GDF-15 concentrations were performed using multivariable linear regression models adjusting for the main potential confounders. ResultsThe MEDLIFE index was inversely associated with GDF-15. Compared with participants in the lowest quartile of the MEDLIFE score, GDF-15 mean percentage differences (95% CI) were −3.0% (−8.0, 2.3) for the second quartile, −8.7% (−13.0, −4.1) for the third quartile, and −10.1% (−15.0, −4.9) for the fourth quartile (p-trend<0.001). Block 3 of MEDLIFE, and particularly doing sufficient physical activity, adequate sleep duration, and participating in collective sports, was individually linked to lower concentrations of GDF-15. Results remained similar after excluding participants with cardiovascular disease, type 2 diabetes, or obesity. ConclusionsA Mediterranean lifestyle was associated with reduced levels of GDF-15, suggesting that a combination of multiple lifestyles may be an integral approach to reduce chronic inflammation and disease burden in older adults.

Does the trained immune system play an important role in the extreme longevity that is seen in the Sardinian blue zone?

Villages in the island of Sardinia in the Mediterranean that display exceptional longevity are clustered within a defined mountainous region. Because of their unique location we hypothesize that these villages had a unique infectious disease exposure relevant to the observed successful longevity. These highland villages had a significant exposure to malaria in the first half of the 20th century after which malaria was eliminated due to vector control mechanisms. In addition, there is likely a high incidence of Helicobacter pylori infections among shepherds in Sardinia, the primary occupation of many living in the LBZ, as well as helminth infections among children. This suggests that individuals living in the LBZ had a unique infectious disease exposure. Specifically, we hypothesize that the continued high exposure of residents in the LBZ to these infectious agents prior to the 1950s lead to the generation of a uniquely trained (or imprinted) immune system. Once some of these diseases were eliminated in the latter half of the century, individuals within the LBZ were equipped with a trained immune system that was uniquely capable of not only responding effectively to common infections but also responding in a manner that maximized maintaining tissue health. In addition, there are lifestyle factors that also favor such a trained immune system. This hypothesis may help explain the slow progression of chronic immune mediated diseases as well as other chronic non-transmissible age-related diseases seen in the Sardinian LBZ and serve as a template for future studies that support or refute this hypothesis.

Loss of Y in leukocytes as a risk factor for critical COVID-19 in men

BackgroundThe COVID-19 pandemic, which has a prominent social and economic impact worldwide, shows a largely unexplained male bias for the severity and mortality of the disease. Loss of chromosome Y (LOY) is a risk factor candidate in COVID-19 due to its prior association with many chronic age-related diseases, and its impact on immune gene transcription.MethodsPublicly available scRNA-seq data of PBMC samples derived from male patients critically ill with COVID-19 were reanalyzed, and LOY status was added to the annotated cells. We further studied LOY in whole blood for 211 COVID-19 patients treated at intensive care units (ICU) from the first and second waves of the pandemic. Of these, 139 patients were subject to cell sorting for LOY analysis in granulocytes, low-density neutrophils (LDNs), monocytes, and PBMCs.ResultsReanalysis of available scRNA-seq data revealed LDNs and monocytes as the cell types most affected by LOY. Subsequently, DNA analysis indicated that 46%, 32%, and 29% of critically ill patients showed LOY above 5% cut-off in LDNs, granulocytes, and monocytes, respectively. Hence, the myeloid lineage that is crucial for the development of severe COVID-19 phenotype is affected by LOY. Moreover, LOY correlated with increasing WHO score (median difference 1.59%, 95% HDI 0.46% to 2.71%, p=0.025), death during ICU treatment (median difference 1.46%, 95% HDI 0.47% to 2.43%, p=0.0036), and history of vessel disease (median difference 2.16%, 95% HDI 0.74% to 3.7%, p=0.004), among other variables. In 16 recovered patients, sampled during ICU stay and 93–143 days later, LOY decreased significantly in whole blood and PBMCs. Furthermore, the number of LDNs at the recovery stage decreased dramatically (median difference 76.4 per 10,000 cell sorting events, 95% HDI 55.5 to 104, p=6e−11).ConclusionsWe present a link between LOY and an acute, life-threatening infectious disease. Furthermore, this study highlights LOY as the most prominent clonal mutation affecting the myeloid cell lineage during emergency myelopoiesis. The correlation between LOY level and COVID-19 severity might suggest that this mutation affects the functions of monocytes and neutrophils, which could have consequences for male innate immunity.

Brain ageing in schizophrenia: evidence from 26 international cohorts via the ENIGMA Schizophrenia consortium

Schizophrenia (SZ) is associated with an increased risk of life-long cognitive impairments, age-related chronic disease, and premature mortality. We investigated evidence for advanced brain ageing in adult SZ patients, and whether this was associated with clinical characteristics in a prospective meta-analytic study conducted by the ENIGMA Schizophrenia Working Group. The study included data from 26 cohorts worldwide, with a total of 2803 SZ patients (mean age 34.2 years; range 18–72 years; 67% male) and 2598 healthy controls (mean age 33.8 years, range 18–73 years, 55% male). Brain-predicted age was individually estimated using a model trained on independent data based on 68 measures of cortical thickness and surface area, 7 subcortical volumes, lateral ventricular volumes and total intracranial volume, all derived from T1-weighted brain magnetic resonance imaging (MRI) scans. Deviations from a healthy brain ageing trajectory were assessed by the difference between brain-predicted age and chronological age (brain-predicted age difference [brain-PAD]). On average, SZ patients showed a higher brain-PAD of +3.55 years (95% CI: 2.91, 4.19; I2 = 57.53%) compared to controls, after adjusting for age, sex and site (Cohen’s d = 0.48). Among SZ patients, brain-PAD was not associated with specific clinical characteristics (age of onset, duration of illness, symptom severity, or antipsychotic use and dose). This large-scale collaborative study suggests advanced structural brain ageing in SZ. Longitudinal studies of SZ and a range of mental and somatic health outcomes will help to further evaluate the clinical implications of increased brain-PAD and its ability to be influenced by interventions.

Diagnosis of COVID-19 in a geriatric patient hospitalised for fall with initial misinterpreted aspiration pneumonia

BACKGROUND SARS-CoV-2 is a virus which is more aggressive in aged patients with associated chronic age-related diseases. Although it is known that clinical picture of COVID-19 is already multifaceted, very little is still known about the infectious syndrome in aged patients. We present a case of an aged patient hospitalized for fall affected from Covid19 pneumonia, initially misinterpreted for an aspiration pneumonia. CASE PRESENTATION We describe the case of a 92 years patient with chronic heart diseases, hospitalized for fall complicated by head trauma. She was diagnosed with an aspiration pneumonia due to the fall so that she was put under antibiotics treatment. Despite four days of antibiotics treatment, the patient presented high fever and dry cough motivating in an epidemic period the nasopharyngeal PCR test for the research of SARS-CoV-2 which resulted positive. DISCUSSION AND CONCLUSION Aspiration pneumonia resulting from a fall is a common finding in geriatric patients, that’s why the diagnosis of COVID-19 was delayed. The geriatric population often have an altered clinical presentation of diseases, in particular regarding infectious diseases. The correct interpretation of some suspicious findings such as regular blood tests would have led more quickly to a diagnosis of non-aspiration pneumonia. Inflammatory markers and white blood cell count resulted within the normal range. Moreover, lymphopenia, considered as one of the biological features of COVID-19, was the only tract that appeared once the patient started to have symptoms. The presence of confusion as a sign of persisting infection in an older patient should not be underestimated, expression of a possible involvement of nervous system in SARS-CoV-2 infection. The common diagnosis of aspiration pneumonia in the geriatric field, the aspecific signs and symptoms of COVID-19 disease, the complex picture of our patient, prove that in geriatrics an apparently simple diagnosis could instead be insidious and complex.