Age-dependent Factors Research Articles

Evidence for a role of human blood-borne factors in mediating age-associated changes in molecular circadian rhythms.

Aging is associated with a number of physiologic changes including perturbed circadian rhythms; however, mechanisms by which rhythms are altered remain unknown. To test the idea that circulating factors mediate age-dependent changes in peripheral rhythms, we compared the ability of human serum from young and old individuals to synchronize circadian rhythms in culture. We collected blood from apparently healthy young (age 25-30) and old (age 70-76) individuals at 14:00 and used the serum to synchronize cultured fibroblasts. We found that young and old sera are equally competent at initiating robust ~24 hr oscillations of a luciferase reporter driven by clock gene promoter. However, cyclic gene expression is affected, such that young and old sera promote cycling of different sets of genes. Genes that lose rhythmicity with old serum entrainment are associated with oxidative phosphorylation and Alzheimer's Disease as identified by STRING and IPA analyses. Conversely, the expression of cycling genes associated with cholesterol biosynthesis increased in the cells entrained with old serum. Genes involved in the cell cycle and transcription/translation remain rhythmic in both conditions. We did not observe a global difference in the distribution of phase between groups, but found that peak expression of several clock-controlled genes (PER3, NR1D1, NR1D2, CRY1, CRY2, and TEF) lagged in the cells synchronized ex vivo with old serum. Taken together, these findings demonstrate that age-dependent blood-borne factors affect circadian rhythms in peripheral cells and have the potential to impact health and disease via maintaining or disrupting rhythms respectively.

Age-dependent predictors of effective reinforcement motor learning across childhood.

Across development, children must learn motor skills such as eating with a spoon and drawing with a crayon. Reinforcement learning, driven by success and failure, is fundamental to such sensorimotor learning. It typically requires a child to explore movement options along a continuum (grip location on a crayon) and learn from probabilistic rewards (whether the crayon draws or breaks). Here, we studied the development of reinforcement motor learning using online motor tasks to engage children aged 3 to 17 and adults (cross-sectional sample, N=385). Participants moved a cartoon penguin across a scene and were rewarded (animated cartoon clip) based on their final movement position. Learning followed a clear developmental trajectory when participants could choose to move anywhere along a continuum and the reward probability depended on final movement position. Learning was incomplete or absent in 3 to 8-year-olds and gradually improved to adult-like levels by adolescence. A reinforcement learning model fit to each participant identified three age-dependent factors underlying improvement: amount of exploration after a failed movement, learning rate, and level of motor noise. We predicted, and confirmed, that switching to discrete targets and deterministic reward would improve 3 to 8-year-olds' learning to adult-like levels by increasing exploration after failed movements. Overall, we show a robust developmental trajectory of reinforcement motor learning abilities under ecologically relevant conditions i.e., continuous movement options mapped to probabilistic reward. This learning appears to be limited by immature spatial processing and probabilistic reasoning abilities in young children and can be rescued by reducing the demands in these domains.

Evidence for a role of human blood-borne factors in mediating age-associated changes in molecular circadian rhythms.

Aging is associated with a number of physiologic changes including perturbed circadian rhythms; however, mechanisms by which rhythms are altered remain unknown. To test the idea that circulating factors mediate age-dependent changes in peripheral rhythms, we compared the ability of human serum from young and old individuals to synchronize circadian rhythms in culture. We collected blood from apparently healthy young (age 25-30) and old (age 70-76) individuals at 14:00 and used the serum to synchronize cultured fibroblasts. We found that young and old sera are equally competent at initiating robust ~24h oscillations of a luciferase reporter driven by clock gene promoter. However, cyclic gene expression is affected, such that young and old sera promote cycling of different sets of genes. Genes that lose rhythmicity with old serum entrainment are associated with oxidative phosphorylation and Alzheimer's Disease as identified by STRING and IPA analyses. Conversely, the expression of cycling genes associated with cholesterol biosynthesis increased in the cells entrained with old serum. Genes involved in the cell cycle and transcription/translation remain rhythmic in both conditions. We did not observe a global difference in the distribution of phase between groups, but found that peak expression of several clock-controlled genes (PER3, NR1D1, NR1D2, CRY1, CRY2, and TEF) lagged in the cells synchronized ex vivo with old serum. Taken together, these findings demonstrate that age-dependent blood-borne factors affect circadian rhythms in peripheral cells and have the potential to impact health and disease via maintaining or disrupting rhythms respectively.

Pharmacokinetic Modeling of Bepotastine for Determination of Optimal Dosage Regimen in Pediatric Patients with Allergic Rhinitis or Urticaria.

Bepotastine, a second-generation antihistamine for allergic rhinitis and urticaria, is widely used in all age groups but lacks appropriate dosing guidelines for pediatric patients, leading to off-label prescriptions. We conducted this study to propose an optimal dosing regimen for pediatric patients based on population pharmacokinetic (popPK) and physiologically based pharmacokinetic (PBPK) models using data from two previous trials. A popPK model was built using NONMEM software. A one-compartment model with first-order absorption and absorption lag time described our data well, with body weight incorporated as the only covariate. A PBPK model was developed using PK-Sim software version 10, and the model well predicted the drug concentrations obtained from pediatric patients. Furthermore, the final PBPK model showed good concordance with the known properties of bepotastine. Appropriate pediatric doses for different weight and age groups were proposed based on the simulations. Discrepancies in recommended doses from the two models were likely due to the incorporation of age-dependent physiological factors in the PBPK model. In conclusion, our study is the first to suggest an optimal oral dosing regimen of bepotastine in pediatric patients using both approaches. This is expected to foster safer and more productive use of the drug.

Age-Dependent Female Survival Advantage in Hepatocellular Carcinoma: A Multicenter Cohort Study

Hepatocellular carcinoma (HCC) has a higher incidence in males, but the association of sex with survival remains controversial. This study aimed to examine the effect of sex on HCC survival and its association with age. Among 33,238 patients with HCC from 12 Chinese tertiary hospitals, 4175 patients who underwent curative-intent hepatectomy or ablation were analyzed. Cancer-specific survival (CSS) was analyzed using Cox regression and Kaplan-Meier methods. Two propensity score methods and multiple mediation analysis were applied to mitigate confounding. To explore the effect of estrogen, a candidate sex-specific factor that changes with age, female participants' history of estrogen use, and survival were analyzed. There were 3321 males and 854 females included. A sex-related disparity of CSS was present and showed a typical age-dependent pattern: a female survival advantage over males appeared at the perimenopausal age of 45 to 54 years (hazard risk [HR], 0.77; 5-year CSS, 85.7% vs 70.6%; P= .018), peaked at the early postmenopausal age of 55 to 59 years (HR, 0.57; 5-year CSS, 89.8% vs 73.5%; P= .015), and was not present in the premenopausal (<45 y) and late postmenopausal groups (≥60 y). Consistent patterns were observed in patients after either ablation or hepatectomy. These results were sustained with propensity score analyses. Confounding or mediation effects accounted for only 19.5% of sex survival disparity. Female estrogen users had significantly longer CSS than nonusers (HR, 0.74; 5-year CSS, 79.6% vs 72.5%; P= .038). A female survival advantage in HCC depends on age, and this may be associated with age-dependent, sex-specific factors.

Pharmacotherapeutic potential of walnut (Juglans spp.) in age-related neurological disorders.

Global and regional trends of population aging spotlight major public health concerns. As one of the most common adverse prognostic factors, advanced age is associated with a remarkable incidence risk of many non-communicable diseases, affecting major organ systems of the human body. Age-dependent factors and molecular processes can change the nervous system's normal function and lead to neurodegenerative disorders. Oxidative stress results from of a shift toward reactive oxygen species (ROS) production in the equilibrium between ROS generation and the antioxidant defense system. Oxidative stress and neuroinflammation caused by Amyloid-ß protein deposition in the human brain are the most likely pathogenesis of Alzheimer's disease (AD). Walnut extracts could reduce Amyloid-ß fibrillation and aggregation, indicating their beneficial effects on memory and cognition. Walnut can also improve movement disabilities in Parkinson's disease due to their antioxidant and neuroprotective effect by reducing ROS and nitric oxide (NO) generation and suppressing oxidative stress. It is noteworthy that Walnut compounds have potential antiproliferative effects on Glioblastoma (the most aggressive primary cerebral neoplasm). This effective therapeutic agent can stimulate apoptosis of glioma cells in response to oxidative stress, concurrent with preventing angiogenesis and migration of tumor cells, improving the quality of life and life expectancy of patients with glioblastoma. Antioxidant Phenolic compounds of the Walnut kernel could explain the significant anti-convulsion ability of Walnut to provide good prevention and treatment for epileptic seizures. Moreover, the anti-inflammatory effect of Walnut oil could be beneficial in treating multiple sclerosis. In this study, we review the pharmaceutical properties of Walnut in age-related neurological disorders.

Sex differences in the associations of body size and body shape with platelets in the UK Biobank cohort

BackgroundObesity is accompanied by low-grade inflammation and leucocytosis and increases the risk of venous thromboembolism. Associations with platelet count, however, are unclear, because several studies have reported positive associations only in women. Associations with body shape are also unclear, because waist and hip circumferences reflect overall body size, as well as body shape, and are correlated strongly positively with body mass index (BMI).MethodsWe evaluated body shape with the allometric body shape index (ABSI) and hip index (HI), which reflect waist and hip size among individuals with the same weight and height and are uncorrelated with BMI. We examined the associations of BMI, ABSI, and HI with platelet count, mean platelet volume (MPV), and platelet distribution width (PDW) in multivariable linear regression models for 125,435 UK Biobank women and 114,760 men. We compared men with women, post-menopausal with pre-menopausal women, and older (≥ 52 years) with younger (< 52 years) men.ResultsBMI was associated positively with platelet count in women, more strongly in pre-menopausal than in post-menopausal, and weakly positively in younger men but strongly inversely in older men. Associations of BMI with platelet count were shifted towards the inverse direction for daily alcohol consumption and current smoking, resulting in weaker positive associations in women and stronger inverse associations in men, compared to alcohol ≤ 3 times/month and never smoking. BMI was associated inversely with MPV and PDW in pre-menopausal women but positively in post-menopausal women and in men. ABSI was associated positively with platelet count, similarly in women and men, while HI was associated weakly inversely only in women. ABSI was associated inversely and HI positively with MPV but not with PDW and only in women. Platelet count was correlated inversely with platelet size and positively with leucocyte counts, most strongly with neutrophils.ConclusionsCompeting factors determine the associations of BMI with platelet count. Factors with sexually dimorphic action (likely thrombopoietin, inflammatory cytokines, or cortisol), contribute to a positive association, more prominently in women than in men, while age-dependent factors (likely related to liver damage and fibrosis), contribute to an inverse association, more prominently in men than in women.

Age-Dependent Effects of Transgenic 2D2 Mice Used to Induce Passive Experimental Autoimmune Encephalomyelitis in C57BL/6 Mice

Introduction: Multiple sclerosis (MS) is a neurodegenerative autoimmune disease that worsens with age. Here, we examined the influence of age on passive experimental autoimmune encephalomyelitis (P-EAE), a model to study MS, using young and mature adult 2D2 transgenic donor mice to induce pathology in WT C57BL6/J mice. Methods: Lymphocytes from young adult (i.e., 10-week-old) or mature adult (i.e., 6-month-old) transgenic donor mice were characterized by flow cytometry prior to injection of cultured leukocytes into adult female WT recipient mice, with a special focus on transgenic T cell phenotypes. Results: Our findings show age-dependent changes in memory T cell phenotypes correlated with more severe clinical and histological disease when donor cells originated from young as compared to mature adult mice. Conclusion: Not only do these results demonstrate that the age of the 2D2 transgenic donor mice is critical in establishing P-EAE, but the differential effects might also identify age-dependent factors that contribute to EAE and perhaps MS.

Determinants of RSV epidemiology following suppression through pandemic contact restrictions

IntroductionCOVID-19 related non-pharmaceutical interventions (NPIs) led to a suppression of RSV circulation in winter 2020/21 in the UK and an off-season resurgence in Summer 2021. We explore how the parameters of RSV epidemiology shape the size and dynamics of post-suppression resurgence and what we can learn about them from the resurgence patterns observed so far. MethodsWe developed an age-structured dynamic transmission model of RSV and sampled the parameters governing RSV seasonality, infection susceptibility and post-infection immunity, retaining simulations fitting the UK’s pre-pandemic epidemiology by a set of global criteria consistent with likelihood calculations. From Spring 2020 to Summer 2021 we assumed a reduced contact frequency, returning to pre-pandemic levels from Spring 2021. We simulated transmission forwards until 2023 and evaluated the impact of the sampled parameters on the projected trajectories of RSV hospitalisations and compared these to the observed resurgence. ResultsSimulations replicated an out-of-season resurgence of RSV in 2021. If unmitigated, paediatric RSV hospitalisation incidence in the 2021/22 season was projected to increase by 30–60% compared to pre-pandemic levels. The increase was larger if infection risk was primarily determined by immunity acquired from previous exposure rather than age-dependent factors, exceeding 90 % and 130 % in 1–2 and 2–5 year old children, respectively. Analysing the simulations replicating the observed early outbreak in 2021 in addition to pre-pandemic RSV data, we found they were characterised by weaker seasonal forcing, stronger age-dependence of infection susceptibility and higher baseline transmissibility. ConclusionCOVID-19 mitigation measures in the UK stopped RSV circulation in the 2020/21 season and generated immunity debt leading to an early off-season RSV epidemic in 2021. A stronger dependence of infection susceptibility on immunity from previous exposure increases the size of the resurgent season. The early onset of the RSV resurgence in 2021, its marginally increased size relative to previous seasons and its decline by January 2022 suggest a stronger dependence of infection susceptibility on age-related factors, as well as a weaker effect of seasonality and a higher baseline transmissibility. The pattern of resurgence has been complicated by contact levels still not back to pre-pandemic levels. Further fitting of RSV resurgence in multiple countries incorporating data on contact patterns will be needed to further narrow down these parameters and to better predict the pathogen’s future trajectory, planning for a potential expansion of new immunisation products against RSV in the coming years.

Visual imagery vividness declines across the lifespan

The capacity to elicit vivid visual mental images varies within an extensive range across individuals between hyper- and aphantasia. It is not clear, however, whether imagery vividness is constant across the lifespan or changes during development and later in life. Without enforcing the constraints of strict experimental procedures and representativity across the entire population, our purpose was to explore the self-reported level of imagery vividness and determine the relative proportions of aphantasic/hyperphantasic participants in different age groups. Relying on the frequently used Vividness of Visual Imagery Questionnaire, we collected data on a random sample of 2252 participants between the ages of 12–60 years. We found a novel developmental pattern that describes a declining ability to elicit vivid visual mental images in the group averages of different age groups from adolescence to middle age. This effect involves both a decreasing proportion of individuals with vivid visual imagery vividness and an increasing proportion of individuals with low imagery vividness as maturation (based on bone age assessments in adolescents) and ageing progress. These findings may shed some light on the developmental mechanisms of our internal, stimulus-independent processes, and might also help to determine genetic, maturational, and age-dependent factors in the cases of hyper- and aphantasia.

Post-lockdown changes of age-specific susceptibility and its correlation with adherence to social distancing measures

Social distancing measures are effective in reducing overall community transmission but much remains unknown about how they have impacted finer-scale dynamics. In particular, much is unknown about how changes of contact patterns and other behaviors including adherence to social distancing, induced by these measures, may have impacted finer-scale transmission dynamics among different age groups. In this paper, we build a stochastic age-specific transmission model to systematically characterize the degree and variation of age-specific transmission dynamics, before and after lifting the lockdown in Georgia, USA. We perform Bayesian (missing-)data-augmentation model inference, leveraging reported age-specific case, seroprevalence and mortality data. We estimate that overall population-level transmissibility was reduced to 41.2% with 95% CI [39%, 43.8%] of the pre-lockdown level in about a week of the announcement of the shelter-in-place order. Although it subsequently increased after the lockdown was lifted, it only bounced back to 62% [58%, 67.2%] of the pre-lockdown level after about a month. We also find that during the lockdown susceptibility to infection increases with age. Specifically, relative to the oldest age group (> 65+), susceptibility for the youngest age group (0–17 years) is 0.13 [0.09, 0.18], and it increases to 0.53 [0.49, 0.59] for 18–44 and 0.75 [0.68, 0.82] for 45–64. More importantly, our results reveal clear changes of age-specific susceptibility (defined as average risk of getting infected during an infectious contact incorporating age-dependent behavioral factors) after the lockdown was lifted, with a trend largely consistent with reported age-specific adherence levels to social distancing and preventive measures. Specifically, the older groups (> 45) (with the highest levels of adherence) appear to have the most significant reductions of susceptibility (e.g., post-lockdown susceptibility reduced to 31.6% [29.3%, 34%] of the estimate before lifting the lockdown for the 6+ group). Finally, we find heterogeneity in case reporting among different age groups, with the lowest rate occurring among the 0–17 group (9.7% [6.4%, 19%]). Our results provide a more fundamental understanding of the impacts of stringent lockdown measures, and finer evidence that other social distancing and preventive measures may be effective in reducing SARS-CoV-2 transmission. These results may be exploited to guide more effective implementations of these measures in many current settings (with low vaccination rate globally and emerging variants) and in future potential outbreaks of novel pathogens.

Development of age-estimation formula using postmortem oral findings: A pilot study.

The goal of this pilot study was to develop an age-estimation formula and assess its effectiveness after evaluating individual intraoral findings. A total of 198 Japanese adults were included, and intraoral findings were collected from the corpses. To analyze the condition of each tooth, 20 items were established for intraoral findings, and seven tooth states were established. Logistic regression analysis was used to estimate the impact of age on each intraoral finding. Sequentially, linear regression was applied to verify the correlation between age and type of tooth, and multiple regression was used to correlate age-dependent factors. The intraoral findings with age dependency were tooth stump, edentulous jaw, attrition, no caries, dental prostheses, partial dentures, and complete dentures. Tooth stump, attrition, and dental prostheses showed positive multicollinearity. Missing tooth, extant tooth, normal teeth, and untreated lost teeth were age-correlated. Multiple regression analysis included age as the response variable and five factors as the explanatory variables in a new age-estimation formula, resulting in±10years for 86.96% of cases (60-69years old), 76.47% (70-79years old), and 61.05% of all cases. The multiple correlation was 0.551, and the contribution rate of the multiple regression formula was 0.304. The accuracy of the proposed age-estimation formula was within±10years for 61.05% of all subjects. However, the accuracy of age estimation in subjects aged 60-79years was excellent (76.47-86.96%), which showed that this age-estimation formula would be effective for estimating the age of middle-aged to older subjects.

Vaccination and non-pharmaceutical interventions for COVID-19: a mathematical modelling study

SummaryBackgroundThe dynamics of vaccination against SARS-CoV-2 are complicated by age-dependent factors, changing levels of infection, and the relaxation of non-pharmaceutical interventions (NPIs) as the perceived risk declines, necessitating the use of mathematical models. Our aims were to use epidemiological data from the UK together with estimates of vaccine efficacy to predict the possible long-term dynamics of SARS-CoV-2 under the planned vaccine rollout.MethodsIn this study, we used a mathematical model structured by age and UK region, fitted to a range of epidemiological data in the UK, which incorporated the planned rollout of a two-dose vaccination programme (doses 12 weeks apart, protection onset 14 days after vaccination). We assumed default vaccine uptake of 95% in those aged 80 years and older, 85% in those aged 50–79 years, and 75% in those aged 18–49 years, and then varied uptake optimistically and pessimistically. Vaccine efficacy against symptomatic disease was assumed to be 88% on the basis of Pfizer-BioNTech and Oxford-AstraZeneca vaccines being administered in the UK, and protection against infection was varied from 0% to 85%. We considered the combined interaction of the UK vaccination programme with multiple potential future relaxations (or removals) of NPIs, to predict the reproduction number (R) and pattern of daily deaths and hospital admissions due to COVID-19 from January, 2021, to January, 2024.FindingsWe estimate that vaccination alone is insufficient to contain the outbreak. In the absence of NPIs, even with our most optimistic assumption that the vaccine will prevent 85% of infections, we estimate R to be 1·58 (95% credible intervals [CI] 1·36–1·84) once all eligible adults have been offered both doses of the vaccine. Under the default uptake scenario, removal of all NPIs once the vaccination programme is complete is predicted to lead to 21 400 deaths (95% CI 1400–55 100) due to COVID-19 for a vaccine that prevents 85% of infections, although this number increases to 96 700 deaths (51 800–173 200) if the vaccine only prevents 60% of infections. Although vaccination substantially reduces total deaths, it only provides partial protection for the individual; we estimate that, for the default uptake scenario and 60% protection against infection, 48·3% (95% CI 48·1–48·5) and 16·0% (15·7–16·3) of deaths will be in individuals who have received one or two doses of the vaccine, respectively.InterpretationFor all vaccination scenarios we investigated, our predictions highlight the risks associated with early or rapid relaxation of NPIs. Although novel vaccines against SARS-CoV-2 offer a potential exit strategy for the pandemic, success is highly contingent on the precise vaccine properties and population uptake, both of which need to be carefully monitored.FundingNational Institute for Health Research, Medical Research Council, and UK Research and Innovation.

Vaccination and Non-Pharmaceutical Interventions: When Can the UK Relax About COVID-19?

Background: The announcement of efficacious vaccine candidates against SARS-CoV-2 has been met with worldwide acclaim and relief. Many countries already have detailed plans for vaccine targeting based on minimising severe illness, death and healthcare burdens. Normally, relatively simple relationships between epidemiological parameters, vaccine efficacy and vaccine uptake predict the success of any immunisation programme. However, the dynamics of vaccination against SARS-CoV-2 is made more complex by age-dependent factors, changing levels of infection and the potential relaxation of non-pharmaceutical interventions (NPIs) as the perceived risk declines. Methods: In this study we use an age-structured mathematical model, matched to a range of epidemiological data, which also captures the roll-out of a two-dose vaccination programme targeted at specific age groups. Findings: We consider the interaction between the UK vaccination programme and future re- laxation (or removal) of NPIs. Our predictions highlight the population-level risks of early relaxation leading to a pronounced wave of infection, hospital admissions and deaths. Only vaccines that offer high transmission-blocking efficacy with high uptake in the general population allow relaxation of NPIs without a huge surge in deaths. Interpretation: While the novel vaccines against SARS-CoV-2 offer a potential exit strategy for this outbreak, this is highly contingent on the transmission blocking action of the vaccine and the population uptake, both of which need to be carefully monitored as vaccine programmes are rolled out in the UK and other countries.Funding Statement: This research was funded by the National Institute for Health Research (NIHR) [Policy Research Programme, Mathematical & Economic Modelling for Vaccination and Immunisation Evaluation, and Emergency Response; NIHR200411], the Medical Research Council through the COVID- 19 Rapid Response Rolling Call [grant number MR/V009761/1] and through the JUNIPER modelling consortium [grant number EP/V030477/1]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Declaration of Interests: All authors declare that they have no competing interests.Ethics Approval Statement: The data were supplied from the CHESS database after anonymisation under strict data protection protocols agreed between the University of Warwick and Public Health England. The ethics of the use of these data for these purposes was agreed by Public Health England with the Government’s SPI-M(O) / SAGE committees.

ACCELERATED CELL DEATH 6 Acts on Natural Leaf Senescence and Nitrogen Fluxes in Arabidopsis.

As the last step of leaf development, senescence is a molecular process involving cell death mechanism. Leaf senescence is trigged by both internal age-dependent factors and environmental stresses. It must be tightly regulated for the plant to adopt a proper response to environmental variation and to allow the plant to recycle nutrients stored in senescing organs. However, little is known about factors that regulate both nutrients fluxes and plant senescence. Taking advantage of variation for natural leaf senescence between Arabidopsis thaliana accessions, Col-0 and Ct-1, we did a fine mapping of a quantitative trait loci for leaf senescence and identified ACCELERATED CELL DEATH 6 (ACD6) as the causal gene. Using two near-isogeneic lines, differing solely around the ACD6 locus, we showed that ACD6 regulates rosette growth, leaf chlorophyll content, as well as leaf nitrogen and carbon percentages. To unravel the role of ACD6 in N remobilization, the two isogenic lines and acd6 mutant were grown and labeled with 15N at the vegetative stage in order to determine 15N partitioning between plant organs at harvest. Results showed that N remobilization efficiency was significantly lower in all the genotypes with lower ACD6 activity irrespective of plant growth and productivity. Measurement of N uptake at vegetative and reproductive stages revealed that ACD6 did not modify N uptake efficiency but enhanced nitrogen translocation from root to silique. In this study, we have evidenced a new role of ACD6 in regulating both sequential and monocarpic senescences and disrupting the balance between N remobilization and N uptake that is required for a good seed filling.

RGL2 as an age-dependent factor regulates colon cancer progression

Colon cancer is the fourth leading cause of cancer-related death, and exhibited clinical differences among patients of different ages, including malignancy, metastasis, and mortality rate. Few studies, however, focus on the communications between aging and colon cancer. Here we identified age-dependent differentially expressed genes (DEGs) in colon cancer using TCGA transcriptome data. Through analyzing multi-omics high throughput data, including ATAC-Seq, DNaseI-Seq and ChIP-Seq, we obtained six age-dependent transcription factors in colon cancer, and their age-dependent targets, significantly affecting patients’ overall survivals. Transcription factor ETS1 potentially functioned in both aging process and colon cancer progression through regulating its targets, RGL2 and SLC2A3. In addition, comparing with its relative lower expression levels in elderly patients, higher levels of RGL2 were detected in young patients, and significantly associated with larger tumor size, higher metastasis, and invasions of colon cancer, consistent with the clinical traits that young patients’ colon cancer exhibited late stages with more aggressiveness. Thus, these elements may serve as keys linking aging and colon cancer, and providing new insights and basis for mechanism researches, as well as diagnosis and therapies of colon cancer, especially in young patients.

Glioblastoma as an age-related neurological disorder in adults.

BackgroundAdvanced age is a major risk factor for the development of many diseases including those affecting the central nervous system. Wild-type isocitrate dehydrogenase glioblastoma (IDHwt GBM) is the most common primary malignant brain cancer and accounts for ≥90% of all adult GBM diagnoses. Patients with IDHwt GBM have a median age of diagnosis at 68–70 years of age, and increasing age is associated with an increasingly worse prognosis for patients with this type of GBM.MethodsThe Surveillance, Epidemiology, and End Results, The Cancer Genome Atlas, and the Chinese Glioma Genome Atlas databases were analyzed for mortality indices. Meta-analysis of 80 clinical trials was evaluated for log hazard ratio for aging to tumor survivorship.ResultsDespite significant advances in the understanding of intratumoral genetic alterations, molecular characteristics of tumor microenvironments, and relationships between tumor molecular characteristics and the use of targeted therapeutics, life expectancy for older adults with GBM has yet to improve.ConclusionsBased upon the results of our analysis, we propose that age-dependent factors that are yet to be fully elucidated, contribute to IDHwt GBM patient outcomes.

The Age-Related Risk of Severe Outcomes Due to COVID-19 Infection: A Rapid Review, Meta-Analysis, and Meta-Regression.

Increased age appears to be a strong risk factor for COVID-19 severe outcomes. However, studies do not sufficiently consider the age-dependency of other important factors influencing the course of disease. The aim of this review was to quantify the isolated effect of age on severe COVID-19 outcomes. We searched Pubmed to find relevant studies published in 2020. Two independent reviewers evaluated them using predefined inclusion and exclusion criteria. We extracted the results and assessed seven domains of bias for each study. After adjusting for important age-related risk factors, the isolated effect of age was estimated using meta-regression. Twelve studies met our inclusion criteria: four studies for COVID-19 disease severity, seven for mortality, and one for admission to ICU. The crude effect of age (5.2% and 13.4% higher risk of disease severity and death per age year, respectively) substantially decreased when adjusting for important age-dependent risk factors (diabetes, hypertension, coronary heart disease/cerebrovascular disease, compromised immunity, previous respiratory disease, renal disease). Adjusting for all six comorbidities indicates a 2.7% risk increase for disease severity (two studies), and no additional risk of death per year of age (five studies). The indication of a rather weak influence of age on COVID-19 disease severity after adjustment for important age-dependent risk factors should be taken in consideration when implementing age-related preventative measures (e.g., age-dependent work restrictions).

PERSISTENT CONCERNS: QUESTIONS FOR RESEARCH ON ETHNIC-RACIAL IDENTITY DEVELOPMENT

Research on ethnic-racial identity (ERI) and its development has increased exponentially over the past decade. In this paper we discuss five questions that the Lifespan ERI Study Group grappled with in our effort propose a lifespan model of ERI: (1) When does ERI development begin and end? (2) How do we account for age-dependent and contextually-initiated factors in ERI? (3) Should there be a reference point for healthy ERI, and if so, what is it? (4) How do the multiplicities of identity (intersectionality, multiracialism, whiteness) figure into our conceptualization of ERI? (5) How do we understand the role of ERI in pursuit of equity, diversity, and social justice? We note that these are persistent questions in ERI research, and thus our goal is to present our collective reckoning with these issues as well as our ponderings about why they persist. We conclude with recommendations forthe kinds of research questions, designs, and methods that developmental science, in particular, needs to pursue.

P0552EXPRESSION OF CNDP1 PROTEIN IS REGULATED BY AGE-DEPENDENT AND AKI-RELATED ASTRAGALUS MEMBRANACEOUS EFFECTS IN MICE

Abstract Background and Aims Astragalus membranaceus (AM) is widely used for herbal medicine in Asia (see http://nccih.nih.gov/health/astragalus). Until now, numerous findings about the AM effects have been provided in various tissues and organs; however, the therapeutic effects of AM against chronic kidney disease (CKD) remain unclear. Recent findings suggest that acute kidney injury (AKI), which has been previously believed to heal completely, is a promoting factor for CKD pathogenesis or progression. Our recent findings have been observed that susceptibility to AKI as well as AM effects against AKI was significant in old mice, suggesting that AM effects exert an age-dependent manner in kidney. Therefore, we further examined the therapeutic effect of AM against age-dependent AKI pathogenicity. Method Female C57BL/6 mice were collected blood in advance (0.2 ml as normal), separated to two groups, and administered with AM powder-mixed sterilized 0.5% methylcellulose 400 (w/v) (AM-administered group) or with sterilized 0.5% methylcellulose 400 (control group), respectively by two hours before surgery. Left renal artery was exposed and occluded by non-traumatic small clips for 20 minutes. Twenty hours after the renal reperfusion, we collected blood (0.2 ml as reaction) and acquired kidney from each mouse. These serum samples were measured to detect serum creatinine and urea nitrogen. The dissected kidneys were used for Western blot analysis to determine the expression of AM-target protein candidates, which were selected as both age-dependent and renal disease-related factors from research data base (NCBI, Bethesda MD USA). Results Sorting with the data base, we isolated a metabolic product, carnosine (beta-alanyl-L-histidine), which is abundant in young human blood samples and exerted a scavenger effects against the anti-oxidative stress. Carnosine is degraded by carnosinase encoded by CNDP1 gene, and its metabolism revealed renoprotective characterization including scavenger of reactive oxygens in various tissues. Furthermore, recent epidemiologic studies showed association between pathogenesis of diabetic nephropathy and CNDP1 gene polymorphism. Therefore, here we examined the levels of CNDP1 protein by Western blot analysis. CNDP1 protein was upregulated in ischemia-reperfusion kidneys significantly from old mice (52 weeks old), compared to those from young mice (6-8 weeks old) which showed little increased levels. The levels of CNDP1 protein were down-regulated by AM administration prior to ischemia-reperfusion in both old and young kidneys. These findings suggest that pharmacological effects of AM normalized carnosine metabolism by regulating expression of CNDP1, which plays a critical role in AKI pathogenesis of aged kidney. Conclusion AM administration can reduce day-to-day generated AKI by carnosine upregulation at least in part. The AM effects involved in carnosine metabolism would play a critical role in prolonging activity of aged kidney.