Role of Senescence and Aging in SARS-CoV-2 Infection and COVID-19 Disease

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has resulted in a global pandemic associated with substantial morbidity and mortality worldwide, with particular risk for severe disease and mortality in the elderly population. SARS-CoV-2 infection is driven by a pathological hyperinflammatory response which results in a dysregulated immune response. Current advancements in aging research indicates that aging pathways have fundamental roles in dictating healthspan in addition to lifespan. Our review discusses the aging immune system and highlights that senescence and aging together, play a central role in COVID-19 pathogenesis. In our review, we primarily focus on the immune system response to SARS-CoV-2 infection, the interconnection between severe COVID-19, immunosenescence, aging, vaccination, and the emerging problem of Long-COVID. We hope to highlight the importance of identifying specific senescent endotypes (or “sendotypes”), which can used as determinants of COVID-19 severity and mortality. Indeed, identified sendotypes could be therapeutically exploited for therapeutic intervention. We highlight that senolytics, which eliminate senescent cells, can target aging-associated pathways and therefore are proving attractive as potential therapeutic options to alleviate symptoms, prevent severe infection, and reduce mortality burden in COVID-19 and thus ultimately enhance healthspan

Genomic, Proteomic and Phenotypic Biomarkers of COVID-19 Severity::Protocol for a Retrospective Observational Study

Background:Background - Health organisations and countries around the world have found it difficult to control the spread of the coronavirus disease 2019. To minimise the impact on the NHS and improve patient care, there is a drive for rapid tests capable of detecting individuals who are at high risk of contracting severe COVID-19. Early work focused on single omic approaches, highlighting a limited amount of information.Objective:Objective - The Covid Response Study (COVRES, NCT05548829) aims to carry out an integrated multi-omic analysis of factors contributing to host susceptibility to SARS-CoV-2 among a patient cohort of 1000 people from the geographically isolated island of Ireland.Methods:Methods - The protocol below describes the study to be carried out in Northern Ireland (NI-COVRES) by Ulster University, the Republic of Ireland component will be described separately. All participants (n=519) were recruited from the Western Health and Social Care Trust, Northern Ireland, forty patients are also being followed up at 1, 3, 6 and 12 months to assess the longitudinal impact of infection on symptoms, general health, and immune response, this is ongoing. Data will be sourced from whole blood, saliva samples, and clinical data from the Northern Ireland Electronic Care Record, general health questionnaire, and the GHQ12 mental health survey. Saliva and blood samples were processed for DNA and RNA prior to whole genomic sequencing, RNA sequencing, DNA methylation, microbiome, 16S, and proteomic analysis. Multi-omics data will be combined with clinical data to produce sensitive and specific prognostic models of severity risk.Results:Results - An initial profile of the cohort has been completed: n=249 hospitalised and n=270 non-hospitalised patients were recruited, 64% were female, the mean age was 45 years. High levels of comorbidity were evident in the hospitalised cohort, with cardiovascular disease and metabolic and respiratory disorders (P<0.001) being the most significant.Conclusions:Conclusion – This study will provide a comprehensive opportunity to study multi-omic mechanisms of COVID-19 severity in re-contactable participants. Clinical Trial: Trial Registration - The trial has been registered as an observational study on clinicaltrials.gov as NCT05548829. An outline of the trial protocol is included; SPIRIT checklist (Supplementary Figure 1)

Prognostic value of the 6-gene OncoMasTR test in hormone receptor–positive HER2-negative early-stage breast cancer: Comparative analysis with standard clinicopathological factors

Aim: The aim of the study was to assess the prognostic performance of a 6-gene molecular score (OncoMasTR Molecular Score [OMm]) and a composite risk score (OncoMasTR Risk Score [OM]) and to conduct a within-patient comparison against four routinely used molecular and clinicopathological risk assessment tools: Oncotype DX Recurrence Score, Ki67, Nottingham Prognostic Index and Clinical Risk Category, based on the modified Adjuvant! Online definition and three risk factors: patient age, tumour size and grade. Methods: Biospecimens and clinicopathological information for 404 Irish women also previously enrolled in the Trial Assigning Individualized Options for Treatment [Rx] were provided by 11 participating hospitals, as the primary objective of an independent translational study. Gene expression measured via RT-qPCR was used to calculate OMm and OM. The prognostic value for distant recurrence-free survival (DRFS) and invasive disease-free survival (IDFS) was assessed using Cox proportional hazards models and Kaplan-Meier analysis. All statistical tests were two-sided ones. Results: OMm and OM (both with likelihood ratio statistic [LRS] P Discussion: Both OncoMasTR scores were significantly prognostic for DRFS and IDFS and provided additional prognostic information to the molecular and clinicopathological risk factors/tools assessed. OM was also the most accurate risk classification tool for identifying DR. A concise 6-gene signature with superior risk stratification was shown to increase prognosis reliability, which may help clinicians optimise treatment decisions. Trial registration: ClinicalTrials.gov NCT02050750 NCT00310180.</p