•INNOTEST HCV Ab IV is one of three WHO-prequalified EIAs for HCV screening in plasma/serum.•This was the first formal evaluation of a WHO-prequalified EIA in DBS samples.•Sensitivity and specificity ...in venous or fingerstick DBS versus plasma were 100 %.•Agreement was 100 % between all sample types in undiluted samples.•DBS represent an alternative sample type for this assay.
Dried blood spots (DBS) have potential to improve access to screening for antibodies to hepatitis C virus (HCV). However, although several studies on off-label use of DBS have been performed, to date no HCV antibody serology test is formally approved for use with DBS. This study evaluated the performance of the INNOTEST® HCV Ab IV enzyme immunoassay in paired DBS and plasma samples, to determine whether DBS may be added to the intended use.
Adults with no history of HCV treatment were prospectively enrolled from two sites in Ukraine. DBS were prepared from fingerstick whole blood (fDBS) and venous whole blood (vDBS) samples. Undiluted and serially diluted DBS and plasma samples were tested.
Samples from 149 HCV positive and 151 HCV negative participants were included.
Sensitivity and specificity of the INNOTEST® HCV Ab IV assay were both 100 % (95 % confidence intervals 95.7–100) for samples collected on fDBS or vDBS compared with plasma as the reference standard. In all undiluted samples, negative and positive percentage agreement and overall rate of agreement were 100 % between all sample types (Cohen's kappa coefficient of 1). In serially diluted samples, agreement was high (>95 %) between fDBS and vDBS, and as expected, positive percentage agreement between both DBS sample types and plasma was lower (>66 %).
Performance of the INNOTEST® HCV Ab IV assay in DBS was acceptable, thus whole blood collected on DBS may represent an alternative sample type for this assay in settings where venous blood collection is not possible.
Repurposing drugs capable of extending lifespan and health span has a huge untapped potential in translational geroscience. Here, we searched for known compounds that elicit a similar gene expression ...signature to caloric restriction and identified rilmenidine, an I1‐imidazoline receptor agonist and prescription medication for the treatment of hypertension. We then show that treating Caenorhabditis elegans with rilmenidine at young and older ages increases lifespan. We also demonstrate that the stress‐resilience, health span, and lifespan benefits of rilmenidine treatment in C. elegans are mediated by the I1‐imidazoline receptor nish‐1, implicating this receptor as a potential longevity target. Consistent with the shared caloric‐restriction‐mimicking gene signature, supplementing rilmenidine to calorically restricted C. elegans, genetic reduction of TORC1 function, or rapamycin treatment did not further increase lifespan. The rilmenidine‐induced longevity required the transcription factors FOXO/DAF‐16 and NRF1,2,3/SKN‐1. Furthermore, we find that autophagy, but not AMPK signaling, was needed for rilmenidine‐induced longevity. Moreover, transcriptional changes similar to caloric restriction were observed in liver and kidney tissues in mice treated with rilmenidine. Together, these results reveal a geroprotective and potential caloric restriction mimetic effect by rilmenidine that warrant fresh lines of inquiry into this compound.
Rilmenidine has prolongevity and health preserving effects in C. elegans, increased stress resistance and increased autophagy. The stress‐resilience, healthspan, and lifespan benefits of rilmenidine treatment in C. elegans are mediated by the I1‐imidazoline receptor nish‐1.
Abstract
Aging clocks emerge have emerged as promising molecular estimators of biological age based on DNA methylation or transcriptomic profiles. Among other insights, they revealed “ground zero” of ...aging during mouse embryogenesis characterized by the lowest biological age. To model the biological age dynamics during human embryogenesis, we established a differentiation culture system that mimics embryonic kidney development from human iPSCs. We then applied multiple aging clocks to the samples from hiPSC to kidney organoid stages. This analyses revealed the lowest biological age around the intermediate mesoderm stage, indicating a potential rejuvenation event at an early stage of renal development. A principal component analysis suggested that development in this system may comprise two processes with distinct contributions to aging, with one process increasing monotonically during development, while the other increasing at primitive streak and decreasing after the mesoderm phase. We further examined the relationship between these two processes and our previously-established transcriptomic signatures of aging and reprogramming. Interestingly, the former process may represent mostly age-related genes, while the latter process reprogramming-related genes. These findings suggest the occurrence of “ground zero” in a cell culture model of early embryonic development and characterize it in the context of molecular pathways and transcriptomic signatures.
Partial reprogramming by cyclic short-term expression of Yamanaka factors holds promise for shifting cells to younger states and consequently delaying the onset of many diseases of aging. However, ...the delivery of transgenes and potential risk of teratoma formation present challenges for in vivo applications. Recent advances include the use of cocktails of compounds to reprogram somatic cells, but the characteristics and mechanisms of partial cellular reprogramming by chemicals remain unclear. Here, we report a multi-omics characterization of partial chemical reprogramming in fibroblasts from young and aged mice. We measured the effects of partial chemical reprogramming on the epigenome, transcriptome, proteome, phosphoproteome, and metabolome. At the transcriptome, proteome, and phosphoproteome levels, we saw widescale changes induced by this treatment, with the most notable signature being an upregulation of mitochondrial oxidative phosphorylation. Furthermore, at the metabolome level, we observed a reduction in the accumulation of aging-related metabolites. Using both transcriptomic and epigenetic clock-based analyses, we show that partial chemical reprogramming reduces the biological age of mouse fibroblasts. We demonstrate that these changes have functional impacts, as evidenced by changes in cellular respiration and mitochondrial membrane potential. Taken together, these results illuminate the potential for chemical reprogramming reagents to rejuvenate aged biological systems and warrant further investigation into adapting these approaches for in vivo age reversal.
Background and aims
India has a significant burden of hepatitis C virus (HCV) infection and has committed to achieving national elimination by 2030. This will require a substantial scale‐up in ...testing and treatment. The “HEAD‐Start Project Delhi” aimed to enhance HCV diagnosis and treatment pathways among the general population.
Methods
A prospective study was conducted at 5 district hospitals (Arm 1: one‐stop shop), 15 polyclinics (Arm 2: referral for viral load (VL) testing and treatment) and 62 screening camps (Arm 3: referral for treatment). HCV prevalence, retention in the HCV care cascade, and turn‐around time were measured.
Results
Between January and September 2019, 37 425 participants were screened for HCV. The median (IQR) age of participants was 35 (26‐48) years, with 50.4% male and 49.6% female. A significantly higher proportion of participants in Arm 1 (93.7%) and Arm 3 (90.3%) received a VL test compared with Arm 2 (52.5%, P < .001). Of those confirmed positive, treatment was initiated at significantly higher rates for participants in both Arms 1 (85.6%) and 2 (73.7%) compared to Arm 3 (41.8%, P < .001). Arm 1 was found to be a cost‐saving strategy compared to Arm 2, Arm 3, and no action.
Conclusions
Delivery of all services at a single site (district hospitals) resulted in a higher yield of HCV seropositive cases and retention compared with sites where participants were referred elsewhere for VL testing and/or treatment. The highest level of retention in the care cascade was also associated with the shortest turn‐around times.
Development is tightly connected to aging, but whether pharmacologically targeting development can extend life remains unknown. Here, we subjected genetically diverse UMHET3 mice to rapamycin for the ...first 45 days of life. The mice grew slower and remained smaller than controls for their entire lives. Their reproductive age was delayed without affecting offspring numbers. The treatment was sufficient to extend the median life span by 10%, with the strongest effect in males, and helped to preserve health as measured by frailty index scores, gait speed, and glucose and insulin tolerance tests. Mechanistically, the liver transcriptome and epigenome of treated mice were younger at the completion of treatment. Analogous to mice, rapamycin exposure during development robustly extended the life span of
and reduced its body size. Overall, the results demonstrate that short-term rapamycin treatment during development is a novel longevity intervention that acts by slowing down development and aging, suggesting that aging may be targeted already early in life.
Abstract
Heterochronic parabiosis is a powerful rejuvenation model in aging research. Due to limitations in the duration of blood sharing and/or physical attachment, it is currently unclear if ...parabiosis retards the molecular signatures of aging or affects healthspan/lifespan in the mouse. Here, we describe a long-term heterochronic parabiosis model, which appears to slow down the aging process. We observed a “deceleration” of biological age based on molecular aging biomarkers estimated with DNA methylation clock and RNA-seq signature analysis. The slowing of biological aging was accompanied by systemic amelioration of aging phenotypes. Consistent with these findings, we found that aged mice, which underwent heterochronic parabiosis, had an increased healthspan and lifespan. Overall, our study re-introduces a prolonged parabiosis and detachment model as a novel rejuvenation therapy, suggesting that a systemic reset of biological age in old organisms can be achieved through the exposure to young environment.
Heterochronic parabiosis (HPB) is known for its functional rejuvenation effects across several mouse tissues. However, its impact on biological age and long-term health is unknown. Here we performed ...extended (3-month) HPB, followed by a 2-month detachment period of anastomosed pairs. Old detached mice exhibited improved physiological parameters and lived longer than control isochronic mice. HPB drastically reduced the epigenetic age of blood and liver based on several clock models using two independent platforms. Remarkably, this rejuvenation effect persisted even after 2 months of detachment. Transcriptomic and epigenomic profiles of anastomosed mice showed an intermediate phenotype between old and young, suggesting a global multi-omic rejuvenation effect. In addition, old HPB mice showed gene expression changes opposite to aging but akin to several life span-extending interventions. Altogether, we reveal that long-term HPB results in lasting epigenetic and transcriptome remodeling, culminating in the extension of life span and health span.
An increasing aging population poses a significant challenge to societies worldwide. A better understanding of the molecular, cellular, organ, tissue, physiological, psychological, and even ...sociological changes that occur with aging is needed in order to treat age-associated diseases. The field of aging research is rapidly expanding with multiple advances transpiring in many previously disconnected areas. Several major pharmaceutical, biotechnology, and consumer companies made aging research a priority and are building internal expertise, integrating aging research into traditional business models and exploring new go-to-market strategies. Many of these efforts are spearheaded by the latest advances in artificial intelligence, namely deep learning, including generative and reinforcement learning. To facilitate these trends, the Center for Healthy Aging at the University of Copenhagen and Insilico Medicine are building a community of Key Opinion Leaders (KOLs) in these areas and launched the annual conference series titled "Aging Research and Drug Discovery (ARDD)" held in the capital of the pharmaceutical industry, Basel, Switzerland (www.agingpharma.org). This ARDD collection contains summaries from the 6
annual meeting that explored aging mechanisms and new interventions in age-associated diseases. The 7
annual ARDD exhibition will transpire 2
-4
of September, 2020, in Basel.
IntroductionTo achieve the elimination of hepatitis C virus (HCV), substantial scale-up in access to testing and treatment is needed. This will require innovation and simplification of the care ...pathway, through decentralisation of testing and treatment to primary care settings and task-shifting to non-specialists. The objective of this study was to evaluate the feasibility and effectiveness of decentralisation of HCV testing and treatment using rapid diagnostic tests (RDTs) in primary healthcare clinics (PHCs) among high-risk populations, with referral of seropositive patients for confirmatory viral load testing and treatment.MethodsThis observational study was conducted between December 2018 and October 2019 at 25 PHCs in three regions in Malaysia. Each PHC was linked to one or more hospitals, for referral of seropositive participants for confirmatory testing and pretreatment evaluation. Treatment was provided in PHCs for non-cirrhotic patients and at hospitals for cirrhotic patients.ResultsDuring the study period, a total of 15 366 adults were screened at the 25 PHCs, using RDTs for HCV antibodies. Of the 2020 (13.2%) HCV antibody-positive participants, 1481/2020 (73.3%) had a confirmatory viral load test, 1241/1481 (83.8%) were HCV RNA-positive, 991/1241 (79.9%) completed pretreatment assessment, 632/991 (63.8%) initiated treatment, 518/632 (82.0%) completed treatment, 352/518 (68.0%) were eligible for a sustained virological response (SVR) cure assessment, 209/352 (59.4%) had an SVR cure assessment, and SVR was achieved in 202/209 (96.7%) patients. A significantly higher proportion of patients referred to PHCs initiated treatment compared with those who had treatment initiated at hospitals (71.0% vs 48.8%, p<0.001).ConclusionsThis study demonstrated the effectiveness and feasibility of a simplified decentralised HCV testing and treatment model in primary healthcare settings, targeting high-risk groups in Malaysia. There were good outcomes across most steps of the cascade of care when treatment was provided at PHCs compared with hospitals.
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