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Werner syndrome (WS) is a premature aging disorder caused by WRN protein deficiency. Here, we report on the generation of a human WS model in human embryonic stem cells (ESCs). Differentiation of WRN-null ESCs to mesenchymal stem cells (MSCs) recapitulates features of premature cellular aging, a global loss of H3K9me3, and changes in heterochromatin architecture. We show that WRN associates with heterochromatin proteins SUV39H1 and HP1α and nuclear lamina–heterochromatin anchoring protein LAP2β. Targeted knock-in of catalytically inactive SUV39H1 in wild-type MSCs recapitulates accelerated cellular senescence, resembling WRN-deficient MSCs. Moreover, decrease in WRN and heterochromatin marks are detected in MSCs from older individuals. Our observations uncover a role for WRN in maintaining heterochromatin stability and highlight heterochromatin disorganization as a potential determinant of human aging.

Large cutaneous ulcers are, in severe cases, life threatening 1 , 2 . As the global population ages, non-healing ulcers are becoming increasingly common 1 , 2 . Treatment currently requires the transplantation of pre-existing epithelial components, such as skin grafts, or therapy using cultured cells 2 . Here we develop alternative supplies of epidermal coverage for the treatment of these kinds of wounds. We generated expandable epithelial tissues using in vivo reprogramming of wound-resident mesenchymal cells. Transduction of four transcription factors that specify the skin-cell lineage enabled efficient and rapid de novo epithelialization from the surface of cutaneous ulcers in mice. Our findings may provide a new therapeutic avenue for treating skin wounds and could be extended to other disease situations in which tissue homeostasis and repair are impaired. Four transcription factors that specify keratinocyte cell fate, facilitate in vivo reprogramming of wound-resident mesenchymal cells, epithealization and regeneration of skin epithelial tissues in mice.

Although there is accumulating evidence regarding the additional protective effect of folic acid against adverse pregnancy outcomes other than neural tube defects, these effects have not been elucidated in detail. We evaluated whether folic acid supplementation is associated with favorable maternal and fetal outcomes. This was a secondary analysis of 215 pregnant women who were enrolled in our prior study. With additional data from telephone interviews regarding prenatal folic acid supplementation, existing demographic, maternal and fetal data were statistically analyzed. The concentration of folic acid in maternal blood was significantly higher following folic acid supplementation (24.6 ng/mL vs.11.8 ng/mL). In contrast, homocysteine level in maternal blood decreased with folic acid supplementation (5.5 µmol/mL vs. 6.8 µmol/mL). The rates of both preeclampsia (odds ratio [OR], 0.27; 95% confidence interval [CI], 0.09-0.76) and small for gestational age (SGA; 9.2% vs. 20.0%; OR, 0.42; 95% CI, 0.18-0.99) were lower in the folic acid supplementation group than those in the control group. Other pregnancy outcomes had no association with folic acid supplementation. The findings indicate that folic acid supplementation may help to prevent preeclampsia and SGA. Further studies are warranted to elucidate the favorable effects of folic acid supplementation on pregnancy outcomes.

In vivo genome editing represents a powerful strategy for both understanding basic biology and treating inherited diseases. However, it remains a challenge to develop universal and efficient in vivo genome-editing tools for tissues that comprise diverse cell types in either a dividing or non-dividing state. Here, we describe a versatile in vivo gene knock-in methodology that enables the targeting of a broad range of mutations and cell types through the insertion of a minigene at an intron of the target gene locus using an intracellularly linearized single homology arm donor. As a proof-of-concept, we focused on a mouse model of premature-aging caused by a dominant point mutation, which is difficult to repair using existing in vivo genome-editing tools. Systemic treatment using our new method ameliorated aging-associated phenotypes and extended animal lifespan, thus highlighting the potential of this methodology for a broad range of in vivo genome-editing applications.

Dietary restriction promotes resistance to surgical stress in multiple organisms. Counterintuitively, current medical protocols recommend short-term carbohydrate-rich drinks (carbohydrate loading) prior to surgery, part of a multimodal perioperative care pathway designed to enhance surgical recovery. Despite widespread clinical use, preclinical and mechanistic studies on carbohydrate loading in surgical contexts are lacking. Here we demonstrate in ad libitum -fed mice that liquid carbohydrate loading for one week drives reductions in solid food intake, while nearly doubling total caloric intake. Similarly, in humans, simple carbohydrate intake is inversely correlated with dietary protein intake. Carbohydrate loading-induced protein dilution increases expression of hepatic fibroblast growth factor 21 (FGF21) independent of caloric intake, resulting in protection in two models of surgical stress: renal and hepatic ischemia-reperfusion injury. The protection is consistent across male, female, and aged mice. In vivo, amino acid add-back or genetic FGF21 deletion blocks carbohydrate loading-mediated protection from ischemia-reperfusion injury. Finally, carbohydrate loading induction of FGF21 is associated with the induction of the canonical integrated stress response (ATF3/4, NF-kB), and oxidative metabolism (PPARγ). Together, these data support carbohydrate loading drinks prior to surgery and reveal an essential role of protein dilution via FGF21. Surgery poses significant risks for patients, with attempts to mitigate these risks using multimodal perioperative care pathways. Here, the authors show that preoperative hypercaloric carbohydrate drinks not only alleviate surgical stress but also demonstrates the replicability of this protection using FGF21 treatment alone.

Hair graying, a prototypical sign of human aging, is a progressive loss of pigmentation from growing hair shafts caused by disease and as a side effect of medications. Cerebrolysin is a neuropeptide preparation that mimics the effect of endogenous neurotrophic factors. Cerebrolysin has been widely used in neurologic conditions, such as cerebral stroke, Alzheimer’s disease, and dementia, among others. Cerebrolysin treatment has achieved to regain or maintain the cognitive ability of affected patients; however, up to date, there are no reports about the reactivation of hair pigmentation. We describe a previously not described effect occurring on patients receiving Cerebrolysin treatment for neurologic diseases and whether this effect is associated in reactivation of melanocytes and melanin expression. Here, we report five patients (mean age, 70.6 years), who also had age-related hair graying and scalp hair repigmentation during Cerebrolysin treatment. Macroscopic analysis revealed hair repigmentation consisted in diffuse darkening of the scalp hair. Impregnation and immunostaining analysis were performed on scalp biopsies taken before and after Cerebrolysin treatment; the results showed greater melanin and melanocyte marker MART-1/Melan-A staining following Cerebrolysin treatment. We present, to our knowledge, the first report on hair repigmentation is a previously not described effect occurring following Cerebrolysin treatment.

Glioma tumour-initiating cells (GTICs) can originate upon the ă transformation of neural progenitor cells (NPCs). Studies on GTICs have ă focused on primary tumours from which GTICs could be isolated and the ă use of human embryonic material. Recently, the somatic genomic landscape ă of human gliomas has been reported. RTK (receptor tyrosine kinase) and ă p53 signalling were found dysregulated in similar to 90% and 86% of ă all primary tumours analysed, respectively. Here we report on the use of ă human-induced pluripotent stem cells (hiPSCs) for modelling ă gliomagenesis. Dysregulation of RTK and p53 signalling in hiPSC-derived ă NPCs (iNPCs) recapitulates GTIC properties in vitro. In vivo ă transplantation of transformed iNPCs leads to highly aggressive tumours ă containing undifferentiated stem cells and their differentiated ă derivatives. Metabolic modulation compromises GTIC viability. Last, ă screening of 101 anti-cancer compounds identifies three molecules ă specifically targeting transformed iNPCs and primary GTICs. Together, ă our results highlight the potential of hiPSCs for studying human ă tumourigenesis.

To estimate the performance, efficacy, modes of operation, hydrodynamic instabilities, and methodologies for harnessing energy from the pump as turbine (PAT), it is necessary to characterize these hydraulic turbomachines in all their modes of operation using an experimental test rig that simulates actual operating conditions. In this process, the characteristic curve of four quadrants of a turbomachine is constructed, especially its five modes: pump mode, brake pump mode, turbine mode, brake turbine mode, and reverse pump mode. In addition, with dynamic sensors installed in the pump volute, it is possible to know the hydrodynamic phenomena within PAT, finding its average behavior and frequency response, which is a tool for diagnosing the machine’s condition.

Aging and age‐associated disease are a major medical and societal burden in need of effective treatments. Cellular reprogramming is a biological process capable of modulating cell fate and cellular age. Harnessing the rejuvenating benefits without altering cell identity via partial cellular reprogramming has emerged as a novel translational strategy with therapeutic potential and strong commercial interests. Here, we explore the aging‐related benefits of partial cellular reprogramming while examining limitations and future directions for the field. Partial cellular reprogramming is able to improve or restore multiple age‐related phenotypes including lifespan, healthspan, epigenetic age, aging hallmarks, and tissue regeneration.

In this study, we investigated age‐related changes in clinical laboratory data and their association with mortality in dogs from the Golden Retriever Lifetime Study. By analyzing complete blood count (CBC) and biochemistry data from 2′412 Golden Retrievers over 16,678 visits, we observed significant changes during the first 2 years of life and throughout aging. Based on these observations, we developed a biological aging clock using a LASSO model to predict age based on blood markers, achieving an accuracy of R = 0.78. Although the biological age clock and pace of aging did not significantly improve mortality prediction, a model incorporating all blood biomarkers showed better predictive power for lifetime (C‐index = 0.763) and 1‐year mortality (AUC = 0.817). Our findings underscore the importance of comprehensive blood analysis for aging and mortality prediction in dogs and open the door for the development of novel methods to investigate aging in companion animals. We analyzed clinical data from 2412 Golden Retrievers to examine age‐related changes and their association with mortality. A biological aging clock using blood markers achieved R = 0.78 but did not improve mortality prediction. A full biomarker model predicted lifetime (C‐index = 0.763) and 1‐year mortality (AUC = 0.817) more effectively. Results highlight the possibility to use comprehensive blood analysis for predicting aging and mortality in dogs.