Blistering failure of elastic coatings with applications to corrosion resistance.

A variety of polymeric surfaces, such as anti-corrosion coatings and polymer-modified asphalts, are prone to blistering when exposed to moisture and air. As water and oxygen diffuse through the material, dissolved species are produced, which generate osmotic pressure that deforms and debonds the coating. These mechanisms are experimentally well-supported; however, comprehensive macroscopic models capable of predicting the formation osmotic blisters, without extensive data-fitting, is scant. Here, we develop a general mathematical theory of blistering and apply it to the failure of anti-corrosion coatings on carbon steel. The model is able to predict the irreversible, nonlinear blister growth dynamics, which eventually reaches a stable state, ruptures, or undergoes runaway delamination, depending on the mechanical and adhesion properties of the coating. For runaway delamination, the theory predicts a critical delamination length, beyond which unstable corrosion-driven growth occurs. The model is able to fit multiple sets of blister growth data with no fitting parameters. Corrosion experiments are also performed to observe undercoat rusting on carbon steel, which yielded trends comparable with model predictions. The theory is used to define three dimensionless numbers which can be used for engineering design of elastic coatings capable of resisting visible deformation, rupture, and delamination.

Human Exonuclease 1 (EXO1) Regulatory Functions in DNA Replication with Putative Roles in Cancer.

Human exonuclease 1 (EXO1), a 5'→3' exonuclease, contributes to the regulation of the cell cycle checkpoints, replication fork maintenance, and post replicative DNA repair pathways. These processes are required for the resolution of stalled or blocked DNA replication that can lead to replication stress and potential collapse of the replication fork. Failure to restart the DNA replication process can result in double-strand breaks, cell-cycle arrest, cell death, or cellular transformation. In this review, we summarize the involvement of EXO1 in the replication, DNA repair pathways, cell cycle checkpoints, and the link between EXO1 and cancer.

Pharmacological interventions in human aging.

Pharmacological interventions are emerging as potential avenues of alleviating age-related disease. However, the knowledge of ongoing clinical trials as they relate to aging and pharmacological interventions is dispersed across a variety of mediums. In this review we summarize 136 age-related clinical trials that have been completed or are ongoing. Furthermore, we establish a database that describe the trials (AgingDB, www.agingdb.com) keeping track of the previous and ongoing clinical trials, alongside their outcomes. The aim of this review and database is to give people the ability to easily query for their trial of interest and stay up to date on the latest results. In sum, herein we give an overview of the current pharmacological strategies that have been applied to target human aging.

Metabolic reprogramming by Acly inhibition using SB-204990 alters glucoregulation and modulates molecular mechanisms associated with aging.

ATP-citrate lyase is a central integrator of cellular metabolism in the interface of protein, carbohydrate, and lipid metabolism. The physiological consequences as well as the molecular mechanisms orchestrating the response to long-term pharmacologically induced Acly inhibition are unknown. We report here that the Acly inhibitor SB-204990 improves metabolic health and physical strength in wild-type mice when fed with a high-fat diet, while in mice fed with healthy diet results in metabolic imbalance and moderated insulin resistance. By applying a multiomic approach using untargeted metabolomics, transcriptomics, and proteomics, we determined that, in vivo, SB-204990 plays a role in the regulation of molecular mechanisms associated with aging, such as energy metabolism, mitochondrial function, mTOR signaling, and folate cycle, while global alterations on histone acetylation are absent. Our findings indicate a mechanism for regulating molecular pathways of aging that prevents the development of metabolic abnormalities associated with unhealthy dieting. This strategy might be explored for devising therapeutic approaches to prevent metabolic diseases.

Emergence of heartbeat frailty in advanced age I: perspectives from life-long EKG recordings in adult mice.

The combined influences of sinoatrial nodal (SAN) pacemaker cell automaticity and its response to autonomic input determine the heart's beating interval variability and mean beating rate. To determine the intrinsic SAN and autonomic signatures buried within EKG RR interval time series change in advanced age, we measured RR interval variability before and during double autonomic blockade at 3-month intervals from 6 months of age until the end of life in long-lived (those that achieved the total cohort median life span of 24 months and beyond) C57/BL6 mice. Prior to 21 months of age, time-dependent changes in intrinsic RR interval variability and mean RR interval were relatively minor. Between 21 and 30 months of age, however, marked changes emerged in intrinsic SAN RR interval variability signatures, pointing to a reduction in the kinetics of pacemaker clock mechanisms, leading to reduced synchronization of molecular functions within and among SAN cells. This loss of high-frequency signal processing within intrinsic SAN signatures resulted in a marked increase in the mean intrinsic RR interval. The impact of autonomic signatures on RR interval variability were net sympathetic and partially compensated for the reduced kinetics of the intrinsic SAN RR interval variability signatures, and partially, but not completely, shifted the EKG RR time series intervals to a more youthful pattern. Cross-sectional analyses of other subsets of C57/BL6 ages indicated that at or beyond the median life span of our longitudinal cohort, noncardiac, constitutional, whole-body frailty was increased, energetic efficiency was reduced, and the respiratory exchange ratio increased. We interpret the progressive reduction in kinetics in intrinsic SAN RR interval variability signatures in this context of whole-body frailty beyond 21 months of age to be a manifestation of "heartbeat frailty."

Inhibition of the neuromuscular acetylcholine receptor with atracurium activates FOXO/DAF-16-induced longevity.

Transcriptome-based drug screening is emerging as a powerful tool to identify geroprotective compounds to intervene in age-related disease. We hypothesized that, by mimicking the transcriptional signature of the highly conserved longevity intervention of FOXO3 (daf-16 in worms) overexpression, we could identify and repurpose compounds with similar downstream effects to increase longevity. Our in silico screen, utilizing the LINCS transcriptome database of genetic and compound interventions, identified several FDA-approved compounds that activate FOXO downstream targets in mammalian cells. These included the neuromuscular blocker atracurium, which also robustly extends both lifespan and healthspan in Caenorhabditis elegans. This longevity is dependent on both daf-16 signaling and inhibition of the neuromuscular acetylcholine receptor subunit unc-38. We found unc-38 RNAi to improve healthspan, lifespan, and stimulate DAF-16 nuclear localization, similar to atracurium treatment. Finally, using RNA-seq transcriptomics, we identify atracurium activation of DAF-16 downstream effectors. Together, these data demonstrate the capacity to mimic genetic lifespan interventions with drugs, and in doing so, reveal that the neuromuscular acetylcholine receptor regulates the highly conserved FOXO/DAF-16 longevity pathway.

A cross-sectional study of functional and metabolic changes during aging through the lifespan in male mice.

Aging is associated with distinct phenotypical, physiological, and functional changes, leading to disease and death. The progression of aging-related traits varies widely among individuals, influenced by their environment, lifestyle, and genetics. In this study, we conducted physiologic and functional tests cross-sectionally throughout the entire lifespan of male C57BL/6N mice. In parallel, metabolomics analyses in serum, brain, liver, heart, and skeletal muscle were also performed to identify signatures associated with frailty and age-dependent functional decline. Our findings indicate that declines in gait speed as a function of age and frailty are associated with a dramatic increase in the energetic cost of physical activity and decreases in working capacity. Aging and functional decline prompt organs to rewire their metabolism and substrate selection and toward redox-related pathways, mainly in liver and heart. Collectively, the data provide a framework to further understand and characterize processes of aging at the individual organism and organ levels.

Protecting the Aging Genome.

Mounting evidence suggests that DNA damage plays a central role in aging. Multiple tiers of defense have evolved to reduce the accumulation of DNA damage, including reducing damaging molecules, repairing DNA damage, and inducing senescence or apoptosis in response to persistent DNA damage. Mutations in or failure of these pathways can lead to accelerated or premature aging and age-related decline in vital organs, supporting the hypothesis that maintaining a pristine genome is paramount for human health. Understanding how we cope with DNA damage could inform on the aging process and further on how deficient DNA maintenance manifests in age-related phenotypes. This knowledge may lead to the development of novel interventions promoting healthspan.

New methodologies in ageing research.

Ageing is arguably the most complex phenotype that occurs in humans. To understand and treat ageing as well as associated diseases, highly specialised technologies are emerging that reveal critical insight into the underlying mechanisms and provide new hope for previously untreated diseases. Herein, we describe the latest developments in cutting edge technologies applied across the field of ageing research. We cover emerging model organisms, high-throughput methodologies and machine-driven approaches. In all, this review will give you a glimpse of what will be pushing the field onwards and upwards.

Disulfiram Treatment Normalizes Body Weight in Obese Mice.

Obesity is a top public health concern, and a molecule that safely treats obesity is urgently needed. Disulfiram (known commercially as Antabuse), an FDA-approved treatment for chronic alcohol addiction, exhibits anti-inflammatory properties and helps protect against certain types of cancer. Here, we show that in mice disulfiram treatment prevented body weight gain and abrogated the adverse impact of an obesogenic diet on insulin responsiveness while mitigating liver steatosis and pancreatic islet hypertrophy. Additionally, disulfiram treatment reversed established diet-induced obesity and metabolic dysfunctions in middle-aged mice. Reductions in feeding efficiency and increases in energy expenditure were associated with body weight regulation in response to long-term disulfiram treatment. Loss of fat tissue and an increase in liver fenestrations were also observed in rats on disulfiram. Given the potent anti-obesogenic effects in rodents, repurposing disulfiram in the clinic could represent a new strategy to treat obesity and its metabolic comorbidities.

Management of newly diagnosed single brain metastasis with surgical resection and permanent I-125 seeds without upfront whole brain radiotherapy.

In this retrospective study, we evaluate the efficacy of surgical resection and I-125 seeds, without upfront whole brain radiotherapy (WBRT), for newly diagnosed single brain metastasis. About 40 women and 32 men underwent gross total resection and placement of permanent low-activity I-125 seeds at our institution (1997-2007). Primary systemic cancer sites varied. At follow-up (median 16 months), local control rate was 93%. Distant brain failures occurred in 23 (32%) patients: 5 patients within 3 months and 18 patients >3 months; brain failure underwent further treatment (i.e., radiosurgery in 13, WBRT in 5, surgical resection with I-125 seeds in 2). Four patients developed radiation necrosis. All 72 patients had stable or improved Karnofsky Performance Score at 1 month after surgery. Median actuarial survival rate was 14 months; 2-year survival rate was 27%. Permanent I-125 brachytherapy at initial operation without WBRT provided excellent local control. 67 patients (93%) never required WBRT, thus avoiding potential long-term radiation-induced neurotoxicity.

Of Aging Mice and Men: Gait Speed Decline Is a Translatable Trait, With Species-Specific Underlying Properties.

In the last two decades, great strides were made in our ability to extend the life span of model organisms through dietary and other manipulations. Survival curves provide evidence of altered aging processes but are uninformative on what lead to that increase in life span. Longitudinal assessments of health and function during intervention studies could help in the identification of predictive biomarkers for health and survival. Comparable biomarkers of healthspan are necessary to effectively translate interventions into human clinical trials. Gait speed is a well-established predictive biomarker of healthspan in humans for risk of disability, health outcomes and mortality, and is relatively simple to assess noninvasively in rodents. In this study, we assessed and compared gait speed in males from two species (mice and humans), from young adulthood to advanced old age. Although gait speed decreases nonlinearly with age in both species, the underlying drivers of this change in gait speed were different, with humans exhibiting a shortened step length, and mice displaying a decrease in cadence. Future longitudinal and interventional studies in mice should examine the predictive value of longitudinal declines in gait speed for health and survival.

Latest advances in aging research and drug discovery.

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 6th annual meeting that explored aging mechanisms and new interventions in age-associated diseases. The 7th annual ARDD exhibition will transpire 2nd-4th of September, 2020, in Basel.

Aging and drug discovery.

Multiple interventions in the aging process have been discovered to extend the healthspan of model organisms. Both industry and academia are therefore exploring possible transformative molecules that target aging and age-associated diseases. In this overview, we summarize the presented talks and discussion points of the 5th Annual Aging and Drug Discovery Forum 2018 in Basel, Switzerland. Here academia and industry came together, to discuss the latest progress and issues in aging research. The meeting covered talks about the mechanistic cause of aging, how longevity signatures may be highly conserved, emerging biomarkers of aging, possible interventions in the aging process and the use of artificial intelligence for aging research and drug discovery. Importantly, a consensus is emerging both in industry and academia, that molecules able to intervene in the aging process may contain the potential to transform both societies and healthcare.

Conditioned medium derived from rat amniotic epithelial cells confers protection against inflammation, cancer, and senescence.

Amniotic epithelial cells (AECs) are a class of fetal stem cells that derives from the epiblast and resides in the amnion until birth. AECs are suitable candidates for regenerative medicine because of the ease of collection, their low immunogenicity and inability to form tumors after transplantation. Even though human AECs have been widely investigated, the fact remains that very little is known about AECs isolated from rat, one of the most common animal models in medical testing. In this study, we showed that rat AECs retained stemness properties and plasticity, expressed the pluripotency markers Sox2, Nanog, and Oct4 and were able to differentiate toward the osteogenic lineage. The addition of conditioned medium collected from rat AECs to lipopolysaccharide-activated macrophages elicited anti-inflammatory properties through a decrease of Tnfa expression and slowed tumor cell proliferation in vitro and in vivo. The senescence-associated secretory phenotype was also significantly lower upon incubation of senescent human IMR-90 fibroblast cells with conditioned medium from rat AECs. These results confirm the potential of AECs in the modulation of inflammatory mechanisms and open new therapeutic possibilities for regenerative medicine and anti-aging therapies as well.