Cellular senescence is a state of stable cell cycle arrest associated with macromolecular alterations and secretion of proinflammatory cytokines and molecules. From their initial discovery in the ...1960s, senescent cells have been hypothesized as potential contributors to the age-associated loss of regenerative potential. Here, we discuss recent evidence that implicates cellular senescence as a central regulatory mechanism of the aging process. We provide a comprehensive overview of age-associated pathologies in which cellular senescence has been implicated. We describe mechanisms by which senescent cells drive aging and diseases, and we discuss updates on exploiting these mechanisms as therapeutic targets. Finally, we critically analyze the use of senotherapeutics and their translation to the clinic, highlighting limitations and suggesting ideas for future applications and developments.
There is increasing evidence of the detrimental role of senescent cells in aging.Clearance of senescent cells has been shown to improve age-associated pathologies in animal models, leading to promising new clinical trials.Different mechanisms of senescent cells can be exploited pharmacologically to develop new therapeutic targets.
The development of genetic tools allowed for the validation of the pro-aging and pro-disease functions of senescent cells in vivo. These discoveries prompted the development of ...senotherapies-pharmaceutical interventions aimed at interfering with the detrimental effect of senescent cells-that are now entering the clinical stage. However, unequivocal identification and examination of cellular senescence remains highly difficult because of the lack of universal and specific markers. Here, to overcome the limitation of measuring individual markers, we describe a detailed two-phase algorithmic assessment to quantify various senescence-associated parameters in the same specimen. In the first phase, we combine the measurement of lysosomal and proliferative features with the expression of general senescence-associated genes to validate the presence of senescent cells. In the second phase we measure the levels of pro-inflammatory markers for specification of the type of senescence. The protocol can help graduate-level basic scientists to improve the characterization of senescence-associated phenotypes and the identification of specific senescent subtypes. Moreover, it can serve as an important tool for the clinical validation of the role of senescent cells and the effectiveness of anti-senescence therapies.
The Time-Resolved Observations of Precipitation structure and storm Intensity with a Constellation of Smallsats (TROPICS) mission was selected by NASA as part of the Earth Venture-Instrument (EVI-3) ...program. The overarching goal for TROPICS is to provide nearly all-weather observations of 3D temperature and humidity, as well as cloud ice and precipitation horizontal structure, at high temporal resolution to conduct high-value science investigations of tropical cyclones. TROPICS will provide rapid-refresh microwave measurements (median refresh rate better than 60 min for the baseline mission) which can be used to observe the thermodynamics of the troposphere and precipitation structure for storm systems at the mesoscale and synoptic scale over the entire storm life cycle. TROPICS comprises six Cube-Sats in three low-Earth orbital planes. Each CubeSat will host a high-performance radiometer to provide temperature profiles using seven channels near the 118.75 GHz oxygen absorption line, water vapour profiles using three channels near the 183 GHz water vapour absorption line, imagery in a single channel near 90 GHz for precipitation measurements (when combined with higher-resolution water vapour channels), and a single channel near 205 GHz which is more sensitive to precipitation-sized ice particles. This observing system offers an unprecedented combination of horizontal and temporal resolution to measure environmental and inner-core conditions for tropical cyclones on a nearly global scale and is a major leap forward in the temporal resolution of several key parameters needed for assimilation into advanced data assimilation systems capable of utilizing rapid-update radiance or retrieval data.Launch readiness is currently projected for late 2019.
Changes in growing season climate are often the foci of research exploring forest response to climate change. By contrast, little is known about tree growth response to projected declines in winter ...snowpack and increases in soil freezing in seasonally snow‐covered forest ecosystems, despite extensive documentation of the importance of winter climate in mediating ecological processes. We conducted a 5‐year snow‐removal experiment whereby snow was removed for the first 4–5 weeks of winter in a northern hardwood forest at the Hubbard Brook Experimental Forest in New Hampshire, USA. Our results indicate that adverse impacts of reduced snowpack and increased soil freezing on the physiology of Acer saccharum (sugar maple), a dominant species across northern temperate forests, are accompanied by a 40 ± 3% reduction in aboveground woody biomass increment, averaged across the 6 years following the start of the experiment. Further, we find no indication of growth recovery 1 year after cessation of the experiment. Based on these findings, we integrate spatial modeling of snowpack depth with forest inventory data to develop a spatially explicit, regional‐scale assessment of the vulnerability of forest aboveground growth to projected declines in snowpack depth and increased soil frost. These analyses indicate that nearly 65% of sugar maple basal area in the northeastern United States resides in areas that typically experience insulating snowpack. However, under the RCP 4.5 and 8.5 emissions scenarios, we project a 49%–95% reduction in forest area experiencing insulating snowpack by the year 2099 in the northeastern United States, leaving large areas of northern forest vulnerable to these changes in winter climate, particularly along the northern edge of the region. Our study demonstrates that research focusing on growing season climate alone overestimates the stimulatory effect of warming temperatures on tree and forest growth in seasonally snow‐covered forests.
Climate change is projected to reduce the depth and duration of insulating winter snowpack and increase the severity of soil freezing across northern forests. Using a 5‐year snow removal experiment in New Hampshire, USA we show that these changes in winter climate result in a 40% reduction in growth of sugar maple trees, a dominant species across northern hardwood forests. Furthermore, we estimate a 95% reduction in forest area experiencing insulating snowpack by the year 2099 in the Northeastern U.S. These findings indicate that research considering only growing season climate overestimates tree growth response to warming in seasonally snow‐covered ecosystems.
The LIFE MED HISS project aims at setting up a surveillance system on the long term effects of air pollution on health, using data from National Health Interview Surveys and other currently available ...sources of information in most European countries. Few studies assessed the long term effect of air pollution on hospital admissions in European cohorts.
The objective of this paper is to estimate the long term effect of fine particulate matter (PM2.5) and nitrogen dioxide (NO2) on first-ever (incident) cause-specific hospitalizations in Italy.
We used data from the Italian Longitudinal Study (ILS), a cohort study based on the 1999–2000 National Health Interview Survey (NHIS), followed up for hospitalization (2001–2008) at individual level. The survey contains information on crucial potential confounders: occupational/educational/marital status, body mass index (BMI), smoking habit and physical activity.
Annual mean exposure to PM2.5 and NO2 was assigned starting from simulated gridded data at spatial resolution of 4 × 4 km2 firstly integrated with data from monitoring stations and then up-scaled at municipality level.
Statistical analyses were conducted using Cox proportional hazard models with robust variance estimator.
For each cause of hospitalization we estimated the hazard ratios (HRs) adjusted for confounders with 95% Confidence Interval (CI) related to a 10 μg/m3 increase in pollutants. For PM2.5 and NO2, respectively, we found positive associations for circulatory system diseases 1.05(1.03–1.06); 1.05(1.03–1.07), myocardial infarction 1.15(1.12–1.18); 1.15(1.12–1.18), lung cancer 1.18(1.10–1.26); 1.20(1.12–1.28), kidney cancer 1.24(1.11–1.29); 1.20(1.07–1.33), all cancers (but lung) 1.06(1.04–1.08); 1.06(1.04–1.08) and Low Respiratory Tract Infections (LRTI) 1.07 (1.04–1.11); 1.05 (1.02–1.08).
Our results add new evidence on the effects of air pollution on first-ever (incident) hospitalizations, both in urban and rural areas. We demonstrated the feasibility of a low-cost monitoring system based on available data.
•A low-cost monitoring system to study effect of air pollution has been tested.•This surveillance system could be implemented in all European countries.•Italian Health Interview Survey has been followed-up for hospitalizations.•For PM2.5 and NO2 we found effects of air pollution on first-ever hospitalizations.•The adverse health effects can be seen both in urban and rural areas.
•Oxygen-sensing pathways are involved in regulating different hallmarks of aging.•Chronic hypoxic and hyperoxic conditions associate with various pathologies.•Mild and regulated oxygen oscillations ...might promote longevity.•Hyperbaric chambers and hypoxia mimetic drugs have therapeutic potential.
Aging is characterized by a progressive loss of tissue integrity and functionality due to disrupted homeostasis. Molecular oxygen is pivotal to maintain tissue functions, and aerobic species have evolved a sophisticated sensing system to ensure proper oxygen supply and demand. It is not surprising that aberrations in oxygen and oxygen-associated pathways subvert health and promote different aspects of aging. In this review, we discuss emerging findings on how oxygen-sensing mechanisms regulate different cellular and molecular processes during normal physiology, and how dysregulation of oxygen availability lead to disease and aging. We describe various clinical manifestations associated with deregulation of oxygen balance, and how oxygen-modulating therapies and natural oxygen oscillations influence longevity. We conclude by discussing how a better understanding of oxygen-related mechanisms that orchestrate aging processes may lead to the development of new therapeutic strategies to extend healthy aging.
Among the principal causative factors for the development of complications related to aging is a diet rich in fats and sugars, also known as the Western diet. This diet advocates numerous changes ...that might increase the susceptibility to initiate cancer and/or to create a tissue microenvironment more conducive to the growth of malignant cells, thus favoring the progression of cancer and metastasis. Hypercaloric diets in general lead to oxidative stress generating reactive oxygen species and induce endoplasmic reticulum stress. Our results demonstrate that mice bearing tumors fed with a Western diet presented bigger tumor mass with increased insulin sensitivity in these tissues. Several markers of insulin signaling, such as AKT phosphorylation and mTOR pathway, are promoted in tumors of Western diet-fed animals. This process is associated with increased macrophage infiltration, activation of unfolded protein response pathway, and initiation of epithelial-mesenchymal transition (EMT) process in these tumor tissues. Summing up, we propose that the Western diet accelerates the aging-related processes favoring tumor development.
Current land surface models use increasingly complex descriptions of the processes that they represent. Increase in complexity is accompanied by an increase in the number of model parameters, many of ...which cannot be measured directly at large spatial scales. A Monte Carlo framework was used to evaluate the sensitivity and identifiability of ten parameters controlling surface and subsurface runoff generation in the Variable Infiltration Capacity model (VIC). Using the Monte Carlo Analysis Toolbox (MCAT), parameter sensitivities were studied for four U.S. watersheds along a hydroclimatic gradient, based on a 20‐year data set developed for the Model Parameter Estimation Experiment (MOPEX). Results showed that simulated streamflows are sensitive to three parameters when evaluated with different objective functions. Sensitivity of the infiltration parameter (b) and the drainage parameter (exp) were strongly related to the hydroclimatic gradient. The placement of vegetation roots played an important role in the sensitivity of model simulations to the thickness of the second soil layer (thick2). Overparameterization was found in the base flow formulation indicating that a simplified version could be implemented. Parameter sensitivity was more strongly dictated by climatic gradients than by changes in soil properties. Results showed how a complex model can be reduced to a more parsimonious form, leading to a more identifiable model with an increased chance of successful regionalization to ungauged basins. Although parameter sensitivities are strictly valid for VIC, this model is representative of a wider class of macroscale hydrological models. Consequently, the results and methodology will have applicability to other hydrological models.
Exposure to environmental toxins is associated with a variety of age‐related diseases including cancer and neurodegeneration. For example, in Parkinson's disease (PD), chronic environmental exposure ...to certain toxins has been linked to the age‐related development of neuropathology. Neuronal damage is believed to involve the induction of neuroinflammatory events as a consequence of glial cell activation. Cellular senescence is a potent anti‐cancer mechanism that occurs in a number of proliferative cell types and causes the arrest of proliferation of cells at risk of malignant transformation following exposure to potentially oncogenic stimuli. With age, senescent cells accumulate and express a senescence‐associated secretory phenotype (SASP; that is the robust secretion of many inflammatory cytokines, growth factors and proteases). Whereas cell senescence in peripheral tissues has been causally linked to a number of age‐related pathologies, little is known about the induction of cellular senescence and the SASP in the brain. On the basis of recently reported findings, we propose that environmental stressors associated with PD may act in part by eliciting senescence and the SASP within non neuronal glial cells in the ageing brain, thus contributing to the characteristic decline in neuronal integrity that occurs in this disorder.
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