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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. © 2021, The Author(s), under exclusive licence to Springer Nature Limited.

Cellular senescence is a state of stable proliferative arrest triggered by damaging signals. Senescent cells persist during aging and promote age-related pathologies via the pro-inflammatory senescence-associated secretory phenotype (SASP), whose regulation depends on environmental factors. In vivo, a major environmental variable is oxygenation, which varies among and within tissues. Here, we demonstrate that senescent cells express lower levels of detrimental pro-inflammatory SASP factors in physiologically hypoxic environments, as measured in culture and in tissues. Mechanistically, exposure of senescent cells to low-oxygen conditions leads to AMPK activation and AMPK-mediated suppression of the mTOR-NF-κB signaling loop. Finally, we demonstrate that treatment with hypoxia-mimetic compounds reduces SASP in cells and tissues and improves strength in chemotherapy-treated and aged mice. Our findings highlight the importance of oxygen as a determinant for pro-inflammatory SASP expression and offer a potential new strategy to reduce detrimental paracrine effects of senescent cells. © 2021 Elsevier Inc.

The cellular state of “senescence” has proven difficult to define, presenting an obstacle for progress in the field. This perspective provides a consensus on the cellular and molecular features of senescence from 26 field leaders. © 2019 Elsevier Inc. Cellular senescence is a cell state implicated in various physiological processes and a wide spectrum of age-related diseases. Recently, interest in therapeutically targeting senescence to improve healthy aging and age-related disease, otherwise known as senotherapy, has been growing rapidly. Thus, the accurate detection of senescent cells, especially in vivo, is essential. Here, we present a consensus from the International Cell Senescence Association (ICSA), defining and discussing key cellular and molecular features of senescence and offering recommendations on how to use them as biomarkers. We also present a resource tool to facilitate the identification of genes linked with senescence, SeneQuest (available at http://Senequest.net). Lastly, we propose an algorithm to accurately assess and quantify senescence, both in cultured cells and in vivo. © 2019 Elsevier Inc.

Background: Evidence on the association between short-term exposure to desert dust and health outcomes is controversial. Objectives: We aimed to estimate the short-term effects of particulate matter ≤ 10 μm (PM10) on mortality and hospital admissions in 13 Southern European cities, distinguishing between PM10 originating from the desert and from other sources. Methods: We identified desert dust advection days in multiple Mediterranean areas for 2001–2010 by combining modeling tools, back-trajectories, and satellite data. For each advection day, we estimated PM10 concentrations originating from desert, and computed PM10 from other sources by difference. We fitted city-specific Poisson regression models to estimate the association between PM from different sources (desert and non-desert) and daily mortality and emergency hospitalizations. Finally, we pooled city-specific results in a random-effects meta-analysis. Results: On average, 15% of days were affected by desert dust at ground level (desert PM10 > 0 μg/m3). Most episodes occurred in spring–summer, with increasing gradient of both frequency and intensity north–south and west–east of the Mediterranean basin. We found significant associations of both PM10 concentrations with mortality. Increases of 10 μg/m3 in non-desert and desert PM10 (lag 0–1 days) were associated with increases in natural mortality of 0.55% (95% CI: 0.24, 0.87%) and 0.65% (95% CI: 0.24, 1.06%), respectively. Similar associations were estimated for cardio-respiratory mortality and hospital admissions. Conclusions: PM10 originating from the desert was positively associated with mortality and hospitalizations in Southern Europe. Policy measures should aim at reducing population exposure to anthropogenic airborne particles even in areas with large contribution from desert dust advections. © 2016, Public Health Services, US Dept of Health and Human Services. All Rights Reserved.

© Kohli et al. P16Ink4ais a potent cell cycle inhibitor engaged to support cell cycle arrest during cellular senescence. However, in tumors carrying mutations in key downstream effectors, p16Ink4ais highly expressed but fails to block cell proliferation. p16Ink4a-overexpressing tumor cells are highly aggressive and no targeted interventions are available. To study the effect of specific therapies, we generated murine sarcomas by overexpressing RAS oncogene and disrupting p53 activity. We observed that p16Ink4a--overxpressing murine sarcoma cells were resistant to ABT-263 and ABT-737, anticancer small molecules previously shown to eliminate p16Ink4a+senescent cells. We then generated sarcoma cells carrying a suicide and reporter gene, called 3MR, under the regulation of the full p16Ink4apromoter. Activation of the suicide efficiently killed p16Ink4a-overxpressing sarcoma cells in vitro and in vivo. These data suggest that suicide gene therapy could represent an important therapeutic approach for the treatment of highly aggressive p16Ink4a+cancers.

BACKGROUND: Evidence on the association between short-term exposure to desert dust and health outcomes is controversial. OBJECTIVES: We aimed to estimate the short-term effects of particulate matter 0 mu g/m(3)). Most episodes occurred in spring-summer, with increasing gradient of both frequency and intensity north-south and west-east of the Mediterranean basin. We found significant associations of both PM10 concentrations with mortality. Increases of 10 mu g/m(3) in non-desert and desert PM10 (lag 0-1 days) were associated with increases in natural mortality of 0.55% (95% CI: 0.24, 0.87%) and 0.65% (95% CI: 0.24, 1.06%), respectively. Similar associations were estimated for cardio-respiratory mortality and hospital admissions. CONCLUSIONS: PM10 originating from the desert was positively associated with mortality and hospitalizations in Southern Europe. Policy measures should aim at reducing population exposure to anthropogenic airborne particles even in areas with large contribution from desert dust advections.

BACKGROUND: Few recent studies examined acute effects on health of individual chemical species in the particulate matter (PM) mixture, and most of them have been conducted in North America. Studies in Southern Europe are scarce. The aim of this study is to examine the relationship between particulate matter constituents and daily hospital admissions and mortality in five cities in Southern Europe. METHODS: The study included five cities in Southern Europe, three cities in Spain: Barcelona (2003-2010), Madrid (2007-2008) and Huelva (2003-2010); and two cities in Italy: Rome (2005-2007) and Bologna (2011-2013). A case-crossover design was used to link cardiovascular and respiratory hospital admissions and total, cardiovascular and respiratory mortality with a pre-defined list of 16 PM10 and PM2.5 constituents. Lags 0 to 2 were examined. City-specific results were combined by random-effects meta-analysis. RESULTS: Most of the elements studied, namely EC, SO4(2-), SiO2, Ca, Fe, Zn, Cu, Ti, Mn, V and Ni, showed increased percent changes in cardiovascular and/or respiratory hospitalizations, mainly at lags 0 and 1. The percent increase by one interquartile range (IQR) change ranged from 0.69% to 3.29%. After adjustment for total PM levels, only associations for Mn, Zn and Ni remained significant. For mortality, although positive associations were identified (Fe and Ti for total mortality; EC and Mg for cardiovascular mortality; and NO3(-) for respiratory mortality) the patterns were less clear. CONCLUSIONS: The associations found in this study reflect that several PM constituents, originating from different sources, may drive previously reported results between PM and hospital admissions in the Mediterranean area. The research described in this article was conducted under the grant agreement European Commission, Environment LIFE10/IT/327. We thank the Instituto Nacional de Estadística and the Agència de Salut Pública de Barcelona for providing the mortality data, the Consorci Sanitari de Barcelona (Cat-Salut) for providing hospitalization data for Barcelona and the Agencia Estatal de Meteorologia (Ministerio de Agricultura, Alimentación y Medio Ambiente) for providing the weather data for Spain. Sí

Objectives: While several studies have reported associations of daily exposures to PM2.5 (particles less than 2.5 μm) with mortality, few studies have examined the impact of its constituents such as black carbon (BC), which is also a significant contributor to global climate change. Methods: We assessed the association between daily concentrations of BC and total, cardiovascular and respiratory mortality in two southern Mediterranean cities. Daily averages of BC were collected for 2 years in Barcelona, Spain and Athens, Greece. We used case-crossover analysis and examined single and cumulative lags up to 3 days. Results: We observed associations between BC and all mortality measures. For a 3-day moving average, cardiovascular mortality increased by 4.5% (95% CI 0.7 to 8.5) and 2.0% (95% CI 0 to 4.0) for an interquartile change in BC in Athens and Barcelona, respectively. Considerably higher effects for respiratory mortality and for those above age 65 were observed. In addition, BC exhibited much greater toxicity per microgram than generic PM2.5. Conclusions: Our findings suggest that BC, derived in western industrialised nations primarily from diesel engines and biomass burning, poses a significant burden to public health, particularly in European cities with high-traffic density.

Background: Few recent studies examined acute effects on health of individual chemical species in the particulate matter (PM) mixture, and most of them have been conducted in North America. Studies in Southern Europe are scarce. The aim of this study is to examine the relationship between particulate matter constituents and daily hospital admissions and mortality in five cities in Southern Europe. Methods: The study included five cities in Southern Europe, three cities in Spain: Barcelona (2003-2010), Madrid (2007-2008) and Huelva (2003-2010); and two cities in Italy: Rome (2005-2007) and Bologna (2011-2013). A case-crossover design was used to link cardiovascular and respiratory hospital admissions and total, cardiovascular and respiratory mortality with a pre-defined list of 16 PM10and PM2.5constituents. Lags 0 to 2 were examined. City-specific results were combined by random-effects meta-analysis. Results: Most of the elements studied, namely EC, SO4 2-, SiO2,Ca, Fe, Zn, Cu, Ti, Mn, V and Ni, showed increased percent changes in cardiovascular and/or respiratory hospitalizations, mainly at lags 0 and 1. The percent increase by one interquartile range (IQR) change ranged from 0.69% to 3.29%. After adjustment for total PM levels, only associations for Mn, Zn and Ni remained significant. For mortality, although positive associations were identified (Fe and Ti for total mortality; EC and Mg for cardiovascular mortality; and NO3 -for respiratory mortality) the patterns were less clear. Conclusions: The associations found in this study reflect that several PM constituents, originating from different sources, may drive previously reported results between PM and hospital admissions in the Mediterranean area. © 2014 Elsevier Ltd.

Background: An association between occurrence of wildfires and mortality in the exposed population has been observed in several studies with controversial results for cause-specific mortality. In the Mediterranean area, forest fires usually occur during spring-summer, they overlap with Saharan outbreaks, are associated with increased temperature and their health effects are probably due to an increase in particulate matter. Aim and methods: We analysed the effects of wildfires and particulate matter (PM10) on mortality in 10 southern European cities in Spain, France, Italy and Greece (2003-2010), using satellite data for exposure assessment and Poisson regression models, simulating a case-crossover approach. Results: We found that smoky days were associated with increased cardiovascular mortality (lag 0-5, 6.29%, 95% CIs 1.00 to 11.85). When the effect of PM10 (per 10 mg/m3) was evaluated, there was an increase in natural mortality (0.49%), cardiovascular mortality (0.65%) and respiratory mortality (2.13%) on smoke-free days, but PM10-related mortality was higher on smoky days (natural mortality up to 1.10% and respiratory mortality up to 3.90%) with a suggestion of effect modification for cardiovascular mortality (3.42%, p value for effect modification 0.055), controlling for Saharan dust advections. Conclusions: Smoke is associated with increased cardiovascular mortality in urban residents, and PM10 on smoky days has a larger effect on cardiovascular and respiratory mortality than on other days.

Previous studies reported significant variability of air pollutants across Europe with the lowest concentrations generally found in Northern Europe and the highest in Southern European countries. Within the MED-PARTICLES project the spatial and temporal variations of long-term PM and gaseous pollutants data were investigated in traffic and urban background sites across Southern Europe. The highest PM levels were observed in Greece and Italy (Athens, Thessaloniki, Turin and Rome) while all traffic sites showed high NO2levels, frequently exceeding the established limit value. High PM2.5/PM10ratios were calculated indicating that fine particles comprise a large fraction of PM10, with the highest values found in the urban background sites. It seems that although in traffic sites the concentrations of both PM2.5and PM10are significantly higher than those registered in urban background sites, the coarse fraction PM2.5-10is more important at the traffic sites. This fact is probably due to the high levels of resuspended road dust in sites highly affected by traffic, a phenomenon particularly relevant for Mediterranean countries. The long-term trends of air pollutants revealed a significant decrease of the concentration levels for PM, SO2and CO while for NO2no clear trend or slightly increasing trends were observed. This reduction could be attributed to the effectiveness of abatement measures and strategies and also to meteorological conditions and to the economic crisis that affected Southern Europe. © 2014 Elsevier B.V.

We investigated the short-term effects of particles with aerodynamic diameter less than 2.5μm (PM2.5), between 2.5 and 10μm (PM2.5-10) and less than 10μm (PM10) on deaths from diabetes, cardiac and cerebrovascular causes, lower respiratory tract infections (LRTI) and chronic obstructive pulmonary disease (COPD) in 10 European Mediterranean metropolitan areas participating in the MED-PARTICLES project during 2001-2010.In the first stage of the analysis, data from each city were analyzed separately using Poisson regression models, whereas in the second stage, the city-specific air pollution estimates were combined to obtain overall estimates. We investigated the effects following immediate (lags 0-1), delayed (lags 2-5) and prolonged exposure (lags 0-5) and effect modification patterns by season. We evaluated the sensitivity of our results to co-pollutant exposures or city-specific model choice. We applied threshold models to investigate the pattern of selected associations.For a 10μg/m3 increase in two days' PM2.5 exposure there was a 1.23% (95% confidence interval (95% CI): -1.63%, 4.17%) increase in diabetes deaths, while six days' exposure statistically significantly increased cardiac deaths by 1.33% (95% CI: 0.27, 2.40%), COPD deaths by 2.53% (95% CI: -0.01%, 5.14%) and LRTI deaths by 1.37% (95% CI: -1.94%, 4.78%). PM2.5 results were robust to co-pollutant adjustments and alternative modeling approaches. Stronger effects were observed in the warm season. Coarse particles displayed positive, even if not statistically significant, associations with mortality due to diabetes and cardiac causes that were more variable depending on exposure period, co-pollutant and seasonality adjustment.Our findings provide support for positive associations between PM2.5 and mortality due to diabetes, cardiac causes, COPD, and to a lesser degree to cerebrovascular causes, in the European Mediterranean region, which seem to drive the particles short-term health effects. © 2014 Elsevier Ltd.