Dynamic measures of resilience-the ability to resist and recover from a challenge-may be informative of the rate of aging before overt manifestations such as chronic disease, disability, and frailty. ...From this perspective mid-life resilience may predict longevity and late-life health. To test this hypothesis, we developed simple, reproducible, clinically relevant challenges, and outcome measures of physical resilience that revealed differences between and within age groups of genetically heterogeneous mice, and then examined associations between mid-life resilience and both lifespan and late-life measures of physiological function. We demonstrate that time to recovery from isoflurane anesthesia and weight change following a regimen of chemotherapy significantly differed among young, middle-aged, and older mice, and were more variable in older mice. Females that recovered faster than the median time from anesthesia (more resilient) at 12 months of age lived 8% longer than their counterparts, while more resilient males in mid-life exhibited better cardiac (fractional shortening and left ventricular volumes) and metabolic (glucose tolerance) function at 24 months of age. Moreover, female mice with less than the median weight loss at Day 3 of the cisplatin challenge lived 8% longer than those that lost more weight. In contrast, females who had more weight loss between Days 15 and 20 were relatively protected against early death. These data suggest that measures of physical resilience in mid-life may provide information about individual differences in aging, lifespan, and key parameters of late-life health.
Cellular senescence is emerging as a driver of idiopathic pulmonary fibrosis (IPF), a progressive and fatal disease with limited effective therapies. The senescence-associated secretory phenotype ...(SASP), involving the release of inflammatory cytokines and profibrotic growth factors by senescent cells, is thought to be a product of multiple cell types in IPF, including lung fibroblasts. NF-κB is a master regulator of the SASP, and its activity depends on the phosphorylation of p65/RelA. The purpose of this study was to assess the role of Pim-1 kinase as a driver of NF-κB-induced production of inflammatory cytokines from low-passage IPF fibroblast cultures displaying markers of senescence. Our results demonstrate that Pim-1 kinase phosphorylates p65/RelA, activating NF-κB activity and enhancing IL-6 production, which in turn amplifies the expression of
, generating a positive feedback loop. In addition, targeting Pim-1 kinase with a small molecule inhibitor dramatically inhibited the expression of a broad array of cytokines and chemokines in IPF-derived fibroblasts. Furthermore, we provide evidence that Pim-1 overexpression in low-passage human lung fibroblasts is sufficient to drive premature senescence, in vitro. These findings highlight the therapeutic potential of targeting Pim-1 kinase to reprogram the secretome of senescent fibroblasts and halt IPF progression.
To ascertain whether heart failure (HF) itself is a senescent phenomenon independent of age, and how this is reflected at a molecular level in the circulating progenitor cell niche, and at a ...substrate level using a novel electrocardiogram (ECG)-based artificial intelligence platform.
Between October 14, 2016, and October 29, 2020, CD34
progenitor cells were analyzed by flow cytometry and isolated by magnetic-activated cell sorting from patients of similar age with New York Heart Association functional classes IV (n = 17) and I-II (n = 10) heart failure with reduced ejection fraction and healthy controls (n = 10). CD34
cellular senescence was quantitated by human telomerase reverse transcriptase expression and telomerase expression by quantitative polymerase chain reaction, and senescence-associated secretory phenotype (SASP) protein expression assayed in plasma. An ECG-based artificial intelligence (AI) algorithm was used to determine cardiac age and difference from chronological age (AI ECG age gap).
CD34
counts and telomerase expression were significantly reduced and AI ECG age gap and SASP expression increased in all HF groups compared with healthy controls. Expression of SASP protein was closely associated with telomerase activity and severity of HF phenotype and inflammation. Telomerase activity was more closely associated with CD34
cell counts and AI ECG age gap.
We conclude from this pilot study that HF may promote a senescent phenotype independent of chronological age. We show for the first time that the AI ECG in HF shows a phenotype of cardiac aging beyond chronological age, and appears to be associated with cellular and molecular evidence of senescence.
Public health agencies' ability to protect health in the wake of COVID-19 largely depends on public trust. In February 2022 we conducted a first-of-its-kind nationally representative survey of 4,208 ...US adults to learn the public's reported reasons for trust in federal, state, and local public health agencies. Among respondents who expressed a "great deal" of trust, that trust was not related primarily to agencies' ability to control the spread of COVID-19 but, rather, to beliefs that those agencies made clear, science-based recommendations and provided protective resources. Scientific expertise was a more commonly reported reason for "a great deal" of trust at the federal level, whereas perceptions of hard work, compassionate policy, and direct services were emphasized more at the state and local levels. Although trust in public health agencies was not especially high, few respondents indicated that they had no trust. Lower trust was related primarily to respondents' beliefs that health recommendations were politically influenced and inconsistent. The least trusting respondents also endorsed concerns about private-sector influence and excessive restrictions and had low trust in government overall. Our findings suggest the need to support a robust federal, state, and local public health communications infrastructure; ensure agencies' authority to make science-based recommendations; and develop strategies for engaging different segments of the public.
The Lot–Garonne fluvial system is known for its historic heavy metal pollution resulting from mining and smelting activities since the late 19th century. Here, we report
137Cs activities and heavy ...metal (Cd, Zn, Cu, Pb and V) concentration–depth profiles from sediment cores retrieved in 2001 from three reservoirs in the Lot River. High mean sedimentation rates of 2.4–2.8
cm
a
−1 are indicated by
137Cs dating. The reservoir sediments have recorded the heavy metal deposition and thus allow establishing a connection between the temporal evolution of the heavy metal pollution and historical changes in smelting and waste-treatment proceedings. Based on heavy metal concentrations in sediments upstream of the anthropogenic inputs and bottom-sediments of the furthest downstream core (interpreted as old soil or riverbed), concentrations of ∼17, ∼82, ∼0.33 and ∼28
mg
kg
−1 for Cu, Zn, Cd and Pb, respectively, are proposed as natural background values for the Lot fluvial system. The geoaccumulation index (
I
geo Müller, G., 1979. Schwermetalle in den Sedimenten des Rheins-Veränderungen seit. Umschav 79, 133–149.) revealed that the Lot River sediments must be considered as “severely polluted” in Cd and Zn. Moreover, despite remediation efforts undertaken in the former smelting site, the Lot River is still “severely” (
I
geo
∼
4) and “moderately to severely” (
I
geo
>
2) impacted by Cd and Zn inputs, respectively.
Reservoir sediments provide fine-scale information on the historical record of metal pollution in a watershed.
The free radicals OH, HO^sub 2^, RO^sub 2^, and NO^sub 3^ are known to be the driving force for most chemical processes in the atmosphere. Since the low concentration of the above radicals makes ...measurements particularly difficult, only relatively few direct measurements of free radical concentrations have been reported to date.We present a comprehensive set of simultaneous radical measurements performed by Laser Induced Fluorescence (LIF), Matrix Isolation -Electron spin Resonance (MI-ESR), Peroxy Radical Chemical Amplification (PERCA), and Differential Optical Absorption Spectroscopy (DOAS) during the BERLIner OZonexperiment (BERLIOZ) during July and August of 1998 near Berlin, Germany. Most of the above radical species were measured by more than one technique and an intercomparison gave good agreement. This data set offered the possibility to study and quantify the role of each radical at a rural, semi-polluted site in the continental boundary layer and to investigate interconnections and dependencies among these free radicals.In general (box) modelled diurnal profiles of the different radicals reproduced the measurements quite well, however measured absolute levels are frequently lower than model predictions. These discrepancies point to disturbing deficiencies in our understanding of the chemical system in urban air masses.In addition considerable night-time peroxy radical production related to VOC reactions with NO^sub 3^ and O^sub 3^ could be quantified.PUBLICATION ABSTRACT
Bilateral oophorectomy in premenopausal women is a unique condition causing the abrupt and premature loss of ovarian hormones, primarily estrogen. Bilateral oophorectomy causes an alteration of ...several fundamental aging processes at the cellular, tissue, organ, and system levels, leading to multimorbidity, frailty, and reduced survival. However, many questions remain unanswered.
We present an interferometric pump-probe technique for the characterization of attosecond electron wave packets (WPs) that uses a free WP as a reference to measure a bound WP. We demonstrate our ...method by exciting helium atoms using an attosecond pulse (AP) with a bandwidth centered near the ionization threshold, thus creating both a bound and a free WP simultaneously. After a variable delay, the bound WP is ionized by a few-cycle infrared laser precisely synchronized to the original AP. By measuring the delay-dependent photoelectron spectrum we obtain an interferogram that contains both quantum beats as well as multipath interference. Analysis of the interferogram allows us to determine the bound WP components with a spectral resolution much better than the inverse of the AP duration.
Trimethyl aconitate (
2) affords, by reduction in dimethylformamide–Et
4NBr at a mercury cathode in 75% yield and high stereoselectivity, pentamethyl-1-(2-methoxy-2-oxoethyl)-1,2,3,4,5-cyclopentane ...pentacarboxylate (
6). The product structure, the substoichiometric current consumption and cyclovoltammetry indicate that product formation occurs by means of a base that is electrogenerated from
2. The base induces a catalytic cycle of two successive Michael additions, where
2 acts as an acceptor and its conjugated base
2d as a donor. X-ray structure analysis of the main diastereomer of
6 and quantum chemical calculations show that the most stable out of 16 diastereomers is formed as the main product. This indicates that the cathodically initiated tandem-Michael addition is controlled thermodynamically. In the presence of an excess of dimethyl maleate,
2 undergoes a cathodic heterocoupling to afford hexamethyl cyclopentane hexacarboxylate (
8).
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