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In the intratracheal bleomycin (ITB) model of acute lung injury (ALI), macrophages are recruited to the lung and participate in the inflammation and resolution that follows injury. Macrophage origin is influential in determining activation; however, the specific phenotype of recruited and resident macrophages is not known. Inducible nitric oxide synthase (iNOS) has been implicated in the pathogenesis of ALI; however, the effects of its inhibition are mixed. Here we examined how macrophage origin determines the phenotypic response to ALI. Further, we hypothesize cell specific iNOS is key to determining activation and recruitment. Using a chimeric mouse approach, we have identified recruited and resident macrophage populations. We also used the chimeric mouse approach to create either pulmonary or bone marrow NOS2 -/- mice and systemically inhibited iNOS via 1400 W. We evaluated macrophage populations at the peak of inflammation (8 days) and the beginning of resolution (15 days) following ITB. These studies demonstrate tissue resident macrophages adopt a M2 phenotype specifically, but monocyte originated macrophages activate along a spectrum. Additionally, we demonstrated that monocyte originating macrophage derived iNOS is responsible for recruitment to the lung during the inflammatory phase. Further, we show that macrophage activation is dependent upon cellular origin. Finally, these studies suggest pulmonary derived iNOS is detrimental to the lung following ITB. In conclusion, macrophage origin is a key determinant in response to ALI and iNOS is central to recruitment and activation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Golden, Venosa and Gow.)

A growing body of literature suggests that higher engagement in a range of activities can be beneficial for cognitive health in old age. Such studies typically rely on self-report questionnaires to assess level of engagement. These questionnaires are highly heterogeneous across studies, limiting generalisability. In particular, the most appropriate domains of activity engagement remain unclear. The Victoria Longitudinal Study-Activity Lifestyle Questionnaire comprises one of the broadest and most diverse collections of activity items, but different studies report different domain structures. This study aimed to help establish a generalisable domain structure of the Victoria Longitudinal Study-Activity Lifestyle Questionnaire. The questionnaire was adapted for use in a sample of UK-based older adults (336 community-dwelling adults aged 65-92 with no diagnosed cognitive impairment). An exploratory factor analysis was conducted on 29 items. The final model retained 22 of these items in a six-factor structure. Activity domains were: Manual (e.g., household repairs), Intellectual (e.g., attending a public lecture), Games (e.g., card games), Religious (e.g., attending religious services), Exercise (e.g., aerobics) and Social (e.g., going out with friends). Given that beneficial activities have the potential to be adapted into interventions, it is essential that future studies consider the most appropriate measurement of activity engagement across domains. The factor structure reported here offers a parsimonious and potentially useful way for future studies to assess engagement in different kinds of activities., Competing Interests: The authors have declared that no competing interests exist.

Background: Intergenerational engagement could benefit health and wellbeing within an ageing population. This systematic review evaluated the impacts of intergenerational engagement on cognitive, social, and health outcomes in healthy older adults and older adults with mild cognitive impairment., Research Design and Methods: Comprehensive literature searches were undertaken, with records filtered according to pre-registered criteria. Study quality was formally assessed, and a narrative synthesis of the findings produced., Results: Forty-four studies were reviewed. Regarding quantitative evidence, 4 out of 8 studies found significant intergenerational engagement effects on cognitive outcomes, 15 of 24 on social outcomes, and 21 of 31 on health-related outcomes. Qualitative evidence was also important for understanding perceived impacts and experiences of intergenerational programmes. Only 11 studies fully met criteria for high quality research, of which the majority focused on social outcomes., Discussion and Implications: There are a range of potential benefits of intergenerational engagement, most notably regarding anxiety, generativity, cross-age attitudes, and physical activity. However, heterogeneity in programme context, sample design, dosage, and duration indicate that more research is required to enable wider implementation and generalisability. Scientific rigour in both quantitative and qualitative research should also be employed as far as possible, to provide the highest quality evidence., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Healthy aging requires people to adopt and maintain beneficial behaviors in all stages of the life span. Supporting behavior change, including via the motivation to make and maintain those changes, is therefore important for the promotion of healthy aging. The aim of this overview is to introduce theoretical frameworks from the psychology of motivation that lend themselves to the development of effective interventions promoting behavior change conducive to healthy aging. We discuss theoretical frameworks referring to the determinants, properties, and functionality of goals aimed at behavior change, and consider the implications of the various theories for designing interventions to support healthy aging. We first consider theories that focus on beliefs and attitudes as determinants of goals, then we address theories that focus on the structure and content as important properties of goals, and, finally, we examine theories drawing on conscious and nonconscious processes underlying the functionality of these goals. We will present if-then planning and mental contrasting, as well as nudging and boosting, that is, novel strategies of behavior change that support the creation of scalable interventions for healthy aging across the life span. Against this background, new perspectives emerge for modern, state-of-the-art, and individually tailored interventions with the aim of enhancing older people's healthy living., (© The Author(s) 2021. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Intratracheal bleomycin causes pulmonary injury, inflammation and fibrosis. The characteristic patchy nature of the injury makes analysis challenging. Histological assessment of lung injury is a useful tool to evaluate damage, however quantification is not standardized. We propose a multi-factorial approach to assess morphological changes subsequent to intratracheal bleomycin mediated lung injury. Lungs were inflation fixed with paraformaldehyde, sectioned and stained with hematoxylin and eosin. Whole slide images were scanned and ten 400x images were randomly chosen throughout the tissue for further analysis. Using ImageJ software, alveolar wall width was measured, nuclei were counted and airspace was quantified. Morphological changes were identified in mice instilled with bleomycin. This combination offers a robust measure of lung morphology especially in a heterogenous injury., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships which have or could be perceived to have influenced the work reported in this article., (© 2021 The Authors. Published by Elsevier Inc.)

Activated macrophages have been implicated in lung injury and fibrosis induced by the cytotoxic alkylating agent, nitrogen mustard (NM). Herein, we determined if macrophage activation is associated with histone modifications and altered miRNA expression. Treatment of rats with NM (0.125 mg/kg, i.t.) resulted in increases in phosphorylation of H2A.X in lung macrophages at 1 d and 3 d post-exposure. This DNA damage response was accompanied by methylation of histone (H) 3 lysine (K) 4 and acetylation of H3K9, marks of transcriptional activation, and methylation of H3K36 and H3K9, marks associated with transcriptional repression. Increases in histone acetyl transferase and histone deacetylase were also observed in macrophages 1 d and 28 d post-NM exposure. PCR array analysis of miRNAs (miR)s involved in inflammation and fibrosis revealed unique and overlapping expression profiles in macrophages isolated 1, 3, 7, and 28 d post-NM. An IPA Core Analysis of predicted mRNA targets of differentially expressed miRNAs identified significant enrichment of Diseases and Functions related to cell cycle arrest, apoptosis, cell movement, cell adhesion, lipid metabolism, and inflammation 1 d and 28 d post NM. miRNA-mRNA interaction network analysis revealed highly connected miRNAs representing key upstream regulators of mRNAs involved in significantly enriched pathways including miR-34c-5p and miR-27a-3p at 1 d post NM and miR-125b-5p, miR-16-5p, miR-30c-5p, miR-19b-3p and miR-148b-3p at 28 d post NM. Collectively, these data show that NM promotes histone remodeling and alterations in miRNA expression linked to lung macrophage responses during inflammatory injury and fibrosis., (Copyright © 2021 Elsevier Inc. All rights reserved.)

The modification of protein cysteine residues underlies some of the diverse biological functions of nitric oxide (NO) in physiology and disease. The formation of stable nitrosothiols occurs under biologically relevant conditions and time scales. However, the factors that determine the selective nature of this modification remain poorly understood, making it difficult to predict thiol targets and thus construct informatics networks. In this review, the biological chemistry of NO will be considered within the context of nitrosothiol formation and degradation whilst considering how specificity is achieved in this important post-translational modification. Since nitrosothiol formation requires a formal one-electron oxidation, a classification of reaction mechanisms is proposed regarding which species undergoes electron abstraction: NO, thiol or S-NO radical intermediate. Relevant kinetic, thermodynamic and mechanistic considerations will be examined and the impact of sources of NO and the chemical nature of potential reaction targets is also discussed.

Slowed processing speed is considered a hallmark feature of cognitive decline in cerebral small vessel disease (SVD); however, it is unclear whether SVD's association with slowed processing might be due to its association with overall declining general cognitive ability. We quantified the total MRI-visible SVD burden of 540 members of the Lothian Birth Cohort 1936 (age: 72.6 ± 0.7 years; 47% female). Using latent growth curve modelling, we tested associations between total SVD burden at mean age 73 and changes in general cognitive ability, processing speed, verbal memory and visuospatial ability, measured at age 73, 76, 79 and 82. Covariates included age, sex, vascular risk and childhood cognitive ability. In the fully adjusted models, greater SVD burden was associated with greater declines in general cognitive ability (standardised β: -0.201; 95% CI: [-0.36, -0.04]; p FDR  = 0.022) and processing speed (-0.222; [-0.40, -0.04]; p FDR  = 0.022). SVD burden accounted for between 4 and 5% of variance in declines of general cognitive ability and processing speed. After accounting for the covariance between tests of processing speed and general cognitive ability, only SVD's association with greater decline in general cognitive ability remained significant, prior to FDR correction (-0.222; [-0.39, -0.06]; p = 0.008; p FDR  = 0.085). Our findings do not support the notion that SVD has a specific association with declining processing speed, independent of decline in general cognitive ability (which captures the variance shared across domains of cognitive ability). The association between SVD burden and declining general cognitive ability supports the notion of SVD as a diffuse, whole-brain disease and suggests that trials monitoring SVD-related cognitive changes should consider domain-specific changes in the context of overall, general cognitive decline.

Fatty acid nitroalkenes are reversibly-reactive electrophiles that are endogenously detectable at nM concentrations and display anti-inflammatory, pro-survival actions. These actions are elicited through the alteration of signal transduction proteins via a Michael addition on nucleophilic cysteine thiols. Nitrated fatty acids (NO 2 -FAs), like 9- or 10-nitro-octadec-9-enolic acid, will act on signal transduction proteins directly or on key regulatory proteins to cause an up-regulation or down-regulation of the protein's expression, yielding an anti-inflammatory response. These responses have been characterized in many organ systems, such as the cardiovascular system, with the pulmonary system less well defined. Macrophages are one of the most abundant immune cells in the lung and are essential in maintaining lung homeostasis. Despite this, macrophages can play a role in both acute and chronic lung injury due to up-regulation of anti-inflammatory signal transduction pathways and down-regulation of pro-inflammatory pathways. Through their propensity to alter signal transduction pathways, NO 2 -FAs may be able to reduce macrophage activation during pulmonary injury. This review will focus on the implications of NO 2 -FAs on macrophage activation in the lung and the signal transduction pathways that may be altered, leading to reduced pulmonary injury.

Bleomycin is a cancer therapeutic known to cause lung injury which progresses to fibrosis. Evidence suggests that macrophages contribute to this pathological response. Tumor necrosis factor (TNF)α is a macrophage-derived pro-inflammatory cytokine implicated in lung injury. Herein, we investigated the role of TNFα in macrophage responses to bleomycin. Treatment of mice with bleomycin (3 U/kg, i.t.) caused histopathological changes in the lung within 3 d which culminated in fibrosis at 21 d. This was accompanied by an early (3-7 d) influx of CD11b + and iNOS + macrophages into the lung, and Arg-1 + macrophages at 21 d. At this time, epithelial cell dysfunction, defined by increases in total phospholipids and SP-B was evident. Treatment of mice with anti-TNFα antibody (7.5 mg/kg, i.v.) beginning 15-30 min after bleomycin, and every 5 d thereafter reduced the number and size of fibrotic foci and restored epithelial cell function. Flow cytometric analysis of F4/80 + alveolar macrophages (AM) isolated by bronchoalveolar lavage and interstitial macrophages (IM) by tissue digestion identified resident (CD11b - CD11c + ) and immature infiltrating (CD11b + CD11c - ) AM, and mature (CD11b + CD11c + ) and immature (CD11b + CD11c - ) IM subsets in bleomycin treated mice. Greater numbers of mature (CD11c + ) infiltrating (CD11b + ) AM expressing the anti-inflammatory marker, mannose receptor (CD206) were observed at 21 d when compared to 7 d post bleomycin. Mature proinflammatory (Ly6C + ) IM were greater at 7 d relative to 21 d. These cells transitioned into mature anti-inflammatory/pro-fibrotic (CD206 + ) IM between 7 and 21 d. Anti-TNFα antibody heightened the number of CD11b + AM in the lung without altering their activation state. Conversely, it reduced the abundance of mature proinflammatory (Ly6C + ) IM in the tissue at 7 d and immature pro-fibrotic IM at 21 d. Taken together, these data suggest that TNFα inhibition has beneficial effects in bleomycin induced injury, restoring epithelial function and reducing numbers of profibrotic IM and the extent of pulmonary fibrosis., (Copyright © 2021. Published by Elsevier Inc.)

Objectives: Retirement is a major life transition in the second half of life, and it can be associated with changes in leisure activity engagement. Although theories of retirement adjustment have emphasized the need to find meaningful activities in retirement, little is known about the nature of changes in leisure activity during the retirement transition and their association with mental health. Methods: Based on four annual waves of the 'Health, Aging and Retirement Transitions in Sweden' study, we investigated the longitudinal association of leisure activity engagement and depressive symptoms using bivariate dual change score models. We distinguished intellectual, social, and physical activity engagement. Results: We found increases in all three domains of activity engagement after retirement. Although level and change of activity and depressive symptoms were negatively associated, the coupling parameters were not significant, thus the direction of effects remains unclear. Conclusion: The results highlight the need to consider the role of lifestyle changes for retirement adjustment and mental health.

Fatty acid nitroalkenes are reversibly-reactive electrophiles, endogenously detectable at nM concentrations, displaying anti-inflammatory actions. Nitroalkenes like 9- or 10-nitro-octadec-9-enoic acid (e.g. nitro-oleic acid, OA-NO 2 ) pleiotropically suppress cardiovascular inflammatory responses, with pulmonary responses less well defined. C57BL/6 J male mice were intratracheally administered bleomycin (3 U/kg, ITB), to induce pulmonary inflammation and acute injury, or saline and were treated with 50 μL OA-NO 2 (50 μg) or vehicle in the same instillation and 72 h post-exposure to assess anti-inflammatory properties. Bronchoalveolar lavage (BAL) and lung tissue were collected 7d later. ITB mice lost body weight, with OA-NO 2 mitigating this loss (-2.3 ± 0.94 vs -0.4 ± 0.83 g). Histology revealed ITB induced cellular infiltration, proteinaceous debris deposition, and tissue injury, all significantly reduced by OA-NO 2 . Flow cytometry analysis of BAL demonstrated loss of Siglec F + /F4/80 + /CD45 + alveolar macrophages with ITB (89 ± 3.5 vs 30 ± 3.7%). Analysis of CD11b/CD11c expressing cells showed ITB-induced non-resident macrophage infiltration (4 ± 2.3 vs 43 ± 2.4%) was decreased by OA-NO 2 (24 ± 2.4%). Additionally, OA-NO 2 attenuated increases in mature, activated interstitial macrophages (23 ± 4.8 vs. 43 ± 5.4%) in lung tissue digests. Flow analysis of CD31 - /CD45 - /Sca-1 + mesenchymal cells revealed ITB increased CD44 + populations (1 ± 0.4 vs 4 ± 0.4MFI), significantly reduced by OA-NO 2 (3 ± 0.4MFI). Single cell analysis of mesenchymal cells by western blotting showed profibrotic ZEB1 protein expression induced by ITB. Lung digest CD45 + cells revealed ITB increased HMGB1 + cells, with OA-NO 2 suppressing this response. Inhibition of HMGB1 expression correlated with increased basal phospholipid production and SP-B expression in the lung lining. These findings indicate OA-NO 2 inhibits ITB-induced pro-inflammatory responses by modulating resident cell function., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Nitrogen mustard (NM) and sulfur mustard are cytotoxic alkylating agents that cause severe and progressive damage to the respiratory tract. Evidence indicates that macrophages play a key role in the acute inflammatory phase and the later resolution/profibrotic phase of the pathogenic response. These diverse roles are mediated by inflammatory macrophages broadly classified as M1 proinflammatory and M2 anti-inflammatory that sequentially accumulate in the lung in response to injury. The goal of the present study was to identify signaling mechanisms contributing to macrophage activation in response to mustards. To accomplish this, we used RNA sequencing to analyze the gene expression profiles of lung macrophages isolated 1 and 28 days after intratracheal exposure of rats to NM (0.125 mg/kg) or phosphate-buffered saline control. We identified 641 and 792 differentially expressed genes 1 and 28 days post-NM exposure, respectively. These genes are primarily involved in processes related to cell movement and are regulated by cytokines, including tumor necrosis factor-α, interferon-γ, and interleukin-1β. Some of the most significantly enriched canonical pathways included STAT3 and NF-κB signaling. These cytokines and pathways may represent potential targets for therapeutic intervention to mitigate mustard-induced lung toxicity., (© 2020 New York Academy of Sciences.)

Nitrogen mustard (NM) causes acute lung injury, which progresses to fibrosis. This is associated with a macrophage-dominant inflammatory response and the production of proinflammatory/profibrotic mediators, including tumor necrosis factor alpha (TNF-α). Herein, we refined magnetic resonance imaging (MRI) and computed tomography (CT) imaging methodologies to track the progression of NM-induced lung injury in rodents and assess the efficacy of anti-TNF-α antibody in mitigating toxicity. Anti-TNF-α antibody was administered to rats (15 mg/kg, every 8 days, intravenously) beginning 30 min after treatment with phosphate-buffered saline control or NM (0.125 mg/kg, intratracheally). Animals were imaged by MRI and CT prior to exposure and 1-28 days postexposure. Using MRI, we characterized acute lung injury and fibrosis by quantifying high-signal lung volume, which represents edema, inflammation, and tissue consolidation; these pathologies were found to persist for 28 days following NM exposure. CT scans were used to assess structural components of the lung and to register changes in tissue radiodensities. CT scans showed that in control animals, total lung volume increased with time. Treatment of rats with NM caused loss of lung volume; anti-TNF-α antibody mitigated this decrease. These studies demonstrate that MRI and CT can be used to monitor lung disease and the impact of therapeutic intervention., (© 2020 New York Academy of Sciences.)

The use of chemical warfare agents (CWAs) in military conflicts and against civilians is a recurrent problem. Despite ongoing CWA research using in vitro or in vivo models, progress to elucidate mechanisms of toxicity and to develop effective therapies, decontamination procedures, and general countermeasures is still limited. Novel scientific approaches to address these questions are needed to expand perspectives on existing knowledge and gain new insights. To achieve this, the use of ex vivo techniques like precision-cut tissue slices (PCTSs) can be a valuable approach. Existing studies employing this economical and relatively easy to implement method show model suitability and comparability with the use of in vitro and in vivo models. In this article, we review research on CWAs in PCTSs to illustrate the advantages of the approach and to promote future applications., (© 2020 New York Academy of Sciences.)

Brain iron deposits (IDs) are indicative of microvessel dysfunction which may predispose to small vessel disease (SVD) brain damage and worsen cognition later in life. Visible perivascular spaces in the centrum semiovale (CSO-PVS) are SVD features linked with microvessel dysfunction. We examined possible associations of CSO-PVS volume and count with brain IDs and cognitive abilities in 700 community-dwelling individuals from the Lothian Birth Cohort 1936 who underwent detailed cognitive testing and multimodal brain MRI at mean age 72.7 years. Brain IDs were assessed automatically followed by manual editing. PVS were automatically assessed in the centrum semiovale and deep corona radiata supraventricular. General factors of overall cognitive function (g), processing speed (g-speed) and memory (g-memory) were used in the analyses. Median (IQR) volumes of IDs and CSO-PVS expressed as a percentage of intracranial volume were 0.0021 (0.011) and 0.22 (0.13)% respectively. Median count of CSO-PVS was 410 (IQR = 201). Total volumes of CSO-PVS and ID, adjusted for head size, were correlated (Spearman ρ = 0.13, p < 0.001). CSO-PVS volume, despite being correlated with all three cognitive measures, was only associated with g-memory (B = -114.5, SE = 48.35, p = 0.018) in general linear models, adjusting for age, sex, vascular risk factors, childhood intelligence and white matter hyperintensity volume. The interaction of CSO-PVS count with diabetes (B = -0.0019, SE = 0.00093, p = 0.041) and volume with age (B = 1.57, SE = 0.67, p = 0.019) were also associated with g-memory. Linear regression models did not replicate these associations. Therefore, it does not seem that CSO-PVS burden is directly associated with general cognitive ability in older age.

Inflammatory macrophages are known to contribute to ozone toxicity. Farnesoid X receptor (FXR) is a nuclear receptor involved in regulating bile acid and lipid homeostasis; it also exerts anti-inflammatory activity by suppressing macrophage NF-κB. Herein, we analyzed the role of FXR in regulating macrophage activation in the lung following ozone exposure. Treatment of wild-type (WT) mice with ozone (0.8 ppm, 3 h) resulted in increases in proinflammatory (F4/80+CD11c+CD11b+Ly6CHi) and anti-inflammatory (F4/80+CD11c+CD11b+Ly6CLo) macrophages in the lung. The accumulation of proinflammatory macrophages was increased in FXR-/- mice compared with WT mice; however, anti-inflammatory macrophage activation was blunted as reflected by reduced arginase and mannose receptor expression, a response correlated with decreased Nur77. This was associated with prolonged oxidative stress, as measured by 4-hydroxynonenal-modified proteins in the lung. Loss of FXR was accompanied by protracted increases in lung NF-κB activity and its target, inducible nitric oxide synthase in response to ozone. Levels of Tnf-α, Il-1β, Ccr2, Ccl2, Cx3cr1, and Cx3cl1 were also increased in lungs of FXR-/- relative to WT mice; conversely, genes regulating lipid homeostasis including Lxrα, Apoe, Vldlr, Abcg1, and Abca1 were downregulated, irrespective of ozone exposure. In FXR-/- mice, ozone caused an increase in total lung phospholipids, with no effect on SP-B or SP-D. Dyslipidemia was correlated with blunting of ozone-induced increases in positive end-expiratory pressure-dependent quasi-static pressure volume curves indicating a stiffer lung in FXR-/- mice. These findings identify FXR as a regulator of macrophage activation following ozone exposure suggesting that FXR ligands may be useful in mitigating inflammation and oxidative stress induced by pulmonary irritants., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: Cycling Without Age is a global initiative in which trained volunteers take adults living in care homes or supported housing environments out on specially designed trishaws. Despite its global success, there is limited research on the effect the initiative has on the older adults taking part. The current study therefore assessed changes in mood and wellbeing to determine whether there were short-term benefits of participation. Methods: Forty-nine older adults (69% female; 67-100 years old ( M = 84.1, SD = 7.6)) living in care homes and supported housing environments were recruited; 35 participants completed all measures and comprise the analytical sample. Participants completed the Warwick-Edinburgh Mental Wellbeing Scale and UWIST Mood Adjective Checklist immediately before a ride (baseline); they repeated the measures on completion of the ride (follow-up). Participants also completed baseline and follow-up measures on a day in which they did not go on a ride. Mixed ANOVA compared differences in baseline and follow-up mood and wellbeing scores on ride and no ride days. Results: For all mood and wellbeing measures, there were significant interactions between day (ride or no ride) and measurement occasion (baseline or follow-up). Analyses revealed significant improvement in mood and wellbeing at follow-up on ride days versus no ride days. Conclusion: Short-term positive changes in mood and wellbeing were reported as a result of participation in the Cycling Without Age initiative for older adults in care home and supported living environments. Further research is needed to explore the longevity of benefits and longer-term changes., Competing Interests: Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2020.)

Research has suggested that individuals who play a musical instrument throughout adulthood have better preserved executive function. However, mixed results have been found for associations between musical activity and visuo-spatial abilities, and less is known about associations with fluid intelligence. We explored differences between musicians (N = 30) and non-musicians (N = 30) aged 60-93 years old across a range of neuropsychological measures of cognitive function. Musicians performed significantly better than non-musicians on all domains, which remained after adjusting for age, gender, educational history, languages spoken and physical activity. As a cross-sectional comparison, the results should not be overstated; however, they are consistent with findings suggesting learning a musical instrument throughout the life course may be associated with cognitive benefits. Identifying potential lifestyle factors that have cognitive benefits in later life, such as musical experience, is an important step in developing intervention strategies for cognitive aging.

The personal and societal impact of age-related cognitive decline supports the development of effective interventions. While some strategies, such as cognitive training, exercise or socio-intellectual engagement, appear beneficial, few studies have examined the association between personality and intervention efficacy. A systematic review was therefore conducted to summarise and synthesise the literature regarding the influence of personality traits on the effectiveness of non-pharmacological interventions for cognitive ageing. A systematic search of PubMed, PsycINFO and Web of Science was carried out. Of the 2100 papers identified by the search strategy, 10 studies were retained that met the relevant criteria (e.g., intervention studies with one or more cognitive outcomes and a measure of personality). Of these, two studies reported that higher levels of Openness to Experience were associated with greater improvement in memory performance after cognitive training interventions. Another found a positive association between Openness and improvement in divergent thinking following a novel group-based problem solving programme. One social intervention study reported positive moderating effects of Conscientiousness and Agreeableness, and mixed effects of Extraversion. Mixed evidence was also found regarding Need for Cognition, with one study reporting a positive association with memory improvement and another reporting less improvement in divergent thinking. Others found no evidence of personality influencing intervention outcomes. Due to the relatively small and heterogeneous sample of studies identified, any conclusions should currently be considered preliminary. These findings highlight the need for further research exploring the role of personality in intervention efficacy, so that interventions might be better tailored to individuals., Competing Interests: Declaration of Competing Interest All authors declare that we have no conflicts of interest., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

Nitrogen mustard (NM) is a cytotoxic vesicant known to cause acute lung injury which progresses to fibrosis. Herein, we developed a murine model of NM-induced pulmonary toxicity with the goal of assessing inflammatory mechanisms of injury. C57BL/6J mice were euthanized 1-28 d following intratracheal exposure to NM (0.08 mg/kg) or PBS control. NM caused progressive alveolar epithelial thickening, perivascular inflammation, bronchiolar epithelial hyperplasia, interstitial fibroplasia and fibrosis, peaking 14 d post exposure. Enlarged foamy macrophages were also observed in the lung 14 d post NM, along with increased numbers of microparticles in bronchoalveolar lavage fluid (BAL). Following NM exposure, rapid and prolonged increases in BAL cells, protein, total phospholipids and surfactant protein (SP)-D were also detected. Flow cytometric analysis showed that CD11b + Ly6G - F4/80 + Ly6C hi proinflammatory macrophages accumulated in the lung after NM, peaking at 3 d. This was associated with macrophage expression of HMGB1 and TNFα in histologic sections. CD11b + Ly6G - F4/80 + Ly6C lo anti-inflammatory/pro-fibrotic macrophages also increased in the lung after NM peaking at 14 d, a time coordinate with increases in TGFβ expression and fibrosis. NM exposure also resulted in alterations in pulmonary mechanics including increases in tissue elastance and decreases in compliance and static compliance, most prominently at 14 d. These findings demonstrate that NM induces structural and inflammatory changes in the lung that correlate with aberrations in pulmonary function. This mouse model will be useful for mechanistic studies of mustard lung injury and for assessing potential countermeasures., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Published by Elsevier Inc.)

Nitrogen mustard (NM) is a vesicant known to target the lung, causing acute injury which progresses to fibrosis. Evidence suggests that activated macrophages contribute to the pathologic response to NM. In these studies, we analyzed the role of lung lipids generated following NM exposure on macrophage activation and phenotype. Treatment of rats with NM (0.125 mg/kg, i.t.) resulted in a time-related increase in enlarged vacuolated macrophages in the lung. At 28 days postexposure, macrophages stained positively for Oil Red O, a marker of neutral lipids. This was correlated with an accumulation of oxidized phospholipids in lung macrophages and epithelial cells and increases in bronchoalveolar lavage fluid (BAL) phospholipids and cholesterol. RNA-sequencing and immunohistochemical analysis revealed that lipid handling pathways under the control of the transcription factors liver-X receptor (LXR), farnesoid-X receptor (FXR), peroxisome proliferator-activated receptor (PPAR)-ɣ, and sterol regulatory element-binding protein (SREBP) were significantly altered following NM exposure. Whereas at 1-3 days post NM, FXR and the downstream oxidized low-density lipoprotein receptor, Cd36, were increased, Lxr and the lipid efflux transporters, Abca1 and Abcg1, were reduced. Treatment of naïve lung macrophages with phospholipid and cholesterol enriched large aggregate fractions of BAL prepared 3 days after NM exposure resulted in upregulation of Nos2 and Ptgs2, markers of proinflammatory activation, whereas large aggregate fractions prepared 28 days post NM upregulated expression of the anti-inflammatory markers, Il10, Cd163, and Cx3cr1, and induced the formation of lipid-laden foamy macrophages. These data suggest that NM-induced alterations in lipid handling and metabolism drive macrophage foam cell formation, potentially contributing to the development of pulmonary fibrosis., (© The Author(s) 2019. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Surfactant protein-D (SP-D) is a regulator of pulmonary innate immunity whose oligomeric state can be altered through S -nitrosylation to regulate its signaling function in macrophages. Here, we examined how nitrosylation of SP-D alters the phenotypic response of macrophages to stimuli both in vivo and in vitro. Bronchoalveolar lavage (BAL) from C57BL6/J and SP-D-overexpressing (SP-D OE) mice was incubated with RAW264.7 cells ± LPS. LPS induces the expression of the inflammatory genes Il1b and Nos2 , which is reduced 10-fold by SP-D OE-BAL. S -nitrosylation of the SP-D OE-BAL (SNO-SP-D OE-BAL) abrogated this inhibition. SNO-SP-D OE-BAL alone induced Il1b and Nos2 expression. PCR array analysis of macrophages incubated with SP-D OE-BAL (±LPS) shows increased expression of repair genes, Ccl20 , Cxcl1 , and Vcam1 , that was accentuated by LPS. LPS increases inflammatory gene expression, Il1a , Nos2 , Tnf , and Ptgs2 , which was accentuated by SNO-SP-D OE-BAL but inhibited by SP-D OE-BAL. The transcription factor NF-κB was identified as a target for SNO-SP-D by IPA, which was confirmed by Trans-AM ELISA in vitro. In vivo, SP-D overexpression increases the burden of infection in a Pneumocystis model while increasing cellular recruitment. Expression of iNOS and the production of NO metabolites were significantly reduced in SP-D OE mice relative to C57BL6/J. Inflammatory gene expression was increased in infected C57BL6/J mice but decreased in SP-D OE. SP-D oligomeric structure was disrupted in C57BL6/J infected mice but unaltered within SP-D OE. Thus SP-D modulates macrophage phenotype and the balance of multimeric to trimeric SP-D is critical to this regulation.

Objective: Mean speed of responding is the most commonly used measure in the assessment of reaction time (RT). An alternative measure is intraindividual variability (IIV): the inconsistency of responding across multiple trials of a test. IIV has been suggested as an important indicator of central nervous system functioning, and as such, there has been increasing interest in the associations between IIV and brain imaging metrics. Results however, have been inconsistent. The present seeks to provide a comprehensive evaluation of the associations between a variety of measures of brain white matter integrity and individual differences in choice RT (CRT) IIV., Method: MRI brain scans of members of the Lothian Birth Cohort 1936 were assessed to obtain measures of the volume and severity of white matter hyperintensities, and the integrity of brain white matter tracts. CRT was assessed with a 4 CRT task on a separate occasion. Data were analyzed using multiple regression (N range = 358-670)., Results: Greater volume of hyperintensities and more severe hyperintensities in frontal regions were associated with higher CRT IIV. White matter tract integrity, as assessed by both fractional anisotropy and mean diffusivity, showed the smallest effect sizes in associations with CRT IIV. Associations with hyperintensities were attenuated and no longer significant after controlling for M CRT., Conclusions: Taken together, the results of the present study suggested that IIV was not incrementally predictive of white matter integrity over mean speed. This is in contrast to previous reports, and highlights the need for further study. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

From 19th to 22nd November 2018, 26 researchers representing nine countries and a variety of academic disciplines met in Snekkersten, Denmark, to reach evidence-based consensus about physical activity and older adults. It was recognised that the term 'older adults' represents a highly heterogeneous population. It encompasses those that remain highly active and healthy throughout the life-course with a high intrinsic capacity to the very old and frail with low intrinsic capacity. The consensus is drawn from a wide range of research methodologies within epidemiology, medicine, physiology, neuroscience, psychology and sociology, recognising the strength and limitations of each of the methods. Much of the evidence presented in the statements is based on longitudinal associations from observational and randomised controlled intervention studies, as well as quantitative and qualitative social studies in relatively healthy community-dwelling older adults. Nevertheless, we also considered research with frail older adults and those with age-associated neurodegenerative diseases, such as Alzheimer's and Parkinson's disease, and in a few cases molecular and cellular outcome measures from animal studies. The consensus statements distinguish between physical activity and exercise. Physical activity is used as an umbrella term that includes both structured and unstructured forms of leisure, transport, domestic and work-related activities. Physical activity entails body movement that increases energy expenditure relative to rest, and is often characterised in terms of intensity from light, to moderate to vigorous. Exercise is defined as a subset of structured physical activities that are more specifically designed to improve cardiorespiratory fitness, cognitive function, flexibility balance, strength and/or power. This statement presents the consensus on the effects of physical activity on older adults' fitness, health, cognitive functioning, functional capacity, engagement, motivation, psychological well-being and social inclusion. It also covers the consensus on physical activity implementation strategies. While it is recognised that adverse events can occur during exercise, the risk can be minimised by carefully choosing the type of activity undertaken and by consultation with the individual's physician when warranted, for example, when the individual is frail, has a number of co-morbidities, or has exercise-related symptoms, such as chest pain, heart arrhythmia or dizziness. The consensus was obtained through an iterative process that began with the presentation of the state-of-the-science in each domain, followed by group and plenary discussions. Ultimately, the participants reached agreement on the 30-item consensus statements., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Activities running in community-based-settings offer a method of delivering multimodal interventions to older adults beyond cognitive training programmes. This systematic review and meta-analysis investigated the impact of randomised controlled trials (RCTs) of 'real-world' interventions on the cognitive abilities of healthy older adults. Database searches were performed between October 2016 and September 2018. Forty-three RCTs were eligible for inclusion with 2826 intervention participants and 2234 controls. Interventions to enhance cognitive ability consisted of participation in activities that were physical (25 studies), cognitive (9 studies), or mixed (i.e., physical and cognitive; 7 studies), and two studies used other interventions that included older adults assisting schoolchildren and engagement via social network sites. Meta-analysis revealed that Trail Making Test (TMT) A, p =  0.05, M = 0.43, 95% CI [-0.00, 0.86], digit symbol substitution, p =  0.05, M = 0.30, 95% CI [0.00, 0.59], and verbal fluency, p =  0.04, M = 0.31, 95% CI [0.02, 0.61], improved after specific types of interventions versus the control groups (which were either active, wait-list or passive controls). When comparing physical activity interventions against all control groups, TMT A, p =  0.04, M = 0.25, 95% CI [0.01, 0.48], and digit span forward, p =  0.05, M = 0.91, 95% CI [-0.00, 1.82], significantly improved. Results remained non-significant for all outcomes when comparing cognitive activity interventions against all control groups. Results therefore suggest that healthy older adults are more likely to see cognitive improvements when involved in physical activity interventions. In addition, TMT A was the only measure that consistently showed significant improvements following physical activity interventions. Visuospatial abilities (as measured by TMT A) may be more susceptible to improvement following physical activity-based interventions, and TMT A may be a useful tool for detecting differences in that domain., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

In the version of this article originally published, the name of author Martin H. de Borst was coded incorrectly in the XML. The error has now been corrected in the HTML version of the paper.

Pulmonary lymphangioleiomyomatosis (LAM) is a slow-progressing metastatic disease that is driven by mutations in the tumor suppressor tuberous sclerosis complex 1/2 (TSC1/2). Rapamycin inhibits LAM cell proliferation and is the only approved treatment, but it cannot cause the regression of existing lesions and can only stabilize the disease. However, in other cancers, immunotherapies such as checkpoint blockade against PD-1 and its ligand PD-L1 have shown promise in causing tumor regression and even curing some patients. Thus, we asked whether PD-L1 has a role in LAM progression. In vitro, PD-L1 expression in murine Tsc2-null cells is unaffected by mTOR inhibition with torin but can be upregulated by IFN-γ. Using immunohistochemistry and single-cell flow cytometry, we found increased PD-L1 expression both in human lung tissue from patients with LAM and in Tsc2-null lesions in a murine model of LAM. In this model, PD-L1 is highly expressed in the lung by antigen-presenting and stromal cells, and activated T cells expressing PD-1 infiltrate the affected lung. In vivo treatment with anti-PD-1 antibody significantly prolongs mouse survival in the model of LAM. Together, these data demonstrate that PD-1/PD-L1-mediated immunosuppression may occur in LAM, and suggest new opportunities for therapeutic targeting that may provide benefits beyond those of rapamycin.

Nitrogen mustard (NM) is a vesicant known to cause acute pulmonary injury which progresses to fibrosis. Macrophages contribute to both of these pathologies. Surfactant protein (SP)-D is a pulmonary collectin that suppresses lung macrophage activity. Herein, we analyzed the effects of loss of SP-D on NM-induced macrophage activation and lung toxicity. Wild-type (WT) and SP-D-/- mice were treated intratracheally with PBS or NM (0.08 mg/kg). Bronchoalveolar lavage (BAL) fluid and tissue were collected 14 days later. In WT mice, NM caused an increase in total SP-D levels in BAL; multiple lower molecular weight forms of SP-D were also identified, consistent with lung injury and oxidative stress. Flow cytometric analysis of BAL cells from NM treated WT mice revealed the presence of proinflammatory and anti-inflammatory macrophages. Whereas loss of SP-D had no effect on numbers of these cells, their activation state, as measured by proinflammatory (iNOS, MMP-9), and anti-inflammatory (MR-1, Ym-1) protein expression, was amplified. Loss of SP-D also exacerbated NM-induced oxidative stress and alveolar epithelial injury, as reflected by increases in heme oxygenase-1 expression, and BAL cell and protein content. This was correlated with alterations in pulmonary mechanics. In NM-treated SP-D-/-, but not WT mice, there was evidence of edema, epithelial hypertrophy and hyperplasia, bronchiectasis, and fibrosis, as well as increases in BAL phospholipid content. These data demonstrate that activated lung macrophages play a role in NM-induced lung injury and oxidative stress. Elucidating mechanisms regulating macrophage activity may be important in developing therapeutics to treat mustard-induced lung injury.

High blood pressure is a highly heritable and modifiable risk factor for cardiovascular disease. We report the largest genetic association study of blood pressure traits (systolic, diastolic and pulse pressure) to date in over 1 million people of European ancestry. We identify 535 novel blood pressure loci that not only offer new biological insights into blood pressure regulation but also highlight shared genetic architecture between blood pressure and lifestyle exposures. Our findings identify new biological pathways for blood pressure regulation with potential for improved cardiovascular disease prevention in the future.

Background: We wanted to understand older adults' experiences of learning how to use a tablet computer in the context of an intervention trial, including what they found helpful or unhelpful about the tablet training, to guide future intervention studies. Methods: Mixed methods study using questionnaire and focus group approaches. Forty-three participants aged between 65 and 76 years old from the "Tablet for Healthy Ageing" study (comprising 22 in the intervention group and 21 controls) completed a post-intervention tablet experience questionnaire. Those who completed the tablet training intervention were invited to share their experiences of engaging with new technology in post-intervention focus groups. We conducted three separate focus groups with 14 healthy older adults (10 females). Results: Questionnaire data suggested that the overall experience of the 22 participants who participated in the tablet training intervention was positive. The majority of participants said that it was likely or very likely they would use a tablet in the future. The focus group themes that emerged were related to the perception of tablet training, the experience of using tablets, and suggestions for future studies. Participants mentioned that their confidence was increased, that they enjoyed being part of a social group and downloading applications, but they also felt challenged at times. Advantages of using tablets included the ability to keep in touch with family and friends, a motivation to contribute to the community, and the potential for tablets to improve mental abilities and overall health and wellbeing. Participants made suggestions that would enable tablet usage, including improvement of features, and suggestions that would improve future tablet training studies, including smaller classes. Conclusion: Our findings have implications for the development of interventions utilizing new technologies that might promote the health and wellbeing of older adults.

A number of candidate genes for reading and language impairment have been replicated, primarily in samples of children with developmental disability or delay, although these genes are also supported in adolescent population samples. The present study used a systematic approach to test 14 of these candidate genes for association with reading assessed in late adulthood (two cohorts with mean ages of 70 and 79 years). Gene-sets (14 candidates, axon-guidance and neuron migration pathways) and individual SNPs within each gene of interest were tested for association using imputed data referenced to the 1000 genomes European panel. Using the results from the genome-wide association (GWA) meta-analysis of the two cohorts (N = 1217), a competitive gene-set analysis showed that the candidate gene-set was associated with the reading index (p = .016) at a family wise error rate corrected significance level. Neither axon guidance nor neuron migration pathways were significant. Whereas individual SNP associations within CYP19A1, DYX1C1, CNTNAP2 and DIP2A genes (p < .05) did not reach corrected significance their allelic effects were in the same direction as past available reports. These results suggest that reading skill in normal adults shares the same genetic substrate as reading in adolescents, and clinically disordered reading, and highlights the utility of adult samples to increase sample sizes in the genetic study of developmental disorders.

Rationale: A primary goal of therapy for patients with peripheral artery disease (PAD) and intermittent claudication is increased ambulatory function. Supervised exercise rehabilitation was recently shown to confer superior walking benefits to pharmacological or surgical interventions. Increases in plasma inorganic nitrite, via oral nitrate, have been shown to increase exercise performance in both human and animal models, especially in hypoxic conditions., Objective: To determine whether a 36-session exercise rehabilitation program while consuming oral inorganic nitrate (4.2 mmol concentrated beetroot juice) would produce superior benefits over exercise plus placebo in pain-free walking and markers of increased skeletal muscle perfusion in patients with PAD and intermittent claudication., Methods and Results: This was a randomized, double-blind, per-protocol study design. After the 12-week protocol, claudication onset time on a maximal treadmill test increased by 59.2±57.3 s for the exercise plus placebo group (n=13) and by 180.3±46.6 s for the exercise plus beetroot juice group (n=11; P≤0.05). This produced a between treatment medium to large standardized effect size (Cohen d) of 0.62 (95% CI, -0.23 to +1.44). The data for 6-minute walk distance showed a similar pattern with increases of 24.6±12.1 and 53.3±19.6 m ( P≤0.05) in the exercise plus placebo and exercise plus beetroot juice groups, respectively. Measures of gastrocnemius perfusion, including ankle-brachial index, peak reactive hyperemic blood flow, and tissue deoxygenation characteristics, during exercise (assessed my near-infrared spectroscopy) all changed significantly for the exercise plus beetroot juice group with moderate-to-large effect sizes over exercise plus placebo changes., Conclusions: Although it is premature to speculate on overall clinical utility of a nitrate-based therapy for PAD, this early pilot study evidence is encouraging. Specifically, our data suggests that increasing plasma nitrite before exercise may allow PAD subjects to train with less pain, at higher workloads for longer durations at each training session, thereby maximizing the beneficial peripheral vascular and skeletal muscle adaptations., Clinical Trial Registration: URL: http://www.clinicaltrials.gov . Unique identifier: NCT01684930 and NCT01785524.

Objective: We conducted a U.K.-wide survey to collect information on people's beliefs, fears, perceptions, and attitudes to cognitive aging., Methods: This community-based aging survey included 3,146 adults aged 40 years and over., Results: Respondents believed memory might be the earliest cognitive skill to decline (mean: 59.4 years), followed by speed of thinking (mean: 64.9). Those in their 40s were more pessimistic, because they estimated cognitive changes would start up to 15 years earlier than respondents aged over 70. Having a purpose in life, healthy eating, challenging the mind, sleep, and physical activity ranked higher in terms of perceived importance for maintaining or improving cognitive skills. However, less than 50% engaged in any of these activities. Although 91% believed there are things people can do to maintain or improve their cognitive skills, more than 40% were unsure or did not know how to do so. Respondents who strongly agreed that changes in cognitive skills might be a sign of something more serious were significantly more likely to do various activities to benefit their cognitive skills., Conclusion: Results suggest that people are less aware of the potential cognitive benefits of certain activities, such as exercise and diet. It is important to build awareness about the benefits of lifestyles and activities for cognitive health., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Nano- and microencapsulation has proven to be a useful technique for the construction of drug delivery vehicles for use in vascular medicine. However, the possibility of using these techniques within the lung as an inhalation delivery mechanism has not been previously considered. A critical element of particle delivery to the lung is the degree of penetrance that can be achieved with respect to the airway tree. In this study we examined the effectiveness of near infrared (NIR) dye (Cy7) labeled calcium carbonate (vaterite) particles of 3.15, 1.35, and 0.65 μm diameter in reaching the respiratory portion of the lung. First of all, it was shown that, interaction vaterite particles and the components of the pulmonary surfactant occurs a very strong retardation of the recrystallization and dissolution of the particles, which can subsequently be used to create systems with a prolonging release of bioactive substances after the particles penetrate the distal sections of the lungs. Submicro- and microparticles, coated with Cy7 labeled albumin as a model compound, were delivered to mouse lungs via tracheostomy with subsequent imaging performed 24, 48, and 72 h after delivery by in vivo fluorescence. 20 min post administration particles of all three sizes were visible in the lung, with the deepest penetrance observed with 0.65 μm particles. In vivo biodistribution was confirmed by fluorescence tomography imaging of excised organs post 72 h. Laser scanning confocal microscopy shows 0.65 μm particles reaching the alveolar space. The delivery of fluorophore to the blood was assessed using Cy7 labeled 0.65 μm particles. Cy7 labeled 0.65 μm particles efficiently delivered fluorescent material to the blood with a peak 3 h after particle administration. The pharmacokinetics of NIR fluorescence dye will be shown. These studies establish that by using 0.65 μm particles loaded with Cy7 we can efficiently access the respiratory portion of the lung, which represents a potentially efficient delivery mechanism for both the lung and the vasculature.

Here we examine the organ level toxicology of both carbon black (CB) and silver nanoparticles (AgNP). We aim to determine metal-specific effects to respiratory function, inflammation and potential interactions with lung lining fluid (LLF). C57Bl6/J male mice were intratracheally instilled with saline (control), low (0.05 μg/g) or high (0.5 μg/g) doses of either AgNP or CB 15 nm nanospheres. Lung histology, cytology, surfactant composition and function, inflammatory gene expression, and pulmonary function were measured at 1, 3, and 7 days post-exposure. Acutely, high dose CB resulted in an inflammatory response, increased neutrophilia and cytokine production, without alteration in surfactant composition or respiratory mechanics. Low dose CB had no effect. Neither low nor high dose AgNPs resulted in an acute inflammatory response, but there was an increase in work of breathing. Three days post-exposure with CB, a persistent neutrophilia was noted. High dose AgNP resulted in an elevated number of macrophages and invasion of lymphocytes. Additionally, AgNP treated mice displayed increased expression of IL1B, IL6, CCL2, and IL10. However, there were no significant changes in respiratory mechanics. At day 7, inflammation had resolved in AgNP-treated mice, but tissue stiffness and resistance were significantly decreased, which was accompanied by an increase in surfactant protein D (SP-D) content. These data demonstrate that the presence of metal alters the response of the lung to nanoparticle exposure. AgNP-surfactant interactions may alter respiratory function and result in a delayed immune response, potentially due to modified airway epithelial cell function.

Fully characterizing age differences in the brain is a key task for combating aging-related cognitive decline. Using propensity score matching on 2 independent, narrow-age cohorts, we used data on childhood cognitive ability, socioeconomic background, and intracranial volume to match participants at mean age of 92 years (n = 42) to very similar participants at mean age of 73 years (n = 126). Examining a variety of global and regional structural neuroimaging variables, there were large differences in gray and white matter volumes, cortical surface area, cortical thickness, and white matter hyperintensity volume and spatial extent. In a mediation analysis, the total volume of white matter hyperintensities and total cortical surface area jointly mediated 24.9% of the relation between age and general cognitive ability (tissue volumes and cortical thickness were not significant mediators in this analysis). These findings provide an unusual and valuable perspective on neurostructural aging, in which brains from the 8th and 10th decades of life differ widely despite the same cognitive, socioeconomic, and brain-volumetric starting points., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

We aimed to assess whether and how changes in brain volume and increases in white matter hyperintensity (WMH) volume over three years predict gait speed and its change independently of demographics, vascular risk factors and physical status. We analyzed 443 individuals from the Lothian Birth Cohort 1936, at mean age 73 and 76 years. Gait speed at age 76 was predicted by age, grip strength and body mass index at mean age 73, three-year brain volume decrease and WMH volume increase, explaining 26.1% of variance. Decline in gait speed to age 76 was predicted by the same five variables explaining 40.9% of variance. In both analyses, grip strength and body mass index explained the most variance. A clinically significant decline in gait speed (≥ 0.1 m/s per year) occurred in 24.4%. These individuals had more structural brain changes. Brain volume and WMH changes were independent predictors of gait dysfunction and its three-year change, but the impact of malleable physical factors such as grip strength or body mass index was greater.

Introduction: The hippocampus plays an important role in cognitive abilities which often decline with advancing age., Methods: In a longitudinal study of community-dwelling adults, we investigated whether there were coupled changes in hippocampal structure and verbal memory, working memory, and processing speed between the ages of 73 ( N  = 655) and 76 years ( N  = 469). Hippocampal structure was indexed by hippocampal volume, hippocampal volume as a percentage of intracranial volume (H&#95;ICV), fractional anisotropy (FA), mean diffusivity (MD), and longitudinal relaxation time (T1)., Results: Mean levels of hippocampal volume, H&#95;ICV, FA, T1, and all three cognitive abilities domains decreased, whereas MD increased, from age 73 to 76. At baseline, higher hippocampal volume was associated with better working memory and verbal memory, but none of these correlations survived correction for multiple comparisons. Higher FA, lower MD, and lower T1 at baseline were associated with better cognitive abilities in all three domains; only the correlation between baseline hippocampal MD and T1, and change in the three cognitive domains, survived correction for multiple comparisons. Individuals with higher hippocampal MD at age 73 experienced a greater decline in all three cognitive abilities between ages 73 and 76. However, no significant associations with changes in cognitive abilities were found with hippocampal volume, FA, and T1 measures at baseline. Similarly, no significant associations were found between cognitive abilities at age 73 and changes in the hippocampal MRI biomarkers between ages 73 and 76., Conclusion: Our results provide evidence to better understand how the hippocampus ages in healthy adults in relation to the cognitive domains in which it is involved, suggesting that better hippocampal MD at age 73 predicts less relative decline in three important cognitive domains across the next 3 years. It can potentially assist in diagnosing early stages of aging-related neuropathologies, because in some cases, accelerated decline could predict pathologies.

Individuals differ markedly in brain structure, and in how this structure degenerates during ageing. In a large sample of human participants (baseline n = 731 at age 73 years; follow-up n = 488 at age 76 years), we estimated the magnitude of mean change and variability in changes in MRI measures of brain macrostructure (grey matter, white matter, and white matter hyperintensity volumes) and microstructure (fractional anisotropy and mean diffusivity from diffusion tensor MRI). All indices showed significant average change with age, with considerable heterogeneity in those changes. We then tested eleven socioeconomic, physical, health, cognitive, allostatic (inflammatory and metabolic), and genetic variables for their value in predicting these differences in changes. Many of these variables were significantly correlated with baseline brain structure, but few could account for significant portions of the heterogeneity in subsequent brain change. Physical fitness was an exception, being correlated both with brain level and changes. The results suggest that only a subset of correlates of brain structure are also predictive of differences in brain ageing.

Background: New technologies provide opportunities for the delivery of broad, flexible interventions with older adults. Focus groups were conducted to: (1) understand older adults' familiarity with, and barriers to, interacting with new technologies and tablets; and (2) utilize user-engagement in refining an intervention protocol., Methods: Eighteen older adults (65-76 years old; 83.3% female) who were novice tablet users participated in discussions about their perceptions of and barriers to interacting with tablets. We conducted three separate focus groups and used a generic qualitative design applying thematic analysis to analyse the data. The focus groups explored attitudes toward tablets and technology in general. We also explored the perceived advantages and disadvantages of using tablets, familiarity with, and barriers to interacting with tablets. In two of the focus groups, participants had previous computing experience (e.g., desktop), while in the other, participants had no previous computing experience. None of the participants had any previous experience with tablet computers., Results: The themes that emerged were related to barriers (i.e., lack of instructions and guidance, lack of knowledge and confidence, health-related barriers, cost); disadvantages and concerns (i.e., too much and too complex technology, feelings of inadequacy, and comparison with younger generations, lack of social interaction and communication, negative features of tablets); advantages (i.e., positive features of tablets, accessing information, willingness to adopt technology); and skepticism about using tablets and technology in general. After brief exposure to tablets, participants emphasized the likelihood of using a tablet in the future., Conclusions: Our findings suggest that most of our participants were eager to adopt new technology and willing to learn using a tablet. However, they voiced apprehension about lack of, or lack of clarity in, instructions and support. Understanding older adults' perceptions of technology is important to assist with introducing it to this population and maximize the potential of technology to facilitate independent living., Competing Interests: Conflict of Interest Statement: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer, SL, declared a shared affiliation, with no collaboration, with one of the authors, AG, to the handling Editor.

Elevated blood pressure is a major risk factor for cardiovascular disease and has a substantial genetic contribution. Genetic variation influencing blood pressure has the potential to identify new pharmacological targets for the treatment of hypertension. To discover additional novel blood pressure loci, we used 1000 Genomes Project-based imputation in 150 134 European ancestry individuals and sought significant evidence for independent replication in a further 228 245 individuals. We report 6 new signals of association in or near HSPB7 , TNXB , LRP12 , LOC283335 , SEPT9 , and AKT2 , and provide new replication evidence for a further 2 signals in EBF2 and NFKBIA . Combining large whole-blood gene expression resources totaling 12 607 individuals, we investigated all novel and previously reported signals and identified 48 genes with evidence for involvement in blood pressure regulation that are significant in multiple resources. Three novel kidney-specific signals were also detected. These robustly implicated genes may provide new leads for therapeutic innovation.

Both aging and chronic inflammation produce complex structural and biochemical alterations to the lung known to impact work of breathing. Mice deficient in surfactant protein D (Sftpd) develop progressive age-related lung pathology characterized by tissue destruction/remodeling, accumulation of foamy macrophages and alteration in surfactant composition. This study proposes to relate changes in tissue structure seen in normal aging and in chronic inflammation to altered lung mechanics using a computational model. Alterations in lung function in aging and Sftpd -/- mice have been inferred from fitting simple mechanical models to respiratory impedance data (Zrs), however interpretation has been confounded by the simultaneous presence of multiple coexisting pathophysiologic processes. In contrast to the inverse modeling approach, this study uses simulation from experimental measurements to recapitulate how aging and inflammation alter Zrs. Histologic and mechanical measurements were made in C57BL6/J mice and congenic Sftpd-/- mice at 8, 27 and 80 weeks of age (n = 8/group). An anatomic computational model based on published airway morphometry was developed and Zrs was simulated between 0.5 and 20 Hz. End expiratory pressure dependent changes in airway caliber and recruitment were estimated from mechanical measurements. Tissue elements were simulated using the constant phase model of viscoelasticity. Baseline elastance distribution was estimated in 8-week-old wild type mice, and stochastically varied for each condition based on experimentally measured alteration in elastic fiber composition, alveolar geometry and surfactant composition. Weighing reduction in model error against increasing model complexity allowed for identification of essential features underlying mechanical pathology and their contribution to Zrs. Using a maximum likelihood approach, alteration in lung recruitment and diminished elastic fiber density were shown predictive of mechanical alteration at airway opening, to a greater extent than overt acinar wall destruction. Model-predicted deficits in PEEP-dependent lung recruitment correlate with altered lung lining fluid composition independent of age or genotype.

Objective: To test the efficacy of a tablet computer training intervention to improve cognitive abilities of older adults., Design: Prospective randomized controlled trial., Setting: Community-based aging intervention study, Edinburgh, UK., Participants: Forty-eight healthy older adults aged 65 to 76 years were recruited at baseline with no or minimal tablet experience; 43 completed follow-up testing., Intervention: Twenty-two participants attended a weekly 2-hour class for 10 weeks during which they learned how to use a tablet and various applications on it., Measurements: A battery of cognitive tests from the WAIS-IV measuring the domains of Verbal Comprehension, Perceptual Processing, Working Memory, and Processing Speed, as well as health, psychological, and well-being measures., Results: A 2 × 2 mixed model ANOVA suggested that the tablet intervention group (N = 22) showed greater improvements in Processing Speed (η 2  = 0.10) compared with controls (N = 21), but did not differ in Verbal Comprehension, Perceptual Processing, or Working Memory (η 2 ranged from -0.03 to 0.04)., Conclusions: Engagement in a new mentally challenging activity (tablet training) was associated with improved processing speed. Acquiring skills in later life, including those related to adopting new technologies, may therefore have the potential to reduce or delay cognitive changes associated with ageing. It is important to understand how the development of these skills might further facilitate everyday activities, and also improve older adults' quality of life., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

We examined whether apolipoprotein E (APOE) status interacts with vascular risk factors (VRFs) to predict the progression of white matter hyperintensities (WMHs) on brain MRI scans over a specific period of life in older age when the risk of dementia increases. At age 73 years, baseline VRFs were assessed via self-reported history of diabetes, hypertension, smoking, and hypercholesterolemia, and via objective measures of blood HbA1c, body mass index, diastolic and systolic blood pressure, and blood high-density lipoprotein to total cholesterol (HDL) ratio. APOE e4 allele was coded as either present or absent. WMH progression was measured on MRI over 3 years in 434 older adults, in a same-year-of-birth cohort. APOE e4 carriers with either a self-reported diagnosis of diabetes (β = 0.160, p = 0.002) or higher glycated hemoglobin levels (β = 0.114, p = 0.014) exhibited greater WMH progression, and the former survived correction for multiple testing. All other APOE-VRF interactions were nonsignificant (β interaction < 0.056, p > 0.228). The results suggest that carrying the APOE "risk" e4 allele increases the risk of greater age-related WMH progression over the early part of the eighth decade of life, when combined with poorer glycemic control. The interaction effect was robust to co-occurring VRFs, suggesting a possible target for mitigating brain and cognitive aging at this age., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Nitrogen mustard (NM)-induced lung injury is associated with an accumulation of proinflammatory/cytotoxic M1 and antiinflammatory/wound repair M2 macrophages, which have been implicated in tissue injury and repair. Herein, we analyzed the effects of valproic acid (VPA), a histone deacetylase (HDAC) inhibitor with antiinflammatory and antioxidant activity, on lung macrophages responding to NM. Treatment of rats with NM (0.125 mg/kg, i.t.) resulted in structural alterations in the lung and a macrophage-rich inflammatory cell infiltrate, at 3 d and 7 d. This was accompanied by expression of PCNA, a marker of proliferation, and CYPb5, HO-1, and MnSOD, markers of oxidative stress. Administration of VPA (300 mg/kg/day; i.p.), beginning 30 min after NM, reduced increases in PCNA, CYPb5, HO-1, and MnSOD. This was associated with increases in immature CD11b+CD43+ M1 macrophages in the lung, and decreases in mature CD11b+CD43- M2 macrophages 3 d post NM, suggesting delayed maturation and phenotypic switching. VPA also attenuated NM-induced increases in lung iNOS+ and CCR2+ M1 macrophages, a response correlated with downregulation of NOS2, IL12B, PTGS2, MMP-9, and CCR2 expression. Conversely, numbers of CD68+, CD163+ , and ATR-1α+ M2 macrophages increased after VPA, along with the expression of IL10, ApoE, and ATR-1A. NM exposure resulted in increased HDAC activity and upregulation of HDAC2 and acetylated H3K9 in the lung. Whereas VPA blunted the effects of NM on HDAC2 expression, histone H3K9 acetylation increased. These data suggest that alterations in the balance between histone acetylases and deacetylases contribute to lung macrophage maturation and activation following NM exposure., (© The Author 2017. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Structural measures of the hippocampus have been linked to a variety of memory processes and also to broader cognitive abilities. Gross volumetry has been widely used, yet the hippocampus has a complex formation, comprising distinct subfields which may be differentially sensitive to the deleterious effects of age, and to different aspects of cognitive performance. However, a comprehensive analysis of multidomain cognitive associations with hippocampal deformations among a large group of cognitively normal older adults is currently lacking. In 654 participants of the Lothian Birth Cohort 1936 (mean age = 72.5, SD = 0.71 years), we examined associations between the morphology of the hippocampus and a variety of memory tests (spatial span, letter-number sequencing, verbal recall, and digit backwards), as well as broader cognitive domains (latent measures of speed, fluid intelligence, and memory). Following correction for age, sex, and vascular risk factors, analysis of memory subtests revealed that only right hippocampal associations in relation to spatial memory survived type 1 error correction in subiculum and in CA1 at the head (β = 0.201, p = 5.843 × 10 -4 , outward), and in the ventral tail section of CA1 (β = -0.272, p = 1.347 × 10 -5 , inward). With respect to latent measures of cognitive domains, only deformations associated with processing speed survived type 1 error correction in bilateral subiculum (β absolute ≤ 0.247, p < 1.369 × 10 -4 , outward), bilaterally in the ventral tail section of CA1 (β absolute ≤ 0.242, p < 3.451 × 10 -6 , inward), and a cluster at the left anterior-to-dorsal region of the head (β = 0.199, p = 5.220 × 10 -6 , outward). Overall, our results indicate that a complex pattern of both inward and outward hippocampal deformations are associated with better processing speed and spatial memory in older age, suggesting that complex shape-based hippocampal analyses may provide valuable information beyond gross volumetry., (Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.)

Exposure to World Trade Center (WTC) dust has been linked to respiratory disease in humans. In the present studies we developed a rodent model of WTC dust exposure to analyze lung oxidative stress and inflammation, with the goal of elucidating potential epigenetic mechanisms underlying these responses. Exposure of mice to WTC dust (20μg, i.t.) was associated with upregulation of heme oxygenase-1 and cyclooxygenase-2 within 3days, a response which persisted for at least 21days. Whereas matrix metalloproteinase was upregulated 7days post-WTC dust exposure, IL-6RA1 was increased at 21days; conversely, expression of mannose receptor, a scavenger receptor important in particle clearance, decreased. After WTC dust exposure, increases in methylation of histone H3 lysine K4 at 3days, lysine K27 at 7days and lysine K36, were observed in the lung, along with hypermethylation of Line-1 element at 21days. Alterations in pulmonary mechanics were also observed following WTC dust exposure. Thus, 3days post-exposure, lung resistance and tissue damping were decreased. In contrast at 21days, lung resistance, central airway resistance, tissue damping and tissue elastance were increased. These data demonstrate that WTC dust-induced inflammation and oxidative stress are associated with epigenetic modifications in the lung and altered pulmonary mechanics. These changes may contribute to the development of WTC dust pathologies., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Gait and balance impairment is highly prevalent in older people. We aimed to assess whether and how single markers of small vessel disease (SVD) or a combination thereof explain gait and balance function in the elderly. We analysed 678 community-dwelling healthy subjects from the Lothian Birth Cohort 1936 at the age of 71-74 years who had undergone comprehensive risk factor assessment, gait and balance assessment as well as brain MRI. We investigated the impact of individual SVD markers (white matter hyperintensity - WMH, microbleeds, lacunes, enlarged perivascular spaces, brain atrophy) as seen on structural brain MRI and of a global SVD score on the patients' performance. A regression model revealed that age, sex, and hypertension significantly explained gait speed. Among SVD markers white matter hyperintensity (WMH) score or volume were additional significant and independent predictors of gait speed in the regression model. A similar association was seen with the global SVD score. Our study confirms a negative impact of SVD-related morphologic brain changes on gait speed in addition to age, sex and hypertension independent from brain atrophy. The presence of WMH seems to be the major driving force for SVD on gait impairment in healthy elderly subjects., Competing Interests: The authors declare no competing financial interests.