The activity of chaperone-mediated autophagy (CMA), a catabolic pathway for selective degradation of cytosolic proteins in lysosomes, decreases with age, but the consequences of this functional ...decline in vivo remain unknown. In this work, we have generated a conditional knockout mouse to selectively block CMA in liver. We have found that blockage of CMA causes hepatic glycogen depletion and hepatosteatosis. The liver phenotype is accompanied by reduced peripheral adiposity, increased energy expenditure, and altered glucose homeostasis. Comparative lysosomal proteomics revealed that key enzymes in carbohydrate and lipid metabolism are normally degraded by CMA and that impairment of their regulated degradation contributes to the metabolic abnormalities observed in CMA-defective animals. These findings highlight the involvement of CMA in regulating hepatic metabolism and suggest that the age-related decline in CMA may have a negative impact on the energetic balance in old organisms.
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•Blockage of liver CMA leads to hepatosteatosis and altered glucose metabolism•Hepatic CMA failure has a negative impact on the whole-body energetic balance•Metabolic enzymes are a major component of the subproteome degraded by CMA•CMA degradation of metabolic enzymes contributes to regulation of metabolism
Schneider et al. show that loss of LAMP-2A, the limiting component of chaperone-mediated autophagy (CMA), in the liver results in perturbations in hepatic carbohydrate and lipid metabolism. CMA selectively degrades enzymes in carbohydrate and lipid metabolism, and failure of CMA, as occurs with age, may underlie the associated metabolic dysregulation.
The objective of this study was to assess the validity of prevalent and incident self-reported diabetes compared with multiple reference definitions and to assess the reliability (repeatability) of a ...self-reported diagnosis of diabetes. Data from 10,321 participants in the Atherosclerosis Risk in Communities (ARIC) Study who attended visit 4 (1996-1998) were analyzed. Prevalent self-reported diabetes was compared with reference definitions defined by fasting glucose and medication use obtained at visit 4. Incident self-reported diabetes was assessed during annual follow-up telephone calls and was compared with reference definitions defined by fasting glucose, hemoglobin A1c, and medication use obtained during an in-person visit attended by a subsample of participants (n = 1,738) in 2004-2005. The sensitivity of prevalent self-reported diabetes ranged from 58.5% to 70.8%, and specificity ranged from 95.6% to 96.8%, depending on the reference definition. Similarly, the sensitivity of incident self-reported diabetes ranged from 55.9% to 80.4%, and specificity ranged from 84.5% to 90.6%. Percent positive agreement of self-reported diabetes during 9 years of repeat assessments ranged from 92.7% to 95.4%. Both prevalent self-reported diabetes and incident self-reported diabetes were 84%-97% specific and 55%-80% sensitive as compared with reference definitions using glucose and medication criteria. Self-reported diabetes was >92% reliable over time.
IMPORTANCE: Prior studies have shown decreases in stroke mortality over time, but data on validated stroke incidence and long-term trends by race are limited. OBJECTIVE: To study trends in stroke ...incidence and subsequent mortality among black and white adults in the Atherosclerosis Risk in Communities (ARIC) cohort from 1987 to 2011. DESIGN, SETTING, AND PARTICIPANTS: Prospective cohort study of 14 357 participants (282 097 person-years) free of stroke at baseline was facilitated in 4 different US communities. Participants were recruited for the purpose of studying all stroke hospitalizations and deaths and for collection of baseline information on cardiovascular risk factors (via interviews and physical examinations) in 1987-1989. Participants were followed up (via examinations, annual phone interviews, active surveillance of discharges from local hospitals, and linkage with the National Death Index) through December 31, 2011. The study physician reviewers adjudicated all possible strokes and classified them as definite or probable ischemic or hemorrhagic events. MAIN OUTCOMES AND MEASURES: Trends in rates of first-ever stroke per 10 years of calendar time were estimated using Poisson regression incidence rate ratios (IRRs), with subsequent mortality analyzed using Cox proportional hazards regression models and hazard ratios (HRs) overall and by race, sex, and age divided at 65 years. RESULTS: Among 1051 (7%) participants with incident stroke, there were 929 with incident ischemic stroke and 140 with incident hemorrhagic stroke (18 participants had both during the study period). Crude incidence rates were 3.73 (95% CI, 3.51-3.96) per 1000 person-years for total stroke, 3.29 (95% CI, 3.08-3.50) per 1000 person-years for ischemic stroke, and 0.49 (95% CI, 0.41-0.57) per 1000 person-years for hemorrhagic stroke. Stroke incidence decreased over time in white and black participants (age-adjusted IRRs per 10-year period, 0.76 95% CI, 0.66-0.87; absolute decrease of 0.93 per 1000 person-years overall). The decrease in age-adjusted incidence was evident in participants age 65 years and older (age-adjusted IRR per 10-year period, 0.69 95% CI, 0.59-0.81; absolute decrease of 1.35 per 1000 person-years) but not evident in participants younger than 65 years (age-adjusted IRR per 10-year period, 0.97 95% CI, 0.76-1.25; absolute decrease of 0.09 per 1000 person-years) (P = .02 for interaction). The decrease in incidence was similar by sex. Of participants with incident stroke, 614 (58%) died through 2011. The mortality rate was higher for hemorrhagic stroke (68%) than for ischemic stroke (57%). Overall, mortality after stroke decreased over time (hazard ratio HR, 0.80 95% CI, 0.66-0.98; absolute decrease of 8.09 per 100 strokes after 10 years per 10-year period). The decrease in mortality was mostly accounted for by the decrease at younger than age 65 years (HR, 0.65 95% CI, 0.46-0.93; absolute decrease of 14.19 per 100 strokes after 10 years per 10-year period), but was similar across race and sex. CONCLUSIONS AND RELEVANCE: In a multicenter cohort of black and white adults in US communities, stroke incidence and mortality rates decreased from 1987 to 2011. The decreases varied across age groups, but were similar across sex and race, showing that improvements in stroke incidence and outcome continued to 2011.
Summary
Photoprotection has become integral in the prevention of keratinocyte cancer and photoaging. Organic ultraviolet (UV) filters such as oxybenzone and octinoxate have become controversial due ...to their potential impact on the environmental and their potential human health risks. As such, inorganic UV filters, zinc oxide (ZnO) and titanium dioxide (TiO2), have become paramount in discussions about photoprotection. ZnO and TiO2 are used in sunscreens as nanoparticles, which denotes a size <100 nm. The smaller size of these mineral particles increases their cosmetic acceptability by users as they are much less visible after application. ZnO has a broad UVA‐UVB absorption curve, while TiO2 provides better UVB protection. Overall, the human health risks with inorganic filters are extremely low given a lack of percutaneous absorption; however, there is potential risk when exposed via inhalation, prompting recommendations against spray sunscreen products with nanoparticles. At this time, the known risk to the environment is low though the risk stratification may evolve with increasing usage of these filters and higher environmental concentrations. The continued practice of photoprotection is critical. The public should be counseled to seek shade, use photoprotective clothing including hats and glasses in addition to sunscreens on sun‐exposed skin. For those concerned about emerging evidence of environmental impact of organic UV filters, based on current evidence, ZnO and TiO2‐containing sunscreens are safe alternatives.
The modern era of drug development for Alzheimer's disease began with the proposal of the cholinergic hypothesis of memory impairment and the 1984 research criteria for Alzheimer's disease. Since ...then, despite the evaluation of numerous potential treatments in clinical trials, only four cholinesterase inhibitors and memantine have shown sufficient safety and efficacy to allow marketing approval at an international level. Although this is probably because the other drugs tested were ineffective, inadequate clinical development methods have also been blamed for the failures. Here, we review the development of treatments for Alzheimer's disease during the past 30 years, considering the drugs, potential targets, late‐stage clinical trials, development methods, emerging use of biomarkers and evolution of regulatory considerations in order to summarize advances and anticipate future developments. We have considered late‐stage Alzheimer's disease drug development from 1984 to 2013, including individual clinical trials, systematic and qualitative reviews, meta‐analyses, methods, commentaries, position papers and guidelines. We then review the evolution of drugs in late clinical development, methods, biomarkers and regulatory issues. Although a range of small molecules and biological products against many targets have been investigated in clinical trials, the predominant drug targets have been the cholinergic system and the amyloid cascade. Trial methods have evolved incrementally: inclusion criteria have largely remained focused on mild‐to‐moderate Alzheimer's disease criteria, recently extending to early or prodromal Alzheimer disease or ‘mild cognitive impairment due to Alzheimer's disease’, for drugs considered to be disease modifying. The duration of trials has remained at 6–12 months for drugs intended to improve symptoms; 18‐ to 24‐month trials have been established for drugs expected to attenuate clinical course. Cognitive performance, activities of daily living, global change and severity ratings have persisted as the primary clinically relevant outcomes. Regulatory guidance and oversight have evolved to allow for enrichment of early‐stage Alzheimer's disease trial samples using biomarkers and phase‐specific outcomes. In conclusion, validated drug targets for Alzheimer's disease remain to be developed. Only drugs that affect an aspect of cholinergic function have shown consistent, but modest, clinical effects in late‐phase trials. There is opportunity for substantial improvements in drug discovery and clinical development methods.
IMPORTANCE: Midlife vascular risk factors have been associated with late-life dementia. Whether these risk factors directly contribute to brain amyloid deposition is less well understood. OBJECTIVE: ...To determine if midlife vascular risk factors are associated with late-life brain amyloid deposition, measured using florbetapir positron emission tomography (PET). DESIGN, SETTING, AND PARTICIPANTS: The Atherosclerosis Risk in Communities (ARIC)–PET Amyloid Imaging Study, a prospective cohort study among 346 participants without dementia in 3 US communities (Washington County, Maryland; Forsyth County, North Carolina; and Jackson, Mississippi) who have been evaluated for vascular risk factors and markers since 1987-1989 with florbetapir PET scans in 2011-2013. Positron emission tomography image analysis was completed in 2015. EXPOSURES: Vascular risk factors at ARIC baseline (age 45-64 years; risk factors included body mass index ≥30, current smoking, hypertension, diabetes, and total cholesterol ≥200 mg/dL) were evaluated in multivariable models including age, sex, race, APOE genotype, and educational level. MAIN OUTCOMES AND MEASURES: Standardized uptake value ratios (SUVRs) were calculated from PET scans and a mean global cortical SUVR was calculated. Elevated florbetapir (defined as a SUVR >1.2) was the dependent variable. RESULTS: Among 322 participants without dementia and with nonmissing midlife vascular risk factors at baseline (mean age, 52 years; 58% female; 43% black), the SUVR (elevated in 164 50.9% participants) was measured more than 20 years later (median follow-up, 23.5 years; interquartile range, 23.0-24.3 years) when participants were between 67 and 88 (mean, 76) years old. Elevated body mass index in midlife was associated with elevated SUVR (odds ratio OR, 2.06; 95% CI, 1.16-3.65). At baseline, 65 participants had no vascular risk factors, 123 had 1, and 134 had 2 or more; a higher number of midlife risk factors was associated with elevated amyloid SUVR at follow-up (30.8% n = 20, 50.4% n = 62, and 61.2% n = 82, respectively). In adjusted models, compared with 0 midlife vascular risk factors, the OR for elevated SUVR associated with 1 vascular risk factor was 1.88 (95% CI, 0.95-3.72) and for 2 or more vascular risk factors was 2.88 (95% CI, 1.46-5.69). No significant race × risk factor interactions were found. Late-life vascular risk factors were not associated with late-life brain amyloid deposition (for ≥2 late-life vascular risk factors vs 0: OR, 1.66; 95% CI, 0.75-3.69). CONCLUSIONS AND RELEVANCE: An increasing number of midlife vascular risk factors was significantly associated with elevated amyloid SUVR; this association was not significant for late-life risk factors. These findings are consistent with a role of vascular disease in the development of Alzheimer disease.
Investigating lactate dynamics in brain tissue is challenging, partly because in vivo data at cellular resolution are not available. We monitored lactate in cortical astrocytes and neurons of mice ...using the genetically encoded FRET sensor Laconic in combination with two-photon microscopy. An intravenous lactate injection rapidly increased the Laconic signal in both astrocytes and neurons, demonstrating high lactate permeability across tissue. The signal increase was significantly smaller in astrocytes, pointing to higher basal lactate levels in these cells, confirmed by a one-point calibration protocol. Trans-acceleration of the monocarboxylate transporter with pyruvate was able to reduce intracellular lactate in astrocytes but not in neurons. Collectively, these data provide in vivo evidence for a lactate gradient from astrocytes to neurons. This gradient is a prerequisite for a carrier-mediated lactate flux from astrocytes to neurons and thus supports the astrocyte-neuron lactate shuttle model, in which astrocyte-derived lactate acts as an energy substrate for neurons.
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•Genetically encoded sensor reports intracellular lactate levels in vivo using 2PLSM•Astrocytes and neurons accumulate intravenously applied L-lactate•Astrocytes maintain significantly higher lactate levels than neurons•This lactate gradient is a prerequisite for a carrier-mediated lactate flux from astrocytes to neurons
Mächler et al. used the genetically encoded FRET lactate sensor Laconic in combination with in vivo two-photon laser scanning microscopy to monitor lactate dynamics in astrocytes and neurons. Their data support the astrocyte-neuron lactate shuttle model, in which astrocyte-derived lactate acts as an energy substrate for neurons.
IMPORTANCE: Vascular risk factors have been associated with cognitive decline. Midlife exposure to these factors may be most important in conferring late-life risk of cognitive impairment. ...OBJECTIVES: To examine Atherosclerosis Risk in Communities (ARIC) participants in midlife and to explore associations between midlife vascular risk factors and 25-year dementia incidence. DESIGN, SETTING, AND PARTICIPANTS: This prospective cohort investigation of the Atherosclerosis Risk in Communities (ARIC) Study was conducted from 1987-1989 through 2011-2013. The dates of this analysis were April 2015 through August 2016. The setting was ARIC field centers (Washington County, Maryland; Forsyth County, North Carolina; Jackson, Mississippi; and Minneapolis suburbs, Minnesota). The study comprised 15 744 participants (of whom 27.1% were black and 72.9% white) who were aged 44 to 66 years at baseline. MAIN OUTCOMES AND MEASURES: Demographic and vascular risk factors were measured at baseline (obesity, smoking, diabetes, prehypertension, hypertension, and hypercholesterolemia) as well as presence of the APOE ε4 genotype. After the baseline visit, participants had 4 additional in-person visits, for a total of 5 in-person visits, hospitalization surveillance, telephone calls, and repeated cognitive evaluations. Most recently, in 2011-2013, through the ARIC Neurocognitive Study (ARIC-NCS), participants underwent a detailed neurocognitive battery, informant interviews, and adjudicated review to define dementia cases. Additional cases were identified through the Telephone Interview for Cognitive Status–Modified or informant interview, for participants not attending the ARIC-NCS visit, or by an International Classification of Diseases, Ninth Revision dementia code during a hospitalization. Fully adjusted Cox proportional hazards regression was used to evaluate associations of baseline vascular and demographic risk factors with dementia. RESULTS: In total, 1516 cases of dementia (57.0% female and 34.9% black, with a mean SD age at visit 1 of 57.4 5.2 years) were identified among 15 744 participants. Black race (hazard ratio HR, 1.36; 95% CI, 1.21-1.54), older age (HR, 8.06; 95% CI, 6.69-9.72 for participants aged 60-66 years), lower educational attainment (HR, 1.61; 95% CI, 1.28-2.03 for less than a high school education), and APOE ε4 genotype (HR, 1.98; 95% CI, 1.78-2.21) were associated with increased risk of dementia, as were midlife smoking (HR, 1.41; 95% CI, 1.23-1.61), diabetes (HR, 1.77; 95% CI, 1.53-2.04), prehypertension (HR, 1.31; 95% CI, 1.14-1.51), and hypertension (HR, 1.39; 95% CI, 1.22-1.59). The HR for dementia for diabetes was almost as high as that for APOE ε4 genotype. CONCLUSIONS AND RELEVANCE: Midlife vascular risk factors are associated with increased risk of dementia in black and white ARIC Study participants. Further studies are needed to evaluate the mechanism of and opportunities for prevention of the cognitive sequelae of these risk factors in midlife.
Studies performed in the liver in the 1960s led to the identification of lysosomes and the discovery of autophagy, the process by which intracellular proteins and organelles are degraded in ...lysosomes. Early studies in hepatocytes also uncovered how nutritional status regulates autophagy and how various circulating hormones modulate the activity of this catabolic process in the liver. The intensive characterization of hepatic autophagy over the years has revealed that lysosome-mediated degradation is important not only for maintaining liver homeostasis in normal physiological conditions, but also for an adequate response of this organ to stressors such as proteotoxicity, metabolic dysregulation, infection and carcinogenesis. Autophagic malfunction has also been implicated in the pathogenesis of common liver diseases, suggesting that chemical manipulation of this process might hold potential therapeutic value. In this Review--intended as an introduction to the topic of hepatic autophagy for clinical scientists--we describe the different types of hepatic autophagy, their role in maintaining homeostasis in a healthy liver and the contribution of autophagic malfunction to liver disease.
This study focuses on ethnic competition as a contextual explanation of cross-national differences in anti-immigrant prejudice. It contributes to the existing literature by refining the concept of ...ethnic competition into a socio-economic and a cultural aspect, which is reflected in two different measures of outgroup size. To improve cross-national comparability, the outgroup size measure is based on foreign country of birth instead of citizenship. Moreover, as outgroup size does not only measure competition, but also contact opportunities and familiarity with immigration, intergroup contact theory is taken into account and a non-linear relationship between outgroup size and perceived ethnic threat is tested. This study employs multi-level linear regression and uses the first round data set of the European Social Survey. The main conclusions of this analysis are that economic and social competition between groups might play a lesser role in the explanation of cross-national differences in anti-immigrant attitudes than often assumed, and that it might be rather lacking familiarity and fear of conflict over values and culture that drive the relationship between outgroup size and anti-immigrant attitudes.
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