A Year at the Forefront of Proteostasis and Aging

During aging, animals experience a decline in proteostasis activity, including loss of stress-response activation, culminating in the accumulation of misfolded proteins and toxic aggregates, which are causal in the onset of some chronic diseases. Finding genetic and pharmaceutical treatments that can increase organismal proteostasis and lengthen life is an ongoing goal of current research. The regulation of stress responses by cell non-autonomous mechanisms appears to be a potent way to impact organismal healthspan. In this Review, we cover recent findings in the intersection of proteostasis and aging, with a special focus on articles and preprints published between November 2021 and October 2022. A significant number of papers published during this time increased our understanding of how cells communicate with each other during proteotoxic stress. Finally, we also draw attention to emerging datasets that can be explored to generate new hypotheses that explain age-related proteostasis collapse

Of mice and men: opposing effects of nicotinamide riboside on skeletal muscle physiology at rest and during exercise.

Funder: European Union's Horizon 202

Analgesic efficacy of Lysine Clonixinate, paracetamol and dipyrone in lower third molar extraction. A randomized controlled trial

Objective: The purpose of this study is to compare the analgesic effect of lysine clonixinate, paracetamol and dipyrone after lower third molar extraction.Material and Methods: The sample consisted of 90 individuals, with clinical indication for inferior third molars extraction. The mean age of the sample was 22.3 years (DP±2.5). The individuals received the medication in unidentified bottles along with the intake instructions. The postoperative pain parameters were measured according to Visual Analogical Scale (VAS) and the data was evaluated using the Kruskal-Wallis Test and Friedman Test, with the latter used to test different time intervals for each one of the drugs.Results: The final sample consisted of 64 individuals, including 23 males (45.9%) and 41 females (64.1%) The mean age of the entire sample was 22.3 years (±2.5). The average length of the procedures was 33.9 minutes (±9.8).The distribution of mean values for this variable showed little variance for the different drugs (p=0.07).Conclusion: Lysine Clonixinate did not show any substantial impact on the postoperative pain control when compared to other drugs

Impact is a Gcn2 inhibitor that limits lifespan in caenorhabditis elegans

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)The General Control Nonderepressible 2 (GCN2) kinase is a conserved member of the integrated stress response (ISR) pathway that represses protein translation and helps cells to adapt to conditions of nutrient shortage. As such, GCN2 is required for longevity and stress resistance induced by dietary restriction (DR). IMPACT is an ancient protein that inhibits GCN2. Results: Here, we tested whether IMPACT down-regulation mimics the effects of DR in C. elegans. Knockdown of the C. elegans IMPACT homolog impt-1 activated the ISR pathway and increased lifespan and stress resistance of worms in a gcn-2-dependent manner. Impt-1 knockdown exacerbated DR-induced longevity and required several DR-activated transcription factors to extend lifespan, among them SKN-1 and DAF-16, which were induced during larval development and adulthood, respectively, in response to impt-1 RNAi. Conclusions: IMPACT inhibits the ISR pathway, thus limiting the activation of stress response factors that are beneficial during aging and required under DR.The General Control Nonderepressible 2 (GCN2) kinase is a conserved member of the integrated stress response (ISR) pathway that represses protein translation and helps cells to adapt to conditions of nutrient shortage. As such, GCN2 is required for longev141115CNQP - CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICOFAPESP - FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULOConselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)444424/2014-8474397/2011-42010/52557-02015/01316-72015/04264-82012/24490-42009/52047-52014/17145-42012/04064-02014/25068-02014/25270-32014/10814-8We thank Dr. T. Keith Blackwell and Dr. David Ron for providing the Patf-

Human Ageing Genomic Resources:updates on key databases in ageing research

Ageing is a complex and multifactorial process. For two decades, the Human Ageing Genomic Resources (HAGR) have aided researchers in the study of various aspects of ageing and its manipulation. Here, we present the key features and recent enhancements of these resources, focusing on its six main databases. One database, GenAge, focuses on genes related to ageing, featuring 307 genes linked to human ageing and 2205 genes associated with longevity and ageing in model organisms. AnAge focuses on ageing, longevity, and life-history across animal species, containing data on 4645 species. DrugAge includes information about 1097 longevity drugs and compounds in model organisms such as mice, rats, flies, worms and yeast. GenDR provides a list of 214 genes associated with the life-extending benefits of dietary restriction in model organisms. CellAge contains a catalogue of 866 genes associated with cellular senescence. The LongevityMap serves as a repository for genetic variants associated with human longevity, encompassing 3144 variants pertaining to 884 genes. Additionally, HAGR provides various tools as well as gene expression signatures of ageing, dietary restriction, and replicative senescence based on meta-analyses. Our databases are integrated, regularly updated, and manually curated by experts. HAGR is freely available online (https://genomics.senescence.info/).</p

Frequência e perfil de suscetibilidade aos carbapenêmicos de bastonetes Gram-negativos não fermentadores de glicose isolados de amostras clínicas entre 2007 e 2012

Introdução: Um dos grandes problemas nos serviços de saúde é a ocorrência de infecções relacionadas com assistência à saúde (IRAS) por microrganismos resistentes a vários antimicrobianos. Objetivos: Descrever a frequência e o perfil de suscetibilidade de Pseudomonas aeruginosa e Acinetobacter baumannii aos carbapenêmicos no hospital da Fundação Santa Casa de Franca, São Paulo, Brasil. Métodos: Retrospectivamente, a suscetibilidade de P. aeruginosa e A. baumannii aos carbapenêmicos foi analisada em 304 isolados clínicos entre 2007 e 2012, a partir de um banco de dados do setor de microbiologia do laboratório clínico do hospital da Fundação Santa Casa de Franca, São Paulo, Brasil. Resultados: Das cepas isoladas e identificadas, 236 (5,3%) P. aeruginosa eram suscetíveis a imipenem (2007 - 69,6% a 2012 - 41,7%) e meropenem (2007 - 63,3% a 2012 - 25%). Além disso, todos os 68 (1,7%) isolados de A. baumannii eram suscetíveis aos dois antibióticos. Conclusão: Não foi identificada resistência de A. baumannii aos carbapenêmicos, no entanto houve diminuição da suscetibilidade aos carbapenêmicos no decorrer dos anos para P. aeruginosa.Introduction: One of the major problems in health services is the occurrence of healthcare-associated infections (HAIs) by microorganisms resistant to various antimicrobials. Objectives: To describe the frequency and susceptibility profile of Pseudomonas aeruginosa and Acinetobacter baumannii to carbapenems in the hospital from Fundação Santa Casa de Franca, São Paulo, Brazil. Methods: The susceptibility of P. aeruginosa and A. baumannii to carbapenems from 304 clinical isolates between 2007 and 2012 was retrospectively analyzed from a microbiology database at the clinical laboratory of the hospital of Fundação Santa Casa de Franca, São Paulo, Brazil. Results: From isolated and identified strains, 236 (5.3%) P. aeruginosa were susceptible to imipenem (2007 - 69.6% to 2012 - 41.7%) and meropenem (2007 - 63.3% to 2012 - 25%). In addition, all 68 (1.7%) A. baumannii isolates were susceptible to both antibiotics. Conclusion: A. baumannii resistance to carbapenems was not identified; however, there was a decrease in susceptibility to carbapenems over the years for P. aeruginosa

Human Ageing Genomic Resources:updates on key databases in ageing research

Ageing is a complex and multifactorial process. For two decades, the Human Ageing Genomic Resources (HAGR) have aided researchers in the study of various aspects of ageing and its manipulation. Here, we present the key features and recent enhancements of these resources, focusing on its six main databases. One database, GenAge, focuses on genes related to ageing, featuring 307 genes linked to human ageing and 2205 genes associated with longevity and ageing in model organisms. AnAge focuses on ageing, longevity, and life-history across animal species, containing data on 4645 species. DrugAge includes information about 1097 longevity drugs and compounds in model organisms such as mice, rats, flies, worms and yeast. GenDR provides a list of 214 genes associated with the life-extending benefits of dietary restriction in model organisms. CellAge contains a catalogue of 866 genes associated with cellular senescence. The LongevityMap serves as a repository for genetic variants associated with human longevity, encompassing 3144 variants pertaining to 884 genes. Additionally, HAGR provides various tools as well as gene expression signatures of ageing, dietary restriction, and replicative senescence based on meta-analyses. Our databases are integrated, regularly updated, and manually curated by experts. HAGR is freely available online (https://genomics.senescence.info/).</p

Dietary sulfur amino acid restriction upregulates DICER to confer beneficial effects

Dietary restriction (DR) improves health and prolongs lifespan in part by upregulating type III endoribonuclease DICER in adipose tissue. In this study, we aimed to specifically test which missing dietary component was responsible for DICER upregulation. Methods: We performed a nutrient screen in mouse preadipocytes and validated the results in vivo using different kinds of dietary interventions in wild type or genetically modified mice and worms, also testing the requirement of DICER on the effects of the diets. Results: We found that sulfur amino acid restriction (i.e., methionine or cysteine) is sufficient to increase Dicer mRNA expression in preadipocytes. Consistently, while DR increases DICER expression in adipose tissue of mice, this effect is blunted by supplementation of the diet with methionine, cysteine, or casein, but not with a lipid or carbohydrate source. Accordingly, dietary methionine or protein restriction mirrors the effects of DR. These changes are associated with alterations in serum adiponectin. We also found that DICER controls and is controlled by adiponectin. In mice, DICER plays a role in methionine restriction-induced upregulation of Ucpl in adipose tissue. In C. elegans, DR and a model of methionine restriction also promote DICER expression in the intestine (an analog of the adipose tissue) and prolong lifespan in a DICER-dependent manner. Conclusions: We propose an evolutionary conserved mechanism in which dietary sulfur amino acid restriction upregulates DICER levels in adipose tissue leading to beneficial health effects29124135CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICO - CNPQCOORDENAÇÃO DE APERFEIÇOAMENTO DE PESSOAL DE NÍVEL SUPERIOR - CAPESFUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPESP305069/2015-2; 304995/2014-288887.143923/2017-002017/01184-9; 2017/07975-8; 2017/22057-5; 2015/03292-8; 2012/07259-7; 2016/02207-0; 2010/52557-0; 2015/01316-7; 2012/50558-5; 2015/19530-5We thank Elzira Elisabeth Saviani and Emanoel Cabral for valuable technical support. We thank the National Institute of Science and Technology on Photonics Applied to Cell Biology (INFABIC) at the Universidade Estadual de Campinas to provide access to microscopes, the Caenorhabditis Genetics Center (CGC) for worms and Dr. Amy Pasquinelli for the dcr-1 RNAi clone. CGC is funded by NIH Office of Research Infrastructure Programs ( P40 OD010440 ). We thank Carmen Perrone for sharing the composition of the methionine restriction diet, for valuable discussion and for sharing samples of rats exposed to methionine restriction. This study was funded by grants of the Fundação de Amparo à Pesquisa do Estado de São Paulo ( 2017/01184-9 , 2017/07975-8 , 2017/22057-5 , 2015/03292-8 , 2012/07259-7 , 2016/02207-0 , 2010/52557-0 , 2015/01316-7 , 2012/50558-5 and 2015/19530-5 ), Conselho Nacional de Desenvolvimento Científico e Tecnológico ( 305069/2015-2 and 304995/2014-2 ) and the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - German Academic Exchange Service ( PROBRAL - 88887.143923/2017-00 )

Effects of supplementation of tropical fruit processing by-products on lipid profile, retinol levels and intestinal function in Wistar rats

Abstract Fruits agro-industrial by-products may have a great variety of bioactive compounds that promote health. Thus, the effects of supplementation with acerola, cashew and guava processing by-products for 28 days on retinol level, lipid profile and on some aspects related to intestinal function in rats were investigated. The animals supplemented with different fruit by-products presented similar weight gain, faecal pH values and intestinal epithelial structures; however, they showed higher moisture and Lactobacillus spp. and Bifidobacterium spp. counts in faeces compared to the control group. Supplementation with the cashew by-product decreased the blood glucose, acerola and guava by-products reduced serum lipid levels and all fruit by-products tested increased serum and hepatic retinol. The results indicated that acerola and guava by-products possess a potential hypolipidemic effect. The three fruit by-products increase the hepatic retinol deposition and the faecal populations of beneficial bacterial groups and modulated aspects of intestinal function. The findings of this study can contribute to sustainable fruticulture and support future clinical studies with the supplementation of by-products

Essential oil composition and antioxidant and antimicrobial properties of Campomanesia pubescens O. Berg, Native of Brazilian Cerrado

In this study, the essential oil composition, total contents of phenolics and proanthocyanidins, antioxidant and antimicrobial activities from different plant parts (root, stem, leaf and fruit) of Campomanesia pubescens (DC) O. Berg from Brazilian Cerrado are reported. The root essential oil is distinguished from others by having only one representative of monoterpenes (alpha-terpenylacetate). The aerial parts of C. pubescens are rich in volatile terpenes, as expected, especially in fruits whose essential oil contained approximately 80 % of monoterpenes. The essential oils showed antimicrobial activity against oral pathogens. The root essential oil showed the strongest inhibition against Fusobacterium nucleatum (ATCC 25586). The leaf extract presented the highest concentration of phenolic and proanthocyanidins compounds. The lowest concentration necessary for inhibition of DPPH to 50 % ranged between 6.6 ± 1.6 and 56.6 ± 2.3 μg/mL. The leaf extract exhibited the highest inhibition, close to BHT.Colegio de Farmacéuticos de la Provincia de Buenos Aire