Increased fidelity of protein synthesis extends lifespan.

Loss of proteostasis is a fundamental process driving aging. Proteostasis is affected by the accuracy of translation, yet the physiological consequence of having fewer protein synthesis errors during multi-cellular organismal aging is poorly understood. Our phylogenetic analysis of RPS23, a key protein in the ribosomal decoding center, uncovered a lysine residue almost universally conserved across all domains of life, which is replaced by an arginine in a small number of hyperthermophilic archaea. When introduced into eukaryotic RPS23 homologs, this mutation leads to accurate translation, as well as heat shock resistance and longer life, in yeast, worms, and flies. Furthermore, we show that anti-aging drugs such as rapamycin, Torin1, and trametinib reduce translation errors, and that rapamycin extends further organismal longevity in RPS23 hyperaccuracy mutants. This implies a unified mode of action for diverse pharmacological anti-aging therapies. These findings pave the way for identifying novel translation accuracy interventions to improve aging.

C. elegans: A biosensor for host-microbe interactions.

Microbes are an integral part of life on this planet. Microbes and their hosts influence each other in an endless dance that shapes how the meta-organism interacts with its environment. Although great advances have been made in microbiome research over the past 20 years, the mechanisms by which both hosts and their microbes interact with each other and the environment are still not well understood. The nematode Caenorhabditis elegans has been widely used as a model organism to study a remarkable number of human-like processes. Recent evidence shows that the worm is a powerful tool to investigate in fine detail the complexity that exists in microbe-host interactions. By combining the large array of genetic tools available for both organisms together with deep phenotyping approaches, it has been possible to uncover key effectors in the complex relationship between microbes and their hosts. In this perspective, we survey the literature for insightful discoveries in the microbiome field using the worm as a model. We discuss the latest conceptual and technological advances in the field and highlight the strengths that make C. elegans a valuable biosensor tool for the study of microbe-host interactions.

Transcriptome analysis of Caenorhabditis elegans lacking heme peroxidase SKPO-1 reveals an altered response to Enterococcus faecalis.

The nematode Caenorhabditis elegans is commonly used as a model organism in studies of the host immune response. The worm encodes twelve peroxidase-cyclooxygenase superfamily members, making it an attractive model in which to study the functions of heme peroxidases. In previous work, loss of one of these peroxidases, SKPO-1 (ShkT-containing peroxidase), rendered C. elegans more sensitive to the human, Gram-positive pathogen Enterococcus faecalis. SKPO-1 was localized to the hypodermis of the animals where it also affected cuticle development as indicated by a morphological phenotype called "dumpy." In this work, a better understanding of how loss of skpo-1 impacts both sensitivity to pathogen as well as cuticle development was sought by subjecting a deletion mutant of skpo-1 to transcriptome analysis using RNA sequencing following exposure to control (Escherichia coli) and pathogenic (E. faecalis) feeding conditions. Loss of skpo-1 caused a general upregulation of genes encoding collagens and other proteins related to cuticle development. On E. faecalis, these animals also failed to upregulate guanylyl cyclases that are often involved in environmental sensing. Hoechst straining revealed increased permeability of the cuticle and atomic force microscopy exposed the misalignment of the cuticular annuli and furrows. These findings provide a basis for better understanding of the morphological as well as the pathogen sensitivity phenotypes associated with loss of SKPO-1 function.

Mechanical properties measured by atomic force microscopy define health biomarkers in ageing C. elegans.

Genetic and environmental factors are key drivers regulating organismal lifespan but how these impact healthspan is less well understood. Techniques capturing biomechanical properties of tissues on a nano-scale level are providing new insights into disease mechanisms. Here, we apply Atomic Force Microscopy (AFM) to quantitatively measure the change in biomechanical properties associated with ageing Caenorhabditis elegans in addition to capturing high-resolution topographical images of cuticle senescence. We show that distinct dietary restriction regimes and genetic pathways that increase lifespan lead to radically different healthspan outcomes. Hence, our data support the view that prolonged lifespan does not always coincide with extended healthspan. Importantly, we identify the insulin signalling pathway in C. elegans and interventions altering bacterial physiology as increasing both lifespan and healthspan. Overall, AFM provides a highly sensitive technique to measure organismal biomechanical fitness and delivers an approach to screen for health-improving conditions, an essential step towards healthy ageing.

The Role of the Microbiome in Drug Response.

The microbiome is known to regulate many aspects of host health and disease and is increasingly being recognized as a key mediator of drug action. However, investigating the complex multidirectional relationships between drugs, the microbiota, and the host is a challenging endeavor, and the biological mechanisms that underpin these interactions are often not well understood. In this review, we outline the current evidence that supports a role for the microbiota as a contributor to both the therapeutic benefits and side effects of drugs, with a particular focus on those used to treat mental disorders, type 2 diabetes, and cancer. We also provide a snapshot of the experimental and computational tools that are currently available for the dissection of drug-microbiota-host interactions. The advancement of knowledge in this area may ultimately pave the way for the development of novel microbiota-based strategies that can be used to improve treatment outcomes.

Host-Microbe-Drug-Nutrient Screen Identifies Bacterial Effectors of Metformin Therapy.

Metformin is the first-line therapy for treating type 2 diabetes and a promising anti-aging drug. We set out to address the fundamental question of how gut microbes and nutrition, key regulators of host physiology, affect the effects of metformin. Combining two tractable genetic models, the bacterium E. coli and the nematode C. elegans, we developed a high-throughput four-way screen to define the underlying host-microbe-drug-nutrient interactions. We show that microbes integrate cues from metformin and the diet through the phosphotransferase signaling pathway that converges on the transcriptional regulator Crp. A detailed experimental characterization of metformin effects downstream of Crp in combination with metabolic modeling of the microbiota in metformin-treated type 2 diabetic patients predicts the production of microbial agmatine, a regulator of metformin effects on host lipid metabolism and lifespan. Our high-throughput screening platform paves the way for identifying exploitable drug-nutrient-microbiome interactions to improve host health and longevity through targeted microbiome therapies. VIDEO ABSTRACT.

Handgrip strength and lean mass are independently related to brain atrophy among alcoholics.

BACKGROUND: In neurodegenerative disorders or in normal aging humans a relationship between muscle mass and/or performance and brain volume was observed, that is not dependent on age or other confounding factors. The aim of the present study is to analyse the relationship between lean mass and handgrip strength in alcoholics, who frequently show brain and muscle atrophy. METHODS: It was included 101 male patients aged 58.35 ± 11.59 years, and 44 controls, all of them workers of our hospital, drinkers of less than 20 g ethanol/day, of similar age. Patients and controls underwent dominant handgrip assessment with a Collins' dynamometer, whole body composition analysis by densitometry, and brain computed tomography (CT) examination, with further calculation of several indices indicative of brain atrophy. MAIN RESULTS: 1) Brain atrophy is a very common finding among alcoholics, both among cirrhotics and non-cirrhotics. 2) Alcoholics show a marked reduction in handgrip strength, and also in lean mass, especially at the arms and legs -but not in the trunk, even if patients with ascites were excluded.3) There is a relationship between reduced lean mass and brain atrophy, and a close correlation between handgrip strength and brain atrophy, that is independent of age and liver function. 4) Total fat amount is not different among alcoholics and controls, but there are marked differences in fat distribution: alcoholics show less fat in arms, but more fat in trunk, so that if we calculate the peripheral fat/trunk fat index, marked differences were observed among alcoholics and controls. Neither total fat nor fat distribution were related to brain atrophy. CONCLUSION: among alcoholics, as in other neurodegenerative conditions, there is a relationship between reduced lean mass and brain atrophy, and a close correlation between handgrip strength and brain atrophy, that is independent of age, duration of ethanol consumption and liver function.

Oxidative stress in the oral cavity is driven by individual-specific bacterial communities.

The term "bacterial dysbiosis" is being used quite extensively in metagenomic studies, however, the identification of harmful bacteria often fails due to large overlap between the bacterial species found in healthy volunteers and patients. We hypothesized that the pathogenic oral bacteria are individual-specific and they correlate with oxidative stress markers in saliva which reflect the inflammatory processes in the oral cavity. Temporally direct and lagged correlations between the markers and bacterial taxa were computed individually for 26 volunteers who provided saliva samples during one month (21.2 ± 2.7 samples/volunteer, 551 samples in total). The volunteers' microbiomes differed significantly by their composition and also by their degree of microbiome temporal variability and oxidative stress markers fluctuation. The results showed that each of the marker-taxa pairs can have negative correlations in some volunteers while positive in others. Streptococcus mutans, which used to be associated with caries before the metagenomics era, had the most prominent correlations with the oxidative stress markers, however, these correlations were not confirmed in all volunteers. The importance of longitudinal samples collections in correlation studies was underlined by simulation of single sample collections in 1000 different combinations which produced contradictory results. In conclusion, the distinct intra-individual correlation patterns suggest that different bacterial consortia might be involved in the oxidative stress induction in each human subject. In the future, decreasing cost of DNA sequencing will allow to analyze multiple samples from each patient, which might help to explore potential diagnostic applications and understand pathogenesis of microbiome-associated oral diseases.

Time Series Analysis of the Microbiota of Children Suffering From Acute Infectious Diarrhea and Their Recovery After Treatment.

Gut microbiota is closely related to acute infectious diarrhea, one of the leading causes of mortality and morbidity in children worldwide. Understanding the dynamics of the recovery from this disease is of clinical interest. This work aims to correlate the dynamics of gut microbiota with the evolution of children who were suffering from acute infectious diarrhea caused by a rotavirus, and their recovery after the administration of a probiotic, Saccharomyces boulardii CNCM I-745. The experiment involved 10 children with acute infectious diarrhea caused by a rotavirus, and six healthy children, all aged between 3 and 4 years. The children who suffered the rotavirus infection received S. boulardii CNCM I-745 twice daily for the first 5 days of the experiment. Fecal samples were collected from each participant at 0, 3, 5, 10, and 30 days after probiotic administration. Microbial composition was characterized by 16S rRNA gene sequencing. Alpha and beta diversity were calculated, along with dynamical analysis based on Taylor's law to assess the temporal stability of the microbiota. All children infected with the rotavirus stopped having diarrhea at day 3 after the intervention. We observed low alpha diversities in the first 5 days (p-value < 0.05, Wilcoxon test), larger at 10 and 30 days after probiotic treatment. Canonical correspondence analysis (CCA) showed differences in the gut microbiota of healthy children and of those who suffered from acute diarrhea in the first days (p-value < 0.05, ADONIS test), but not in the last days of the experiment. Temporal variability was larger in children infected with the rotavirus than in healthy ones. In particular, Gammaproteobacteria class was found to be abundant in children with acute diarrhea. We identified the microbiota transition from a diseased state to a healthy one with time, whose characterization may lead to relevant clinical data. This work highlights the importance of using time series for the study of dysbiosis related to diarrhea.

Soluble Klotho and Brain Atrophy in Alcoholism.

AIM: Fibroblast growth factor (FGF-23) and α-Klotho (Klotho) levels may be altered in inflammatory conditions, possibly as compensatory mechanisms. Klotho exerts a protective effect on neurodegeneration and improves learning and cognition. No data exist about the association of Klotho and FGF-23 levels with brain atrophy observed in alcoholics. The aim of this study is to explore these relationships. SHORT SUMMARY: FGF-23 and Klotho levels are altered in inflammation, possibly as compensatory mechanisms. Klotho enhances learning, but its role in ethanol-mediated brain atrophy is unknown. We found higher FGF-23 and lower Klotho levels in 131 alcoholics compared with 41 controls. Among cirrhotics, Klotho was higher and inversely related to brain atrophy. METHODS: The study was performed on 131 alcoholic patients (54 cirrhotics) and 41 age- and sex-matched controls, in whom a brain computed tomography (CT) was performed and several indices were calculated. RESULTS: Marked brain atrophy was observed among patients when compared with controls. Patients also showed higher FGF-23 and lower Klotho values. However, among cirrhotics, Klotho values were higher. Klotho was inversely related to brain atrophy (for instance, ventricular index (ρ = -0.23, P = 0.008)), especially in cirrhotics. Klotho was also directly related to tumor necrosis factor (TNF) alpha (ρ = 0.22; P = 0.026) and inversely to transforming growth factor (TGF)-ß (ρ = -0.34; P = 0.002), but not to C-reactive protein (CRP) or malondialdehyde levels. FGF-23 was also higher among cirrhotics but showed no association with CT indices. CONCLUSIONS: Klotho showed higher values among cirrhotics, and was inversely related to brain atrophy. FGF-23, although high among patients, especially cirrhotics, did not show any association with brain atrophy. Some inflammatory markers or cytokines, such as CRP or TGF-ß were related to brain atrophy.

Lipid profile and bone mineral density in heavy alcoholics.

BACKGROUND & AIMS: Some studies have illustrated the association between serum lipid profile and bone mineral density (BMD) or fractures. None of these studies was performed among alcoholics, despite the fact that alcoholism may affect both bone mass and lipid metabolism. We here analyse the relationship of serum lipid profile with bone mass among a population of 280 heavy alcoholics (29 women). METHODS: patients underwent a densitometric assessment of BMD and determination of a serum lipid panel. Castelli index (Total cholesterol/HDL cholesterol) and the LDL/HDL cholesterol index were calculated. RESULTS: There was a direct correlation between both total cholesterol and LDL-cholesterol and femoral neck (r = 0.17 and r = 0.20, respectively) and lumbar spine (r = 0.16 and r = 0.20) T score, total BMD (r = 0.14 and r = 0.18) or pelvis BMD (r = 0.16 and r = 0.23; p < 0.025 in all cases). HDL-cholesterol showed no relationship with BMD. Serum triglycerides were also directly related to T score at the lumbar spine (ρ = 0.13; p = 0.032) and pelvis BMD (ρ = 0.13; p = 0.037). Pelvis BMD was significantly related to Castelli index (ρ = 0.15) and LDL/HDL index (ρ = 0.18; p < 0.015 in both cases). Multivariate analysis showed that the association between the serum lipid panel and BMD was independent of liver function and body mass index. CONCLUSIONS: Therefore, BMD was directly related to total cholesterol and LDL cholesterol in heavy alcoholism. This counter intuitive observation adds to others derived from several similar studies conducted in different population groups but not in alcoholics as of yet. The mechanisms that explain the association between serum lipids and bone metabolism need further investigation.

Health and Disease Imprinted in the Time Variability of the Human Microbiome.

The animal microbiota (including the human microbiota) plays an important role in keeping the physiological status of the host healthy. Research seeks greater insight into whether changes in the composition and function of the microbiota are associated with disease. We analyzed published 16S rRNA and shotgun metagenomic sequencing (SMS) data pertaining to the gut microbiotas of 99 subjects monitored over time. Temporal fluctuations in the microbial composition revealed significant differences due to factors such as dietary changes, antibiotic intake, age, and disease. This article shows that a fluctuation scaling law can describe the temporal changes in the gut microbiota. This law estimates the temporal variability of the microbial population and quantitatively characterizes the path toward disease via a noise-induced phase transition. Estimation of the systemic parameters may be of clinical utility in follow-up studies and have more general applications in fields where it is important to know whether a given community is stable or not. IMPORTANCE The human microbiota correlates closely with the health status of its host. This article analyzes the microbial composition of several subjects under different conditions over time spans that ranged from days to months. Using the Langevin equation as the basis of our mathematical framework to evaluate microbial temporal stability, we proved that stable microbiotas can be distinguished from unstable microbiotas. This initial step will help us to determine how temporal microbiota stability is related to a subject's health status and to develop a more comprehensive framework that will provide greater insight into this complex system.

Mining metagenomic whole genome sequences revealed subdominant but constant Lactobacillus population in the human gut microbiota.

The genus Lactobacillus includes over 215 species that colonize plants, foods, sewage and the gastrointestinal tract (GIT) of humans and animals. In the GIT, Lactobacillus population can be made by true inhabitants or by bacteria occasionally ingested with fermented or spoiled foods, or with probiotics. This study longitudinally surveyed Lactobacillus species and strains in the feces of a healthy subject through whole genome sequencing (WGS) data-mining, in order to identify members of the permanent or transient populations. In three time-points (0, 670 and 700 d), 58 different species were identified, 16 of them being retrieved for the first time in human feces. L. rhamnosus, L. ruminis, L. delbrueckii, L. plantarum, L. casei and L. acidophilus were the most represented, with estimated amounts ranging between 6 and 8 Log (cells g(-1) ), while the other were detected at 4 or 5 Log (cells g(-1) ). 86 Lactobacillus strains belonging to 52 species were identified. 43 seemingly occupied the GIT as true residents, since were detected in a time span of almost 2 years in all the three samples or in 2 samples separated by 670 or 700 d. As a whole, a stable community of lactobacilli was disclosed, with wide and understudied biodiversity.