Long-term NMN treatment increases lifespan and healthspan in mice in a sex dependent manner.

Nicotinamide adenine dinucleotide (NAD) is essential for many enzymatic reactions, including those involved in energy metabolism, DNA repair and the activity of sirtuins, a family of defensive deacylases. During aging, levels of NAD + can decrease by up to 50% in some tissues, the repletion of which provides a range of health benefits in both mice and humans. Whether or not the NAD + precursor nicotinamide mononucleotide (NMN) extends lifespan in mammals is not known. Here we investigate the effect of long-term administration of NMN on the health, cancer burden, frailty and lifespan of male and female mice. Without increasing tumor counts or severity in any tissue, NMN treatment of males and females increased activity, maintained more youthful gene expression patterns, and reduced overall frailty. Reduced frailty with NMN treatment was associated with increases in levels of Anerotruncus colihominis, a gut bacterium associated with lower inflammation in mice and increased longevity in humans. NMN slowed the accumulation of adipose tissue later in life and improved metabolic health in male but not female mice, while in females but not males, NMN increased median lifespan by 8.5%, possible due to sex-specific effects of NMN on NAD + metabolism. Together, these data show that chronic NMN treatment delays frailty, alters the microbiome, improves male metabolic health, and increases female mouse lifespan, without increasing cancer burden. These results highlight the potential of NAD + boosters for treating age-related conditions and the importance of using both sexes for interventional lifespan studies.

Linking anatomical and histological traits of the digestive tract to resource consumption and assimilation of omnivorous tetra fishes.

This study explores the interplay between digestive tract traits, food intake, and assimilation in omnivorous tetra fishes (Psalidodon bifasciatus, P. aff. gymnodontus, and Bryconamericus ikaa) from the Iguaçu River basin, an ecologically significant region known for high endemism. We hypothesize that variations in digestive tracts across species would be associated with differences in diet, isotopic composition in fish tissues, and overall diet assimilation. To test this, we employed stereoscopic and light microscopy to characterize the gross anatomy, histomorphology, and histochemistry of fish digestive tracts. Additionally, we used stomach content and stable isotope analyses to trace fish diets. While these tetra fishes shared histological structures, disparities were noted in anatomical digestive traits and diet preferences. The smallest species, B. ikaa, with a shorter intestine, had fewer pyloric caeca and primarily consumed animal-based diets. Conversely, P. bifasciatus and P. aff. gymnodontus, with longer intestines, displayed numerous pyloric caeca and consumed a balanced mix of animal and plant items. Despite anatomical and dietary differences, all three species predominantly assimilated animal-origin food. The tetra fishes had histological variations among digestive tract segments, with the esophagus having the thickest muscular layer, gradually thinning towards the posterior intestine. The final portion of the intestine exhibited a significant expansion in the lumen perimeter, while the esophagus had the smallest lumen area. Goblet cells were most concentrated in the posterior intestine for all species. The gross anatomy of these tetra fishes aligns with their omnivorous habit, while diet assimilation was dominated by animal-origin food. These findings provide crucial insights into the structural and tissue characteristics of their digestive systems, laying the groundwork for deeper exploration into the physiological aspects of their digestive tracts and enhancing our understanding of their feeding strategies.

TIME-seq reduces time and cost of DNA methylation measurement for epigenetic clock construction.

Epigenetic 'clocks' based on DNA methylation have emerged as the most robust and widely used aging biomarkers, but conventional methods for applying them are expensive and laborious. Here we develop tagmentation-based indexing for methylation sequencing (TIME-seq), a highly multiplexed and scalable method for low-cost epigenetic clocks. Using TIME-seq, we applied multi-tissue and tissue-specific epigenetic clocks in over 1,800 mouse DNA samples from eight tissue and cell types. We show that TIME-seq clocks are accurate and robust, enriched for polycomb repressive complex 2-regulated loci, and benchmark favorably against conventional methods despite being up to 100-fold less expensive. Using dietary treatments and gene therapy, we find that TIME-seq clocks reflect diverse interventions in multiple tissues. Finally, we develop an economical human blood clock (R > 0.96, median error = 3.39 years) in 1,056 demographically representative individuals. These methods will enable more efficient epigenetic clock measurement in larger-scale human and animal studies.

Incidental Adrenal Masses: A Case Report of an Adrenal Oncocytoma.

A 59-year-old woman underwent an abdominal and pelvic computed tomography (CT) scan to rule out non-obstructive urolithiasis. The patient was asymptomatic, with the exception of occasional bilateral low back pain. A physical examination did not reveal any notable findings. The CT scan revealed the presence of an incidental solid left adrenal lesion, which displaced the body of the pancreas and the left kidney. The lesion measured 7 cm × 6.5 cm and exhibited a rounded morphology with well-defined margins. It showed progressive and heterogeneous contrast uptake. Additionally, magnetic resonance imaging (MRI) was performed, confirming the presence of an adrenal lesion with intense and heterogeneous hypersignal on T2. The lesion also demonstrated heterogeneous and persistent enhancement in a dynamic study. Furthermore, there were some indistinct and non-specific hypointense areas identified on both T1 and T2 sequences. The lesion exhibited moderately restricted diffusion. Although the imaging features were non-specific, there were no indications of invasion or distant metastasis, which made a benign large adrenal mass the most likely diagnosis. Non-functioning pheochromocytoma, lipid-poor adrenal adenoma, as well as metastasis or primary adrenal carcinoma, were considered differential diagnoses. The patient underwent an elective adrenalectomy, during which the identified lesion was completely resected. The patient's postoperative recovery was uneventful, and she was discharged three days after the procedure. Subsequent histopathological evaluation revealed an oncocytic neoplasm of the adrenal cortex - specifically, an oncocytoma.

Insights into environmental caffeine contamination in ecotoxicological biomarkers and potential health effects of Danio rerio.

Caffeine (CAF) exposures have been shown to cause several pharmacological and biological effects in target and non-target organisms. Although there are already several ecotoxicological studies with CAF in non-target organisms, they are focused on marine organisms, with relevant concentrations in these ecosystems, therefore, less ecologically relevant to freshwater ecosystems (the main ecoreceptor of this type of anthropogenic contaminant). The present study aimed to assess the chronic effects (28 days) of sub-lethal and environmentally relevant concentrations of CAF (0.16, 0.42, 1.09, 2.84, 7.40, 19.23, and 50 µg/L) in Danio rerio. Biochemical endpoints as biomarkers of antioxidant defense, biotransformation, lipid peroxidation, energy sources, and neurotransmission were assessed. CAF exposure induced alterations in antioxidant defenses (superoxide dismutase and glutathione reductase activities, and glutathione content) preventing lipid peroxidation. Lactate dehydrogenase activity decreased in all the concentrations tested, while acetylcholinesterase activity was only affected by the highest concentrations tested (19.23 and 50 µg/L). We also utilized a multi-biomarker approach (Integrated Biomarker Response version 2, IBRv2) to investigate the effects of CAF in the dispersion scope of individual biochemical responses of D. rerio. IBRv2 showed that the concentration of 50 µg/L promotes the highest stress. However, the results showed that CAF induced disturbances in the metabolic pathways studied in D. rerio. These results demonstrated the toxic effects of CAF on freshwater fish, compromising their physiological functions and evidencing the need for monitoring the residues of CAF released into the inland aquatic environments. Furthermore, this research evidence that phylogenetically and physiologically different species may present different biological responses with concern for ecologically relevant environmental conditions. In this sense, the present study generated ecotoxicologically relevant data, that can be considered by environment regulators, since the here-endpoints evaluated showed sensitivity and consistency in the evaluation of caffeine risks in freshwater environments.

Ursolic acid-rich extract presents trypanocidal action in vitro but worsens mice under experimental acute Chagas disease.

Chagas disease is a neglected tropical disease with only two drugs available for treatment and the plant Cecropia pachystachya has several compounds with antimicrobial and anti-inflammatory activities. This study aimed to evaluate a supercritical extract from C. pachystachya leaves in vitro and in vivo against Trypanosoma cruzi. A supercritical CO2 extraction was used to obtain the extract (CPE). Cytotoxicity and immunostimulation ability were evaluated in macrophages, and the in vitro trypanocidal activity was evaluated against epimastigotes and trypomastigotes forms. In vivo tests were done by infecting BALB/c mice with blood trypomastigotes forms and treating animals orally with CPE for 10 days. The parasitemia, survival rate, weight, cytokines and nitric oxide dosage were evaluated. CPE demonstrated an effect on the epi and trypomastigotes forms of the parasite (IC50 17.90 ± 1.2 µg/mL; LC50 26.73 ± 1.2 µg/mL) and no changes in macrophages viability, resulting in a selectivity index similar to the reference drug. CPE-treated animals had a worsening compared to non-treated, demonstrated by higher parasitemia and lower survival rate. This result was attributed to the anti-inflammatory effect of CPE, demonstrated by the higher IL-10 and IL-4 values observed in the treated mice compared to the control ones. CPE demonstrated a trypanocidal effect in vitro and a worsening in the in vivo infection due to its anti-inflammatory activity.

Effect of probiotic therapy on periodontal tissues and intestinal mucosa of rats with ligature-induced periodontitis / Efeito da terapia probiótica nos tecidos periodontais e mucosa intestinal de ratos com periodontite induzida por ligadura

INTRODUCTION: As periodontitis is caused by dysbiotic biofilm, it is believed that therapy with probiotics can act to control the mechanisms of adhesion and colonization, competing with invading microorganisms. OBJECTIVE: Evaluate probiotic therapy effect on periodontal tissues and intestinal mucosa of rats with ligature-induced periodontitis. METHODS: 32 Wistar rats were divided into four groups (n=8): Control Group (CG); Periodontal disease (PD); Probiotic (PROB); PD + probiotic (PDPRO). PD and PDPRO received a ligature over the first lower molars and PROB and PDPRO the probiotic Lactobacillus acidophilus based were given orally for 44 days. The animals were euthanized and the blood was collected for evaluation of triglyceride and cholesterol concentrations. The hemimandibles were collected for histomorphometric and radiographic analysis. The duodenum was removed for morphological evaluation and gingival tissue around the molars was collected for analysis of IL-17. RESULTS: The ANOVA one-way test was used followed by Tukey Test. PDPRO had a significantly lower bone loss than the PD (p<0.05) and a smaller number of osteoclasts on PDPRO when compared to the PD. As for IL-17, there was a decrease in the PDPRO when compared to the PD. The histomorphometry of the duodenum showed that there was a significant increase in the width of the villi in PROB only. CONCLUSION: The therapy with probiotics was effective to avoid the development of periodontitis by reducing alveolar bone loss and inflammation modulation and increasing the width of the duodenum villi, which may help to restabilize the balance of the gastrointestinal tract.

INTRODUÇÃO: Como a periodontite é causada por biofilme disbiótico, acredita-se que a terapia com probióticos possa atuar no controle dos mecanismos de adesão e colonização, competindo com microrganismos invasores. OBJETIVO: Avaliar o efeito da terapia probiótica nos tecidos periodontais e mucosa intestinal de ratos com periodontite induzida por ligadura. MÉTODOS: 32 ratos Wistar foram divididos em quatro grupos (n=8): Grupo Controle (GC); Doença periodontal (PD); Probiótico (PROB); PD + probiótico (PDPRO). PD e PDPRO receberam ligadura sobre os primeiros molares inferiores e PROB e PDPRO, o probiótico à base de Lactobacillus acidophilus dado via oral por 44 dias. Os animais foram sacrificados e o sangue coletado para avaliação das concentrações de triglicerídeos e colesterol total. As hemimandíbulas foram coletadas para análise histomorfométrica e radiográfica. O duodeno foi removido para avaliação morfológica e o tecido gengival ao redor dos molares foi coletado para análise de IL-17. RESULTADOS: Foi usado Teste ANOVA seguido pelo Teste de Tukey. PDPRO teve uma perda óssea significativamente menor do que o PD (p<0.05) e um menor número de osteoclastos no PDPRO quando comparado ao PD. Já para IL-17, houve diminuição do PDPRO em relação ao PD. A histomorfometria do duodeno mostrou que houve aumento significativo da largura das vilosidades no PROB somente. CONCLUSÃO: A terapia com probiótico foi eficaz para evitar o desenvolvimento de periodontite por reduzir a perda óssea alveolar e a modulação da inflamação e aumentar a largura das vilosidades duodenais, o que pode ajudar a estabilizar o equilíbrio do trato gastrointestinal.

Loss of epigenetic information as a cause of mammalian aging.

All living things experience an increase in entropy, manifested as a loss of genetic and epigenetic information. In yeast, epigenetic information is lost over time due to the relocalization of chromatin-modifying proteins to DNA breaks, causing cells to lose their identity, a hallmark of yeast aging. Using a system called "ICE" (inducible changes to the epigenome), we find that the act of faithful DNA repair advances aging at physiological, cognitive, and molecular levels, including erosion of the epigenetic landscape, cellular exdifferentiation, senescence, and advancement of the DNA methylation clock, which can be reversed by OSK-mediated rejuvenation. These data are consistent with the information theory of aging, which states that a loss of epigenetic information is a reversible cause of aging.

Incidence and clinical results of tendinous injuries in calcaneus and pilon fractures.

PURPOSE: The aims of this study were: (1) to define the incidence of tendinous injuries in calcaneus and pilon fractures with different fracture severity and (2) to determine the clinical impact of such injuries. STUDY DESIGN AND METHODS: CT-scans of 121 patients with calcaneus and pilon fractures were retrospectively analyzed over a 4-year period. The tendinous injuries were identified and correlated with the type of fracture (location and classification). Clinical analysis was performed using the American Orthopedic Foot and Ankle Society (AOFAS) and SF-36 (Short Form-36 Health Survey) scores. RESULTS: Tendinous injuries were observed in 36% of all CT-scans analyzed, with the most common injury being incarceration (n = 20) and dislocation (n = 24). Calcaneus fractures sanders type 3/4 were 9 times more prone to tendon injury (p < 0.001; OR 8.67; 95% CI 2.49-30.24). Pilon fractures Ruedi-Allgower type 2/3 were 8 times more prone to tendon injury (p = 0.005; OR 7.5; 95% CI 1.72-32.80). No significant differences (p > 0.05) were found in AOFAS and SF-36 scores between patients with/without tendon injuries for fractures with the same severity. CONCLUSION: The incidence of tendon injuries in calcaneus/pilon fractures is high and may be underreported. Calcaneus fractures are prone to peroneal tendon injury. In pilon fractures, it is important to look for tibialis posterior tendon injury, especially entrapment. The presence of tendinous injuries does not affect function and pain for the same type of calcaneus and pilon fractures at the long term. LEVEL OF EVIDENCE: Level 3 retrospective study.

Interface trabalho-tratamento hemodialítico em pacientes com insuficiência renal crônica: revisão de escopo / Interfaz trabajo-tratamiento hemodialítico en pacientes con insuficiencia renal crónica: revisión de alcance / Work-hemodialysis treatment interface in patients with chronic kidney disease: a scoping review

Resumo Objetivo Analisar as evidências científicas sobre o impacto do tratamento hemodialítico no trabalho de pacientes com insuficiência renal crônica. Métodos Revisão de escopo realizada por meio de buscas em cinco bases de dados: PubMed, LILACS, CINAHL, PsyInfo e Scopus. Foram incluídos estudos publicados entre 2010 e 2020, nos idiomas português, espanhol e inglês, de abordagem qualitativa ou quantitativa, com pacientes em tratamento hemodialítico para insuficiência renal crônica, que tivessem foco no trabalho, emprego ou produtividade. Resultados Os 18 estudos incluídos na revisão mostram o impacto do tratamento hemodialítico na relação com o trabalho e as razões associadas à desempregabilidade. Tais razões envolvem características sociodemográficas, debilidade física, tratamento e apoio familiar e do empregador. Conclusão Após o início da hemodiálise, nota-se o comprometimento da capacidade funcional tanto física como psicológica dos pacientes, sendo necessárias alterações nos hábitos de vida em decorrência das restrições impostas pela insuficiência renal crônica e da diminuição da produtividade.

Resumen Objetivo Analizar las evidencias científicas sobre el impacto del tratamiento hemodialítico en el trabajo de pacientes con insuficiencia renal crónica. Métodos Revisión de alcance realizada mediante búsquedas en cinco bases de datos: PubMed, LILACS, CINAHL, PsyInfo y Scopus. Se incluyeron estudios publicados entre 2010 y 2020, en idioma portugués, español e inglés, de enfoque cualitativo o cuantitativo, con pacientes bajo tratamiento hemodialítico por insuficiencia renal crónica, que estuvieran centrados en el trabajo, empleo o productividad. Resultados Los 18 estudios incluidos en la revisión muestran el impacto del tratamiento hemodialítico en la relación con el trabajo y las razones asociadas al desempleo. Estas razones incluyen características sociodemográficas, debilidad física, tratamiento y apoyo familiar y del empleador. Conclusión Después del inicio de la hemodiálisis, se observa la capacidad funcional de los pacientes comprometida, tanto la física como la psicológica, por lo que los cambios en los hábitos de vida se hacen necesarios como consecuencia de las restricciones impuestas por la insuficiencia renal crónica y de la reducción de la productividad.

Abstract Objective To analyze the scientific evidence on the impact of hemodialysis treatment on the work of patients with chronic kidney disease. Methods This is a scoping review carried out through searches in five databases: PubMed, LILACS, CINAHL, PsyInfo and Scopus. We included studies published between 2010 and 2020, in Portuguese, Spanish and English, with a qualitative or quantitative approach, with patients undergoing hemodialysis for chronic kidney failure, who focused on work, employment or productivity. Results The 18 studies included in the review show the impact of hemodialysis treatment on the relationship with work and the reasons associated with unemployment. Such reasons involve sociodemographic characteristics, physical weakness, treatment and family and employer support. Conclusion After starting hemodialysis, we identified impairment in patients' functional capacity, both physical and psychological, requiring changes in life habits due to restrictions imposed by chronic kidney disease and decreased productivity.

Potent and Specific Activators for Mitochondrial Sirtuins Sirt3 and Sirt5.

Sirtuins are NAD+-dependent protein deacylases involved in metabolic regulation and aging-related diseases. Specific activators for seven human Sirtuin isoforms would be important chemical tools and potential therapeutic drugs. Activators have been described for Sirt1 and act via a unique N-terminal domain of this isoform. For most other Sirtuin isoforms, including mitochondrial Sirt3-5, no potent and specific activators have yet been identified. We here describe the identification and characterization of 1,4-dihydropyridine-based compounds that either act as pan Sirtuin activators or specifically stimulate Sirt3 or Sirt5. The activators bind to the Sirtuin catalytic cores independent of NAD+ and acylated peptides and stimulate turnover of peptide and protein substrates. The compounds also activate Sirt3 or Sirt5 in cellular systems regulating, e.g., apoptosis and electron transport chain. Our results provide a scaffold for potent Sirtuin activation and derivatives specific for Sirt3 and Sirt5 as an excellent basis for further drug development.

Exposure to glyphosate-based herbicide during early stages of development increases insulin sensitivity and causes liver inflammation in adult mice offspring.

OBJECTIVE: To investigate the effect of pre and postnatal exposure to a glyphosate-based herbicide on glucose metabolism and liver histology in adult F1 mice offspring. METHODS: Female mice (C57Bl/6) received 0.5% of glyphosate (Roundup Original DI®) in drinking water or purified water (Glyphosate Group and Control Group respectively) during pregnancy and lactation. Offspring (F1) were submitted to glucose and insulin tolerance tests and euthanized on postnatal day 150. Body and plasma parameters, and liver histology were analyzed. RESULTS: Exposure to glyphosate reduced maternal body weight gain during pregnancy and lactation, with no impacts on litter size. Pre and postnatal exposure to glyphosate did not affect body parameters but increased glucose tolerance on postnatal day 60. In spite of glucose tolerance normalization by postnatal day 143, this effect was associated with higher insulin sensitivity relative to mice in the Control-F1 Group. Mice in the Glyphosate-F1 Group had mild and moderate lobular inflammation in the liver. CONCLUSION: Maternal exposure to glyphosate affected insulin sensitivity and caused hepatic inflammation in adult F1 mice offspring.

Incidental Liver Lesions in children: A practical and evidence-based approach.

Incidental liver lesions are increasingly being discovered in the context of the increased use of ultrasound studies and the majority are benign. In children, although individually rare, the differential diagnosis is broad and therefore a systematic approach is of utmost importance to reduce the radiological and disease burden in children and their families. This review article collected current evidence and provides fundamental information for the clinician regarding specific differential diagnoses and unique imaging features of benign liver lesions in children. Ultimately, we propose a practical stepwise approach mainly involving clinical and radiological workup. Laboratory tests and histopathological examination may be necessary in the presence of red flags or in indeterminate lesions.