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The current increase in lifespan without an equivalent increase in healthspan poses a grave challenge to the healthcare system and a severe burden on society. However, some individuals seem to be able to live a long and healthy life without the occurrence of major debilitating chronic diseases, and part of this trait seems to be hidden in their genome. In this review, we discuss the findings from studies on the genetic component of human longevity and the main challenges accompanying these studies. We subsequently focus on results from genetic studies in model organisms and comparative genomic approaches to highlight the most important conserved longevity-associated pathways. By combining the results from studies using these different approaches, we conclude that only five main pathways have been consistently linked to longevity, namely (1) insulin/insulin-like growth factor 1 signalling, (2) DNA-damage response and repair, (3) immune function, (4) cholesterol metabolism and (5) telomere maintenance. As our current approaches to study the relevance of these pathways in humans are limited, we suggest that future studies on the genetics of human longevity should focus on the identification and functional characterization of rare genetic variants in genes involved in these pathways., (© 2023 The Authors. Journal of Internal Medicine published by John Wiley & Sons Ltd on behalf of Association for Publication of The Journal of Internal Medicine.)

Dietary intervention is a subject of growing interest in the management of inflammatory bowel disease (IBD), as new incident cases across the globe are rapidly rising, suggesting environmental factors as contributing elements. Dietary components and micronutrients have been associated with IBD pathogenesis or reductions in disease severity. Selenium, a diet-derived essential micronutrient that is important for proper immune system function, has received limited attention in the context of IBD. Selenium deficiency is a common finding in patients with IBD, but few clinical trials have been published to address the consequences of this deficiency. Here, we review the physiological and immunological roles of selenium and its putative role in IBD, and draw attention to knowledge gaps and unresolved issues, with the goal of stimulating more research on selenium in IBD. [ABSTRACT FROM AUTHOR]

Background: The minor G-allele of FOXO3 rs2802292 is associated with human longevity. The aim of this study was to test the protective effect of the variant against the association with type 2 Diabetes and NAFLD. Methods: rs2802292 was genotyped in a large population of middle-aged subjects (n = 650) from a small city in Southern Italy. All participants were interviewed to collect information about lifestyle and dietary habits; clinical characteristics were recorded, and blood samples were collected from all subjects. The association between rs2802292 and NAFLD or diabetes was tested using a logistic model and mediation analysis adjusted for covariates. Results: Overall, the results indicated a statistical association between diabetes and rs2802292, especially for the TT genotype (OR = 2.14, 1.01 to 4.53 95% C.I., p = 0.05) or in any case for those who possess the G-allele (OR = 0.45, 0.25 to 0.81 95% C.I., p = 0.008). Furthermore, we found a mediation effect of rs2802292 on diabetes (as mediator) and NAFLD. There is no direct relationship between rs2802292 and NAFLD, but the effect is direct (β = 0.10, −0.003 to 0.12 95% C.I., p = 0.04) on diabetes, but only in TT genotypes. Conclusions: The data on our cohort indicate that the longevity-associated FOXO3 variant may have protective effects against diabetes and NAFLD. [ABSTRACT FROM AUTHOR]

There have been many studies reporting that the regular consumption of fruits and vegetables is associated with reduced risks of cancer and age-related chronic diseases. Recent studies have demonstrated that reducing reactive oxygen species and inflammation by phytochemicals derived from natural sources can extend lifespans in a range of model organisms. Phytochemicals derived from fruits and vegetables have been known to display both preventative and suppressive activities against various types of cancer via in vitro and in vivo research by interfering with cellular processes critical for tumor development. The current challenge lies in creating tailored supplements containing specific phytochemicals for individual needs. Achieving this goal requires a deeper understanding of the molecular mechanisms through which phytochemicals affect human health. In this review, we examine recently (from 2010 to 2024) reported plant extracts and phytochemicals with established anti-aging and anti-cancer effects via the activation of FOXO3 transcriptional factor. Additionally, we provide an overview of the cellular and molecular mechanisms by which these molecules exert their anti-aging and anti-cancer effects in specific model systems. Lastly, we discuss the limitations of the current research approach and outline for potential future directions in this field. [ABSTRACT FROM AUTHOR]

Background: Aging is a prominent risk factor for diverse diseases; therefore, an in-depth understanding of its physiological mechanisms is required. Nonhuman primates, which share the closest genetic relationship with humans, serve as an ideal model for exploring the complex aging process. However, the potential of the nonhuman primate animal model in the screening of human aging markers is still not fully exploited. Multiomics analysis of nonhuman primate peripheral blood offers a promising approach to evaluate new therapies and biomarkers. This study explores aging-related biomarker through multilayer omics, including transcriptomics (mRNA, lncRNA, and circRNA) and proteomics (serum and serum-derived exosomes) in rhesus monkeys (Macaca mulatta). Results: Our findings reveal that, unlike mRNAs and circRNAs, highly expressed lncRNAs are abundant during the key aging period and are associated with cancer pathways. Comparative analysis highlighted exosomal proteins contain more types of proteins than serum proteins, indicating that serum-derived exosomes primarily regulate aging through metabolic pathways. Finally, eight candidate aging biomarkers were identified, which may serve as blood-based indicators for detecting age-related brain changes. Conclusions: Our results provide a comprehensive understanding of nonhuman primate blood transcriptomes and proteomes, offering novel insights into the aging mechanisms for preventing or treating age-related diseases. [ABSTRACT FROM AUTHOR]

Compared to the general population, patients with inflammatory bowel disease (IBD) are less likely to be vaccinated, putting them at an increased risk of vaccine-preventable illnesses. This risk is further compounded by the immunosuppressive therapies commonly used in IBD management. Therefore, developing new treatments for IBD that maintain immune function is crucial, as successful management can lead to better vaccination outcomes and overall health for these patients. Here, we investigate the potential of recombinant banana lectin (rBanLec) as a supporting therapeutic measure to improve IBD control and possibly increase vaccination rates among IBD patients. By examining the therapeutic efficacy of rBanLec in a murine model of experimental colitis, we aim to lay the foundation for its application in improving vaccination outcomes. After inducing experimental colitis in C57BL/6 and BALB/c mice with 2,4,6-trinitrobenzene sulfonic acid, we treated animals orally with varying doses of rBanLec 0.1–10 µg/mL (0.01—1 µg/dose) during the course of the disease. We assessed the severity of colitis and rBanLec's modulation of the immune response compared to control groups. rBanLec administration resulted in an inverse dose–response reduction in colitis severity (less pronounced weight loss, less shortening of the colon) and an improved recovery profile, highlighting its therapeutic potential. Notably, rBanLec-treated mice exhibited significant modulation of the immune response, favoring anti-inflammatory pathways (primarily reduction in a local [TNFα]/[IL-10]) crucial for effective vaccination. Our findings suggest that rBanLec could mitigate the adverse effects of immunosuppressive therapy on vaccine responsiveness in IBD patients. By improving the underlying immune response, rBanLec may increase the efficacy of vaccinations, offering a dual benefit of disease management and prevention of vaccine-preventable illnesses. Further studies are required to translate these findings into clinical practice. [ABSTRACT FROM AUTHOR]

Single nucleotide polymorphisms (SNPs) in homologous regions play a critical role in the field of genetics. However, genotyping these SNPs is challenging due to the presence of repetitive sequences within genome, which demand specific method. We introduce a new, mid-throughput method that simplifies SNP genotyping in homologous DNA sequences by utilizing a combination of multiplex kb level PCR (PCR size 2.5k-3.5 kb) for capturing targeted regions and multiplex nested PCR library construction for next-generation sequencing (Multi-kb level capture-seq). First of all, we randomly selected 7 SNPs in homologous regions and successfully captured 6-plex kb level amplicons (one of segments contains 2 SNPs, while the remaining segments each have only one SNP) in a single tube. And then, the amplification products were subjected to multiplex nested PCR for library construction and sequenced on Illumina platform. We tested this strategy using 600 amplicons from 100 samples and accurately genotyped 96.8% of target SNPs with a coverage depth of ≥ 15×. For the uniformity within the samples, over 66.7% (4/6) of the amplicons had a coverage depth above 0.2-fold of average sequencing depth. To validate the accuracy of this approach, we performed Ligase detection reaction PCR for genotyping the 100 samples, and found that the genotyping data was 97.71% consistent with our NGS results. In conclusion, we have developed a highly efficient and accurate method for SNP genotyping in homologous regions, which offers researchers a new strategy to explore the complex regions of genome., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Inflammatory bowel disease (IBD) belongs to a group of autoimmune conditions characterized by chronic inflammation and mucosal ulceration of the gastrointestinal tract. The etiology of IBD is complex. The etiological factors include environmental factors, among which diet is important. The aim of this study was to evaluate the diet of IBD patients. This case–control study was carried out on 82 patients with IBD; the control group consisted of 80 clinically healthy subjects. Food intake was assessed using a 24 h recall and frequency food questionnaire. Energy intake in the IBD group was insufficient and significantly lower than in the control group. The energy intake in the group of patients with active IBD was significantly lower than in the group of subjects in remission. The total fat and protein intake was significantly lower in the IBD group compared to the healthy subjects. IBD patients were characterized by underconsumption of all food groups analyzed, except for the intake of red meat and poultry. Our study showed inadequate intake of energy and most nutrients in IBD patients, even during the remission period. The study indicates the need for routine assessment of dietary intake and nutrition among IBD patients, as well as potential dietary interventions aimed at improving the energy and nutritional quality of diet in order to optimize treatment outcomes and prevent the development of accompanying diseases. [ABSTRACT FROM AUTHOR]

Backgrounding: Stayability, which may be defined as the probability of a cow remaining in the herd until a reference age or at a specific number of calvings, is usually measured late in the animal's life. Thus, if used as selection criteria, it will increase the generation interval and consequently might decrease the annual genetic gain. Measuring stayability at an earlier age could be a reasonable strategy to avoid this problem. In this sense, a better understanding of the genetic architecture of this trait at different ages and/or at different calvings is important. This study was conducted to identify possible regions with major effects on stayability measured considering different numbers of calvings in Nellore cattle as well as pathways that can be involved in its expression throughout the female's productive life. Results: The top 10 most important SNP windows explained, on average, 17.60% of the genetic additive variance for stayability, varying between 13.70% (at the eighth calving) and 21% (at the fifth calving). These SNP windows were located on 17 chromosomes (1, 2, 4, 6, 7, 8, 9, 10, 11, 12, 13, 14, 18, 19, 20, 27, and 28), and they harbored a total of 176 annotated genes. The functional analyses of these genes, in general, indicate that the expression of stayability from the second to the sixth calving is mainly affected by genetic factors related to reproductive performance, and nervous and immune systems. At the seventh and eighth calvings, genes and pathways related to animal health, such as density bone and cancer, might be more relevant. Conclusion: Our results indicate that part of the target genomic regions in selecting for stayability at earlier ages (from the 2th to the 6th calving) would be different than selecting for this trait at later ages (7th and 8th calvings). While the expression of stayability at earlier ages appeared to be more influenced by genetic factors linked to reproductive performance together with an overall health/immunity, at later ages genetic factors related to an overall animal health gain relevance. These results support that selecting for stayability at earlier ages (perhaps at the second calving) could be applied, having practical implications in breeding programs since it could drastically reduce the generation interval, accelerating the genetic progress. [ABSTRACT FROM AUTHOR]

Transcription regulation is required for correct differential gene expression, which determines the development and function of all cells in the organism throughout the lifespan, ensuring adaptability to continuously changing environments. Altered transcriptional regulation causes gene function rearrangements, which alter the phenotype, including aging rate and lifespan. In this regard, there has recently been a great interest in the application of technologies based on the "rejuvenation" of the transcriptome due to the modification of regulatory mechanisms that determine the level and pattern of gene expression. To develop such an approach to slowing down aging and prolonging life, it is important to understand how the transcription of individual genes and the entire transcriptome changes with age, as well as how the transcriptional machinery of the cell and mechanisms of transcription regulation are related to the aging process and longevity control. Addressing these issues in the review, we discuss the prospects of using transcription regulation as a strategy for extending life and improving its quality. [ABSTRACT FROM AUTHOR]

Metformin, a widely prescribed medication for type 2 diabetes, has garnered increasing attention for its potential neuroprotective properties due to the growing demand for treatments for Alzheimer's, Parkinson's, and motor neuron diseases. This review synthesizes experimental and clinical studies on metformin's mechanisms of action and potential therapeutic benefits for neurodegenerative disorders. A comprehensive search of electronic databases, including PubMed, MEDLINE, Embase, and Cochrane library, focused on key phrases such as "metformin", "neuroprotection", and "neurodegenerative diseases", with data up to September 2023. Recent research on metformin's glucoregulatory mechanisms reveals new molecular targets, including the activation of the LKB1–AMPK signaling pathway, which is crucial for chronic administration of metformin. The pleiotropic impact may involve other stress kinases that are acutely activated. The precise role of respiratory chain complexes (I and IV), of the mitochondrial targets, or of the lysosomes in metformin effects remains to be established by further research. Research on extrahepatic targets like the gut and microbiota, as well as its antioxidant and immunomodulatory properties, is crucial for understanding neurodegenerative disorders. Experimental data on animal models shows promising results, but clinical studies are inconclusive. Understanding the molecular targets and mechanisms of its effects could help design clinical trials to explore and, hopefully, prove its therapeutic effects in neurodegenerative conditions. [ABSTRACT FROM AUTHOR]

The lifespan extension induced by 40% caloric restriction (CR) in rodents is accompanied by postponement of disease, preservation of function, and increased stress resistance. Whether CR elicits the same physiological and molecular responses in humans remains mostly unexplored. In the CALERIE study, 12% CR for 2 years in healthy humans induced minor losses of muscle mass (leg lean mass) without changes of muscle strength, but mechanisms for muscle quality preservation remained unclear. We performed high‐depth RNA‐Seq (387–618 million paired reads) on human vastus lateralis muscle biopsies collected from the CALERIE participants at baseline, 12‐ and 24‐month follow‐up from the 90 CALERIE participants randomized to CR and "ad libitum" control. Using linear mixed effect model, we identified protein‐coding genes and splicing variants whose expression was significantly changed in the CR group compared to controls, including genes related to proteostasis, circadian rhythm regulation, DNA repair, mitochondrial biogenesis, mRNA processing/splicing, FOXO3 metabolism, apoptosis, and inflammation. Changes in some of these biological pathways mediated part of the positive effect of CR on muscle quality. Differentially expressed splicing variants were associated with change in pathways shown to be affected by CR in model organisms. Two years of sustained CR in humans positively affected skeletal muscle quality, and impacted gene expression and splicing profiles of biological pathways affected by CR in model organisms, suggesting that attainable levels of CR in a lifestyle intervention can benefit muscle health in humans. [ABSTRACT FROM AUTHOR]

Some sources report a connection of cellular senescence with chronic pathological conditions; however, the association between particular cellular processes and general health is rarely examined. This study aims to test the relationship of general health with DNA damage pathways that play a crucial role in senescence. The association of ten selected SNPs with subjective and objective general health and functional ability indicators has been tested in 314 oldest-old people from Croatia. Multivariate logistic regression was employed to simultaneously test the impact of variables potentially influencing targeted health and functional ability variables. The best model, explaining 37.1% of the variance, has six independent significant predictors of functional ability scores: rs16847897 in TERC, rs533984 in MRE11A, and rs4977756 in CDKN2B, chronic disease count, Mini-Mental State Examination scores, and age at surveying. In conclusion, the examined ten loci involved in DNA damage repair pathways showed a more significant association with self-rated health and functional ability than with the number of disease or prescribed medicaments. The more frequent, longevity-related homozygote (GG) in rs16847897 was associated with all three aspects of self-assessments—health, mobility, and independence—indicating that this TERC locus might have a true impact on the overall vitality of the oldest-old persons. [ABSTRACT FROM AUTHOR]

This cross-sectional study assesses distinct neuroanatomical dimensions of autism spectrum disorder using novel semisupervised machine learning methods and tests whether the dimensions can serve as endophenotypes also in individuals without autism spectrum disorder. Key Points: Question: Are there multiple distinct dimensions/clusters that coexist to account for the underlying neuroanatomical, clinical, and genetic heterogeneity in autism spectrum disorder (ASD)? Findings: In this cross-sectional study that included 669 adolescents to adults, a 3-dimensional endophenotypic representation to capture the neuroanatomical heterogeneity of ASD was discovered. The 3 clinically distinct dimensions showed partially overlapping imaging and genetic signatures compared with schizophrenia and were present also in the general population. Meaning: This dimensional representation of ASD may quantify disease susceptibility at the individual level and highlight potentially high-risk individuals in the general population and serves as a prototype for precision diagnostics and treatment. Importance: Autism spectrum disorder (ASD) is associated with significant clinical, neuroanatomical, and genetic heterogeneity that limits precision diagnostics and treatment. Objective: To assess distinct neuroanatomical dimensions of ASD using novel semisupervised machine learning methods and to test whether the dimensions can serve as endophenotypes also in non-ASD populations. Design, Setting, and Participants: This cross-sectional study used imaging data from the publicly available Autism Brain Imaging Data Exchange (ABIDE) repositories as the discovery cohort. The ABIDE sample included individuals diagnosed with ASD aged between 16 and 64 years and age- and sex-match typically developing individuals. Validation cohorts included individuals with schizophrenia from the Psychosis Heterogeneity Evaluated via Dimensional Neuroimaging (PHENOM) consortium and individuals from the UK Biobank to represent the general population. The multisite discovery cohort included 16 internationally distributed imaging sites. Analyses were performed between March 2021 and March 2022. Main Outcomes and Measures: The trained semisupervised heterogeneity through discriminative analysis models were tested for reproducibility using extensive cross-validations. It was then applied to individuals from the PHENOM and the UK Biobank. It was hypothesized that neuroanatomical dimensions of ASD would display distinct clinical and genetic profiles and would be prominent also in non-ASD populations. Results: Heterogeneity through discriminative analysis models trained on T1-weighted brain magnetic resonance images of 307 individuals with ASD (mean [SD] age, 25.4 [9.8] years; 273 [88.9%] male) and 362 typically developing control individuals (mean [SD] age, 25.8 [8.9] years; 309 [85.4%] male) revealed that a 3-dimensional scheme was optimal to capture the ASD neuroanatomy. The first dimension (A1: aginglike) was associated with smaller brain volume, lower cognitive function, and aging-related genetic variants (FOXO3; Z = 4.65; P = 1.62 × 10−6). The second dimension (A2: schizophrenialike) was characterized by enlarged subcortical volumes, antipsychotic medication use (Cohen d = 0.65; false discovery rate–adjusted P =.048), partially overlapping genetic, neuroanatomical characteristics to schizophrenia (n = 307), and significant genetic heritability estimates in the general population (n = 14 786; mean [SD] h2, 0.71 [0.04]; P < 1 × 10−4). The third dimension (A3: typical ASD) was distinguished by enlarged cortical volumes, high nonverbal cognitive performance, and biological pathways implicating brain development and abnormal apoptosis (mean [SD] β, 0.83 [0.02]; P = 4.22 × 10−6). Conclusions and Relevance: This cross-sectional study discovered 3-dimensional endophenotypic representation that may elucidate the heterogeneous neurobiological underpinnings of ASD to support precision diagnostics. The significant correspondence between A2 and schizophrenia indicates a possibility of identifying common biological mechanisms across the 2 mental health diagnoses. [ABSTRACT FROM AUTHOR]

Malnutrition is an important issue in patients with inflammatory bowel diseases (IBDs) including Crohn's disease (CD) and ulcerative colitis (UC). It is caused by altered digestion and absorption within the small bowel, inadequate food intake, and drug–nutrient interactions in patients. Malnutrition is an essential problem because it is related to an increased risk of infections and poor prognosis in patients. It is known that malnutrition is also related to an increased risk of postsurgery complications in IBD patients. Basic nutritional screening involves anthropometric parameters with body mass index (BMI) and others (fat mass, waist-to-hip ratio, muscle strength), medical history concerning weight loss, and biochemical parameters (including the Prognostic Nutritional Index). Besides standard nutritional screening tools, including the Subjective Global Assessment (SGA), Nutritional Risk Score 2002 (NRS 2002), and Malnutrition Universal Screening Tool (MUST), specific nutritional screening tools are used in IBD patients, such as the Saskatchewan Inflammatory Bowel Disease–Nutrition Risk Tool (SaskIBD-NR Tool and IBD-specific Nutritional Screening Tool). There is a higher risk of nutrient deficiencies (including iron, zinc, magnesium) and vitamin deficiencies (including folic acid, vitamin B12 and D) in IBD patients. Therefore, regular evaluation of nutritional status is important in IBD patients because many of them are undernourished. An association between plasma ghrelin and leptin and nutritional status in IBD patients has been observed. According to some authors, anti-tumor necrosis factor (anti-TNFα) therapy (infliximab) can improve nutritional status in IBD patients. On the other hand, improvement in nutritional status may increase the response rate to infliximab therapy in CD patients. Optimization of nutritional parameters is necessary to improve results of conservative and surgical treatment and to prevent postoperative complications in patients with IBDs. This review presents basic nutritional screening tools, anthropometric and laboratory parameters, dietary risk factors for IBDs, common nutrient deficiencies, associations between anti-TNFα therapy and nutritional status, selected features regarding the influence of nutritional status, and surgical outcome in IBD patients. [ABSTRACT FROM AUTHOR]

In Germany and worldwide, the average age of the population is continuously rising. With this general increase in chronological age, the focus on biological age, meaning the actual health and fitness status, is becoming more and more important. The key question is to what extent the age-related decline in fitness is genetically predetermined or malleable by environmental factors and lifestyle.Many epigenetic studies in aging research have provided interesting insights in this nature-versus-nurture debate. In most model organisms, aging is associated with specific epigenetic changes, which can be countered by certain interventions like moderate caloric restriction or increased physical activity. Since these interventions also have positive effects on lifespan and health, epigenetics appears to be the interface between environmental factors and the aging process. This notion is supported by the fact that an epigenetic drift occurs through the life course of identical twins, which is related to the different manifestations of aging symptoms. Furthermore, biological age can be determined with high precision based on DNA methylation patterns, further emphasizing the importance of epigenetics in aging.This article provides an overview of the importance of genetic and epigenetic parameters for life expectancy. A major focus will be on the possibilities of maintaining a young epigenome through lifestyle and environmental factors, thereby slowing down biological aging., (© 2024. The Author(s).)

The age pyramid of Roma populations tips strongly towards the younger age groups and is characterized by a low number of elderly individuals. There is a vast range of environmental factors that influence the age structure of Roma populations. To explore whether a genetic risk for premature mortality also exists in this ethnic minority, 33 single nucleotide polymorphisms (SNPs) in 23 putative longevity genes were investigated in 308 adult Roma living in Croatia, and in Croatian population sample, composed of 314 "Old" (85-101 yrs.) and 97 "Young" (20-35 yrs.) subjects. The cumulative effect of the investigated SNPs, which have previously been related to human longevity, was summarized within Genetic Longevity Score (GLS). After Bonferroni correction the "Old" and "Young" Croatian age groups differ only in the allele frequency in MRE11A locus (rs533984), while the Roma had significantly different allele frequencies from the surrounding majority population in most of the investigated longevity genes loci (in 16 out of the 33 SNPs). However, the Roma's GLS is equal to those in the "Young" and "Old" Croatian cohorts implying identical chances of surviving to the age of 85 among Roma as in the majority Croatian population, when only genetics is taken into account. [ABSTRACT FROM AUTHOR]

Intronic single‐nucleotide polymorphisms (SNPs) in FOXO3A are associated with human longevity. Currently, it is unclear how these SNPs alter FOXO3A functionality and human physiology, thereby influencing lifespan. Here, we identify a primate‐specific FOXO3A transcriptional isoform, FOXO3A‐Short (FOXO3A‐S), encoding a major longevity‐associated SNP, rs9400239 (C or T), within its 5′ untranslated region. The FOXO3A‐S mRNA is highly expressed in the skeletal muscle and has very limited expression in other tissues. We find that the rs9400239 variant influences the stability and functionality of the primarily nuclear protein(s) encoded by the FOXO3A‐S mRNA. Assessment of the relationship between the FOXO3A‐S polymorphism and peripheral glucose clearance during insulin infusion (Rd clamp) in a cohort of Danish twins revealed that longevity T‐allele carriers have markedly faster peripheral glucose clearance rates than normal lifespan C‐allele carriers. In vitro experiments in human myotube cultures utilizing overexpression of each allele showed that the C‐allele represses glycolysis independently of PI3K signaling, while overexpression of the T‐allele represses glycolysis only in a PI3K‐inactive background. Supporting this finding inducible knockdown of the FOXO3A‐S C‐allele in cultured myotubes increases the glycolytic rate. We conclude that the rs9400239 polymorphism acts as a molecular switch which changes the identity of the FOXO3A‐S‐derived protein(s), which in turn alters the relationship between FOXO3A‐S and insulin/PI3K signaling and glycolytic flux in the skeletal muscle. This critical difference endows carriers of the FOXO3A‐S T‐allele with consistently higher insulin‐stimulated peripheral glucose clearance rates, which may contribute to their longer and healthier lifespans. [ABSTRACT FROM AUTHOR]

Background: Despite increased awareness of diet and nutrition being integral to the management of patients with inflammatory bowel disease (IBD), there are gaps in the knowledge of IBD healthcare providers regarding nutrition. Furthermore, high quality evidence on nutritional assessment and dietary management of IBD is limited. A Delphi consensus from a panel of experts allows for best‐practice guidelines to be developed, especially where high quality evidence is limited. The aim was to develop guidelines for the nutritional assessment and dietary management of IBD using an eDelphi online consensus agreement platform. Methods: Seventeen research topics related to IBD and nutrition were systematically reviewed. Searches in Cochrane, Embase®, Medline® and Scopus® electronic databases were performed. GRADE was used to develop recommendations. Experts from the IBD community (healthcare professionals and patients with IBD) were invited to vote anonymously on the recommendations in a custom‐built online platform. Three rounds of voting were carried out with updated iterations of the recommendations and evaluative text based on feedback from the previous round. Results: From 23,824 non‐duplicated papers, 167 were critically appraised. Fifty‐five participants completed three rounds of voting and 14 GRADE statements and 42 practice statements achieved 80% consensus. Comprehensive guidance related to nutrition assessment, nutrition screening and dietary management is provided. Conclusions: Guidelines on the nutritional assessment and dietary management of IBD have been developed using evidence‐based consensus to improve equality of care. The statements and practice statements developed demonstrate the level of agreement and the quality and strength of the guidelines. Key points: Comprehensive guidelines related to nutrition assessment, nutrition screening and dietary management of inflammatory bowel disease have been developed.Fourteen GRADE statements and 42 practice statements achieved 80% consensus agreementFifty‐five participants comprising experts from the inflammatory bowel disease (IBD) community (healthcare professionals and patients with IBD) took part in the online consensus voting [ABSTRACT FROM AUTHOR]

From pairwise I F i SB ST sb estimates calculated across all SNPs (rare alleles excluded), we found that Boreal caribou were distinguishable from Barren-ground or Mountain caribou, and these differences were more noticeable when habitat selection-associated SNPs only were used (Figure 6). RESULTS Seasonal habitat selection varied between caribou individuals, but with characteristic ecotyp... We used RSFs and determined that caribou selected or avoided a total of 13 habitat variables: they used them nonrandomly within individual seasonal ranges. The type of land cover was also selected, but not shown here as selection was relative to other types (not absolute) gl Variation of habitat selection caribou individuals Habitat selection varied among caribou individuals even when they belonged to the same ecotype (e.g., elevation; Figure 3) and herd, and the same individual could also select different habitats in winter and summer (Figure 4). Winter habitat selection patterns by caribou ecotypes Caribou belonging to all ecotypes consistently selected for areas within their individual winter range that had more snow and were closer to water-saturated soils (e.g., wetlands) (winter regression coefficients for caribou ecotypes in Table S6). [Extracted from the article]

Pharmacogenetics (PGx) is an emerging field of pharmacology focusing on how gene variations affect the patient's response to treatment. Pharmacogenetics is a promising tool to optimize the selection and dosing of medications, including urate-lowering therapies (ULTs) among patients with gout. The global prevalence of gout is rising, and it disproportionately affects specific racial groups and individuals with select socioeconomic status. Genetic and experimental findings have provided evidence that genetic polymorphisms associated with serum urate pathology are also of pharmacogenetic interest. Patients with gout present with several comorbidities, warranting the use of several acute and long-term medications that increase their pill burden and the risk of adverse drug events. Implementing PGx testing can identify individuals who are more or less likely to benefit from a given treatment, improve medication adherence, and reduce pill burden. The purpose of this non-systematic review was to evaluate the contemporary evidence for PGx use in gout management, especially treatment modalities associated with specific genetic polymorphisms that could impact medication safety and efficacy. Strong evidence suggests that individuals carrying the HLA-B*58:01 allele are at a higher risk of serious and life-threatening skin reactions when taking allopurinol. Additionally, racial disparities in the frequency of HLA-B*58:01 warrant genetic screening in high-risk populations, specifically some Asian subgroups and African Americans. Individuals that are G6PD-deficient can develop hemolytic anemia and methemoglobinemia with pegloticase and probenecid use. Patients with the less active form of the drug-metabolizing CYP2C9 are at higher risk for NSAID-related upper gastrointestinal (GI) bleeding. Emerging evidence of clinically significant drug-gene pairs among various gout therapies is growing. Genes found to modulate the response to allopurinol include AOX, ABCG2, and SLC22A12. Meanwhile, UGT1A1 appears to modulate the response to Febuxostat. While CYP2C9 may modulate the toxicity of benzbromarone, SLC22A12 and ABCB1 were found to modulate the response to both benzbromarone and probenecid. The genes CYP2D6, ABCB1, gene cluster (rs6916345 G>A), and SEPHS1 were recently reported to modulate the safety and efficacy of colchicine. Finally, HCG22 and IL1RN are linked with the response to corticosteroid and anakinra, respectively. This review examines and synthesizes the most current level of evidence for using PGx to maximize gout pharmacotherapy. [ABSTRACT FROM AUTHOR]

Human ageing can be characterized by a profile of circulating microRNAs (miRNAs), which are potentially predictors of biological age. They can be used as a biomarker of risk for age-related inflammatory outcomes, and senescent endothelial cells (ECs) have emerged as a possible source of circulating miRNAs. In this paper, a panel of four circulating miRNAs including miR-146a-5p, miR-126-3p, miR-21-5p, and miR-181a-5p, involved in several pathways related to inflammation, and ECs senescence that seem to be characteristic of the healthy ageing phenotype. The circulating levels of these miRNAs were determined in 78 healthy subjects aged between 22 to 111 years. Contextually, extracellular miR-146a-5p, miR-126-3p, miR-21-5p, and miR-181a-5p levels were measured in human ECs in vitro model, undergoing senescence. We found that the levels of the four miRNAs, using ex vivo and in vitro models, progressively increase with age, apart from ultra-centenarians that showed levels comparable to those measured in young individuals. Our results contribute to the development of knowledge regarding the identification of miRNAs as biomarkers of successful and unsuccessful ageing. Indeed, they might have diagnostic/prognostic relevance for age-related diseases. [ABSTRACT FROM AUTHOR]

Accelerated biological aging, which involves the gradual decline of organ or tissue functions and the distortion of physiological processes, underlies several human diseases. Away from the earlier free radical concept, telomere attrition, cellular senescence, proteostasis loss, mitochondrial dysfunction, stem cell exhaustion, and epigenetic and genomic alterations have emerged as biological hallmarks of aging. Moreover, nutrient-sensing metabolic pathways are critical to an organism's ability to sense and respond to nutrient levels. Pharmaceutical, genetic, and nutritional interventions reverting physiological declines by targeting nutrient-sensing metabolic pathways can promote healthy aging and increase lifespan. On this basis, biological aging hallmarks and nutrient-sensing dependent and independent pathways represent evolving drug targets for many age-linked diseases. Here, we discuss and update the scientific community on contemporary advances in how dietary supplements and natural products beneficially revert accelerated biological aging processes to retrograde human aging and age-dependent human diseases, both from the clinical and preclinical studies point-of-view. Overall, our review suggests that dietary/natural products increase healthspan—rather than lifespan—effectively minimizing the period of frailty at the end of life. However, real-world setting clinical trials and basic studies on dietary supplements and natural products are further required to decisively demonstrate whether dietary/natural products could promote human lifespan. [ABSTRACT FROM AUTHOR]

Background: The remarkable growth of genome-wide association studies (GWAS) has created a critical need to experimentally validate the disease-associated variants, 90% of which involve non-coding variants. Methods: To determine how the field is addressing this urgent need, we performed a comprehensive literature review identifying 36,676 articles. These were reduced to 1454 articles through a set of filters using natural language processing and ontology-based text-mining. This was followed by manual curation and cross-referencing against the GWAS catalog, yielding a final set of 286 articles. Results: We identified 309 experimentally validated non-coding GWAS variants, regulating 252 genes across 130 human disease traits. These variants covered a variety of regulatory mechanisms. Interestingly, 70% (215/309) acted through cis-regulatory elements, with the remaining through promoters (22%, 70/309) or non-coding RNAs (8%, 24/309). Several validation approaches were utilized in these studies, including gene expression (n = 272), transcription factor binding (n = 175), reporter assays (n = 171), in vivo models (n = 104), genome editing (n = 96) and chromatin interaction (n = 33). Conclusions: This review of the literature is the first to systematically evaluate the status and the landscape of experimentation being used to validate non-coding GWAS-identified variants. Our results clearly underscore the multifaceted approach needed for experimental validation, have practical implications on variant prioritization and considerations of target gene nomination. While the field has a long way to go to validate the thousands of GWAS associations, we show that progress is being made and provide exemplars of validation studies covering a wide variety of mechanisms, target genes, and disease areas. [ABSTRACT FROM AUTHOR]

Many of the leading causes of death in humans, such as cardiovascular disease, type 2 diabetes and Alzheimer's disease are influenced by biological mechanisms that become dysregulated with increasing age. Hence, by targeting these ageing-related mechanisms, we may be able to improve health in old age. Ageing is partly heritable and genetic studies have been moderately successful in identifying genetic variants associated with ageing-related phenotypes (lifespan, healthspan and longevity). To decipher the mechanisms by which the identified variants influence ageing, studies that focus on their functional validation are vital. In this perspective, we describe the steps that could be taken in the process of functional validation: (1) in silico characterisation using bioinformatic tools; (2) in vitro characterisation using cell lines or organoids; and (3) in vivo characterisation studies using model organisms. For the in vivo characterisation, it is important to focus on translational phenotypes that are indicative of both healthspan and lifespan, such as the frailty index, to inform subsequent intervention studies. The depth of functional validation of a genetic variant depends on its location in the genome and conservation in model organisms. Moreover, some variants may prove to be hard to characterise due to context-dependent effects related to the experimental environment or genetic background. Future efforts to functionally characterise the (newly) identified genetic variants should shed light on the mechanisms underlying ageing and will help in the design of targeted interventions to improve health in old age. [ABSTRACT FROM AUTHOR]

While mitochondrial function is essential for life in all multicellular organisms, a mild impairment of mitochondrial function can extend longevity in model organisms. By understanding the molecular mechanisms involved, these pathways might be targeted to promote healthy aging. In studying two long‐lived mitochondrial mutants in C. elegans, we found that disrupting subunits of the mitochondrial electron transport chain results in upregulation of genes involved in innate immunity, which is driven by the mitochondrial unfolded protein response (mitoUPR) but also dependent on the canonical p38‐mediated innate immune signaling pathway. Both of these pathways are required for the increased resistance to bacterial pathogens and extended longevity of the long‐lived mitochondrial mutants, as is the FOXO transcription factor DAF‐16. This work demonstrates that both the p38‐mediated innate immune signaling pathway and the mitoUPR act in concert on the same innate immunity genes to promote pathogen resistance and longevity and that input from the mitochondria can extend longevity by signaling through these pathways. This indicates that multiple evolutionarily conserved genetic pathways controlling innate immunity also function to modulate lifespan. SYNOPSIS: Mild impairment of mitochondrial function results in enhanced innate immunity and lifespan extension. Both phenotypes are driven by activation of the mitochondrial unfolded protein response but are also dependent on p38‐mediated innate immune signaling. Mild impairment of mitochondrial function enhances innate immunity in a p38‐dependent manner through activation of ATFS‐1.The mitochondrial unfolded protein response and p38‐mediated innate immune signaling pathway act in concert to promote resistance to bacterial pathogens and extend lifespan.The p38‐mediated innate immune signaling pathway plays a key role in determining longevity.Different levels of p38‐mediated innate immune signaling are optimal for different contexts of lifespan extension. [ABSTRACT FROM AUTHOR]

Bipolar disorder's core feature is the pathological disturbances in mood, often accompanied by disrupted thinking and behavior. Its complex and heterogeneous etiology implies that a range of inherited and environmental factors are involved. This heterogeneity and poorly understood neurobiology pose significant challenges to existing drug development paradigms, resulting in scarce treatment options, especially for bipolar depression. Therefore, novel approaches are needed to discover new treatment options. In this review, we first highlight the main molecular mechanisms known to be associated with bipolar depression-mitochondrial dysfunction, inflammation and oxidative stress. We then examine the available literature for the effects of trimetazidine in said alterations. Trimetazidine was identified without a priori hypothesis using a gene-expression signature for the effects of a combination of drugs used to treat bipolar disorder and screening a library of off-patent drugs in cultured human neuronal-like cells. Trimetazidine is used to treat angina pectoris for its cytoprotective and metabolic effects (improved glucose utilization for energy production). The preclinical and clinical literature strongly support trimetazidine's potential to treat bipolar depression, having anti-inflammatory and antioxidant properties while normalizing mitochondrial function only when it is compromised. Further, trimetazidine's demonstrated safety and tolerability provide a strong rationale for clinical trials to test its efficacy to treat bipolar depression that could fast-track its repurposing to address such an unmet need as bipolar depression., (© 2023. The Author(s).)

The world population is getting older and studies aiming to enhance our comprehension of the underlying mechanisms responsible for health span are of utmost interest for longevity and as a measure for health care. In this review, we summarized previous genetic association studies (GWAS) and next-generation sequencing (NGS) of elderly cohorts. We also present the updated hypothesis for the aging process, together with the factors associated with healthy aging. We discuss the relevance of studying older individuals and build databanks to characterize the presence and resistance against late-onset disorders. The identification of about 2 million novel variants in our cohort of more than 1000 elderly Brazilians illustrates the importance of studying highly admixed populations of non-European ancestry. Finally, the ascertainment of nonagenarians and particularly of centenarians who were recovered from COVID-19 or remained asymptomatic opens new avenues of research aiming to enhance our comprehension of biological mechanisms associated with resistance against pathogens., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Genetic variants in FOXO3 are associated with longevity. Here, we assessed whether blood DNA methylation at FOXO3 was associated with cancer risk, survival, and mortality. We used data from eight prospective case–control studies of breast (n = 409 cases), colorectal (n = 835), gastric (n = 170), kidney (n = 143), lung (n = 332), prostate (n = 869), and urothelial (n = 428) cancer and B-cell lymphoma (n = 438). Case–control pairs were matched on age, sex, country of birth, and smoking (lung cancer study). Conditional logistic regression was used to assess associations between cancer risk and methylation at 45 CpGs of FOXO3 included on the HumanMethylation450 assay. Mixed-effects Cox models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for associations with cancer survival (total n = 2286 deaths). Additionally, using data from 1088 older participants, we assessed associations of FOXO3 methylation with overall and cause-specific mortality (n = 354 deaths). Methylation at a CpG in the first exon region of FOXO3 (6:108882981) was associated with gastric cancer survival (HR = 2.39, 95% CI: 1.60–3.56, p = 1.9 × 10−5). Methylation at three CpGs in TSS1500 and gene body was associated with lung cancer survival (p < 6.1 × 10−5). We found no evidence of associations of FOXO3 methylation with cancer risk and mortality. Our findings may contribute to understanding the implication of FOXO3 in longevity. [ABSTRACT FROM AUTHOR]