Biological aging disrupts liver-gut intercommunication, resulting in the development of insulin resistance and type 2 diabetes, coupled with the imbalance of gut microbiome composition known as gut dysbiosis. Fermented red ginseng (FRG) is a renowned functional food substance showing its notable anti-inflammatory and anti-diabetic effects owing to its unique bioactive compounds known as ginsenosides. However, whether FRG could impact biological aging and age-related metabolic dysfunction is still unclear. The current study aimed to determine the health benefits of FRG in improving age-associated impaired insulin homeostasis and gut dysbiosis in 19-month-old male mice. Mice were fed with a normal chow diet (NCD) or NCD with FRG (300 mg/kg) for 14 weeks. FRG supplementation significantly improved insulin homeostasis by activating the hepatic protein kinase B (AKT) and proline-rich AKT substrate of 40 kDa (PRAS40). We also observed suppressed mRNA expression of proinflammatory cytokines and diminished inflammatory infiltrates in the liver of FRG-fed mice compared with NCD-only controls. Furthermore, alongside a decreased ratio of Firmicutes to Bacteroidetes, FRG administration enriched beneficial genera, including Muribaculaceae, Borkfalkiaceae, Parasutterella, and Clostridia vadin BB60 group, whereas FRG reduced the abundance of Erysipelotrichaceae and Dubosiella at the genus level. In summary, we suggest that FRG can be a potential anti-aging dietary supplement to manage age-driven dysregulation of insulin homeostasis and gut microbiota composition.

Importance:Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are fast-growing treatments for type 2 diabetes, obesity, and sleep apnea and are under investigation as potential treatments for many other conditions. The National Institutes of Health's (NIH's) All of Us Research Program offers a robust observational data source for studying questions related to GLP-1RA use in real-world settings. Objective:This article describes key characteristics of All of Us participants who have been prescribed GLP-1RAs. The goals are to present the utility of the All of Us data and describe the strengths and limitations of using this resource for future research on GLP-1RAs. Design:Using the All of Us Controlled Tier Curated Data Repository version 8 (CDRv8), we provide a descriptive analysis of the cohort with GLP-1RA records using cross-sectional surveys, longitudinal electronic health record (EHR) data, and longitudinal Fitbit data. Setting:The All of Us Research Program is a large, federally funded, longitudinal cohort study established in 2018 by NIH. Recruitment efforts are nationwide and target a range of populations to advance precision medicine for all. Participants:Participants are U.S. residents, aged 18 or older at the time of study consent, who were enrolled between May 6, 2018, and October 1, 2023. Exposures:The GLP-1RA cohort included participants with at least two GLP-1RA prescription records on different days at any time point based on their EHRs. Main Outcomes:Frequencies and medians for a range of sociodemographic characteristics, health care utilization patterns, comorbid conditions, GLP-1RA prescription trends, laboratory and observation availability, and Fitbit data. Results:The All of Us GLP-1RA cohort is large (n=15 477), with high data availability across a range of relevant data types. These participants are older and have more comorbid conditions than the entire CDRv8 population. Prescription trends indicate rapid uptake of GLP-1RA drugs since 2014. Conclusions and Relevance:All of Us CDRv8 is a valuable resource for research on GLP-1RAs across a large, heterogeneous cohort of participants. The variety and availability of data offer many possibilities for future observational, real-world research to address unanswered questions about GLP-1RA use and replicate recent findings generated from other datasets.

Insulin receptors (IRs) are widely expressed across all tissues and all cell types. It exists in two functionally distinct isoforms -- IR-A and IR-B -- differing by 12 amino acids due to alternative exon 11 splicing. These isoforms exhibit tissue- and cell-specific expression patterns, with their relative abundance varying throughout development, aging, and disease. Due to their high sequence similarity, distinguishing between IR-A and IR-B using traditional immunological methods has been challenging. Here, we describe a novel Duplex in situ hybridization (ISH) assay that enables the visualization of IR-A and IR-B expression in tissue. Using this approach, we demonstrate for the first time that while both isoforms are expressed in the murine choroid plexus, IR-A is predominant. This method provides a powerful tool for investigating the spatial distribution of insulin receptor isoforms in situ across different tissues. While real-time qPCR can detect IR-A and IR-B transcripts in monocellular in vitro cultures, it lacks the capacity for spatial localization within complex tissues, highlighting the need for and utility of the Duplex ISH technique.

Here we describe organoid cultures derived from pig foliate taste papillae in which the cellular heterogeneity of the lingual epithelium is preserved. Pig taste organoids were maintained long term (18 passages) and continued to express taste stem cell markers (LGR4, LGR6, and SOX2) and taste receptor cell (TRC) markers (cytokeratin 20, ENTPD2, GNAT3, and OTOP1). We show insulin is necessary for optimum proliferation and differentiation of taste organoids. Some TRCs in the organoids contained insulin and the insulin-critical transcription factors MAFA and PAX4. However, we did not see any evidence of the critical glucose-responsive PDX-1 expression either in the native tissue or in the organoids. We optimized differentiation conditions for TRC expression and separately for increased insulin protein content (6.5-fold, P < .01 vs spontaneous differentiation). Insulin production in differentiated organoids was responsive to cAMP stimuli. These results provide a pig model of taste organoid culture that can be used to study taste stem cell dynamics and taste receptor cell differentiation. These findings suggest that taste organoids may serve as a novel renewable model system for studying extra-pancreatic, nonglucose-regulated insulin and its potential role as a trophic factor.

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are currently approved for type 2 diabetes mellitus, obesity, and obstructive sleep apnea. However, due to the presence of GLP-1 receptors on certain neuronal populations in the brain, GLP-1RAs are being investigated for their therapeutic potential in a variety of neurological conditions. We conducted a systematic review and meta-analysis to evaluate the efficacy of GLP-1RAs in neurological disorders. We searched MEDLINE, Embase, Cochrane Library, and ClinicalTrials.gov from inception to 4 August 2024 for randomized controlled trials (RCTs) in adults with Alzheimer’s disease (AD), Parkinson’s disease (PD), ischemic stroke, idiopathic intracranial hypertension (IIH), or hypothalamic obesity (HO) comparing GLP-1RAs to placebo. Primary outcomes included a composite of memory and cognition for AD, MDS-UPDRS Part III (ON and OFF states) for PD, NIHSS for stroke, intracranial pressure for IIH, and body mass index (BMI) for HO. Data synthesis was conducted using Review Manager, with risk of bias assessed via the revised Cochrane Risk of Bias tool and evidence certainty evaluated using the GRADE approach. Fifteen RCTs involving 1341 participants were included. In AD, GLP-1RAs did not improve memory and cognition compared to placebo (standardized mean difference [SMD] -0.01, 95% confidence intervals [CIs] -0.44 to 0.41; low-certainty evidence). In PD, no improvement was observed in MDS-UPDRS Part III (OFF state); however, improvement was noted in the ON state (mean difference [MD] -2.15, 95% CIs -3.46 to -0.83; moderate-certainty evidence). In HO, GLP-1RAs reduced BMI (MD -0.75, 95% CIs -1.35 to -0.15; moderate-certainty evidence). No significant differences were observed for NIHSS in stroke or intracranial pressure in IIH. Low-to-moderate certainty evidence indicates that GLP-1RAs provide modest benefits in specific conditions, including motor function improvement in PD and BMI reduction in HO, without however any evident effects in improving cognition in AD, recovery after stroke, or reducing intracranial pressure in IIH. Future high-quality trials are warranted to identify optimal treatment strategies, understand patient-specific responses, and further explore the mechanisms of action of GLP-1RAs in neurological conditions.

BACKGROUND:Aging is associated with progressive functional deteriorations that affect the metabolic dysfunction in the liver and the alteration of the gut microbial environment. Red ginseng (RG) is one of the widely investigated ginseng products known for its antiaging properties, derived from its unique bioactive compounds known as ginsenosides. OBJECTIVES:This study aimed to discover the potential antiaging effects of bioconverted red ginseng (BRG), a new RG product applied with enzymatic treatments, using an aged mouse model. METHODS:Two different interventional regimes were employed: oral gavage administration and ad libitum intervention. For oral gavage study, 9-wk-old (Young) and 18-mo-old (Old) mice were orally injected with either distilled water or 300 mg/kg BRG for 4 wk (n = 10 per group). For ad libitum study, 19-mo-old mice were fed with a normal chow diet (NCD), NCD with 150 mg/kg BRG (BRG-Low; NCD+BRGL), or NCD with 300 mg/kg BRG (BRG-High; NCD+BRGH) for 14 wk (n = 9-10 per group). Liver tissues were harvested from each group for RNA sequencing, immunoblotting, and mRNA expression analyses. Fecal samples were collected, and 16S rRNA sequencing was conducted to profile gut microbiome composition. RESULTS:The 4-wk BRG administration provided potential modulations in hepatic gene expression profiling in terms of mitigating age-driven liver cholestasis, as well as positive alterations in the gut microbial structure and composition. Moreover, the 14-wk BRG supplementation protected insulin homeostasis through activating the hepatic protein kinase B (AKT)/mechanistic target of rapamycin complex 1 (mTORC1) signaling pathway and inhibiting glycogen synthase kinase (GSK)-3β in aged mice. In the meantime, BRG consumption altered insulin homeostasis-related microbiome structures by not only reducing the Firmicutes/Bacteroidetes ratio and relative abundance of opportunistic taxa, including Erysipelotrichaceae, but also increasing the enrichment of commensal bacteria, such as Muribaculaceae. CONCLUSIONS:Taken together, this study highlights that BRG could be a promising antiaging functional food substance by maintaining insulin homeostasis and the gut microbial equilibrium.

Insulin resistance, stem cell dysfunction, and muscle fiber dystrophy are all age-related events in skeletal muscle (SKM). However, age-related changes in insulin isoforms and insulin receptors in myogenic progenitor satellite cells have not been studied. Since SKM is an extra-pancreatic tissue that does not express mature insulin, we investigated the levels of insulin receptors (INSRs) and a novel human insulin upstream open reading frame (INSU) at the mRNA, protein, and anatomical levels in Baltimore Longitudinal Study of Aging (BLSA) biopsied SKM samples of 27–89-year-old (yrs) participants. Using RT-qPCR and the MS-based selected reaction monitoring (SRM) assay, we found that the levels of INSR and INSU mRNAs and the proteins were positively correlated with the age of human SKM biopsies. We applied RNAscope fluorescence in situ hybridization (FISH) and immunofluorescence (IF) to SKM cryosections and found that INSR and INSU were co-localized with PAX7-labeled satellite cells, with enhanced expression in SKM sections from an 89 yrs old compared to a 27 yrs old. We hypothesized that the SKM aging process might induce compensatory upregulation of INSR and re-expression of INSU, which might be beneficial in early embryogenesis and have deleterious effects on proliferative and myogenic satellite cells with advanced age.

Abstract Pancreatic cancer is more prevalent in older individuals and often carries a poorer prognosis for them. The relationship between the microenvironment and pancreatic cancer is multifactorial, and age-related changes in nonmalignant cells in the tumor microenvironment may play a key role in promoting cancer aggressiveness. Because fibroblasts have profound impacts on pancreatic cancer progression, we investigated whether age-related changes in pancreatic fibroblasts influence cancer growth and metastasis. Proteomics analysis revealed that aged fibroblasts secrete different factors than young fibroblasts, including increased growth/differentiation factor 15 (GDF-15). Treating young mice with GDF-15 enhanced tumor growth, whereas aged GDF-15 knockout mice showed reduced tumor growth. GDF-15 activated AKT, rendering tumors sensitive to AKT inhibition in an aged but not young microenvironment. These data provide evidence for how aging alters pancreatic fibroblasts and promotes tumor progression, providing potential therapeutic targets and avenues for studying pancreatic cancer while accounting for the effects of aging. Significance: Aged pancreatic fibroblasts secrete GDF-15 and activate AKT signaling to promote pancreatic cancer growth, highlighting the critical role of aging-mediated changes in the pancreatic cancer microenvironment in driving tumor progression. See related commentary by Isaacson et al., p. 1185

Incretins are hormones secreted from enteroendocrine cells after nutrient intake that stimulate insulin secretion from β cells in a glucose-dependent manner. Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are the only two known incretins. Dysregulation of incretin secretion and actions are noted in diseases such as obesity and diabetes. In this review, we first summarize our traditional understanding of the physiology of GIP and GLP-1, and our current knowledge of the relationships between GIP and GLP-1 and obesity and diabetes. Next, we present the results from major randomized controlled trials on the use of GLP-1 receptor agonists for managing type 2 diabetes, and emerging data on treating obesity and prediabetes. We conclude with a glimpse of the future with possible complex interactions between nutrients, gut microbiota, the endocannabinoid system, and enteroendocrine cells.