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The article explores the physiological integration of taste and metabolism, emphasizing recent advancements in understanding taste perception, taste receptors, and their implications for health, particularly in the context of added sugars and nonnutritive sweeteners. It discusses the intricate mechanisms of taste transduction, debunking myths such as the tongue taste map, and sheds light on the role of extraoral taste receptors in regulating physiological balance beyond conscious gustation.

Simple Summary: The aim of this study was to explore the potential impact of red ginseng (RG) on age-associated cellular senescence through in vitro, ex vivo, and 19-month-old aged mouse models. In addition to enhancing insulin homeostasis, RG supplementation modified the canonical cellular senescence pathway and inhibited apoptotic markers. Moreover, RG significantly reduced the senescence-associated inflammatory pathway in the liver. Finally, the RG treatment mitigated cellular senescence in primary hepatocytes and mouse embryonic fibroblasts. In conclusion, these findings suggest that RG has a positive influence on the aging process by regulating hepatic cellular senescence and age-related phenotypes. Cellular senescence is defined as an irreversible cell cycle arrest accompanied by morphological and physiological alterations during aging. Red ginseng (RG), processed from fresh ginseng (Panax ginseng C.A. Meyer) with a one-time steaming and drying process, is a well-known beneficial herbal medicine showing antioxidant, anti-inflammatory, and anti-aging properties. The current study aimed to investigate the benefits of RG in alleviating hepatic cellular senescence and its adverse effects in 19-month-old aged mice. We applied two different intervention methods and durations to compare RG's effects in a time-dependent manner: (1) oral gavage injection for 4 weeks and (2) ad libitum intervention for 14 weeks. We observed that 4-week RG administration was exerted to maintain insulin homeostasis against developing age-associated insulin insensitivity and suppressed cellular senescence pathway in the liver and primary hepatocytes. Moreover, with remarkable improvement of insulin homeostasis, 14-week RG supplementation downregulated the activation of c-Jun N-terminal kinase (JNK) and its downstream transcriptional factor nuclear factor-κB (NF-κB) in aged mice. Lastly, RG treatment significantly reduced the senescence-associated β-galactosidase (SA-β-gal)-positive cells in primary hepatocytes and ionizing radiation (IR)-exposed mouse embryonic fibroblasts (MEFs). Taken together, we suggest that RG can be a promising candidate for a senolytic substance by preventing hepatic cellular senescence. [ABSTRACT FROM AUTHOR]

The study of age‐related biomarkers from different biofluids and tissues within the same individual might provide a more comprehensive understanding of age‐related changes within and between compartments as these changes are likely highly interconnected. Understanding age‐related differences by compartments may shed light on the mechanism of their reciprocal interactions, which may contribute to the phenotypic manifestations of aging. To study such possible interactions, we carried out a targeted metabolomic analysis of plasma, skeletal muscle, and urine collected from healthy participants, age 22–92 years, and identified 92, 34, and 35 age‐associated metabolites, respectively. The metabolic pathways that were identified across compartments included inflammation and cellular senescence, microbial metabolism, mitochondrial health, sphingolipid metabolism, lysosomal membrane permeabilization, vascular aging, and kidney function. [ABSTRACT FROM AUTHOR]

The tongue is a complex multifunctional organ that interacts and senses both interoceptively and exteroceptively. Although it is easily visible to almost all of us, it is relatively understudied and what is in the literature is often contradictory or is not comprehensively reported. The tongue is both a motor and a sensory organ: motor in that it is required for speech and mastication, and sensory in that it receives information to be relayed to the central nervous system pertaining to the safety and quality of the contents of the oral cavity. Additionally, the tongue and its taste apparatus form part of an innate immune surveillance system. For example, loss or alteration in taste perception can be an early indication of infection as became evident during the present global SARS-CoV-2 pandemic. Here, we particularly emphasize the latest updates in the mechanisms of taste perception, taste bud formation and adult taste bud renewal, and the presence and effects of hormones on taste perception, review the understudied lingual immune system with specific reference to SARS-CoV-2, discuss nascent work on tongue microbiome, as well as address the effect of systemic disease on tongue structure and function, especially in relation to taste. [ABSTRACT FROM AUTHOR]

(1) Background and aims: Amyloidosis due to aggregation of amyloid-β (Aβ42) is a key pathogenic event in Alzheimer's disease (AD), whereas aggregation of mature islet amyloid polypeptide (IAPP37) in human islets leads to β-cell dysfunction. The aim of this study is to uncover potential biomarkers that might additionally point to therapy for early AD patients. (2) Methods: We used bioinformatic approach to uncover novel IAPP isoforms and developed a quantitative selective reaction monitoring (SRM) proteomic assay to measure their peptide levels in human plasma and CSF from individuals with early AD and controls, as well as postmortem cerebrum of clinical confirmed AD and controls. We used Thioflavin T amyloid reporter assay to measure the IAPP isoform fibrillation propensity and anti-amyloid potential against aggregation of Aβ42 and IAPP37. (3) Results: We uncovered hominid-specific IAPP isoforms: hIAPPβ, which encodes an elongated propeptide, and hIAPPγ, which is processed to mature IAPP25 instead of IAPP37. We found that hIAPPβ was significantly reduced in the plasma of AD patients with the accuracy of 89%. We uncovered that IAPP25 and a GDNF derived DNSP11 were nonaggregating peptides that inhibited the aggregation of IAPP37 and Aβ42. (4) Conclusions: The novel peptides derived from hIAPP isoforms have potential to serve as blood-derived biomarkers for early AD and be developed as peptide based anti-amyloid medicine. [ABSTRACT FROM AUTHOR]

Sodium-glucose cotransporter-2 inhibitors (SGLT2is), such as empagliflozin, lower blood glucose in type 2 diabetes mellitus and improve cardiorenal outcomes regardless of diabetes presence. Whether SGLT2is exert any effects on the brain's metabolism has not been studied. We conducted a single-arm clinical trial to investigate the effects of once daily administration of oral empagliflozin (25 mg) for 14 days on systemic and brain metabolism in 21 non-diabetics aged 55 years old or older. Empagliflozin lowered circulating insulin and elevated β-hydroxybutyrate over 34-h periods, both following its first administration and after 14 days of daily administration, with minor alterations in glucose homeostasis. Levels of phosphorylated insulin-like growth factor-1 receptor (pIGF-1R), phosphorylated insulin receptor (pIR), phosphorylated-in-tyrosine insulin receptor substrate-1 (pY-IRS-1), and phosphorylated protein kinase B or AKT (pAKT) were increased in extracellular vesicles enriched for neuronal origin (NEVs) following the first empagliflozin administration, but not after 14 days. Our finding of IGF-1R upregulation in NEVs is promising because several post-mortem and epidemiological studies support the idea that upregulation of IGF signaling may protect against Alzheimer's disease (AD). Moreover, our finding showing activation of insulin signaling and, in particular, the canonical pathway (pIR, pY-IRS-1, pAKT) in NEVs is important because such changes have been repeatedly associated with neuronal survival. Using brain magnetic resonance spectroscopy (MRS), we detected decreased concentrations of the excitatory neurotransmitter glutamate and its precursor glutamine after empagliflozin administration. This finding is also encouraging since glutamatergic excitotoxicity has long been implicated in AD pathology. Overall, our findings may motivate the repurposing of SGLT2is for use in AD and other, related diseases that are characterized by downregulation of IGF-1/insulin signaling in neurons and excitotoxicity. [ABSTRACT FROM AUTHOR]

Simple Summary: The goal of this study was to examine if BG impacts the aging process, specifically cellular senescence, using in vitro and aged mouse models. Primary mouse embryonic fibroblasts (MEFs) and aged mice (18 months old) showed that BG supplementation retarded cellular senescence. Of note, BG-supplemented aged mice had remarkedly altered hepatic genes involved in the aging process as it caused less activation of the canonical senescence pathway. These observations demonstrated that BG positively impacts the age-related phenotype by controlling the expression of cellular senescence in the liver and other metabolic organs such as skeletal muscle and white adipose tissue. Cellular senescence, one of the hallmarks of aging, refers to permanent cell cycle arrest and is accelerated during the aging process. Black ginseng (BG), prepared by a repeated steaming and drying process nine times from fresh ginseng (Panax ginseng C.A. Meyer), is garnering attention for herbal medicine due to its physiological benefits against reactive oxygen species (ROS), inflammation, and oncogenesis, which are common cues to induce aging. However, which key nodules in the cellular senescence process are regulated by BG supplementation has not been elucidated yet. In this study, we investigated the effects of BG on cellular senescence using in vitro and aged mouse models. BG-treated primary mouse embryonic fibroblasts (MEFs) in which senescence was triggered by ionizing radiation (IR) expressed less senescence-associated β-galactosidase (SA-β-gal)-positive stained cells. In our aged mice (18 months old) study, BG supplementation (300 mg/kg) for 4 weeks altered hepatic genes involved in the aging process. Furthermore, we found BG supplementation downregulated age-related inflammatory genes, especially in the complement system. Based on this observation, we demonstrated that BG supplementation led to less activation of the canonical senescence pathway, p53-dependent p21 and p16, in multiple metabolic organs such as liver, skeletal muscle and white adipose tissue. Thus, we suggest that BG is a potential senolytic candidate that retards cellular senescence. [ABSTRACT FROM AUTHOR]

Extracellular vesicles (EVs) are involved in intercellular communication and are a topic of increasing interest due to their therapeutic potential. The aim of this study was to determine whether human islet-derived EVs contain insulin, and if so, what role do they play in glucose stimulated insulin secretion. We isolated EVs from human islets culture and plasma to probe for insulin. Plasma from hyperglycemic glucose clamp experiments were also used to isolate and measure EV insulin content in response to a secretory stimulus. We performed immunogold electron microscopy for insulin presence in EVs. Co-culture experiments of isolated EVs with fresh islets were performed to examine the effect of EV cargo on insulin receptor signaling. EVs isolated from culture medium contained insulin. Glucose treatment of islets increased the level of EV insulin. Hyperglycemic glucose clamp experiments in humans also lead to increased levels of insulin in plasma-derived EVs. Immunogold electron microscopy and proteinase K-digestion experiments demonstrated that insulin in EVs predominantly associated with the exterior surface of EVs while western blot analyses uncovered the presence of only preproinsulin in EVs. Membrane-bound preproinsulin in EVs was capable of activating insulin signaling pathway in an insulin receptor-dependent manner. The physiological relevance of this finding was observed in priming of human naïve islets by EVs during glucose stimulated insulin secretion. Our data suggest that (1) human islets secret insulin via an alternate pathway (EV-mediated) other than conventional granule-mediated insulin secretion, and (2) EV membrane bound preproinsulin is biologically active. [ABSTRACT FROM AUTHOR]

Human insulin (INS) gene diverged from the ancestral genes of invertebrate and mammalian species millions of years ago. We previously found that mouse insulin gene (Ins2) isoforms are expressed in brain choroid plexus (ChP) epithelium cells, where insulin secretion is regulated by serotonin and not by glucose. We further compared human INS isoform expression in postmortem ChP and islets of Langerhans. We uncovered novel INS upstream open reading frame isoforms and their protein products. In addition, we found a novel alternatively spliced isoform that translates to a 74-amino acid (AA) proinsulin containing a shorter 19-AA C-peptide sequence, herein designated Cα-peptide. The middle portion of the conventional C-peptide contains β-sheet (GQVEL) and hairpin (GGGPG) motifs that are not present in Cα-peptide. Islet amyloid polypeptide (IAPP) is not expressed in ChP, and its amyloid formation was inhibited in vitro more efficiently by Cα-peptide than by C-peptide. Of clinical relevance, the ratio of the 74-AA proinsulin to proconvertase-processed Cα-peptide was significantly increased in islets from type 2 diabetes mellitus autopsy donors. Intriguingly, 100 years after the discovery of insulin, we found that INS isoforms are present in ChP from insulin-deficient autopsy donors. [ABSTRACT FROM AUTHOR]

Epigenetic alterations are a key hallmark of aging but have been limitedly explored in tissues. Here, using naturally aged murine liver as a model and extending to other quiescent tissues, we find that aging is driven by temporal chromatin alterations that promote a refractory cellular state and compromise cellular identity. Using an integrated multi-omics approach and the first direct visualization of aged chromatin, we find that globally, old cells show H3K27me3-driven broad heterochromatinization and transcriptional suppression. At the local level, site-specific loss of H3K27me3 over promoters of genes encoding developmental transcription factors leads to expression of otherwise non-hepatocyte markers. Interestingly, liver regeneration reverses H3K27me3 patterns and rejuvenates multiple molecular and physiological aspects of the aged liver. [Display omitted] • Global increase of H3K27me3 is a common signature of aged liver and other tissues • H3K27me3 is lost at peak regions and gained at lamin-associated domains • Liver regeneration reverses age-related H3K27me3 and transcriptomic patterns Yang et al. find that the histone modification H3K27me3 accumulates in many tissues with age, due to increased time in quiescence. H3K27me3 is gained over lamin-associated domains but reduced at developmental gene promoters with consequent changes in global and local transcription. Liver regeneration breaks quiescence and partially restores youthful patterns. [ABSTRACT FROM AUTHOR]

R5925 --> 586.3 --> Background: Cellular senescence, one of the hallmarks of aging, refers to a permanent cell cycle arrest and is accelerated during the aging process. A senolytic, a small molecule that eliminates senescent cells, can be a potential strategy to extend healthy lifespan and ameliorate age‐associated diseases. Black ginseng (BG) prepared via nine‐times repetitive steaming and drying process from fresh ginseng (Panax ginsengC.A. Meyer) has been reported to its physiological benefits against reactive oxygen species (ROS), inflammation, and oncogenesis which are common cues to induce aging. Therefore, the present study was aimed to investigate the effect of BG on cellular senescence. Methods: Senescence‐associated β‐galactosidase (SA‐β‐gal) staining was performed on primary mouse embryonic fibroblasts (MEFs) treated 5 μg/mL BG extract for 7 days, and then senescence was induced by γ‐ray irradiation (20 Gy). For animal studies, C57BL/6 male mice were divided into three groups: 9‐week‐old mice orally administered distilled water (Young), 21‐month‐old mice received administration of distilled water (Old), and aged mice supplemented 300 mg/kg BG extracts (Old + BG). After 4 weeks of daily injection, PCR array and immunoblotting were conducted to evaluate mRNA expression and protein levels of targets associated with cellular senescence and cell cycle regulation in metabolic organs, liver, skeletal muscle (SKM), and white adipose tissue (WAT). Results: In in vitro study, BG treatment reduced the density of SA‐β‐gal‐positive MEFs after γ‐ray irradiation (Fig. 1). In aged mice study, BG supplementation remarkedly downregulated age‐related hepatic genes, especially in complement component 1q B (C1qb) and C (C1qc), compared to the aged control group. We further examined the canonical Wnt signaling, augmented in a mouse model of accelerated aging, since the complement C1q family activates Wnt signaling by binding to Frizzled receptors. By assessing the related markers, BG supplementation significantly decreased the hepatic β‐catenin expression level; it also slightly reduced the levels of glycogen synthase kinase 3β (GSK3β) and its phosphorylated form (p‐GSK3β). Recent studies have revealed that Wnt signaling involves in mammalian aging by regulating cell fate and proliferation choice. Thus, we evaluated the expressions of p53 and p21, which involves in cell cycle regulation, and both levels decreased in liver samples from Old + BG group compared to the Old group (Fig. 2). In support of this notion, BG treatment decreased the hepatic mRNA expression levels of senescence‐associated secretory phenotypes (SASPs) such as matrix metallopeptidase 12 (Mmp12) and chemokine ligand 2 (Cxcl2). Consistent with the results in the liver, other metabolic organs, SKM and WAT, showed significantly lower p53 expression in Old + BG group over the Old group. Conclusion: The current study indicates that BG could be a potential candidate of senolytics to reversely regulate cellular senescence, resulting from downregulated complement system affecting Wnt signaling pathways and p53/p21 pathway in metabolic organs. [ABSTRACT FROM AUTHOR]

R5518 --> 583.5 --> Aging is a physiological decrease of several biological activities in an organ that all organisms go through. The presence of a gradual deterioration of cell functioning, due to damage accumulation in metabolic organs, accelerates biological aging. Recently, dietary interventions with food‐active compounds have been linked to suppressing the accumulation of senescent cells and senescence‐associated secretory phenotype (SASP). Curcumin has potent biochemical and biological activities, including antioxidant and anti‐inflammatory actions. However, it largely remains unclear how curcumin has anti‐aging properties such as protection of DNA damage and cell survival/cell fate decisions. The objective of this study is to examine the regulatory effect of dietary curcumin on hepatic cellular senescence in the aged mouse model. Aged (18‐20 months old) male C57BL/6 mice were fed a normal chow diet (NCD) or NCD containing 0.4% (w/w) curcumin ‐ equivalent to 2g/day for a 60 kg adult ‐ (NCD+CUR), high fat high sugar diet (HFHSD) or a HFHSD+CUR (N=7‐9 per group) for 15 weeks. Mice given an HFHSD supplemented with curcumin displayed a different metabolic phenotype compared to mice given an HFHSD alone. To examine the phenotypic plasticity led by transcriptomic alteration, we used RNA‐Seq and analyzed differential gene expression in Gene Ontology (GO) terms and KEGG pathway analysis. There were 1687 and 3794 number of genes that showed a significant change with curcumin in NCD and HFHSD groups compared to their respective control groups. There were at least 8‐fold higher uniquely upregulated and 6‐fold uniquely downregulated genes in the HFHSD+CUR group when compared with their NCD counterparts. To this extent, curcumin supplementation altered hepatic gene expression profiling, especially in senescence pathways and their associated genes. Thus, to validate downregulation in senescence pathway involved genes from the RNA‐Seq data results, we compared the distribution of hepatic senescent cells by β‐gal staining in HFHSD groups. It revealed that HFHSD+CUR mice showed less density of the hepatic senescent cell (Figure A). We then mechanistically sought how curcumin regulates the hepatic senescence pathway. We found that curcumin supplementation decreased senescence effectors, specifically p38 and JNK protein expression levels in the liver (Figure B, C). Our findings suggest that the multifaceted therapeutic potential of curcumin can be used as a protective agent for age‐induced metabolic diseases. [ABSTRACT FROM AUTHOR]