Animal Models Of Aging Research Articles

Restoration of norepinephrine release, cognitive performance, and dendritic spines by amphetamine in aged rat brain.

Age-related dysfunctions in specific neurotransmitter systems likely play an important role in cognitive decline even in its most subtle forms. Therefore, preservation or improvement of cognition via augmentation of neurotransmission is a potential therapeutic strategy to prevent further cognitive deficits. Here we identified a particular neuronal vulnerability in the aged Fischer 344 rat brain, an animal model of neurocognitive aging. Specifically, we demonstrated a marked impairment in glutamate-stimulated release of norepinephrine (NE) in the hippocampus and cerebral cortex of aged rats, and established that this release was mediated by N-methyl-D-aspartate (NMDA) receptors. Further, we also demonstrated that this decrease in NE release is fully rescued by the psychostimulant drug amphetamine (AMPH). Moreover, we showed that AMPH increases dendritic spine maturation, and importantly shows preclinical efficacy in restoring memory deficits in the aged rat through its actions to potentiate NE neurotransmission at β-adrenergic receptors. Taken together, our results suggest that deficits in glutamate-stimulated release of NE may contribute to and possibly be a determinant of neuronal vulnerability underlying cognitive decline during aging, and that these deficits can be corrected with currently available drugs. Overall these studies suggest that repurposing of psychostimulants for age-associated cognitive deficits is a potential avenue to delay or prevent cognitive decline and/or frank dementia later in life.

Polyphenols as Potential Geroprotectors.

Significance: Currently, a large amount of evidence of beneficial effects of diets enriched with polyphenols on various aspects of health has been accumulated. These phytochemicals have a geroprotective potential slowing down the pathological processes associated with aging and ensuring longevity. In this study, a comprehensive analysis was conducted to determine the adherence of individual polyphenols to geroprotector criteria. Data from experimental models, clinical trials, and epidemiological studies were analyzed. Recent Advances: Sixty-two polyphenols have been described to increase the life span and improve biomarkers of aging in animal models. They act via evolutionarily conserved molecular mechanisms, including hormesis and maintenance of redox homeostasis, epigenetic regulation, response to cellular damage, metabolic control, and anti-inflammatory and senolytic activity. Epidemiological and clinical studies suggest that certain polyphenols have a potential for prevention and treatment of various diseases, including cancer, metabolic disorders, and cardiovascular conditions in humans. Critical Issues: Among the reviewed phytochemicals, chlorogenic acid, quercetin, epicatechin, genistein, resveratrol, and curcumin were identified as compounds with the highest geroprotective potential. However, there is a lack of unambiguous information on the effectiveness and safety of polyphenols for increasing health span, preventing and treating aging-associated diseases in humans. Future Directions: Further research is needed to fully understand the effects of polyphenols considering their long-term consumption, metabolic modification and bioavailability, complex interactions between different groups of polyphenols and with other phytochemicals, as well as their effects on individuals with different health status. Antioxid. Redox Signal. 40, 564-593.

Bazi Bushen capsule improves the deterioration of the intestinal barrier function by inhibiting NLRP3 inflammasome-mediated pyroptosis through microbiota-gut-brain axis.

The senescence-accelerated prone mouse 8 (SAMP8) is a widely used model for accelerating aging, especially in central aging. Mounting evidence indicates that the microbiota-gut-brain axis may be involved in the pathogenesis and progression of central aging-related diseases. This study aims to investigate whether Bazi Bushen capsule (BZBS) attenuates the deterioration of the intestinal function in the central aging animal model. In our study, the SAMP8 mice were randomly divided into the model group, the BZ-low group (0.5 g/kg/d BZBS), the BZ-high group (1 g/kg/d BZBS) and the RAPA group (2 mg/kg/d rapamycin). Age-matched SAMR1 mice were used as the control group. Next, cognitive function was detected through Nissl staining and two-photon microscopy. The gut microbiota composition of fecal samples was analyzed by 16S rRNA gene sequencing. The Ileum tissue morphology was observed by hematoxylin and eosin staining, and the intestinal barrier function was observed by immunofluorescence. The expression of senescence-associated secretory phenotype (SASP) factors, including P53, TNF-α, NF-κB, IL-4, IL-6, and IL-10 was measured by real-time quantitative PCR. Macrophage infiltration and the proliferation and differentiation of intestinal cells were assessed by immunohistochemistry. We also detected the inflammasome and pyroptosis levels in ileum tissue by western blotting. BZBS improved the cognitive function and neuronal density of SAMP8 mice. BZBS also restored the intestinal villus structure and barrier function, which were damaged in SAMP8 mice. BZBS reduced the expression of SASP factors and the infiltration of macrophages in the ileum tissues, indicating a lower level of inflammation. BZBS enhanced the proliferation and differentiation of intestinal cells, which are essential for maintaining intestinal homeostasis. BZBS modulated the gut microbiota composition, by which BZBS inhibited the activation of inflammasomes and pyroptosis in the intestine. BZBS could restore the dysbiosis of the gut microbiota and prevent the deterioration of intestinal barrier function by inhibiting NLRP3 inflammasome-mediated pyroptosis. These results suggested that BZBS attenuated the cognitive aging of SAMP8 mice, at least partially, by targeting the microbiota-gut-brain axis.

Association of detrusor underactivity with aging and metabolic syndrome: suggestions from animal models.

Detrusor underactivity, a condition in which the bladder muscle does not contract strongly or long enough to empty the bladder completely or within the normal time frame, is a common cause of lower urinary tract symptoms in older individuals of both sexes. Although aging is a known risk factor for detrusor underactivity, its pathophysiological mechanisms are not fully understood. Therefore, establishing animal models that closely mimic the pathophysiology of detrusor underactivity in humans is necessary to elucidate these mechanisms. Metabolic syndrome is a cluster of several risk factors, including obesity, hyperlipidemia, hyperglycemia, and hypertension, which are associated with the development of diabetes, cardiovascular disease, and lower urinary tract dysfunction in both sexes. Notably, bladder dysfunction resulting from detrusor underactivity is observed at an earlier age in animal models with diabetes mellitus than in those without. Recently, detrusor underactivity-like phenotypes have been observed at a relatively early age in animal models with metabolic syndrome, involving obesity, hyperlipidemia, and hypertension, compared with those without. Therefore, this review introduces the association of detrusor underactivity with aging and metabolic syndrome, as well as possible pathophysiological mechanisms for detrusor underactivity from reports of various animal models. Notably, metabolic syndrome may accelerate the onset of age-related detrusor underactivity, and further analysis of old animal models with metabolic syndrome may help elucidate the pathogenesis of detrusor underactivity in humans.

The biological mechanism and emerging therapeutic interventions of liver aging.

Research on liver aging has become prominent and has attracted considerable interest in uncovering the mechanism and therapeutic targets of aging to expand lifespan. In addition, multi-omics studies are widely used to perform further mechanistic investigations on liver aging. In this review, we illustrate the changes that occur with aging in the liver, present the current models of liver aging, and emphasize existing multi-omics studies on liver aging. We integrated the multi-omics data of enrolled studies and reanalyzed them to identify key pathways and targets of liver aging. The results indicated that C-X-C motif chemokine ligand 9 (Cxcl9) was a regulator of liver aging. In addition, we provide a flowchart for liver aging research using multi-omics analysis and molecular experiments to help researchers conduct further research. Finally, we present emerging therapeutic treatments that prolong lifespan. In summary, using cells and animal models of liver aging, we can apply a multi-omics approach to find key metabolic pathways and target genes to mitigate the adverse effects of liver aging.

Inhibitory effect of tea flower polysaccharides on oxidative stress and microglial oxidative damage in aging mice by regulating gut microbiota.

Tea flower polysaccharides (TFPS) have prominent anti-aging effect. In this study, we used an animal model of aging induced by D-galactose in mice to investigate the effect of TFPS on reducing inflammatory factors, lowering oxidative stress levels, and inhibiting oxidative damage to microglia from the perspective of regulating gut microbiota. The results showed that TFPS could improve the homeostasis of gut microbiota in aging mice, reduce the ratio of Firmicutes to Bacteroidota, and significantly increase the abundance of Lactobacillus. At the same time, TFPS reduced the excessive activation of hippocampal microglia in aging mice, significantly down-regulated the levels of pro-inflammatory factors IL-6, IL-1β, TNF-α, and nuclear transcription factor NF-κB, increased the activity of antioxidant enzymes SOD, CAT, and POD, and reduced the content of MDA. Our research results indicate that TFPS can improve the disorder of gut microbiota, alleviate oxidative damage to glial cells, alleviate neuroinflammation, and play a role in delaying aging.

Hypothalamic circuits and aging: keeping the circadian clock updated.

Over the past century, age-related diseases, such as cancer, type-2 diabetes, obesity, and mental illness, have shown a significant increase, negatively impacting overall quality of life. Studies on aged animal models have unveiled a progressive discoordination at multiple regulatory levels, including transcriptional, translational, and post-translational processes, resulting from cellular stress and circadian derangements. The circadian clock emerges as a key regulator, sustaining physiological homeostasis and promoting healthy aging through timely molecular coordination of pivotal cellular processes, such as stem-cell function, cellular stress responses, and inter-tissue communication, which become disrupted during aging. Given the crucial role of hypothalamic circuits in regulating organismal physiology, metabolic control, sleep homeostasis, and circadian rhythms, and their dependence on these processes, strategies aimed at enhancing hypothalamic and circadian function, including pharmacological and non-pharmacological approaches, offer systemic benefits for healthy aging. Intranasal brain-directed drug administration represents a promising avenue for effectively targeting specific brain regions, like the hypothalamus, while reducing side effects associated with systemic drug delivery, thereby presenting new therapeutic possibilities for diverse age-related conditions.

Improvement of Cognitive Functions And Neurotrophic Effects through by Α5‐GABAA Receptor Positive Allosteric Modulation in Animal Models of Risk for Alzheimer’s Disease

AbstractBackgroundReduced GABA/somatostatin (SST) signaling is reported in psychiatric, stress‐related and neurodegenerative disorders. SST+ interneurons from cortical layers and the hippocampus inhibit the dendrites of excitatory neurons, largely through α5‐containing GABAA receptors (α5‐GABAAR). Recently, we showed that an α5‐positive allosteric modulator (α5‐PAM) alleviates working memory deficits and reverses neuronal atrophy in old mice. We then started to investigate the behavioral and neurotrophic effects of this α5‐PAM in animal models of aging, chronic stress, and β‐amyloid load, as risk factor for developing Alzheimer’s disease.MethodThree studies are presented, with ∼12 mice/group, 50% female: 1) Young C57BL6 subjected to unpredictable chronic mild stress (UCMS) to induce cognitive deficits. 2) 22 month‐old C57BL6 developing an age‐related cognitive decline. 3) 5xFAD transgenic mice with progressive amyloid‐related cognitive decline. In all studies, efficacy of chronic administration of GL‐II‐73 (30mg/kg, p.o, for 4 weeks) at rescuing cognitive deficits across 3 domains was assessed. Working memory was assessed in an alternation task, spatial memory in the water maze, and cognitive flexibility in a set‐shifting assay. Brains were then stained using Golgi‐Cox technique (n = 4brain/group; 8cell/brain) for quantification of dendritic length and spine density in the prefrontal cortex and hippocampus (NeuroLucida).ResultChronic treatment in all models reversed cognitive deficits across domains (ps<0.01), with a strong effect on working memory. Chronic treatment also significantly reversed UCMS‐, age‐, or amyloid‐induced dendritic shrinkage and reduction of spine density at apical and basal dendrites (p<0.001 in PFC and CA1).ConclusionTogether, results support that selective α5 targeting of GABAA receptors overcomes chronic stress‐, aging‐, or amyloid‐related cognitive deficits and detriments in neuronal morphology. This represents the first intervention targeting the GABAergic system to have a symptomatic and disease‐modifying therapeutic potential in a transdiagnostic manner. This could represent a major avenue for clinical development for patients suffering from cognitive deficits across brain disorders.

Aβ oligomers reduce neuronal plasticity in an aged animal model of Alzheimer’s disease

AbstractBackgroundAlzheimer’s disease (AD) is characterized by the extracellular accumulation of senile plaques composed of beta‐amyloid (Aβ). Aβ oligomers (AβO) induce damage beginning with loss of synapses, followed by neurite network disorganization and neuronal death. The hippocampus is a cerebral structure and a major place of neuroplasticity and a key structure for memory processing and consolidation. Hippocampal atrophy is well documented in AD. Neuronal plasticity persists during ageing and could adaptative response to cognitive decline during ageing or dementia.Alterations in adult neuronal plasticity and synaptic dysfunctions are detected in rodent models of Alzheimer’s disease. Thus, early dysfunction in neural stem cell production and neuronal differentiation could be linked to reduced neuronal plasticity in AD.MethodIn this study, to investigate the effect of age on neurogenesis, in young (12 weeks), aged and healthy (16 months) mice and in an in vivo model of AD, based on intra‐hippocampal injection of a AβO/protofibril preparation in aged (16 months) mice.Proliferation of cells (BrdU, Ki67), differentiation (DCX) and maturation (NeuN) into neurons were studied in the dendate gyrus of mice. Activation of glial cells was also assessed by immunohistochemistry. In addition, cognitive performance of mice were assessed using the Y‐maze test (short‐term spatial memory) in the same animal.ResultOur results show a decrease in neurogenesis in aged mice compared to young mice. Injection of AβO in the CA1 area was also associated with decreased neurogenesis in the dentate gyrus, neuroinflammation and to reduce performance in the Y‐maze test.This reduction in neuroblast generation was revealed by a decrease in the number of BrdU(+), Ki67(+) and DCX(+) cells in the dentate gyrus.ConclusionWe evidenced a decreased in neuronal plasticity in aging which is exacerbated in our in vivo model of AD and connected to cognitive decline.

Regulation of ROS/inflammasome Axis is Essential for Cardiac Regeneration in Aging Rats Receiving Transplantation of Mesenchymal Stem Cells.

Aging is a biological and gradual deterioration of function in living organisms. Aging is one of the risk factors for heart disease. Although mesenchymal stem cell transplantation shows potential in heart disease treatment, the relationship between stem cell-based therapy and oxidative stress/inflammasome axis regulation remains unclear. This study hypothesized that intervention of stem cells showed protective effect on heart aging induced by D-galactose through regulation of oxidative stress/inflammasome axis. An aging animal model was designed to test the above hypothesis. Experimental animals were divided into three groups, including Sham, D-gal (aging rats induced by d-galactose), and D-gal+WJSC (aging rats receiving mesenchymal stem cells). Compared to the Sham, the experimental results indicate that structural alteration (HE stain and Masson's Trichrome stain), oxidative stress elevation (increase of TBARS level, expression of gp-91 and suppression of Sirt-1 as well as SOD2), increase of aging marker p53, suppression of cardiogenesis marker Troponin T, and inflammasome related protein markers expression (NLRP3, caspase-1 and IL-1 beta) were significantly observed in D-gal. In contrast, all pathological pathways were significantly improved in D-gal+WJSC when compared to D-gal. In addition, migration of stem cells to aging heart tissues was observed in the D-gal+WJSC group. These findings suggest that mesenchymal stem cell transplantation effectively ameliorates aging hearts through oxidative stress/inflammasome axis regulation. The results from this study provide clinical potential for stem cell-based therapy in the treatment of aging hearts.

Phenomic Microglia Diversity as a Druggable Target in the Hippocampus in Neurodegenerative Diseases.

Phenomics, the complexity of microglia phenotypes and their related functions compels the continuous study of microglia in disease animal models to find druggable targets for neurodegenerative disorders. Activation of microglia was long considered detrimental for neuron survival, but more recently it has become apparent that the real scenario of microglia morphofunctional diversity is far more complex. In this review, we discuss the recent literature on the alterations in microglia phenomics in the hippocampus of animal models of normal brain aging, acute neuroinflammation, ischemia, and neurodegenerative disorders, such as AD. Microglia undergo phenomic changes consisting of transcriptional, functional, and morphological changes that transform them into cells with different properties and functions. The classical subdivision of microglia into M1 and M2, two different, all-or-nothing states is too simplistic, and does not correspond to the variety of phenotypes recently discovered in the brain. We will discuss the phenomic modifications of microglia focusing not only on the differences in microglia reactivity in the diverse models of neurodegenerative disorders, but also among different areas of the brain. For instance, in contiguous and highly interconnected regions of the rat hippocampus, microglia show a differential, finely regulated, and region-specific reactivity, demonstrating that microglia responses are not uniform, but vary significantly from area to area in response to insults. It is of great interest to verify whether the differences in microglia reactivity may explain the differential susceptibility of different brain areas to insults, and particularly the higher sensitivity of CA1 pyramidal neurons to inflammatory stimuli. Understanding the spatiotemporal heterogeneity of microglia phenomics in health and disease is of paramount importance to find new druggable targets for the development of novel microglia-targeted therapies in different CNS disorders. This will allow interventions in three different ways: (i) by suppressing the pro-inflammatory properties of microglia to limit the deleterious effect of their activation; (ii) by modulating microglia phenotypic change to favor anti-inflammatory properties; (iii) by influencing microglia priming early in the disease process.

Ethanolic Extract from Seed Residues of Sea Buckthorn (Hippophae rhamnoides L.) Ameliorates Oxidative Stress Damage and Prevents Apoptosis in Murine Cell and Aging Animal Models.

Hippophae rhamnoides L. has been widely used in research and application for almost two decades. While significant progress was achieved in the examination of its fruits and seeds, the exploration and utilization of its by-products have received relatively less attention. This study aims to address this research gap by investigating the effects and underlying mechanisms of sea buckthorn seed residues both in vitro and in vivo. The primary objective of this study is to assess the potential of the hydroalcoholic extract from sea buckthorn seed residues (HYD-SBSR) to prevent cell apoptosis and mitigate oxidative stress damage. To achieve this, an H2O2-induced B16F10 cell model and a D-galactose-induced mouse model were used. The H2O2-induced oxidative stress model using B16F10 cells was utilized to evaluate the cellular protective and reparative effects of HYD-SBSR. The results demonstrated the cytoprotective effects of HYD-SBSR, as evidenced by reduced apoptosis rates and enhanced resistance to oxidative stress alongside moderate cell repair properties. Furthermore, this study investigated the impact of HYD-SBSR on antioxidant enzymes and peroxides in mice to elucidate its reparative potential in vivo. The findings revealed that HYD-SBSR exhibited remarkable antioxidant performance, particularly at low concentrations, significantly enhancing antioxidant capacity under oxidative stress conditions. To delve into the mechanisms underlying HYD-SBSR, a comprehensive proteomics analysis was conducted to identify differentially expressed proteins (DEPs). Additionally, a Gene Ontology (GO) analysis and an Encyclopedia of Genes and Genomes (KEGG) pathway cluster analysis were performed to elucidate the functional roles of these DEPs. The outcomes highlighted crucial mechanistic pathways associated with HYD-SBSR, including the PPAR signaling pathway, fat digestion and absorption, glycerophospholipid metabolism, and cholesterol metabolism. The research findings indicated that HYD-SBSR, as a health food supplement, exhibits favorable effects by promoting healthy lipid metabolism, contributing to the sustainable and environmentally friendly production of sea buckthorn and paving the way for future investigations and applications in the field of nutraceutical and pharmaceutical research.

Galectin-1 as a marker for microglia activation in the aging brain

Microglia cells, the immune cells residing in the brain, express immune regulatory molecules that have a central role in the manifestation of age-related brain characteristics. Our hypothesis suggests that galectin-1, an anti-inflammatory member of the beta-galactoside-binding lectin family, regulates microglia and neuroinflammation in the aging brain. Through our in-silico analysis, we discovered a subcluster of microglia in the aged mouse brain that exhibited increased expression of galectin-1 mRNA. In our Western blotting experiments, we observed a decrease in galectin-1 protein content in our rat primary cortical cultures over time. Additionally, we found that the presence of lipopolysaccharide, an immune activator, significantly increased the expression of galectin-1 protein in microglial cells. Utilizing flow cytometry, we determined that a portion of the galectin-1 protein was localized on the surface of the microglial cells. As cultivation time increased, we observed a decrease in the expression of activation-coupled molecules in microglial cells, indicating cellular exhaustion. In our mixed rat primary cortical cell cultures, we noted a transition of amoeboid microglial cells labeled with OX42(CD11b/c) to a ramified, branched phenotype during extended cultivation, accompanied by a complete disappearance of galectin-1 expression. By analyzing the transcriptome of a distinct microglial subpopulation in an animal model of aging, we established a correlation between chronological aging and galectin-1 expression. Furthermore, our in vitro study demonstrated that galectin-1 expression is associated with the functional activation state of microglial cells exhibiting specific amoeboid morphological characteristics. Based on our findings, we identify galectin-1 as a marker for microglia activation in the context of aging.

Metallothionein I/II Expression and Metal Ion Levels in Correlation with Amyloid Beta Deposits in the Aged Feline Brain.

Brain aging has been correlated with high metallothionein I-II (MT-I/II) expression, iron and zinc dyshomeostasis, and Aβ deposition in humans and experimental animals. In the present study, iron and zinc accumulation, the expression of MT-I/II and Aβ42, and their potential association with aging in the feline brain were assessed. Tissue sections from the temporal and frontal grey (GM) and white (WM) matter, hippocampus, thalamus, striatum, cerebellum, and dentate nucleus were examined histochemically for the presence of age-related histopathological lesions and iron deposits and distribution. We found, using a modified Perl's/DAB method, two types of iron plaques that showed age-dependent accumulation in the temporal GM and WM and the thalamus, along with the age-dependent increment in cerebellar-myelin-associated iron. We also demonstrated an age-dependent increase in MT-I/II immunoreactivity in the feline brain. In cats over 7 years old, Aβ immunoreactivity was detected in vessel walls and neuronal somata; extracellular Aβ deposits were also evident. Interestingly, Aβ-positive astrocytes were also observed in certain cases. ICP-MS analysis of brain content regarding iron and zinc concentrations showed no statistically significant association with age, but a mild increase in iron with age was noticed, while zinc levels were found to be higher in the Mature and Senior groups. Our findings reinforce the suggestion that cats could serve as a dependable natural animal model for brain aging and neurodegeneration; thus, they should be further investigated on the basis of metal ion concentration changes and their effects on aging.

Synthesis and Receptor Binding Studies of α5 GABAAR Selective Novel Imidazodiazepines Targeted for Psychiatric and Cognitive Disorders.

GABA mediates inhibitory actions through various GABAA receptor subtypes, including 19 subunits in human GABAAR. Dysregulation of GABAergic neurotransmission is associated with several psychiatric disorders, including depression, anxiety, and schizophrenia. Selective targeting of α2/3 GABAARs can treat mood and anxiety, while α5 GABAA-Rs can treat anxiety, depression, and cognitive performance. GL-II-73 and MP-III-022, α5-positive allosteric modulators have shown promising results in animal models of chronic stress, aging, and cognitive disorders, including MDD, schizophrenia, autism, and Alzheimer's disease. Described in this article is how small changes in the structure of imidazodiazepine substituents can greatly impact the subtype selectivity of benzodiazepine GABAAR. To investigate alternate and potentially more effective therapeutic compounds, modifications were made to the structure of imidazodiazepine 1 to synthesize different amide analogs. The novel ligands were screened at the NIMH PDSP against a panel of 47 receptors, ion channels, including hERG, and transporters to identify on- and off-target interactions. Any ligands with significant inhibition in primary binding were subjected to secondary binding assays to determine their Ki values. The newly synthesized imidazodiazepines were found to have variable affinities for the benzodiazepine site and negligible or no binding to any off-target profile receptors that could cause other physiological problems.

Effects of 20-hydroxyecdysone on UVB-induced photoaging in hairless mice

We recently reported that exposure of skin to ultraviolet B (UVB) irradiation for 2 weeks induces stress and accelerates skin aging. Interestingly, aldosterone synthase is known to be crucial in generating UVB-induced stress-related responses, suggesting that drugs that regulate its activity can be used as skin antiaging agents. Through extensive drug screening, we have identified 20-hydroxyecdysone (20E), a steroidal prohormone secreted by the prothoracic glands of insects, as a potent inhibitor of UVB-induced aging. Although 20E has been shown to exert antistress and anti-collagenase effects in vitro, its effects in vivo remain unexplored. Furthermore, the pharmacological and physiological effects of 20E on UVB-mediated photoaging are poorly understood. Therefore, in this study, we investigated the effects of 20E on aldosterone synthase and UVB-induced photoaging and skin lesions in hairless mice, focusing on the stress-related hypothalamic–pituitary–adrenal axis. We confirmed that 20E inhibited aldosterone synthase and reduced corticosterone levels. When applied to a UV-induced skin aging animal model, it ameliorated UV-induced stress and protected against the decrease in collagen levels. Importantly, when the aldosterone synthase inhibitor osilodrostat, an FDA-approved drug, was applied to the UV-induced skin aging model, the stress-reducing and antiaging effects of 20E were not observed. Thus, we conclude that 20E inhibits UVB-induced skin aging by blocking aldosterone synthase and is a potential candidate to prevent skin aging.

ANTIOXIDANT THERAPY IN THE ELDERLY WITH TINNITUS: SYSTEMATICS REVIEW

Tinnitus is one of the most prevalent and annoying disorders that affect the ear and the auditory system. It is one of the most important symptoms in neurootology, along with hearing loss, vertigo, dizziness, and nausea. It can cause a variety of somatic and psychological disorders that interfere with a person's quality of life. There is a correlation between oxidative stress and tinnitus. Hair cell apoptosis, cochlear degeneration, alterations to supporting structures and stria vascularis, changes to the nerve fibers of the acoustic nerve, irregular neuronal activity in the auditory pathway, and malfunction in the central cortex are all possible outcomes of oxidative stress. Animal models of aging, noise damage, and ototoxicity have been used to investigate the relationship between oxidative stress and the death of hair cells. Antioxidants are substances that can take on a wide variety of chemical structures, but they are categorized as a single class because they share the ability to neutralize the effects of highly reactive and potentially damaging free radicals. These radicals are produced when foods undergo the necessary oxidation reactions that are a natural part of the digestion process. Antioxidant supplementation with vitamins, minerals, phytochemicals, and alpha-lipoic acid (ALA) might have therapeutic effects on tinnitus by reducing the subjective discomfort and the level of severity caused by the ringing in the ears.

Accounting Gut Microbiota as the Mediator of Beneficial Effects of Dietary (Poly)phenols on Skeletal Muscle in Aging.

Sarcopenia, the age-related loss of muscle mass and function increasing the risk of disability and adverse outcomes in older people, is substantially influenced by dietary habits. Several studies from animal models of aging and muscle wasting indicate that the intake of specific polyphenol compounds can be associated with myoprotective effects, and improvements in muscle strength and performance. Such findings have also been confirmed in a smaller number of human studies. However, in the gut lumen, dietary polyphenols undergo extensive biotransformation by gut microbiota into a wide range of bioactive compounds, which substantially contribute to bioactivity on skeletal muscle. Thus, the beneficial effects of polyphenols may consistently vary across individuals, depending on the composition and metabolic functionality of gut bacterial communities. The understanding of such variability has recently been improved. For example, resveratrol and urolithin interaction with the microbiota can produce different biological effects according to the microbiota metabotype. In older individuals, the gut microbiota is frequently characterized by dysbiosis, overrepresentation of opportunistic pathogens, and increased inter-individual variability, which may contribute to increasing the variability of biological actions of phenolic compounds at the skeletal muscle level. These interactions should be taken into great consideration for designing effective nutritional strategies to counteract sarcopenia.

The Geroprotective Drug Candidate CMS121 Alleviates Diabetes, Liver Inflammation, and Renal Damage in db/db Leptin Receptor Deficient Mice.

db/db mice, which lack leptin receptors and exhibit hyperphagia, show disturbances in energy metabolism and are a model of obesity and type 2 diabetes. The geroneuroprotector drug candidate CMS121 has been shown to be effective in animal models of Alzheimer's disease and aging through the modulation of metabolism. Thus, the hypothesis was that CMS121 could protect db/db mice from metabolic defects and thereby reduce liver inflammation and kidney damage. The mice were treated with CMS121 in their diet for 6 months. No changes were observed in food and oxygen consumption, body mass, or locomotor activity compared to control db/db mice, but a 5% reduction in body weight was noted. Improved glucose tolerance and reduced HbA1c and insulin levels were also seen. Blood and liver triglycerides and free fatty acids decreased. Improved metabolism was supported by lower levels of fatty acid metabolites in the urine. Markers of liver inflammation, including NF-κB, IL-18, caspase 3, and C reactive protein, were lowered by the CMS121 treatment. Urine markers of kidney damage were improved, as evidenced by lower urinary levels of NGAL, clusterin, and albumin. Urine metabolomics studies provided further evidence for kidney protection. Mitochondrial protein markers were elevated in db/db mice, but CMS121 restored the renal levels of NDUFB8, UQCRC2, and VDAC. Overall, long-term CMS121 treatment alleviated metabolic imbalances, liver inflammation, and reduced markers of kidney damage. Thus, this study provides promising evidence for the potential therapeutic use of CMS121 in treating metabolic disorders.

Alterations in histology of the aging salivary gland and correlation with the glandular inflammatory microenvironment

Aging-related salivary dysfunction typically causes reduced saliva volumes, which leads to debilitating consequences, even affecting patient quality of life. Understanding the respective clinicopathological characteristics and molecular mechanisms underlying salivary gland functioning during aging is vital for therapeutic purposes. Here, we provide a detailed atlas of the salivary gland microenvironment during aging, and we identified several phenotypes characteristic of aging salivary glands, including acini atrophy, increased inflammatory cells, altered immune responses, and accumulation of lysosomes and autophagosomes in aging cells, which may reflect progressive degeneration of salivary gland function. Furthermore, our analyses suggested significant enrichment of metabolic pathways in aging glands. Our results revealed complex cellular cross-talk among aging acinar cells, inflammatory factors, and immune responses. A natural aging animal model was established to verify these findings. This study provides mechanistic insights into age-related clinicopathogenesis, important implications for early diagnosis, and identification of new targets for improving salivary gland dysfunction.