Aged Rats Research Articles

Berberine Mitigates Sepsis-Associated Acute Kidney Injury in Aged Rats by Preserving Mitochondrial Integrity and Inhibiting TLR4/NF-κB and NLRP3 Inflammasome Activations

Sepsis-associated acute kidney injury (SA-AKI) presents a severe challenge in the elderly due to increasing incidence, high mortality, and the lack of specific effective treatments. Exploring novel and secure preventive and/or therapeutic approaches is critical and urgent. Berberine (BBR), an isoquinoline alkaloid with anti-inflammatory, antioxidant, and immunomodulatory properties, has shown beneficial effects in various kidney diseases. This study examined whether BBR could protect against SA-AKI in aged rats. Sepsis was induced in 26-month-old male Wistar rats by cecal ligation and puncture (CLP), either with or without BBR pretreatment. CLP induction led to SA-AKI, as indicated by elevated serum levels of malondialdehyde, tumor necrosis factor-alpha, urea nitrogen, creatinine, and neutrophil gelatinase-associated lipocalin (NGAL), along with histopathological features of kidney damage. Key indicators of kidney oxidative stress, mitochondrial dysfunction, apoptosis, and activations of the Toll-like receptor 4/nuclear factor-kappa B (TLR4/NF-κB) signaling, including the nucleotide-binding domain, leucine-rich-containing family, and pyrin domain-containing-3 (NLRP3) inflammasome pathway, were also elevated following CLP induction. BBR pretreatment substantially mitigated these adverse effects, suggesting that it protects against SA-AKI in aged rats by reducing oxidative stress, preserving mitochondrial integrity, and inhibiting key inflammatory pathways. These findings highlight the potential of BBR as a therapeutic agent for managing SA-AKI in elderly populations.

Whole-body vibration elicits 40Hz cortical gamma oscillations and ameliorates age-related cognitive impairment through hippocampal astrocyte synapses in male rats.

Age-related cognitive impairment is a prevalent issue in developed societies. Gamma oscil2lations at 40Hz have been identified as a potential therapeutic approach for age-related cognitive decline and can be induced through various modalities, including auditory, visual, electrical, and magnetic stimulation. In this study, we investigated a novel modality of stimulation: whole-body vibration at 40Hz. We examined the effects of 40Hz vibration on cognitive performance and associated neuronal activity in the brains of aged male rats. Our findings revealed that only vibration at 40Hz, rather than 20Hz or 80Hz, elicited cortical gamma oscillations in aged male rats. Additionally, following 8weeks of prolonged treatment, the implementation of 40Hz whole-body vibration significantly augmented the cognitive function of aged male rats as evidenced by behavioral assessments. Mechanistic studies demonstrated that these beneficial effects were attributed to the reduction of neuronal apoptosis in hippocampal CA1 through regulation of synaptic connections between astrocytes and neurons via 40Hz gamma oscillations. Collectively, this suggests a promising intervention for age-related cognitive decline and identifies neuron-astrocyte synapses as potential therapeutic targets.

The impact of long-term isolation on anxiety, depressive-like and social behavior in aging Wistar-Kyoto (WKY) and spontaneously hypertensive (SHR) male rats.

Aging is a complex process associated with multimorbidity. Hypertension, one of widespread states, is among main causes of age-related alterations in behavior, emotionality and sociability. We studied the effects of long-term isolated housing on anxiety, depressive-like and social behavior as well as changes in the adrenocortical and sympathetic systems in the aging normotensive Wistar Kyoto (WKY) and spontaneously hypertensive rats (SHR). Ten-month-old male rats of both strains were subjected to 90-day isolated or group housing. Surprisingly, social isolation induced only mild effect on anxiety without influencing other affective-related behaviors. No effects of isolated housing on sociability or social novelty preferences were revealed. Despite the adrenal gland hypertrophy in the SHRs, corticosterone levels remained stable within the period of isolation but the expression of nuclear glucocorticoid receptor (Nr3c1) mRNA in the adrenals was lower in the SHR as compared to WKY rats. Pre-existing hypertension, associated with SHR genotype, did not significantly contribute to the effects of social isolation. The data suggest that the aged WKY and SHR rats are relatively resilient to chronic social stress associated with isolated housing.

Peripheral CD4+ T cell phenotype and brain microglial activation associated with cognitive heterogeneity in aged rats.

Cognitive decline is a critical hallmark of brain aging. Although aging is a natural process, there is significant heterogeneity in cognition levels among individuals; however, the underlying mechanisms remain uncertain. In our study, we classified aged male Sprague‒Dawley rats into aged cognition-unimpaired (AU) group and aged cognition-impaired (AI) group by using an attentional set-shifting task. The transcriptome sequencing results of medial prefrontal cortex (mPFC) demonstrated significant differences in microglial activation and inflammatory response pathways between the two groups. Specifically, compared to AU rats, AI rats exhibited a greater presence of CD86-positive microglia and major histocompatibility complex class II (MHC-II)-positive microglia, along with elevated inflammatory molecules, in mPFC. Conversely, AI rats exhibited a reduction in the percentage of microglia expressing CD200R and the anti-inflammatory molecules Arg-1 and TGF-β. Additionally, peripheral blood analysis of AI rats demonstrated elevated levels of Th17 and Th1 cells, along with proinflammatory molecules; however, decreased levels of Treg cells, along with anti-inflammatory molecules, were observed in AI rats. Our research suggested that peripheral Th17/Treg cells and central microglial activation were associated with cognitive heterogeneity in aged rats. These findings may provide a new target for healthy aging.

Oxidative stress and mitochondrial dysfunction contributes to postoperative cognitive dysfunction in elderly rats dependent on NLRP3 activation.

Postoperative cognitive dysfunction (POCD), a complication following procedures such as orthopedic surgery, is associated with a worsened prognosis, especially in the elderly population. Several mechanisms have been proposedfor communication between the immune system and the brain after surgery. In an experimental tibial fracture (TF) model, we aimed to understand the role of the NLR family pyrin domain containing 3 (NLRP3) on oxidative stress and mitochondrial dysfunction as mechanisms underlying POCD in aged and adult rats.Adult or aged male Wistar rats were subjected to the TF model and receivedintracerebroventricularsaline or MCC950 (140ng/kg), a specific small-molecule inhibitor that selectively blocks activation of the NLRP3 inflammasome.We followed the control (sham) and TF groups treated with MCC950 or saline for seven days to determine cognitive function and survival.The prefrontal cortex and hippocampus were isolated for NLRP3 evaluation, cytokine analysis, oxidative stress measurements, myeloperoxidase activity, nitric oxide formation, mitochondrial respiratory chain enzymes, and succinate dehydrogenase (SDH) activity. Seven days after TF induction, NLRP3 levels increased in the hippocampus and prefrontal cortex in both ages, showed an enhancement in aged rats compared to adults, and experienced a reversal with MCC950 administration.The administration of MCC950 restored memory, IL-1β and IL-10 levels, nitrite/nitrate, lipid peroxidation in the hippocampus and prefrontal cortex, and preserved catalase activity in the prefrontal cortex in aged rats. At the same age, the complex I activity alteration in both regions and complex II, IV, and SDH in the prefrontal cortex werereversed. In conclusion, NLRP3 activation contributes to POCD development because it is intrinsically involved in mitochondrial dysfunction and oxidative stress after orthopedic surgery in aged rats.

Evaluation of Noopept Effect on the Neurotransmitter Amino Acids in the Hippocampus in Alcohol Drinking Rats Using in Vivo Microdialysis

The aim of the present work was to study the dynamics of neurotransmitter amino acids after acute Noopept (a dipeptide analogue of piracetam used in clinical practice as a nootropic agent) administration in intact and long-term ethanol (ETOH) exposed rats. Albino male rats were given 10% (vol/vol) ETOH solution as the only source of fluid 24 h / 7 days per week (n = 5). Also we used intact rats of the same age which had no access to ethanol (n = 5). The excitatory and inhibitory amino acids in the extracellular space of the dorsal hippocampus region in freely moving intact and ETOH-exposed rats during prolonged alcohol deprivation were measured using the intracerebral microdialysis method followed by HPLC/ED. There were no significant differences in the level of neurotransmitter amino acids between ETOH-exposed and intact animals. For the first time, in vivo experiments the effect of Noopept (1.5 mg/kg, i.p.) on the level of excitatory amino acids (an increase in ASP by 2.38 times and GLU by 2.28 times) along with an increase in the level of the inhibitory amino acid GLI by 3.13 times only in intact rats was shown. Thus, in ETOH-exposed rats under the adaptive rearrangements in prolonged ethanol withdrawal, the neurochemical mechanisms of the hippocampus seem to be characterized by insensitivity to an acute Noopept administration. Animal neurochemical studies of changes in the mediator amino acids due to the long-term effect of alcohol on the CNS may be of practical importance for the development of optimal strategies and pharmacotherapy.

Unveiling the effects of exercise and protein diet on pancreatic structure in ovariectomized aged rats

Objective: Evaluate structural alterations of the pancreas in ovariectomized elderly female rats that ingested different animal or vegetable protein sources and who underwent moderate resistance exercise. Methods: Female Wistar rats were divided into eight experimental groups: sedentary and non-ovariectomized animals plus vegetable protein diet (CVS) or animal protein diet (CAS); trained and non-ovariectomized rats plus vegetable protein diet (CVT) or animal protein diet (CAT); sedentary and ovariectomized groups plus vegetable protein diet (VOS) or animal protein diet (AOS); trained and ovariectomized animals plus vegetable protein diet (VOT) or animal protein diet (AOT). Results: Our results showed a decrease in pancreatic islet area in sedentary groups submitted to ovariectomy. On the other hand, we observed an increased frequency of minor and medium pancreatic islets in vegetable and animal diets, respectively. Additionally, all groups had a significant difference in volume density of acini, ducts, blood vessels, and pancreatic islets. Finally, immunohistochemistry demonstrated a decrease of glucagon in sedentary ovariectomized groups and a decrease of insulin in ovariectomized groups submitted to resistance training. Conclusion: Both resistance training and dietary intake contributed to pancreatic modifications in estrogen-deprived groups. Accordingly, further studies are needed regarding the structural and functional properties involving both interventions and menopause for a better understanding of our results.

Abstract 4139176: SUMOylation of TP53INP1 Is Involved in miR-30a-5p-Regulated Heart Senescence

Introduction: During natural aging, physiological remodeling of the heart is a critical for the cardiovascular disease and heart failure. miR-30a-5p is related to kidney injury, cancer, and autoimmune diseases. However, whether miR-30a-5p has an effect in cardiac aging has yet to be explored. Hypothesis: This study aimed to characterize the role and mechanism of action of miR-30a-5p in cardiac senescence. Methods: We established miR-30a-5p knockout/overexpressing mouse model. Natural heart aging (18-months-old) and D-galactose-induced aging mouse model were established. The mechanism was explored in D-galactose- or 10-days-cultured cardiomyocytes. Results: miR-30a-5p was downregulated in aged mouse hearts and neonatal rat cardiomyocytes (NRCMs). In vivo, using a combination of echocardiography and different molecular biological approaches, we investigated the role of miR-30a-5p knockout or overexpressed mice on natural- or D-galactose-induced heart aging. In vitro, using RNA-sequence and a series of molecular biology, the mechanism of miR-30a-5p-regulated cardiac senescence was explored in cardiomyocytes. miR-30a-5p knockout mice showed aggravated natural- or D-galactose-induced heart aging compared to wild-type littermate mice, with significantly decreased heart function, increased number of γH2AX-positive cells, reduced telomere length, and upregulated p21 and p53 expression. Cardiac-specific knockdown of miR-30a-5p using adeno-associated virus 9 in D-galactose-induced senescent wild-type mice showed effects similar to those observed in knockout mice. Notably, overexpression of miR-30a-5p in wild-type murine hearts alleviated D-galactose-induced heart senescence by improving heart function, increasing telomere length, decreasing the number of γH2AX-positive cells, and downregulating p53 and p21 expression. This was confirmed in D-galactose-treated or naturally aged NRCMs. Mechanistically, TP53INP1 was identified as a target of miR-30a-5p by mediating the SUMOylation of TP53INP1 and its translocation from the cytoplasm to the nucleus to interact with p53. Further evidence demonstrated that cardiac-specific TP53INP1 deficiency ameliorates miR-30a-5p knockout-aggravated cardiac dysfunction and heart senescence. Conclusions: This study identified miR-30a-5p as a crucial modulator of heart senescence and revealed that the miR-30a-5p–TP53INP1–p53 axis is essential for heart and cardiomyocyte aging.

Caffeic Acid Attenuates Neuronal Apoptosis, Oxidative Stress, and Memory Deficits via Antioxidant Properties in Aging Rats Induced by D-Galactose.

Aging is a main factor related to cognitive deficits. D-Galactose (D-gal), a monosaccharide, increases oxidative stress leading to cellular senescence, memory deficits, and neuronal apoptosis. Caffeic acid (CA) is an antioxidant that can interrupt free radicals and reduce oxidative stress. The present study purposely evaluated the benefits of CA in attenuating loss of neuronal apoptosis, oxidative stress, and memory in D-gal-activated rat brain aging. Male Sprague-Dawley rats were arbitrarily allocated into 6 groups (9 rats per group). The D-gal group was intraperitoneal (i.p.) injected with D-gal (50mg/kg). The CA groups were orally given 20 or 40mg/kg CA for 8weeks. During that time, the co-treatment groups were given 50mg/kg of D-gal and 20 or 40mg/kg of CA. The results reveal that animals receiving only D-gal showed memory deficit in both the novel object location (NOL) and novel object recognition (NOR) tests. Reduction in scavenging enzyme activities and levels of B-cell lymphoma 2 (Bcl-2) protein expression were detected in the D-gal group. Furthermore, D-gal treatment significantly enhanced in the number of p21 positive cells in the subgranular zone (SGZ) of the hippocampal dentate gyrus, Bcl-2 associated X protein (Bax) and caspase3 protein expression, and malondialdehyde (MDA) levels. By contrast, both 20 and 40mg/kg CA treatment alleviated these effects. These consequences confirmed that D-gal-activated brain aging led to enhancing apoptotic protein expression including Bcl-2, Bax, and caspase3 and memory impairments. Nevertheless, CA attenuated these effects in brain aging induced by D-gal via antioxidant properties.

Olive oil protects against cardiac hypertrophy in D-galactose induced aging rats

BackgroundAged heart is defined via structural and mitochondrial dysfunction of the heart. However, there is still no potent compound to improve cardiac function abnormalities in aged individuals. Olive oil (OLO), as an oil with monounsaturated fatty acids, has diverse protective effects on the cardiovascular system, including anti-inflammatory, anti-diabetic, and mitigating effects on blood pressure. In the present study, we evaluated the protective effects of OLO against aging-related cardiac dysfunction.MethodsMale Wistar rats were randomly divided into three groups: Control, D-galactose-induced aging rats (D-GAL group), and aging rats treated with OLO (D-GAL + OLO group). Aging in rats was induced by intraperitoneal injection of D-GAL at 150 mg/kg dose for eight weeks and the D-GAL + OLO group was treated with oral OLO by gavage for eight weeks. The heart tissues were harvested to assay the oxidative stress, molecular parameters, and histological analysis.ResultsThe D-GAL given rats indicated increased cardiomyocyte diameter as cardiac hypertrophy marker (21 ± 0.8, p < 0.001), an increased Malondialdehyde (MDA) level (27 ± 3, p < 0.001), a reduced Superoxide dismutase (SOD) (p < 0.001, 18.12 ± 1.3), and reduction in gene expression of Sirtuin 1 (SIRT1) (p < 0.05, 0.37 ± 0.06), Peroxisome proliferator-activated receptor-gamma coactivator (PGC)-1α (p < 0.001, 0.027 ± 0.04), and Transcription Factor A, Mitochondrial (TFAM) (p < 0.001, 0.023 ± 0.01), Bcl2 (p < 0.001, 0.04 ± 0.004) and an increase in gene expression of Bax (p < 0.001, 23.5 ± 5.4) in comparison with the control animals. Treatment with OLO improved cardiac hypertrophy (14 ± 0.4, p < 0.001), MDA (22 ± 2.5, p < 0.01), SOD (p < 0.001, 34.9 ± 2), SIRT1 (p < 0.05, 1.37 ± 0.46), PGC-1α (p < 0.001, 1.11 ± 0.1), TFAM (p < 0.01, 0.23 ± 0.02), Bcl2 (p < 0.05, 0.35 ± 0.05) and Bax genes (p < 0.01, 0.1 ± 0.03).ConclusionsOverall, OLO protects the heart against D-GAL-induced aging via increasing antioxidant effects, and enhancing cardiac expression of SIRT1, PGC-1α, TFAM, Bcl2 and Bax genes.Graphical

Does age protect against loss of tonotopy after acute deafness in adulthood?

The mammalian auditory system develops a topographical representation of sound frequencies along its pathways, also called tonotopy. In contrast, sensory deprivation during early development results in no or only rudimentary tonotopic organization. This study addresses two questions: (1) How robust is the central tonotopy when hearing fails in adulthood? (2) What role does age play at time of deafness? To address these questions, we deafened young and old adult rats with previously normal hearing. One month after deafening, both groups were unilaterally supplied with cochlear implants and electrically stimulated for 2 h. The central auditory neurons, which were activated as a result of the local electrical intracochlear stimulation, were visualized using Fos staining. While the auditory system of young rats lost the tonotopic organization throughout the brainstem, the auditory system of the older rats mainly sustained its tonotopy. It can be proposed that plasticity prevails in the central auditory system of young adult rats, while network stability prevails in the brains of aging rats. Consequently, age may be an important factor in protecting a hearing-experienced adult auditory system from a rapid loss of tonotopy when suffering from acute hearing loss. Furthermore, the study provides compelling evidence that acute deafness in young adult patients should be diagnosed as early as possible to prevent maladaptation of the central auditory system and thus achieve the optimal hearing outcome with a hearing prosthesis.

Aging-related NADPH diaphorase positive neurodegenerations in the sacral spinal cord of aged non-human primates

Nicotinamide adenine dinucleotide phosphate-diaphorase (NADPH-d) was used to detect neurodegenerations in aged monkeys. Our previous studies have shown that aging-related NADPH-d positive bodies (ANBs) and megaloneurites appeared in the lumbosacral spinal cord of aged rats and dogs, respectively. To determine the occurrence of megaloneurites and ANBs in non-human primates, we used NADPH-d histochemistry to perform an advanced study of aging-related alterations in aged male monkeys. We identified two distinct abnormal NADPH-d positive alterations, which were expressed as ANBs and megaloneurites, mainly distributed in the superficial dorsal horn, dorsal gray commissure, lateral collateral pathway (LCP) and sacral parasympathetic nucleus of the sacral spinal cord in aged monkeys. Meanwhile, large diameter punctate NADPH-d abnormalities occurred and scattered in the lateral white matter of the LCP and dorsal root entry zone at the same level of megaloneurites in the gray matter. Immunohistochemical results showed that megaloneurites and ANBs are two distinct abnormal alterations, with megaloneurites co-localizing with vasoactive intestinal peptide immunoreactivity, whereas ANBs were not co-localized. Both ANBs and megaloneurites provide consistent evidence that the anomalous NADPH-d alterations in the aged sacral spinal cord are referred to as a specialized aging marker in the pelvic visceral organs in non-human primates.

SUMOylation of TP53INP1 is involved in miR-30a-5p-regulated heart senescence.

Heart senescence is critical for cardiac function. This study aimed to characterize the role and mechanism of action of miR-30a-5p in cardiac senescence. miR-30a-5p was downregulated in aged mouse hearts and neonatal rat cardiomyocytes (NRCMs). In vivo, using a combination of echocardiography and different molecular biological approaches, we investigated the role of miR-30a-5p knockout or overexpression in natural- or D-galactose-induced heart aging in mice. In vitro, using RNA sequencing and a series of molecular biology methods, the mechanism by which miR-30a-5p regulates cardiac senescence was explored in cardiomyocytes. miR-30a-5p knockout mice showed aggravated natural- or D-galactose-induced heart aging compared to wild-type littermate mice, with significantly decreased heart function, an increased number of γH2AX-positive cells, reduced telomere length, and upregulated p21 and p53 expression. Cardiac-specific knockdown of miR-30a-5p using adeno-associated virus 9 in D-galactose-induced senescent wild-type mice resulted in effects similar to those observed in knockout mice. Notably, the overexpression of miR-30a-5p in wild-type murine hearts alleviated D-galactose-induced heart senescence by improving heart function, increasing telomere length, decreasing the number of γH2AX-positive cells, and downregulating p53 and p21 expression. This was confirmed in D-galactose-treated or naturally aged NRCMs. Mechanistically, TP53INP1 was identified as a target of miR-30a-5p by mediating the SUMOylation of TP53INP1 and its translocation from the cytoplasm to the nucleus to interact with p53. Furthermore, this study demonstrated that cardiac-specific TP53INP1 deficiency ameliorates miR-30a-5p knockout-aggravated cardiac dysfunction and heart senescence. This study identified miR-30a-5p as a crucial modulator of heart senescence and revealed that the miR-30a-5p-TP53INP1-p53 axis is essential for heart and cardiomyocyte aging.

Sildenafil citrate induces prostatic hyperplasia in BPH model rats and aged rats

Erectile dysfunction (ED), a prevalent disease among middle-aged and elderly males, significantly impacts both patient and partner quality of life. Phosphodiesterase type 5 inhibitor (PDE5i) represents an effective therapeutic method for ED. Given their widespread global utilization, concerns arise regarding potential reproduction-related problems arising from clinical use. During the extensive development of PDE5i, we speculated that the potential of these inhibitors to variably induce prostatic hyperplasia, but this field remains unexplored. In order to verify the male reproductive toxicity of PDE5i, sildenafil citrate at doses of 5, 10 and 20 mg/kg was administered in BPH model rats and aged rats. Anatomical and pathological analyses indicate a compelling association between sildenafil citrate administration and the promotion of prostatic hyperplasia in both BPH model rats and aged rats. Serum analysis showed that serum prostate-binding protein (PBP) exhibited a non-significant but increasing trend following administration of sildenafil citrate to BPH model rats. Furthermore, significant increase in serum levels of E2 and T, as well as T in dorsal lobe prostate tissue of aged rats, were observed compared to the model control group. These results confirm the hypothesis that sildenafil citrate has reproductive toxicity in males.

Alterations in the transcriptome and microRNAs of adipose-derived mesenchymal stem cells from different sites in rats during aging.

Aging is an intricate and gradual process characterized by tissue and cellular dysfunction. Adipose-derived mesenchymal stem cells (ADMSCs) experience a functional decline as part of systemic aging. However, the alterations in ADMSCs across various anatomical sites throughout an individual's lifespan remain unclear. To shed light on these changes, we collected white adipose tissue and brown adipose tissue samples from the epididymis, perirenal, inguinal, and scapular regions of young, adult, and aged rats and subsequently isolated ADMSCs for RNA sequencing. As aging progressed, we observed a reduction in the number of ADMSCs at all anatomical sites. Marker genes of ADMSCs from different sites were identified. Aging triggered notable activation of inflammatory and immune responses while diminishing the ADMSC differentiation capacity and ability to maintain normal tissue morphology. Furthermore, miR-195-5p and miR-497-3p, which promoted cell senescence and apoptosis while inhibiting proliferation and differentiation, were positively correlated with aging. These findings increase our understanding of ADMSC senescence and underscore the unique physiological changes and functions of ADMSCs across different anatomical sites during aging.

Oral Toxicity and Hypotensive Influence of Sericin-Derived Oligopeptides (SDOs) from Yellow Silk Cocoons of Bombyx mori in Rodent Studies.

Sericin-derived oligopeptides (SDOs) from yellow silk cocoons exhibit antihypertensive and hypoglycemic properties in both in vitro and in vivo studies. This study investigated the acute toxicity of SDOs as a novel food for human consumption using female ICR mice and Wistar rats, as well as the chronic toxicity test on both sexes of Wistar rats. Clinical chemistry, hematology, and histopathological studies revealed that SDOs were safe for a single dose of 2000 mg kg-1 body weight (BW) and daily oral administration of 50, 100, and 200 mg kg-1 BW for six months. The chronic toxicity study additionally measured the rats' systolic blood pressure (SBP) and blood sugar monthly as they slowly aged. In the 2nd month for male rats and the 4th month for both sexes, SDOs had a significant hypotensive effect on Wistar rats' blood pressure, lowering it from 130 mmHg to a plateau at 110-115 mmHg. In contrast, the blood pressure of the control rats exceeded 140 mmHg after five months. Nonetheless, the hypoglycemic effect was not observed. Measurements of SBP and blood glucose in aged rats during chronic toxicity tests yielded insights beyond ordinary toxicity, including the health and fitness of the lab rats, perhaps resulting in novel discoveries or areas of study that justify the sacrifice of the animals' lives.

Wnt3a-induced LRP6 phosphorylation enhances osteoblast differentiation to alleviate osteoporosis through activation of mTORC1/β-catenin signaling

ObjectiveOsteoporosis (OP) is a common cause of morbidity and mortality in older individuals. The importance of Wnt3a in osteogenic activity and bone tissue homeostasis is well known. Here, we explored the possible molecular mechanism by which Wnt3a mediates the LRP6/mTORC1/β-catenin axis to regulate osteoblast differentiation in OP. MethodsOP-related key genes were identified through a bioinformatics analysis. A ROS17/2.8 cell differentiation system for rat osteogenic progenitors and a rat model of senile OP were constructed for in vitro and in vivo mechanism verification. ResultsBioinformatics analysis revealed that LRP6 was poorly expressed in OP and may play a key role in the occurrence of OP by affecting osteoblast differentiation. LRP6 knockdown inhibited osteoblast differentiation in an in vitro model. In addition, Wnt3a promoted osteoblast differentiation by inducing LRP6 phosphorylation. Moreover, LRP6 promoted mTORC1 expression, which indirectly promoted β-catenin expression, thus promoting osteoblast differentiation. Finally, an in vivo assay revealed that LRP6 inhibition improved OP. ConclusionOur study provides evidence that Wnt3a induces phosphorylation of LRP6 to activate the mTORC1/β-catenin axis, thus promoting osteoblast differentiation and ultimately improving OP in aged rats.

Bioactive fraction of Musa balbisiana seed mitigates D-galactose-induced brain aging via SIRT1/PGC-1α/FoxO3a activation and intestinal barrier dysfunction by modulating gut microbiota and core metabolites

Aging is an inevitable biological process, and emerging research has highlighted the potential of dietary and pharmacological interventions to decelerate the trajectory of age-related diseases and prolong the health span. This study evaluates the protective effects of Musa balbisiana seed on healthy aging using D-galactose-induced accelerated aging rats. The results suggested that the bioactive ethyl acetate fraction of Musa balbisiana seed extract (BF) exhibited protective effects against aging-induced oxidative stress by reducing oxidative DNA damage, advanced glycation end-product formation, and malondialdehyde levels while restoring antioxidant and glyoxalase enzyme activities. BF also ameliorated neurodegeneration by decreasing acetylcholinesterase enzyme activity and amyloid beta plaque formation. Histopathological analysis demonstrated the protective effects of BF against brain aging, liver disruption, renal damage, and intestinal barrier dysfunction. BF further restored intestinal permeability by upregulating the tight junctions (zonula occludens 1 and 2, claudin 1,2,3 and 4, and occludin) and mucin (mucin 2 and mucin 5ac) gene expression while downregulating the expression of inflammatory cytokines (IL-1β, IL-6, and TNF-α). BF significantly induced the phosphorylation of FoxO3a proteins and upregulated the gene expression of SIRT1, PGC-1α, and TFAM in the hippocampus. Next-generation sequencing (NGS) of 16s rRNA amplicons of fecal metagenomics DNA and metabolites profiling showed that BF intervention restructured the gut microbiota and altered core metabolites related to cholesterol metabolism. Overall, our findings demonstrated the multifaceted protective effects of Musa balbisiana seed against D-galactose-induced aging.

Spermidine attenuates left ventricular dysfunction in estrogen deprived aging rats through mitigating lipid peroxidation and mitochondrial dysfunction

Abstract Background Aging women with postmenopause are particularly susceptible to cardiovascular diseases (CVDs), which are associated with the elevation of oxidative stress and mitochondrial dysfunction. Although hormone replacement therapy (HRT) has been reported to provide cardiometabolic protection, long-term HRT could be linked to CVD consequences. A novel organic therapy with spermidine has shown promise as cardioprotection in several CVDs. However, the effects of spermidine on left ventricular (LV) function, mitochondrial function and oxidative stress in estrogen-deprived aging rats have not been investigated. Purpose To evaluate the effects of spermidine on LV function, mitochondrial function and oxidative stress in estrogen-deprived and D-galactose-induced aging rats Methods Twenty female Wistar rats were randomly assigned to the sham and the ovariectomy (OVX) along with D-galactose (150 mg/kg/day, s.c.) administration throughout the experiment for 12 weeks. OVX with D-galactose-treated rats were divided into three interventional groups: vehicle (ODV), spermidine (20 mg/kg/day, p.o., ODS), and estradiol (50 ug/kg/day, s.c., ODE) (n=5/group) for 8 weeks. The sham group received a vehicle (SVV, n=5). At the end, all rats underwent echocardiography, followed by euthanasia. The hearts were removed for measuring mitochondrial reactive oxygen species (ROS), mitochondrial membrane potential (MMP) changes (ΔΨm), and malondialdehyde (MDA) levels. Results Rats with OVX-induced estrogen deprivation with D-galactose-induced aging had LV impairments indicated by decreased LV ejection fraction, reduced ratio of peak velocity blood flow from left ventricular relaxation in early diastole (E) to peak velocity flow by atrial contraction (A), and increased sympathovagal imbalance (elevated low/high frequency (LF/HF) ratio) (Fig. 1A-C). These estrogen-deprived aging rats also had an increase in cardiac tissue MDA levels, mitochondrial ROS production, and MMP depolarization (Fig. 1D-F). Both spermidine and estrogen similarly demonstrated a significant reduction in all of those detrimental effects, leading to improved LV function (Fig. 1A-F). Conclusion Spermidine exerted cardioprotection comparable to estrogen supplement through mitigating oxidative stress and mitochondrial impairments in cardiac tissue, resulting in improved LV dysfunction and cardiac autonomic balance due to estrogen deprived aging conditions in rats. These findings suggest that spermidine administration could be a promising strategy for cardioprotection in postmenopausal women with aging.

New Insights on the Effects of Krill Oil Supplementation, a High-Fat Diet, and Aging on Hippocampal-Dependent Memory, Neuroinflammation, Synaptic Density, and Neurogenesis.

Krill oil (KO) has been described as having the potential to ameliorate the detrimental consequences of a high-fat diet (HFD) on the aging brain, though the magnitude and mechanism of this benefit is unclear. We thus hypothesized that dietary KO supplementation could counteract the effects of cognitive aging and an HFD on spatial learning, neuroinflammation, neurogenesis, and synaptic density in the cortex and hippocampus of aged rats. Sixteen-month-old Sprague Dawley rats were fed for 12 weeks while being divided into four groups: control (CON); control with KO supplementation (CONKO); high-fat diet (HF); and high-fat diet with KO supplementation (HFKO). We measured food consumption, body mass, spatial memory (Morris water maze), microglia, neurogenesis, cytokine concentrations, and synaptic markers (post-synaptic density-95 and synaptophysin). Predictably, an HFD did induce significant differences in body weights, with the high-fat groups gaining more weight than the low-fat controls. However, KO supplementation did not produce significant changes in the other quantified parameters. Our results demonstrate that the dietary KO dose provided in the current study does not benefit hippocampal or cortical functions in an aging model. Our results provide a benchmark for future dosing protocols that may eventually prove to be beneficial.