Aged Rats Research Articles

Abstract TP362: Estrogen Receptor-Beta Activation Reduces Cognitive Deficits After Stroke in Middle-Aged Female Rats

Introduction: Menopause increases the risk and severity of ischemic stroke (IS), while endogenous 17β-estradiol (E2) naturally protects premenopausal women against IS. The female sex hormone E2 is a potent neuro- and cognitive-protective agent. Studies have shown that periodic E2 or estrogen receptor subtype-beta (ER-β) agonist pre-treatments every 48 hours before an ischemic episode ameliorated ischemic brain damage in young ovariectomized or reproductively senescent (RS) aged female rats. The current study investigates the underlying mechanism of ER-β agonist-mediated neuroprotection. Methods: Retired breeder (9–10 months) Sprague–Dawley female rats were considered RS after remaining in constant diestrus phase for more than a month. The RS rats were exposed to transient middle cerebral artery occlusion (tMCAO; 90 mins) and treated with either ER-β agonist (beta 2, 3-bis(4-hydroxyphenyl) propionitrile; DPN; 1 mg/kg; s.c.) or DMSO vehicle at 4.5 hours after induction of tMCAO. Subsequently, rats were treated with either ER-β agonist or DMSO vehicle every 48 hours (48-h) for ten injections. Forty-eight hours after the last treatment, animals were tested for cognitive deficits via the Morris water maze. At 1-month post-tMCAO, brains were collected for histopathological analysis. A second cohort of RS rats underwent DPN or DMSO treatment for a month; 48-h after last injection, brains were collected for unbiased global metabolomic analysis (conducted by Metabolon Inc.). The metabolomic study was complemented with western blot analysis and enzyme activity measurements of key altered pathways. Results: Data showed significant (p<0.05) decreases in glucose-6-phosphate and increases in 5-phosphyribosyl diphosphate, UDP-galactose, and N-acetylglucoseamine-6-phosphate in the brain of DPN-treated RS female rats as compared to DMSO-treated controls. DPN treatment also changes the enzymatic activity of glycolytic rate limiting enzyme hexokinase. Metabolomics data also showed significant increase in choline and arginine levels in the brain of DPN-treated RS female rats as compared to DMSO-treated controls. Conclusion: The observed changes in glycolytic and amino acid pathway metabolites could enhance brain energy metabolism and increase choline availability, potentially contributing to the improved post-stroke cognitive outcomes in RS rats.

Aberrant expression of messenger and small noncoding RNAomes in aged skin of rats.

The exact mechanisms and key functional molecules involved in skin ageing remain largely unknown. Studies linking the expression of messenger RNAs (mRNAs) and small noncoding RNAs (sncRNAs) to skin ageing are limited. In this study, we performed RNA sequencing to assess the effects of ageing on the expression of mRNAs and sncRNAs in rat skin. Our results revealed that 241 mRNAs, 109 microRNAs (miRNAs), 20 piwi-interacting RNAs (piRNAs), 45 small nucleolar RNAs (snoRNAs), and 7 small nuclear RNAs (snRNAs) were significantly differentially expressed in the skin of aged rats compared to their younger counterparts. Histological validation using RT-qPCR further verified the significant differential expression of 13 mRNAs, 7 miRNAs, 2 piRNAs, 15 snoRNAs, and 1 snRNA. Additionally, several sncRNAs showed differential expression across various tissues, suggesting that they may have broad correlations with ageing. After establishing cellular senescence in skin fibroblasts, we identified 4 mRNAs, 4 miRNAs, and 10 snoRNAs that may mediate skin ageing by modulating fibroblast senescence. Notably, overexpression or knockdown of some differentially expressed RNAs in fibroblasts influenced cellular senescence, indicating that these RNAs could play an important role in the skin ageing process. These findings highlight their potential significance for future treatments of age-related skin disorders.

Effect of Curcumin on Cognitive Impairment in Aged Female Wistar Rats Subjected to Intestinal Ischemia-reperfusion Injury

Cognitive deficit, more common with age, it affects memory and cognitive functions. Intestinal ischemia-reperfusion injury (IIRI) causes systemic inflammation that can damage the brain, particularly the hippocampus. Curcumin, an active ingredient found in turmeric have neuroprotective properties. The aim of this study is to investigate the effect of curcumin on intestinal ischemia reperfusion injury induced-cognitive deficit in aged female Wistar rats. Forty female Wistar rats between 200-250 kg were used in this study, they were weighed and randomly divided into four groups n=10. The animals pretreated with 100 mg/kg for twenty-one days prior to surgical induction of ischemia for two hours followed by reperfusion which lasted for twenty-one days. After twenty-one days, behavioral assessment was done to investigate the behavioral functions. Animals were sacrificed and the brain was harvested, the hippocampus was isolated for biochemical and histological assessment. Data were analyzed using one-way ANOVA followed by Tukey's post hoc test with statistical significance set at p<0.05. The result shows that there was decrease in ability of the rats to recognize novel objects in IIRI groups but was improved curcumin treated groups. There was a reduction in the neurotransmitter level (AchE, Serotonin and Dopamine) in IIRI groups which was revered in the CUR+IIRI groups (p<0.001). Inflammatory markers (TNF-α, MPO) were also significantly reduced in CUR+IIRI group when compared to IIRI group (p<0.001). Histological assessment shows that curcumin preserved hippocampal architecture, whereby reducing IIRI-induced cognitive deficit in aged female Wistar rats. This study showed that curcumin demonstrates significant neuroprotective effects against IIRI-induced Cognitive deficit.

PIK3R3 regulates differentiation and senescence of periodontal ligament stem cells and mitigates age-related alveolar bone loss by modulating FOXO1 expression.

Periodontal diseases are prevalent among middle-aged and elderly individuals. There's still no satisfactory solution for tooth loss caused by periodontal diseases. Human periodontal ligament stem cells (hPDLSCs) is a distinctive subgroup of mesenchymal stem cells, which play a crucial role in periodontal supportive tissues, but their application value hasn't been fully explored yet. As a regulatory subunit of PI3K, PIK3R3's role in stem cell regulation remains poorly comprehended. This study aims to explore the regulatory effect of PIK3R3 on differentiation and senescence of hPDLSCs and the underlying mechanism, as well as whether overexpression of PIK3R3 mitigate alveolar bone loss in aged rats. Human PDLSC lines with both PIK3R3 knockdown and overexpression are established. Osteogenic, adipogenic, chondrogenic and senescent induction are used to test the effect of PIK3R3 on senescence in vitro. Model of alveolar bone loss in aged mice is used to reveal the effect of PIK3R3 in vivo. FOXO1 siRNA is used for mechanism exploration. Knockdown of PIK3R3 inhibits the mRNA and protein expression of markers in osteogenic, adipogenic, and chondrogenic differentiation of hPDLSCs but promotes in vitro senescence of hPDLSCs, including cell proliferation, senescence markers expression, telomerase density and reactive oxygen species. Overexpression of PIK3R3 has the opposite effect. Furthermore, the result of Micro-CT and tissue section shows that overexpression of PIK3R3 in elder rats mitigates alveolar bone loss. Mechanistically, PIK3R3 regulates senescence of hPDLSCs through modulating FOXO1 expression. Expression of FOXO1 is altered when PIK3R3 is knocked down or overexpressed in senescent medium. Knockdown of FOXO1 promotes senescence of hPDLSCs and the senescence promoting effect of knocking down PIK3R3 is weakened when FOXO1 is highly expressed. These findings indicate that PIK3R3 modulates senescence of MSCs by regulating FOXO1 expression and shows promise as a therapeutic target for mitigating age-related alveolar bone loss.

18F]BCPP-EF positron emission tomography of rat ovaries for evaluation of mitochondrial function.

The ovary is an important female organ not only for pregnancy but also for the regulation of life activities via hormone release. Ovarian function is measured by blood hormone levels, but the hormone level reflects only the ovarian reserve and no other essential ovarian functions, such as nurturing and expelling follicles. Ovarian fibrosis is related to essential ovarian function; however, the existing methods for evaluating fibrosis are invasive. Ovarian fibrosis has been reported to be associated with mitochondrial function. We hypothesized that positron emission tomography (PET) imaging of mitochondria could be a new, non-invasive method for evaluating essential ovarian function. In this study, we investigated the age-related changes in ovarian fibrosis using the mitochondrial complex-I (MC-I) PET probe, 2-tert-butyl-4-chloro-5-{6-[2-(2-18F-fluoroethoxy)-ethoxy]-pyridin-3-ylmethoxy}-2H-pyridazin-3-one ([18F]BCPP-EF). Aged rats, whose ovary function decline, exhibited a higher uptake of [18F]BCPP-EF in the ovary than young rats, and this high uptake in aged rats was suppressed by mitoquinone, a superoxide scavenger. Increased [18F]BCPP-EF uptake in the ovary was associated with ovarian fibrosis, but not with AMH level which reflects the ovarian reserve. Furthermore, the measurement of MC protein levels showed that the protein levels of MC-I increased with age, whereas those of MC-V decreased. This study demonstrated that [18F]BCPP-EF can detect age-related changes in essential ovarian function evaluated by ovarian fibrosis. Therefore, [18F]BCPP-EF-PET is a useful non-invasive method for evaluating essential ovarian functions and will contribute to basic research on ovarian aging as well as drug discovery targeting ovarian dysfunction.

Cannabidiol as prophylactic treatment for intestinal ischaemia reperfusion injury in elderly rats

Abstract Introduction The deprivation of blood supply to an intestinal segment, followed by its subsequent restoration, triggers the condition known as intestinal ischaemia-reperfusion syndrome (i-IRI). Throughout this process, proinflammatory and oxidative mediators are produced, released, and distributed via the bloodstream, ultimately causing damage both locally and systemically. Cannabidiol (CBD) is a molecule with antioxidant and anti-inflammatory properties that regulate oxidative stress and inflammatory states. The aim of this study is to evaluate the therapeutic potential of CBD in a model of i-IRI in aged rats. Methods Thirty-six 12-month-old male WAG/RijHsd rats were used, divided into three groups: healthy control group (control), untreated i-IRI group (i-IRI), and CBD-treated i-IRI group (CBD). CBD (10 mg/kg) was administered via the femoral route 30 minutes before reperfusion. Blood samples and intestinal biopsies were taken from six animals in each group, while the other six animals underwent the D-xylose absorption test to evaluate intestinal absorptive function. Results Treatment with CBD significantly reduced the degree of histological injury (DHI) compared to the untreated group (1.78 ± 1.23 vs. 4.5 ± 0.56; p<0.001). It also improved intestinal absorptive function (control group: 2.08 ± 0.16; untreated: 0.96 ± 0.06; CBD: 1.74 ± 0.06 µg/mL; p<0.001). Conclusion The administration of CBD prior to the restoration of the ischaemic insult was effective in reducing damage to the intestinal mucosa and improving absorptive capacity.

Lateral hypothalamic area high-frequency deep brain stimulation rescues memory decline in aged rat: behavioral, molecular, and electrophysiological study.

To examine the effect of DBS of the lateral hypothalamic area (LHA) on age-related memory changes, neuronal firing from CA1, oxidative stress, and the expression of Hsp70, BDNF, and synaptophysin. 72 male rats were randomly allocated into 6 equal groups: a) normal young group (8 W), b) sham young group, c) DBS young group, d) normal old group (24months), e) sham old group and f) DBS old group. Memory tests (passive avoidance and Y maze), oxidative stress markers (MDA, catalase, and GSH) and expression of Nrf2, HO-1, Hsp70, BDNF, and synaptophysin were measured by the end of the experiment. Also, in vivo recording of the neuronal firing of the CA1 region in the hippocampus was done. Old rats show significant decline in memories, antioxidant genes (Nrf2 and HO-1), antioxidants (GSH and catalase), Hsp70, BDNF, and synaptophysin with significant increase in MDA in hippocampus (p < 0.05) and DBS for LHA caused a significant improvement in memories in old rats, with significant rise in fast gamma and theta waves in CA1 region in old rats (p < 0.05). This was associated with a significant increase in antioxidants (GSH and CAT), antioxidant genes (Nrf2, HO-1), Hsp70, BDNF, and synaptophysin with significant reduction in MDA in hippocampus (p < 0.05). DBS for LHA ameliorates the age-induced memory decline. This might be due to increase in fast gamma in CA1, attenuation of oxidative stress, upregulation of Nrf2, HO-1, Hsp70, BDNF, and synaptophysin in the hippocampus.

The effect of three types of water-based training protocols on thymus atrophy and specific indicators of cellular immune senescence in aged male rats

The collective detrimental impact of aged naive lymphocytes and thymus atrophy on the aging of the immune system can be mitigated by exercise. Hence, this research aims to explore the effects of three methods of water-based exercises on immune system aging and thymus atrophy in elderly rats. Thirty-two 24-month-old rats, with an average weight of 320 ± 5 g, were randomly allocated into four groups of endurance training (n = 8), resistance training (n = 8), combined training (n = 8), and control (n = 8).The training protocols (10 weeks) were conducted four times a week in a container measuring 50 × 50x100 cm filled with water at 30 ± 1 °C. The evaluation of naïve and memory T lymphocytes was conducted for the intervention groups based on the expression or lack of expression of the CD28 and CD57 markers in the subsets of CD4 + and CD8 + T cells. Naïve T cells were represented by CD28 + CD57- T lymphocytes, memory T cells were represented by CD28- CD57- T lymphocytes, aged naïve T cells were indicated by CD28 + CD57 + lymphocytes, and aged memory T cells were represented by CD28- CD57 + lymphocytes. The findings of the study showed that all three exercise protocols resulted in a significant decrease in levels of memory CD8, aged CD8, naive and naive CD4 and CD8, and aged memory, as well as an increase in levels of CD4, CD8, CD4 + , and naive CD8 when compared to the control group. It was observed that thymus atrophy, memory CD4, and aged CD4 had a significant decrease only in the combined exercise group compared to the control group, with no significant differences observed in these indicators for the resistance and endurance groups. Furthermore, the ratio of CD4 to CD8 remained unchanged across all groups. The findings of this study suggest greater efficacy of combined training in enhancing specific health indicators of cell immunity among elderly populations. Moreover, engaging in water exercises of all three types of combined, resistance, and endurance training are deemed safe activities for older individuals to bolster their immune system and mitigate the aging process of T cells.

Youthful Stem Cell Microenvironments: Rejuvenating Aged Bone Repair Through Mitochondrial Homeostasis Remodeling.

Extracellularmatrix (ECM) derived from mesenchymal stem cells regulates antioxidant properties and bone metabolism by providing a favorable extracellular microenvironment. However, its functional role and molecular mechanism in mitochondrial function regulation and aged bone regeneration remain insufficiently elucidated. This proteomic analysis has revealed a greater abundance of proteins supporting mitochondrial function in the young ECM (Y-ECM) secreted by young bone marrow-derived mesenchymal stem cells (BMMSCs) compared to the aged ECM (A-ECM). Further studies demonstrate that Y-ECM significantly rejuvenates mitochondrial energy metabolism in adult BMMSCs (A-BMMSCs) through the promotion of mitochondrial respiratory functions and amelioration of oxidative stress. A-BMMSCs cultured on Y-ECM exhibited enhanced multi-lineage differentiation potentials in vitro and ectopic bone formation in vivo. Mechanistically, silencing of silent information regulator type 3 (SIRT3) gene abolished the protective impact of Y-ECM on A-BMMSCs. Notably, a novel composite biomaterial combining hyaluronic acid methacrylate hydrogel microspheres with Y-ECM is developed, which yielded substantial improvements in the healing of bone defects in an aged rat model. Collectively, these findings underscore the pivotal role of Y-ECM in maintaining mitochondrial redox homeostasis and present a promising therapeutic strategy for the repair of aged bone defects.

Ergothioneine improves healthspan of aged animals by enhancing cGPDH activity through CSE-dependent persulfidation.

Ergothioneine (ET), a dietary thione/thiol, is receiving growing attention for its possible benefits in healthy aging and metabolic resilience. Our study investigates ET's effects on healthspan in aged animals, revealing lifespan extension and enhanced mobility in Caenorhabditis elegans, accompanied by improved stress resistance and reduced age-associated biomarkers. In aged rats, ET administration enhances exercise endurance, muscle mass, and vascularization, concomitant with higher NAD+ levels in muscle. Mechanistically, ET acts as an alternative substrate for cystathionine gamma-lyase (CSE), stimulating H2S production, which increases protein persulfidation of more than 300 protein targets. Among these, protein-persulfidation-driven activation of cytosolic glycerol-3-phosphate dehydrogenase (cGPDH) primarily contributes to the ET-induced NAD+ increase. ET's effects are abolished in models lacking CSE or cGPDH, highlighting the essential role of H2S signaling and protein persulfidation. These findings elucidate ET's multifaceted actions andprovide insights into its therapeutic potential for combating age-related muscle decline and metabolic perturbations.

Synergistic Effects of Cordyceps militaris and Alpha-lipoic Acid on Brain Disorders Associated with Age-dependent Oxidative Stress

Background Oxidative stress is the primary factor responsible for the development of neuroinflammation and brain deficits. As aging occurs, the chances of oxidative stress increase due to lifestyle modification, environmental, and genetic factors. The brain is especially susceptible to oxidative damage because of its elevated oxygen consumption, lipid composition, and comparatively inadequate antioxidant defenses. Oxidative stress associated with aging results in DNA damage, mitochondrial dysfunction, and compromised repair mechanisms. Purpose To investigate the efficacy of Cordyceps militaris extract (CME) and alpha-lipoic acid (ALA) in mitigating oxidative stress and neuroinflammation in aged rats and to assess their potential therapeutic effects on cognitive performance, antioxidant enzyme activity, and oxidative stress markers. Methods This study involved using aged rats to evaluate the impact of CME and ALA on oxidative stress and neuroinflammation. The rats were administered CME and ALA, and various assessments were conducted to measure cognitive performance, antioxidant enzyme activity, and oxidative stress markers. Results The administration of CME and ALA to aged rats significantly improved cognitive performance. Additionally, there were an enhancement in antioxidant enzyme activity and a reduction in oxidative stress markers. These findings indicate that both CME and ALA positively mitigate oxidative stress and neuroinflammation. Conclusion CME extract and ALA exhibit therapeutic potential in treating aging-related oxidative stress and inflammation. Their use could be beneficial in combating brain disorders caused by aging, highlighting their importance in the field of geriatric healthcare.

Age-dependent increase in apoptosis is associated with dysregulation of miR-92a/Akt/mTOR and NF-κB signaling pathways in male rats.

Brain aging is the leading risk factor for most neurodegenerative diseases and has been linked with high rates of neuron loss. Thus, identifying molecular mechanisms underlying neuron loss and pharmacological modulation may be of great importance for slowing or preventing age-related diseases. Herein, we investigated the roles of miR-92a, Akt, mTOR, and NF-κB in age-associated apoptosis in the hippocampus (a critical structure involved in brain aging) of male rats alone and in combination with prazosin. Twenty-four male Wistar rats were grouped into young control (3-month-old), aged (18-month-old), and aged + prazosin groups (n = 8 for each). Prazosin (1 mg/kg; i.p.) was administered for 4 weeks to aged rats. Apoptosis was detected by TUNEL staining. Western blot for Akt, mTOR, and NF-κB was conducted. miR-92a gene expression was performed by using RT-PCR. The results indicated a marked enhancement of apoptosis in the aging hippocampus. We also detected substantial up-regulation of NF-κB as well as substantial down-regulation of phosphorylated-Akt and mTOR in the aging hippocampus. Moreover, miR-92a gene expression was markedly reduced in the aging hippocampus. Treatment with prazosin significantly suppressed apoptosis and reversed miR-92a gene expression, as well as Akt, mTOR, and NF-κB protein expressions in the aging hippocampus. Considering the NF-κB regulatory role on miRNAs, our results suggest that NF-κB may be a negative transcriptional regulator of miR-92a, which in turn could regulate the Akt/mTOR signaling. In this regard, NF-κB upregulation may mediate the downregulation of miR-92a/Akt/mTOR axis, and thereby contribute to age-related neurodegeneration. This may provide a novel treatment target for delaying or preventing age-related problems.

Chronic moderate‑intensity exercise can induce physiological hypertrophy in aged cardiomyocytes through autophagy, with minimal Yap/Taz involvement.

Aging is known to cause increased comorbidities associated with cardiovascular decline. Physical exercises were known to be an effective intervention for the age-associated decline in cardiac function. Exercise caused physiological hypertrophy influenced by Yap/Taz, autophagy and myosin heavy chain (MHC) dynamics. However, whether exercise-induced changes are associated with aging has yet to be determined. The present study explored the effects of moderate-intensity exercises on autophagy, MHC dynamics, and Yap/Taz activity to understand their complex interactions at the molecular effects on the cardiac function of aging cardiac tissue. The present study used male Wistar (Rattus norvegicus) rats (80 weeks-old) randomly divided into two groups (n=12): control and intervention. The intervention group was given an intervention using an animal treadmill. After 8 weeks, the animal was sacrificed, and data were collected. Statistical analysis was conducted using an independent t-test or Mann-Whitney U test when appropriate. Exercise in aged rats can induce physiological hypertrophy, as shown by gross measurement and histological features. Yap/Taz did not mediate the effects of exercise on hypertrophy. Autophagy function was shown to increase, which may cause the low expression of Yap/Taz. In conclusion, exercise is a viable intervention in increasing heart mass and potentially delaying the decline in function associated with aging.

Effect of Combining Exercise with Adipose-Derived Mesenchymal Stem Cells in Muscle Atrophy Model of Sarcopenia.

Deterioration in muscle mass, strength, and physical performance due to conditions such as sarcopenia can affect daily activities and quality of life in the elderly. Exercise and mesenchymal stem cells (MSCs) are potential therapies for sarcopenia. This study evaluates the combined effects of exercise and adipose-derived MSCs (ADMSCs) in aged rats with sarcopenia. Eighteen-month-old rats were randomly divided into four groups: control, exercise (Ex), ADMSCs injection (MSC), and ADMSCs injection with exercise (MSC + Ex). Gastrocnemius (GCM) muscle mass increased in the Ex, MSC, and MSC + Ex groups compared to the control group. Although the mean CSA did not differ significantly between the groups, the size distribution of myofibers shifted toward larger sizes in the Ex and MSC + Ex groups. The MSC + Ex group performed best in functional tests, including the rotarod and hot plate tests. The protein expression levels of tumor necrosis factor (TNF) and the p-AMP-activated protein kinase (AMPK)/AMPK ratio in the GCM muscle were the lowest in the MSC + Ex group. This study demonstrates that combining exercise and ADMSC interventions was the most effective treatment for aged sarcopenic rats, suggesting a potential synergistic approach for sarcopenia treatment.

Molecular mechanisms and enhanced functions of Hibiscus sabdariffa L—nanoliposomes as an emerging therapeutic strategy in UV and galactosamine skin aging-induced model

BackgroundSkin aging is a multifactorial disorder that occurs due to extrinsic and intrinsic factors, where a decrease in natural antioxidant defenses and an imbalance between molecular biomarkers occur. The current study aims to develop nanoliposomes for the dermal delivery of Hs and to investigate their effects on skin biomarkers and skin aging.MethodsChemical profiling performed via high-performance liquid chromatography (HPLC)/ESI‒PDA‒MS revealed enrichment in phenolic metabolite contents. Hs-nanolopeosomes were characterized for their mean size, encapsulation efficiency of Hs and ability to penetrate the skin via confocal microscopy. An aged rat model generated via UV and galactosamine injection was evaluated for reduced glutathione (GSH) and malondialdehyde (MDA) levels, in addition to the levels of collagenase and elastase enzymes in the different study groups, which included a healthy control group, an aged group, a prophylactic group, an aged group treated with Hs-nanoliposomes, and a green tea extract-treated group (positive control). Moreover, the Bcl-2/Bax proteins were determined via ELISA, and MMP-1, MMP-2, MMP-9, and TIMP-1 expression was determined via RT‒qPCR in the study groups.ResultsHs-nanoliposomes (~ 400 nm) proved deep skin localization in confocal images. Compared with the aged group and the green tea extract-treated group, the Hs-liposome-treated group presented elevated reduced glutathione and decreased malondialdehyde levels and inhibited collagenase and elastase enzymes. This treatment also decreased the Bcl-2/Bax ratio and downregulated the expression of MMP-1, MMP-2, and MMP-9. However, upregulation of TIMP-1 expression was detected. The outcomes were confirmed by histopathological assays, which revealed reduced saging and collagen damage in the Hs-nanolipid-treated group.ConclusionThe present study proposed a potential antiaging nanobased formulation that can deliver Hs extract deep in the dermis layer to prevent the oxidative stress that leads to aging.

Obesity-associated memory impairment and neuroinflammation precede widespread peripheral perturbations in aged rats

BackgroundObesity and metabolic syndrome are major public health concerns linked to cognitive decline with aging. Prior work from our lab has demonstrated that short-term high fat diet (HFD) rapidly impairs memory function via a neuroinflammatory mechanism. However, the degree to which these rapid inflammatory changes are unique to the brain is unknown. Moreover, deviations in gut microbiome composition have been associated with obesity and cognitive impairment, but how diet and aging interact to impact the gut microbiome, or how rapidly these changes occur, is less clear. Thus, our study investigated the impact of HFD after two distinct consumption durations: 3 months (to model diet-induced obesity) or 3 days (to detect the rapid changes occurring with HFD) on memory function, anxiety-like behavior, central and peripheral inflammation, and gut microbiome profile in young and aged rats.ResultsOur data indicated that both short-term and long-term HFD consumption impaired memory function and increased anxiety-like behavior in aged, but not young adult, rats. These behavioral changes were accompanied by pro- and anti-inflammatory cytokine dysregulation in the hippocampus and amygdala of aged HFD-fed rats at both time points. However, changes to fasting glucose, insulin, and inflammation in peripheral tissues such as the distal colon and visceral adipose tissue were increased in young and aged rats only after long-term, but not short-term, HFD consumption. Furthermore, while subtle HFD-induced changes to the gut microbiome did occur rapidly, robust age-specific effects were only present following long-term HFD consumption.ConclusionsOverall, these data suggest that HFD-evoked neuroinflammation, memory impairment, and anxiety-like behavior in aging develop quicker than, and separately from the peripheral hallmarks of diet-induced obesity.

Role of dexmedetomidine in postoperative cognitive dysfunction and sleep improvement in aged rats by regulating the PI3K/Akt signaling pathway and its mechanism.

This study aims to explore the mechanism of dexmedetomidine (Dex) in improving postoperative cognitive dysfunction (POCD) and postoperative sleep in aged rats through the PI3K/Akt signaling pathway. Splenectomy was used to establish a POCD model in aged rats. Open field test (OFT) and new object recognition test (NORT) were used to observe the cognitive function of rats The awakening and sleep times of rats were recorded. Hematoxylin-eosin, Nissl, and TUNEL staining were adopted to examine histopathological alterations, neuronal cell damage, and apoptosis, respectively; western blot to detect the activation of the PI3K/Akt signaling pathway and the protein level of apoptosis factors Bcl-2, Bax, and cleaved caspase-3; enzyme-linked immunosorbent assay to quantify the concentrations of inflammatory factors IL-6, IL-1β, and TNF-α. On days 1, 7, and 14 post-splenectomy surgery, aged rats exhibited shortened moving distance in OFT, reduced discrimination rate in NORT, prolonged awakening time, and shortened sleep time, while such effect was reversed by further Dex treatment. In addition, neuronal damage, inflammatory response, and apoptosis occurred in the hippocampal CA1 area in aged rats but can be attenuated by Dex treatment. Dex triggered the activation of the PI3K/Akt signaling pathway in the hippocampus in aged rats after surgery, and inhibition of the PI3K/Akt signaling pathway can result in a partial reversal of the alleviating effects observed with Dex treatment. Dex improves POCD and postoperative sleep in aged rats by activating the PI3K/Akt signaling pathway to reduce inflammatory response and apoptosis in the hippocampal CA1 area.

Regulation of Age-Related Lipid Metabolism in Ovarian Cancer.

The mortality rate of ovarian cancer (OC) remains the highest among female gynecological malignancies. Advanced age is the highest risk factor for OC development and progression, yet little is known about the role of the aged tumor microenvironment (TME). We conducted RNA sequencing and lipidomic analysis of young and aged gonadal adipose tissue from rat xenografts before and after OC formation. The rates of tumor formation (p = 0.047) and tumor volume (p = 0.002) were significantly higher in the aged rats than in their young counterparts. RNA sequencing data showed significant differences in gene expression profiles between the groups of young and aged rat adipose tissues (p < 0.05), including S100a8, S100a9, Il1rl1, Lcn2, C3, Hba-a1, Fcna, and Pnpla3. At the time of tumor generation, there were also changes in the lipid components within the gonadal adipose tissues of young and aged rats, with higher levels of free fatty acids (FFAs) and triglycerides (TGs) in aged rats. Furthermore, the aged TME showed changes in immune cell composition, especially inflammation-related cells, including neutrophils, myeloid dendritic cells, CD4+ T cells (non-regulatory), and mast cell activation (p < 0.05). The correlation between S100a8, S100a9, neutrophil, and omega-5, FFA 18:3 levels was also determined. Additionally, omega-5, which is downregulated in aged rats, inhibited OC cell proliferation in vitro (p < 0.001). Our study suggests that the aged TME promotes OC proliferation resulting from age-related changes in gene/pathway expression, lipid metabolism, and immune cell distribution. Targeting the aging adipose microenvironment, particularly lipid metabolism, is a promising therapeutic strategy for OC and warrants further investigation. Significance: The aging microenvironment contributes to OC development and progression because of changes in the immune response regulatory genes S100a8 and S100a9, secreted by adipocytes, preadipocytes, or neutrophils, and by altering omega-5 metabolism.

Effects of combo therapy with coenzyme Q10 and mitochondrial transplantation on myocardial ischemia/reperfusion-induced arrhythmias in aged rats.

Ischemia/reperfusion (IR)-induced ventricular arrhythmia, which mainly occurs after the opening of coronary artery occlusion, poses a clinical problem. This study aims to investigate the effectiveness of pretreatment with coenzyme Q10 (CoQ10) in combination with mitochondrial transplantation on IR-induced ventricular arrhythmias in aged rats. Myocardial IR induction was performed by left anterior descending coronary artery occlusion for 30 min, followed by re-opening for 24 hr. CoQ10 was administered intraperitoneally at a dosage of 10 mg/kg/day for two weeks before inducing IR. At the start of reperfusion, 500 µl of the respiration buffer containing 6×106±5×105 mitochondria/ml of respiration buffer harvested from the pectorals major muscle of young donor rats were injected intramyocardially. To investigate arrhythmias, the heart's electrical activity during ischemia and the first 30 min of reperfusion were recorded by electrocardiogram. After 24 hr of reperfusion, cardiac histopathological changes, creatine kinase-MB, nitric oxide metabolites (NOx), oxidative stress markers (malondialdehyde, total anti-oxidant, superoxide dismutase, and glutathione peroxidase), and the expression of genes regulating mitochondrial fission/fusion were measured. Pretreatment with CoQ10 in combination with mitochondrial transplantation reduced ventricular arrhythmias, cardiac histopathological changes, and creatine kinase-MB levels. Simultaneously, this combined therapeutic approach increased myocardial NOx levels, fostering an improved oxidative balance. It also triggered the down-regulation of mitochondrial fission genes, coupled with the up-regulation of mitochondrial fusion genes. The combination of CoQ10 and mitochondrial transplantation demonstrated a notable anti-arrhythmic effect by elevating NOx levels, reducing oxidative stress, and improving mitochondrial fission/fusion in aged rats with myocardial IRI.

Sex-specific effects of dietary salt intake on circulating Alzheimer's disease-related biomarkers in aged rats

Sex-specific effects of dietary salt intake on circulating Alzheimer's disease-related biomarkers in aged rats