Aged Rats Research Articles

The effect of exposure to RF-EMF from the laboratory simulator of 5G NR base station on physiological parameters and cognitive abilities of male wistar rats of different ages

In this article, the impact of radiofrequency electromagnetic field (RF-EMF) exposure from a simulated base station for the 5G New Radio (5G NR) telecommunication on rats was studied. The base station affects all age groups of the population, thus, for the first time, the experiment was conducted on male Wistar rats of three different ages (juvenile, adult, and presenile). The base station exposure parameters were chosen according to ICNIRP recommendations for limiting the exposure to radiofrequency electromagnetic field: frequency 2.4 GHz with an average specific absorption rate of 0.0076 W/kg and 0.0059 W/kg over the whole body of experimental animals. Throughout the experiment, body weight was examined weekly, and the dynamics of body weight gain was monitored. Rectal and skin surface temperature on the right hind limb was monitored weekly. Testing in the Morris water maze was performed during the last, Week 5, of RF-EMF exposure. After euthanasia, organ weights were determined in experimental and control animals. None of the investigated parameters did show any statistically significant differences between exposed and control animals of the same age. The data obtained can be used to assess the possible consequences of chronic exposure to RF-EMF from 5G NR base stations.

Abstract PO1-14-09: Age-related remodeling of the systemic and breast microenvironment promotes a tumor-permissive locale for ER+ breast cancer in older women

Abstract Introduction: The peak incidence of ER+ breast cancer occurs in women around the age of 70. Compared to younger cohorts, we and others have shown that older patients with ER+ breast cancer have an enrichment of luminal disease and experience fewer recurrences, suggesting overtreatment. Differences in the biological phenotypes of tumors in older women remain poorly understood and treatment remains challenging as older patients are underrepresented in clinical trials. In this study, we hypothesized that aging alters both local and systemic hormones and inflammatory cytokines, creating a permissive environment for tumor formation and growth. To address this hypothesis, we employed a systems biology approach across multiple model systems and tissue samples. Methods: Our study included specimens from two cohorts of patients: (1) n = 90 women without breast cancer obtained from the Komen Tissue Bank, from whom we obtained matched plasma and non-cancerous breast tissue (n = 30 across age groups comprising of young donors (35-45yo), middle-aged donors (55-69yo), and older donors (≥ 70yo); and (2) n = 115 women with ER+ breast cancer (n = 25 young patients, n = 57 middle-aged patients, and n = 33 older patients) obtained from our institutional biobank, including matched plasma, tumor tissue, and tumor-adjacent tissue. From each of these sets of specimens, we measured estrogen disposition using mass spectrometry, a 22-plex panel of inflammatory markers, and transcriptomic changes using RNA-seq. Using scRNA-seq and multiplexed IHC, we further characterized the immune changes that occur with age. Lastly, we used an aged, carcinogen-induced ER+ tumor model in F344 rats (obtained from the NIA) to model tumor development and growth. Results: In the plasma, estradiol (E2) drastically decreased in post-menopausal women, leaving estrone (E1) as the predominant circulating estrogen in older women. However, the breast tumor microenvironment (TME) showed comparable levels of E1 and E2 across age groups. Multi-class concordance analysis of breast cancer tissue from RNA revealed significant increases in gene expression of the HSD17B7 enzyme and decreases in HSD17B2 enzyme across age, likely elevating local E1-to-E2 conversion and yielding high local E2 levels despite low circulating levels specifically in older women. In older patients with ER+ breast cancer, there was a significant increase in a chemokine network characterized by CCL2 and CXCL9 within the TME. scRNA-seq revealed enrichment of inflammatory M2-like macrophages in the aged TME. Immune dysfunction and decreased immunosurveillance in older patients manifested with widespread decreases in the presence of cytotoxic lymphocytes and decreased pathway enrichment of key immune pathways, such as JAK/STAT and IFNy signaling. mIHC analysis revealed decreases in CD4 and CD8 T cells and increases in M2-like macrophages in older patients in both tumor and stromal regions. Lastly, in the carcinogen-induced F344 rat model, aged rats (~ 24mo, human equivalent 60-70yo) had a shorter tumor-free interval than the younger rats (~ 4-6mo, human equivalent 20-30yo), likely due to increases in tumor-promoting inflammation and decreased immune surveillance. Ongoing mechanistic work is focused on macrophage-patient derived organoid co-cultures evaluating the functional relevance of E2, CCL2, and CXCL9 in shaping the aged TME. Conclusions: Our study of systemic and local breast hormones and cytokines in both healthy individuals and breast cancer patients showed that older women with ER+ breast cancer harbor different systemic and local environments compared to younger women. The aged TME is characterized by high E2, cytotoxic lymphocyte depletion, and immune dysfunction, creating a permissive environment for tumor formation. Future translational work should be aimed at chemo-preventative strategies to reduce the age-related chronic inflammation and immune dysfunction. Citation Format: Neil Carleton, Jian Zou, Sanghoon Lee, Dixcy Jaba Sheeba John Mary, Ruxuan Li, Jennifer Atkinson, Ziyu Huang, Hatice Osmanbeyoglu, Peter Lucas, Emilia Diego, Michael Lotze, George Tseng, Jagmohan Hooda, Ioannis Zervantonakis, Priscilla McAuliffe, Steffi Oesterreich, ADRIAN LEE. Age-related remodeling of the systemic and breast microenvironment promotes a tumor-permissive locale for ER+ breast cancer in older women [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-14-09.

Impact of combined alpha-lipoic acid and mitoquinone supplementation on myocardial infarction in aged rats: Heart performance and molecular mechanisms

BackgroundThis study aimed to investigate the effects of combined alpha-lipoic acid (ALA) and mitoquinone (Mito Q) supplementation on cardiac function and the underlying mechanisms in aged rats with myocardial infarction (MI). MethodsThe aged rats underwent left anterior descending artery (LADA) occlusion for 30 min, followed by reperfusion for 24 h. ALA (100 mg/kg, gavage) and Mito Q (10 mg/kg, IP) were administered daily for two weeks before ischemia. Cardiac function, inflammatory, and apoptotic markers were evaluated 24 h after ischemia. ResultsThe results of this study indicated that the administration of the combination of ALA and Mito Q significantly improved cardiac function. This improvement was linked to a reduction in the expression of pro-inflammatory cytokines TNF-α, IL-6, and IL-1β (P < 0.001) and apoptotic markers (Bax, caspase-3, and Cyt-c), as well as a decrease in the percentage of TUNEL-positive cells (P < 0.001). ConclusionThe study revealed that combined intervention synergistically mitigated cardiac dysfunction by suppressing inflammatory and apoptotic pathways in aged rats with MI. Further research is needed to validate the potential of ALA and Mito Q as therapeutic options for elderly people at risk of heart attacks.

Effects of Short-, Medium-, and Long-Term Treatment Using Photobiomodulation Therapy Combined with Static Magnetic Field in Aging Rats

(1) Background: We investigated the detrimental and protective effects of short-, medium, and long-term treatment with different doses of photobiomodulation therapy combined with static magnetic field (PBMT-sMF) during the aging process. (2) Methods: Rats were treated for 15, 30, and 60 weeks with 1, 3, 10, and 30 J of PBMT-sMF or a placebo control. In addition, eight young rats were not subjected to any procedure or treatment and were euthanized at six weeks old. Skin, muscle, bone, kidney, liver, and blood samples were analyzed. (3) Results: No differences between the groups in the morphology of the skin, muscle, and bone was observed. Glutamic pyruvic transaminase levels were increased in the placebo group after 30 and 60 weeks. Glutamic oxaloacetic transaminase levels were also increased in the placebo group after 30 weeks. An increase in creatinine in the PBMT-sMF 3, 10, and 30 J groups compared with that in the young control group was observed. No significant difference in urea levels between the groups was noted. Vascular endothelial growth factor increased in the PBMT-sMF 10 and 30 J groups after 15 weeks of treatment and in the PBMT-sMF 3 J after 60 weeks. Finally, vascular endothelial growth factor decreased in the PBMT-sMF 30 J group after 30 weeks of treatment. (4) Conclusions: PBMT-sMF did not have detrimental effects on the skin, muscle, bone, kidney, or liver after short-, medium-, and long-term treatments in aging rats. In addition, PBMT-sMF may have protective effects on the muscle tissue in aging rats after short- and long-term treatment.

Curcumin attenuates brain aging by reducing apoptosis and oxidative stress.

Brain aging is a physiological event, and oxidative stress and apoptosis are involved in the natural aging process of the brain. Curcumin is a natural antioxidant with potent anti-aging and neuroprotective properties. Therefore, we investigated the protective effects of curcumin on brain apoptosis and oxidative stress, brain-derived neurotrophic factor (BDNF), and vascular endothelial growth factor (VEGF) in aged rats. Old female Wistar rats were randomly divided into three groups (n = 7); as follows: (1) control; (2); saline and (3) curcumin (received 30mg/kg of curcumin, 5 days/week for 8 weeks, intraperitoneally). Our results indicated that treatment with curcumin in aged rats attenuates brain lipid peroxidation, which was accompanied by a significant increase in the BDNF, VEGF, superoxide dismutase (SOD) activity, and anti-apoptotic protein BCl-2. No significant change in brain anti-apoptotic Bax protein levels was observed after curcumin treatment. The study indicates that curcumin could alleviate brain aging which may be due to attenuating oxidative stress, inhibiting apoptosis, and up-regulating SOD activity, which in turn enhances VEGF and BDNF. Therefore, curcumin has potential therapeutic value in the treatment of neurological apoptosis, neurogenesis, and angiogenesis changes caused by brain aging.

The Energy Required to Synthesize Lean and Adipose Tissue in Rats.

Although the energy stored in lean tissue (LT) and adipose tissue (AT) is well known, the energy required to synthesize these tissues is less clear. While elucidating the energy required for AT synthesis may not be so important, the elucidation of the energy required for LT synthesis is important for individuals who aim to increase their skeletal muscle. Theoretically the energy at the point at which ΔLT/Δbody weight (BW) reaches 100% on a regression curve, which indicates the relationship between ΔLT/ΔBW and the energy used to accumulate body tissue, is considered to be the energy expended to synthesize LT. We therefore investigated the relationship using rats. Rats of different ages, and rats in exercised or sedentary states were used because their ΔLT/ΔBW was expected to be different. ΔLT/ΔBW was higher in the 4-wk-old group than in the 8-wk-old group and higher in the exercise group than in the sedentary group. We found a positive correlation between ΔLT/ΔBW and the energy expended to synthesize tissues that accumulated in the body. This energy was lower in the 8-wk-old group, which had a lower ΔLT/ΔBW in comparison to the 4-wk-old group, but was not affected by exercise. The regression curve revealed that the energy expended to synthesize LT was 2.9 kcal/g, while that expended to synthesize AT was 1.1 kcal/g. Therefore, combined with the energy accumulated to the tissues, the energy required to accumulate LT is approximately 4.0 kcal/g, while that required to accumulate AT is approximately 8.5 kcal/g.

Comparing the efficacy of concomitant treatment of resistance exercise and creatine monohydrate versus multiple individual therapies in age related sarcopenia

Aging-related sarcopenia is a degenerative loss of strength and skeletal muscle mass that impairs quality of life. Evaluating NUDT3 gene and myogenin expression as new diagnostic tools in sarcopenia. Also, comparing the concomitant treatment of resistance exercise (EX) and creatine monohydrate (CrM) versus single therapy by EX, coenzyme Q10 (CoQ10), and CrM using aged rats. Sixty male rats were equally divided into groups. The control group, aging group, EX-treated group, the CoQ10 group were administered (500 mg/kg) of CoQ10, the CrM group supplied (0.3 mg/kg of CrM), and a group of CrM concomitant with resistance exercise. Serum lipid profiles, certain antioxidant markers, electromyography (EMG), nudix hydrolase 3 (NUDT3) expression, creatine kinase (CK), and sarcopenic index markers were measured after 12 weeks. The gastrocnemius muscle was stained with hematoxylin–eosin (H&E) and myogenin. The EX-CrM combination showed significant improvement in serum lipid profile, antioxidant markers, EMG, NUDT3 gene, myogenin expression, CK, and sarcopenic index markers from other groups. The NUDT3 gene and myogenin expression have proven efficient as diagnostic tools for sarcopenia. Concomitant treatment of CrM and EX is preferable to individual therapy because it reduces inflammation, improves the lipid serum profile, promotes muscle regeneration, and thus has the potential to improve sarcopenia.

Low-Fat Cheese Ameliorates Glucose Intolerance and Normalizes Insulin Secretion in a Rat Model of Type 2 Diabetes by Promoting β-cell Recovery.

We aimed to determine if cheese could reduce glucose intolerance in aged rats with overt type 2 diabetes (T2D). Male Sprague-Dawley rats treated with high-fat diet and streptozotocin (STZ) exhibited hyperglycemia to elicit T2D. One week after STZ injection, low-fat (LOW) or regular-fat (REG) cheese was provided for 5 weeks and compared with T2D and low-fat diet reference (REF) groups. Food intake and weight gain were similar in all groups. Oral glucose tolerance tests revealed glucose intolerance in T2D rats that was partially ameliorated by LOW but not REG. Insulin secretion during the OGTT was impaired in T2D and REG at 10 min (p<0.05) but the iAUC was highly variable in all groups and statistical differences were not detected (p>0.05). β-cell mass and pancreatic insulin content in T2D and REG were 50% lower than REF (p<0.05) whereas LOW was not significantly different. Although isolated islets from all groups responded to glucose, the absolute amount of insulin secreted by T2D and REG was markedly reduced compared with REF while LOW islets had relatively normal secretion. In conclusion, LOW but not REG cheese enhanced β-cell recovery from HFD/STZ treatment that led to amelioration of glucose tolerance within 5 weeks.

Diet-induced and age-related changes in rats: the impact of N-stearoylethanolamine intake on plasma lipoproteins, adiponectin, and adipocyte cholesterol-phospholipid composition

Adiponectin is secreted by adipose tissue, associated with lipoprotein (LP) metabolism, down-regulated­ in insulin resistance states, and reduced in individuals suffering from obesity and cardiovascular diseases. Phospholipids and cholesterol are the main components of cell membranes and play a critical role in storage and secretory adipocyte functions. N-stearoylethanolamine (NSE) is a minor lipid affecting cell membrane lipids’ composition. Our study aimed to investigate plasma levels of adiponectin and cholesterol of low- and high-density LP (LDL and HDL) and adipocyte cholesterol-phospholipid (Chol-PL) composition of different age rats with high-fat diet (HFD)-induced obesity and insulin resistance and their changes under NSE administration. Our study demonstrated that chronic dietary fat overloading leads to obesity accompanied by impairment of glucose tolerance, a manifestation of dyslipidemia, and changes in plasma adiponectin levels in rats from two age groups (10-month-old and and 24-month-old). Prolonged HFD led to a reduction in plasma adiponectin levels and the growth of adipocyte cholesterol content in rats of different ages. A significant increase in plasma LDL-Chol level and main adipocyte PLs (phosphatidylcholine, phosphatidylethanolamine, sphingomyelin, and lysophosphatidylcholine) was observed in younger rats, whereas not detected in elder animals after dietary fats overloading. The decrease in the content of anionic phospholipids (phosphatidylinositol + phosphatidylserine) was also detected in 10-month-old HFD rats compared to the control animals. NSE administration positively affected the normalization of adiponectin levels in both age HFD groups. It significantly impacted the reduction of LDL-Chol levels and the growth of HDL-Chol concentration in the blood plasma of 10-month-old rats as well as PL-composition of young HFD rats and anionic PL restoring in 24-month-old rats. The positive effect on investigated parameters makes NSE a prospective agent for treating diet-induced and age-related metabolic disorders threatening cardiovascular diseases. Keywords: adiponectin, adipose tissue, aging, cholesterol, dyslipidemia, lipoproteins, N-stearoylethanolamine, phospholipids

L-arginine, inosine and meldonium effect on the vascular wall reactivity of adult rats

Changes in the structure, metabolism and cardiovascular system function that develop during ageing are the basis for the circulatory pathology occurrence in old age. Currently, cardiovascular system diseases are one of the main causes of mortality in almost all developed countries. Therefore, searching for new drugs to correct the metabolism and functions of organs and systems whose activity is disrupted during ageing is an urgent problem. The article presents the study influence results of the synthesis precursor of endothelial relaxing factor - NO (ERF-NO) L-arginine, the purine nucleoside inosine and the β-oxidation inhibitor of fatty acids meldonium on the vascular wall reactivity of adult rats. When used separately, these drugs have been shown to cause slight relaxation of the thoracic aorta isolated segments in adult animals. When L-arginine, inosine and meldonium are used together, there is no summation of their pharmacological effect on blood vessels, however, some vasodilator effect potentiation is observed. The acetylcholine (Ach) vasodilator effect was significantly more than the vasodilator effect of the studied composition (L-arginine + inosine + meldonium), conventionally called Melarginine. It should be noted that, although the vasodilator Ach effect was significant, it was short-term, and the vasodilator effect of the studied combination (Melarginine) was long-lasting. A pronounced vasodilator response to Ach indicates the preservation of the endothelium in adult rats. Therefore, with intact endothelium in adult animals, Melarginine does not cause significant vascular relaxation. In aged rats, which typically exhibit endothelial damage, the effect of Melarginine may be more significant compared to adults. This will be the subject of our further study. Still, Melarginine has a small but long-lasting vasodilatory effect in adult rats, which also helps regulate vascular tone. _________________________________________________________________________________________ Keywords: vessel reactivity; endothelial dysfunction; L-arginine; inosine; meldonium; Melarginine

Investigating the Effect of Resistance-Aerobic Training on the Absorption and Resorption Biomarkers of Bone Tissue in Young, Adult and Elderly Male Rats

Introduction: Exercise training is likely to be a non-pharmacological intervention to improve bone health in children and the elderly. The aim of this study was to investigate the effect of resistance-aerobic training on RUX2, CTX, RANKL and ALP biomarkers in rats of different ages. Methods: In the present experimental study, 30 male Wistar rats were obtained from Instituto Pasteur of Iran and were divided into three groups according to their age: immature (2 weeks old), mature (6 weeks old) and elderly (96 weeks old). In each age group, the mice were randomly divided into two training (n=5) and control (n=5) groups. Six weeks of combined training included three sessions of aerobic training and three sessions of resistance training per week. Extracting genes by PCR method was used. One-way analysis of variance and Tukey's post hoc test and SPSS16 software were used. The significance level P≥0.05 was considered. Results: One-way analysis of variance showed that resistance-aerobic training has had a significant effect on RUNX2, RANKL and ALP variables of rats in different age groups (P &lt; 0.05). This significance was not observed in CTX variable (P &gt; 0.05). On the other hand, the results of Tukey's RUNX2 test were significantly different between the adult training and elderly training groups (p=‌0.019) as well as between the elderly control groups (p = 0.01) and adult training (p = 0.002). Regarding the RANKL variable, it showed that there was a significant difference only between the adult exercise group and the elderly control group (p = 0.01). Conclusion: Resistance-endurance training probably increases absorption and reabsorption biomarkers such as RUX2, RANKL and ALP in immature, mature and elderly male rats.

Sex-specific cardiovascular remodeling leads to a divergent sex-dependent development of heart failure in aged hypertensive rats.

The prevalence of heart failure with preserved ejection fraction (HFpEF) is continuously rising and predominantly affects older women often hypertensive and/or obese or diabetic. Indeed, there is evidence on sex differences in the development of HF. Hence, we studied cardiovascular performance dependent on sex and age as well as pathomechanisms on a cellular and molecular level. We studied 15-week- and 1-year-old female and male hypertensive transgenic rats carrying the mouse Ren-2 renin gene (TG) and compared them to wild-type (WT) controls at the same age. We tracked blood pressure and cardiac function via echocardiography. After sacrificing the 1-year survivors we studied vascular smooth muscle and endothelial function. Isolated single skinned cardiomyocytes were used to determine passive stiffness and Ca2+-dependent force. In addition, Western blots were applied to analyse the phosphorylation status of sarcomeric regulatory proteins, titin and of protein kinases AMPK, PKG, CaMKII as well as their expression. Protein kinase activity assays were used to measure activities of CaMKII, PKG and angiotensin-converting enzyme (ACE). TG male rats showed significantly higher mortality at 1 year than females or WT male rats. Left ventricular (LV) ejection fraction was specifically reduced in male, but not in female TG rats, while LV diastolic dysfunction was evident in both TG sexes, but LV hypertrophy, increased LV ACE activity, and reduced AMPK activity as evident from AMPK hypophosphorylation were specific to male rats. Sex differences were also observed in vascular and cardiomyocyte function showing different response to acetylcholine and Ca2+-sensitivity of force production, respectively cardiomyocyte functional changes were associated with altered phosphorylation states of cardiac myosin binding protein C and cardiac troponin I phosphorylation in TG males only. Cardiomyocyte passive stiffness was increased in TG animals. On a molecular level titin phosphorylation pattern was altered, though alterations were sex-specific. Thus, also the reduction of PKG expression and activity was more pronounced in TG females. However, cardiomyocyte passive stiffness was restored by PKG and CaMKII treatments in both TG sexes. Here we demonstrated divergent sex-specific cardiovascular adaptation to the over-activation of the renin-angiotensin system in the rat. Higher mortality of male TG rats in contrast to female TG rats was observed as well as reduced LV systolic function, whereas females mainly developed HFpEF. Though both sexes developed increased myocardial stiffness to which an impaired titin function contributes to a sex-specific molecular mechanism. The functional derangements of titin are due to a sex-specific divergent regulation of PKG and CaMKII systems.

Sex, Age, and Species Differences of Perfluorooctanoic Acid Modeled by Flow- versus Permeability-limited Physiologically-Based Pharmacokinetic Models.

This study aimed to investigate sex, age, and species differences of perfluorooctanoic acid (PFOA) using physiologically-based pharmacokinetic (PBPK) models in rats and humans. PBPK models were generally developed as either flow- or permeability-limited models. The flow-limited model is cost-effective and allows for human PK prediction through simple allometric scaling, while the permeability-limited model can incorporate detailed information on the disposition process through in vitro-in vivo extrapolation (IVIVE). PFOA was administered via oral or intravenous administration with 5mg/kg in male and female rats of different ages and the data was used to develop the PBPK models. Our results showed that both models successfully captured sex differences in rats, while only the flow-limited model with male rats and the permeability-limited model with both male and female rats provided comparable predictions in the human clinical study. More than the flow-limited model, the permeability-limited model effectively explained sex differences in rats and species differences through IVIVE. Additionally, the ontogeny-based mechanistic description of PFOA disposition enabled the interpretation of age- and sex-dependent pharmacokinetics. Although the flow-limited PBPK model lacked mechanistic interpretability compared to the permeability-limited model, it demonstrated reliable human prediction through simple allometric scaling. In conclusion, the permeability PBPK model could interpret age, sex, and species differences and it could improve the accuracy of human prediction.

Increased anxiolytic effect in aged female rats and increased motoric behavior in aged male rats to acute alcohol administration: Comparison to younger animals

The population of most countries in the world is increasing and understanding risk factors that can influence the health of the older population is critical. Older adults consume alcohol often in a risky, binge manner. Previous work has demonstrated that aged rats are more sensitive to many of the effects of acute ethanol. In the current project aged, adult, and adolescent female and male rats were tested on the elevated plus maze and open field following either a 1.0 g/kg alcohol injection or a saline injection. We report sex- and age-dependent effects whereas aged female rats, but not aged male rats, showed an increased anxiolytic effect of alcohol in the elevated plus maze while aged male rats, but not aged female rats, showed increased stimulatory movement in the open field. In addition, significant age effects were found for both female and male rats. It is proposed that the sex- and age-dependent effects reported in the current studies may be due to differential levels of alcohol-induced allopregnanolone for the anxiolytic effects and differential levels of alcohol-induced dopamine for the stimulatory effects. The current work provides insights into factors influencing alcohol consumption in older adults.

Targeting microbiota–immune–synaptic plasticity to explore the effect of tea polyphenols on improving memory in the aged type 2 diabetic rat model

ABSTRACT Objectives The study aimed to explore whether TP could improve memory in the aged type 2 diabetic rat model by regulating microbiota-immune-synaptic plasticity axis. Methods The experiment was divided into two parts. Firstly, to investigate the effects of TP on the physiopathology of the aged T2DM model rats, rats were randomly divided into the Normal control group, the aged group, the Aged T2DM model group, the TP 75, 150, 300 mg/kg groups, the 150 mg/kg Piracetam group and the 3 mg/kg Rosiglitazone group. Then, to further verify whether TP improved memory in aged T2DM rat model by regulating intestinal flora, the fecal microbiota transplantation (FMT) from the rats in the 300 mg/kg TP group into the rats in the aged T2DM model group was carried out. Effects on gut microbiota, colonic integrity (epithelial tight junction proteins), and endotoxemia (serum LPS) were examined, along with synaptic structure, synaptic plasticity-related structural proteins and inflammation signaling of the hippocampus in our study. Results Our results demonstrated that TP alleviated memory impairments in the aged T2DM rat model. The specific outcomes were as follows: TP 300 mg/kg corrected the gut dysbacteriosis, alleviated intestinal permeability reduction and peripheral/central inflammation, inhibited the TLR4/NF-κB signaling pathway. Meanwhile, TP improved the synaptic plasticity in the hippocampus of the aged T2DM model rats, whose expressions of SYN, PSD 95, NMDAR1 and GluR1 in hippocampus were significantly up-regulated. Surprisingly, rats of the FMT group displayed the same changes. Discussion TP improves the memory in aged T2DM rat model. The mechanism may be related to the alteration of gut flora, which can inhibit hippocampal TLR4/NF-κB signaling to attenuate neuroinflammation, then improve synaptic plasticity. The study proposes that TP interventions aimed at manipulating the gut microbiota may hold great potential as an effective approach for preventing and treating this disease.

Syringaresinol attenuates Tau phosphorylation and ameliorates cognitive dysfunction induced by sevoflurane in aged rats.

Cognitive dysfunction following anesthesia with agents such as sevoflurane is a significant clinical problem, particularly in elderly patients. This study aimed to explore the protective effects of the phytochemical syringaresinol (SYR) against sevoflurane-induced cognitive deficits in aged Sprague-Dawley rats and to determine the underlying mechanisms involved. We assessed the impact of SYR on sevoflurane-induced cognitive impairment, glial activation, and neuronal apoptosis through behavioral tests (Morris water maze), immunofluorescence, Western blotting for key proteins involved in apoptosis and inflammation, and enzyme-linked immunosorbent assays for interleukin-1β, tumor necrosis factor-α, and interleukin-6. SYR treatment mitigated sevoflurane-induced cognitive decline, reduced microglial and astrocyte activation (decreased Iba-1 and GFAP expression), and countered neuronal apoptosis (reduced Bax, cleaved-caspase3, and cleaved-PARP expression). SYR also enhanced Sirtuin-1 (SIRT1) expression and reduced p-Tau phosphorylation; these effects were reversed by the SIRT1 inhibitor EX527. SYR exerts neuroprotective effects on sevoflurane-induced cognitive dysfunction by modulating glial activity, apoptotic signaling, and Tau phosphorylation through the SIRT1 pathway. These findings could inform clinical strategies to safeguard cognitive function in patients undergoing anesthesia.

Altered lactate/pyruvate ratio may be responsible for aging-associated intestinal barrier dysfunction in male rats.

Some evidence points to a link between aging-related increased intestinal permeability and mitochondrial dysfunction in in-vivo models. Several studies have also demonstrated age-related accumulation of the of specific deletion 4834-bp of "common" mitochondrial DNA (mtDNA) in various rat tissues and suggest that this deletion may disrupt mitochondrial metabolism. The present study aimed to investigate possible associations among the mitochondrial DNA (mtDNA) common deletion, mitochondrial function, intestinal permeability, and aging in rats. The study was performed on the intestinal tissue from (24months) and young (4months) rats. mtDNA4834 deletion, mtDNA copy number, mitochondrial membrane potential, and ATP, lactate and pyruvate levels were analyzed in tissue samples. Zonulin and intestinal fatty acid-binding protein (I-FABP) levels were also evaluated in serum. Serum zonulin and I-FABP levels were significantly higher in 24-month-old rats than 4-month-old rats (p = 0.04, p = 0.026, respectively). There is not significant difference in mtDNA4834 copy levels was observed between the old and young intestinal tissues (p > 0.05). The intestinal mitochondrial DNA copy number was similar between the two age groups (p > 0.05). No significant difference was observed in ATP levels in the intestinal tissue lysates between old and young rats (p > 0.05). ATP levels in isolated mitochondria from both groups were also similar. Analysis of MMP using JC-10 in intestinal tissue mitochondria showed that mitochondrial membrane potentials (red/green ratios) were similar between the two age groups (p > 0.05). Pyruvate tended to be higher in the 24-month-old rat group and the L/P ratio was found to be approximately threefold lower in the intestinal tissue of the older rats compared to the younger rats (p < 0.002). The tissue lactate/pyruvate ratio (L/P) was three times lower in old rats than in young rats. Additionally, there were significant negative correlations between intestinal permeability parameters and L/P ratios. The intestinal tissues of aged rats are not prone to accumulate mtDNA common deletion, we suggest that this mutation does not explain the age-related increase in intestinal permeability. It seems to be more likely that altered glycolytic capacity could be a link to increased intestinal permeability with age. This observation strengthens assertions that the balance between glycolysis and mitochondrial metabolism may play a critical role in intestinal barrier functions.

Retraction Note: Declining melatonin levels and MT1 receptor expression in aging rats is associated with enhanced mammary tumor growth and decreased sensitivity to melatonin.

Retraction Note: Declining melatonin levels and MT1 receptor expression in aging rats is associated with enhanced mammary tumor growth and decreased sensitivity to melatonin.

Beam narrowing test: a motor index of post-stroke motor evaluation in an aged rat model of cerebral ischemia.

Each year, 15 million people worldwide suffer from strokes. Consequently, researchers face increasing pressure to develop reliable behavioural tests for assessing functional recovery after a stroke. Our aim was to establish a new motor performance index that can be used to evaluate post-stroke recovery in both young and aged animals. Furthermore, we validate the proposed procedure and recommend the necessary number of animals for experimental stroke studies. Young (n = 20) and aged (n = 27) Sprague-Dawley rats were randomly assigned to receive either sham or stroke surgery. The newly proposed performance index was calculated for the post-stroke acute, subacute and chronic phases. The advantage of using our test over current tests lies in the fact that the newly proposed motor index test evaluates not only the performance of the unaffected side in comparison to the affected one but also assesses overall performance by taking into account speed and coordination. Moreover, it reduces the number of animals needed to achieve a statistical power of 80%. This aspect is particularly crucial when studying aged rodents. Our approach can be used to monitor and assess the effectiveness of stroke therapies in experimental models using aged animals.

Indole-3-Carboxylic Acid Enhanced Anti-cancer Potency of Doxorubicin via Induction of Cellular Senescence in Colorectal Cells

Background: Colorectal cancer (CRC) is the most common gastrointestinal malignancy. Doxorubicin (DOX) is a widely utilized chemotherapy drug, but its efficacy is limited due to dose-dependent toxicity. Here, we aim to explore the effect of indole-3-carboxylic acid on DOX-induced senescence of CRC. Methods: Healthy adult rats and aged rats were compared in terms of their metabolites and functions through non-targeted metabolomics. LS180 cells were treated with DOX to induce senescence, followed by indole-3-carboxylic acid. The effects of this combination were evaluated in xenograft tumor mice. Cell viability, proliferation, and cell cycle were assessed with the Cell Counting Kit-8, colony formation assays, and flow cytometry. The levels of senescence-associated heterochromatin foci (SAHF) were detected by immunofluorescence. Senescence-associated-beta-galactosidase (SA-β-gal) expression was assessed by SA-β-gal staining and immunohistochemistry. Western blot was used to detect the expression of p21 and p53. Results: Compared to healthy adult rats, the serum metabolome in aging rats was altered, and the abundance of indole metabolites, including indoxyl sulfate, indole-3-carboxylic acid, and indole-5-carboxylic acid, was decreased significantly. In LS180 cells, indole-3-carboxylic acid amplified DOX-induced cell senescence, inhibiting cell proliferation and promoting cell cycle arrest. It also boosted DOX-triggered upregulation of SA-β-gal, SAHF, and p21. In nude mice, indole-3-carboxylic acid increased the inhibitory effect of DOX on xenograft tumors. Conclusion: Indole-3-carboxylic acid enhances the cellular senescence and growth arrest induced by DOX, suppressing mouse tumor growth. These findings suggest that a combined treatment of indole-3-carboxylic acid and DOX could be an effective strategy for CRC treatment.