Chronic Low-level Inflammation Research Articles

The Role of PGC-1α in Aging Skin Barrier Function.

Skin provides a physical and immune barrier to protect the body from foreign substances, microbial invasion, and desiccation. Aging reduces the barrier function of skin and its rate of repair. Aged skin exhibits decreased mitochondrial function and prolonged low-level inflammation that can be seen in other organs with aging. Peroxisome proliferator-activated receptor (PPAR)-γ coactivator-1α (PGC-1α), an important transcriptional coactivator, plays a central role in modulating mitochondrial function and antioxidant production. Mitochondrial function and inflammation have been linked to epidermal function, but the mechanisms are unclear. The aim of this review is to discuss the mechanisms by which PGC-1α might exert a positive effect on aged skin barrier function. Initially, we provide an overview of the function of skin under physiological and aging conditions, focusing on the epidermis. We then discuss mitochondrial function, oxidative stress, cellular senescence, and inflamm-aging, the chronic low-level inflammation observed in aging individuals. Finally, we discuss the effects of PGC-1α on mitochondrial function, as well as the regulation and role of PGC-1α in the aging epidermis.

Determination of inflammation by TNF-alpha and IL-10 levels in obese children and adolescents.

childhood obesity is one of the major health problem worldwide. Obesity is associated with low-level chronic inflammation resulting from inflammatory cytokine release in white adipose tissue. We aim to specify inflammatory markers tumor necrosis factor-alpha (TNF-alpha) and interleukin-10 (IL-10) in children and adolescents to determine their relationship with obesity. forty obese patients and 46 controls were included in the study from the pediatric clinic. Blood samples from the study group were centrifuged, and the sera were stored at -80 °C after separation. Serum levels of TNF-alpha and IL-10 were determined using Human ELISA kits for TNF-alpha and IL-10. serum samples from 86 children, including 45 girls (52.3 %) in the study group, were analyzed for TNF-alpha and IL-10 levels. TNF-alpha levels in the obese and control groups were 1.04 ± 0.79 and 0.60 ± 0.72 pg/ml, respectively (p = 0.010). Also, IL-10 levels in the obese and control groups were 0.76 ± 0.62 and 1.54 ± 0.71 pg/ml, respectively (p < 0.001). Gender was not identified as a factor for serum TNF-alpha and IL-10 levels (p = 0.281 and p = 0.477, respectively). Moreover, white blood cell (WBC) and serum C-reactive protein (CRP) levels were higher in the obese patient group than in the control group (p = 0.002 and p = 0.010, respectively). TNF-alpha levels were higher than control in obese patients and it was important in terms of showing that obesity triggers inflammation in the body. IL-10 levels, which inhibit inflammation, were lower in obese patients than controls.

A Pilot Study to Investigate Peripheral Low-Level Chronic LPS Injection as a Model of Neutrophil Activation in the Periphery and Brain in Mice.

Lipopolysaccharide-induced (LPS) inflammation is used as model to understand the role of inflammation in brain diseases. However, no studies have assessed the ability of peripheral low-level chronic LPS to induce neutrophil activation in the periphery and brain. Subclinical levels of LPS were injected intraperitoneally into mice to investigate its impacts on neutrophil frequency and activation. Neutrophil activation, as measured by CD11b expression, was higher in LPS-injected mice compared to saline-injected mice after 4 weeks but not 8 weeks of injections. Neutrophil frequency and activation increased in the periphery 4-12 h and 4-8 h after the fourth and final injection, respectively. Increased levels of G-CSF, TNFa, IL-6, and CXCL2 were observed in the plasma along with increased neutrophil elastase, a marker of neutrophil extracellular traps, peaking 4 h following the final injection. Neutrophil activation was increased in the brain of LPS-injected mice when compared to saline-injected mice 4-8 h after the final injection. These results indicate that subclinical levels of peripheral LPS induces neutrophil activation in the periphery and brain. This model of chronic low-level systemic inflammation could be used to understand how neutrophils may act as mediators of the periphery-brain axis of inflammation with age and/or in mouse models of neurodegenerative or neuroinflammatory disease.

Analysis of Inflammatory Markers in Response to Induction of Reprometabolic Syndrome by a Eucaloric High Fat Diet in Normal Weight Women.

Obesity is associated with chronic low-level inflammation and is known to contribute to metabolic dysfunction and hypogonadotropic hypogonadism, which we have previously termed the 'Reprometabolic Syndrome.' To investigate potential factors involved in obesity-related reproductive endocrine dysfunction, we conducted a secondary analysis of inflammatory markers in a sample of normal weight women exposed to a one-month eucaloric high-fat diet (HFD), which, as reported earlier, induced the relative hypogonadotropic hypogonadism characteristic of Reprometabolic Syndrome. Eighteen healthy women with a BMI between 18.0-24.9kg/m2 and regular menstrual cycles participated in the study. Frequent blood sampling was performed during the early follicular phase before and after the one-month eucaloric HFD intervention (48% of calories from fat). Serum samples pooled from each participant were analyzed using immunoassay to measure levels of 30 cytokines, interleukins, and chemokines. Differences between pre- and post-HFD intervention measures were examined by one-sample t-tests. Exposure to the eucaloric HFD did not result in changes in body weight. HFD-induction of Reprometabolic Syndrome in normal weight women was associated with a significant elevation only in the anti- inflammatory cytokine IL-10 (p = 0.04). Eotaxin, IL-6 and MIP-1β also increased in response to the HFD, but not statistically significantly (p = 0.07). Results suggest that the increase in multiple inflammatory markers, typically associated with obesity, are not primary mediators of the relative hypogonadotropic hypogonadism of Reprometabolic Syndrome. Clinical Trials Registration Number: NCT02653092; Date of Registration: January 6, 2016.

Effects of Exercise Intensities on Changes in Pro-/Anti-inflammatory Cytokines following 8-weeks of Aerobic Exercise Training

Inflammatory cytokines are useful biomarkers in predicting the development of metabolic and cardiovascular diseases and may be positively affected by physical activity and weight loss. Despite much interest in chronic low-level inflammation in the obese population, effects of aerobic training intensity on inflammatory cytokines remain elusive. PURPOSE: The purpose of this study was to investigate effects of 8-week aerobic exercise training at high and low intensities on changes in pro-/anti-inflammatory cytokines. Methods: Fifty three inactive obese Hispanic females (mean BMI = 34.5 kg/m2, aged 34-46 years) were divided into one of three groups: low intensity training group (LT: walking at 55% VO2max, n=16), high intensity training group (HT: running at 70% VO2max, n=18), and control group (CON: no intervention, n=19). LT and HT performed aerobic exercises three times per week at the given intensities. Exercise volume for two exercise groups was equated relative to kilograms of body weight by adjusting duration of exercise session (approximately 60 minutes for LT and 40 minutes for HT per session). Blood samples were collected before and after 8 weeks of intervention to measure levels of adiponectin, C-reactive protein (CRP) and tumor necrosis factor-alpha (TNF-α). Two-way repeated measures ANOVA and Tukey post hoc tests were used for data analysis. Results: Level of adiponectin showed no significant change in any groups after 8 weeks of aerobic exercise intervention. A significant decrease in CRP was observed in the HT group only (4.12 ±.26mg/L mean±SE → 3.89±.37, P=.041), but levels of TNF-a were significantly decreased in both LT (4.57±.24pg/mL → 4.14±.31, P=.019) and HT (4.54±.25 → 4.02±.41, P=.011). No changes were observed in CON. CONCLUSIONS: Significant decreases in CRP and TNF-a were found following high intensity aerobic exercise training while low intensity training reduced TNF-a only. The greater changes of pro-inflammatory cytokines in HT indicates high intensity aerobic exercise training may be more beneficial than low intensity training. Specifically, for controlling low-grade inflammation and immune function in obese Hispanic females. This study confirmed results of previous studies suggesting that longer period of exercise training with distinct fat loss may be required to induce significant changes in adiponectin in obese adults. TAMIU university research grant. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

SHIP1 deficiency causes inflammation-dependent retardation in skeletal growth.

Inflammation and skeletal homeostasis are closely intertwined. Inflammatory diseases are associated with local and systemic bone loss, and post-menopausal osteoporosis is linked to low-level chronic inflammation. Phosphoinositide-3-kinase signalling is a pivotal pathway modulating immune responses and controlling skeletal health. Mice deficient in Src homology 2-containing inositol phosphatase 1 (SHIP1), a negative regulator of the phosphoinositide-3-kinase pathway, develop systemic inflammation associated with low body weight, reduced bone mass, and changes in bone microarchitecture. To elucidate the specific role of the immune system in skeletal development, a genetic approach was used to characterise the contribution of SHIP1-controlled systemic inflammation to SHIP1-dependent osteoclastogenesis. Lymphocyte deletion entirely rescued the skeletal phenotype in Rag2 -/- /Il2rg -/- /SHIP1 -/- mice. Rag2 -/- /Il2rg -/- /SHIP1 -/- osteoclasts, however, displayed an intermediate transcriptomic signature between control and Rag2 +/+ /Il2rg +/+ /SHIP1 -/- osteoclasts while exhibiting aberrant in vitro development and functions similar to Rag2 +/+ /Il2rg +/+ /SHIP1 -/- osteoclasts. These data establish a cell-intrinsic role for SHIP1 in osteoclasts, with inflammation as the key driver of the skeletal phenotype in SHIP1-deficient mice. Our findings demonstrate the central role of the immune system in steering physiological skeletal development.

Associations of inflammatory cytokines and cortisol with nonmotor features of Huntington's disease.

Huntington's disease (HD) is an inherited neurodegenerative disease involving progressive motor abnormalities, cognitive decline, and psychiatric disturbances. Depression and cognitive difficulties are among the most impactful symptoms of HD, yet the pathogenesis of these symptoms is not fully understood. HD involves low-level chronic inflammation and dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, which are linked to depression and cognitive impairment in non-HD populations. However, previous research on the relationships of these pathologies with depression and cognition in HD is limited and inconsistent. Fifty-three adults with the HD gene expansion (30 premanifest and 23 manifest) completed measures of depression and cognitive functioning. Forty-eight out of 53 participants provided hair samples for quantification of cortisol, and 34 participants provided blood samples for quantification of peripheral inflammatory cytokines. We examined the associations of four cytokines (interleukin [IL]-6, IL-10, IL-1β, and tumor necrosis factor [TNF]-α) and cortisol levels with depression and cognitive scores. In unadjusted models, higher levels of plasma IL-6, IL-10, and TNF-α correlated with higher depression scores, and higher levels of IL-10 and TNF-α correlated with poorer cognitive performance. After controlling for age, sex, and body mass index, only the correlations of IL-10 with depression and cognitive performance remained significant. No correlations were evident with hair cortisol. Peripheral inflammation is associated with depression symptoms and cognitive impairment in HD. Our findings suggest that interactions between the immune and nervous systems are important in HD, and highlight the potential of chronic inflammation as a therapeutic target in early stages of HD.

Иммуновоспалительные механизмы старения мочевого пузыря.

Introduction. Despite the absence of a generally accepted theory explaining the mechanisms of aging, existing scientific data indicate a close relationship between aging and chronic low-grade inflammation (low-grade inflammation). This theory of inflammatory aging (inflame-aging) suggests that aging is accompanied by the development of a chronic inflammatory phenotype, which ultimately leads to fibroplastic transformation of tissues, which manifests itself in a functional deficiency of organs and, in particular, the bladder. Aims. To study the role of free radical oxidation, endothelial dysfunction and low-level age-associated inflammation as universal mechanisms of cellular senescence in the process of age-related detrusor rearrangement in experimental animals. Materials and methods. Two groups of laboratory animals were used in the experiment: group 1 (30-month-old white mongrel rats, n=10) and group 2 (10- month-old white mongrel rats, n=10). Markers of low-level age-associated inflammation (TNF-α, IL-6, IL1RA), endothelial dysfunction (ET-1, IL-1β, ESM1), profibrotic status (TGF beta 1 and CTGF), and free radical oxidation (8-isoprostane) were determined in blood and bladder homogenate, malonic dialdehyde, diene conjugates).The Student's criterion was used to compare two groups with a normal distribution. Results and discussion. It was shown that with age in experimental animals, the levels of inflammation markers (TNF-α, IL-6, IL1RA), endothelial dysfunction (ET-1, IL-1β, ESM1), lipid peroxidation (diene conjugates, silicone dialdehyde) and profibrotic cytokines (TGF beta 1 and CTGF) increased, while the levels of antioxidant activity (catalase) decreased statistically significantly.This pattern was revealed both at the systemic (blood plasma) and organ levels (bladder wall). Conclusion. The results of our experimental study confirm the role of chronic low-level inflammation in fibrosis-mediated inflammatory aging of organs and, in particular, in age-associated bladder reconstruction.

Molecular dynamic of omega-3 compounds as an anti-obesity agent into GPR-120 receptor

Obesity is a cause of comorbid diseases such as type 2 diabetes mellitus, dyslipidemia, hypertension which is based on low-level chronic inflammation. The GPR-120 receptor plays a role in insulin sensitization which is related to diabetes mellitus which is a comorbid obesity. Omega-3 fatty acids are believed to possess anti-inflammatory properties, hence potentially serving as a preventive measure against obesity-related comorbidities. The aim of this study is to do a stability analysis of the binding affinity between nine specific chemicals derived from omega-3 and the active site of the human GPR120 receptor using molecular dynamics simulations. Docking analysis was performed using Discovery Studio Visualizer, AutoDock Tools 1.5.6, and molecular dynamic simulation with AMBER 16. In this study, we used neurotensin 8–13 as a natural ligand to bind with the neurotensin receptor. Based on the neurotensin receptor docking results, the ΔG values for the following compounds are close to the values for neurotensin 8–13 -6.41 kcal/mol; docosahexaenoic acid -8.96 kcal/mol; eicosapentaenoic acid -7.41 kcal/mol; and heneicosapentaenoic acid -6.34 kcal/mol. Neurotensin 8–13 forms hydrogen bonds with TYR146, ARG213, and PHE344 of the neurotensin receptor, whereas docosahexaenoic acid forms hydrogen bonds with TYR146. Meanwhile, the average RMSD fluctuations for each system, namely docosahexaenoic acid, eicosapentaenoic acid, and heneicosapentaenoic acid, were 0.672, 0.437, and 0.650, respectively. The SASA of the neurotensin receptor-ligand complex showed similar fluctuations, with the average values for docosahexaenoic acid, eicosapentaenoic acid, and heneicosapentaenoic acid being 230.40, 229.89, and 230.20 nm2.

Beyond Inflammaging: The Impact of Immune System Aging on Age-Related Muscle Decline, Results From the InCHIANTI Study.

Aging is characterized by chronic low-level inflammation and is associated with geriatric syndromes such as sarcopenia and frailty. Our aim was to evaluate the longitudinal variation of muscle area, muscle quality, and muscle strength, relative to the variation of leukocyte-derived markers, and to assess the presence of a pathway of associations among derived leukocyte ratios, and the components of muscle health. The InCHIANTI is a longitudinal cohort study of aging that began in 1998 with follow-up visits every 3 years. Out of the 1 453 participants enrolled at baseline, this study includes 1 179 participants with complete data. Muscle strength was assessed by hand grip strength test, whereas muscle density and fat area were considered as indirect markers of muscle quality, derived from peripheral quantitative computed tomography of the calf. Muscle area was associated with neutrophil-to-lymphocyte ratio (NL-ratio), age, gender, comorbidities, and body mass index (BMI). Muscle density variation over time was inversely associated with age, comorbidities, and BMI, while being positively associated with monocyte-to-lymphocyte ratio (ML-ratio) and male gender. Fat area was inversely associated with age, interleukine-6 (IL-6), male gender, and NL-ratio, while being positively associated with ML-ratio, comorbidities, and BMI. Handgrip strength decreased with age, IL-6 levels, comorbidities, and NL-ratio, but increased with ML-ratio, being male, and having a higher BMI. In a path-analysis model, ML-ratio positively correlates with muscle mass, density, and strength, while NL-ratio only correlates inversely with muscle mass and density. NL-ratio and ML-ratio are associated with aging and may be implicated in age-related mechanisms that affect body composition and muscle strength. These ratios may represent a link between aging of the immune system and decline of muscle health with aging. However, further studies are needed to identify their usefulness for early detection of sarcopenia, myosteatosis, and frailty in the older adult.

The Evaluation of Serum Endocan, Interleukin-6, and CRP Levels Following Sleeve Gastrectomy.

The excessive accumulation of fat tissue in obesity is the source of chronic low-level inflammation and causes future dysmetabolic and cardiovascular disorders. Removal of this excessive fat tissue with the aid of bariatric surgery (BS) techniques, such as sleeve gastrectomy, may reverse adverse inflammatory outcomes. The aim of this study is to investigate the impact of sleeve gastrectomy on inflammatory markers, specifically endocan, IL-6, and CRP, in individuals with obesity. Thirty-two patients with class 3 obesity and class 2 obesity + comorbidities were enrolled in the study. Clinical characteristics including age, comorbidity, body mass index (BMI), waist, and hip circumferences of the participants were noted before and 3 months after sleeve gastrectomy. Blood samples were collected during those periods to assess biochemical features such as serum endocan, interleukin-6 (IL-6), C-reactive peptide, fasting insulin, glycosylated hemoglobin A1c levels, and lipid panel. A statistical package program was used for the analysis of those parameters, and p<0.05 was accepted as significant at a 95.0% confidence interval. BMI reduced from 43.55±6.78 to 36.16±6.14 kg/m2 within 3 months following BS (p<0.001). Preoperative serum endocan, IL-6, and CRP levels were correlated with BMI, and in line with BMI reduction, their serum levels decreased after BS (p<0.05). HOMA-IR also reduced after BS, and both in the pre and post-BS periods correlated with BMI, IL-6, endocan, and CRP levels (p<0.05). The mean total body weight loss was 20.4% within 3 months post-BS. BS techniques are effective in weight loss and reversing the inflammatory processes caused by obesity. Serum endocan, IL-6, and CRP levels are promising markers for describing obesity-related inflammation and objectively checking the alleviation of inflammation following BS.

P-670 Altered immunological conditions in women with PCOS and its correlation with the development and progression in infertile women with severe polycystic ovaries

Abstract Study question What is the impact of the dysfunctional lymphoid cells on the development and progression in infertile women with severe polycystic ovaries syndrome (SPCOS). Summary answer The dysfunctional lymphoid cells in immune system was deeply correlated with follicular remodeling, which prompting the progression of SPCOS. What is known already PCOS has been confirmed as a low-level chronic inflammation impacting on ovulation and luteinization regulated by a cytokine-mediated inflammatory response orchestrated by lymphocytes, granulocytes, and macrophages. However, the exact relationship between immunologic dysfunction and the pathogenesis of PCOS is still not clarified. Study design, size, duration A prospective cohort study including a total of 129 women aged 18 to 35 years were enrolled. PCOS patients with polycystic ovaries (ultrasound measurement of the number of ≥ 80 follicles ≥3 mm in diameter) were referred to SPCOS in this study. Peripheral Blood (PB) were collected to detect the immunological changes by using flow cytometry: CD8+ T cell (CD3+,CD8+); CD4+ T cell (CD3+,CD4+); NK cell (CD45+,CD3-,CD56+); NKT cell (CD45+,CD3+,CD56+); Treg cell (CD4+CD25hi); B cell (CD3-CD19+). Participants/materials, setting, methods PB from SPCOS cohort (n = 64) and healthy controls (n = 115) were collected to detect the immunological conditions. Furthermore, the discarded tissues from SPCOS patients (n = 5) who needed to avoid OHSS by surgical ovarian wedge resection and women undergoing fertility preservation procedures (n = 3) were digested to single cell suspension, which were used to outline the ovarian homeostasis changes by using scRNA-seq. Main results and the role of chance Peripheral blood NK cells from SPCOS patients were significantly decreased than those from healthy group (10.7% vs. 14.9 ± 6.2%, p = 0.04). Conversely, NKT cells in the PB of the SPCOS women were 11.2% vs. 6.9 ± 3.5% (P = 0.02), while B lymphocytes were 15.6% vs. 12.6 ± 4.2% (P = 0.04), compared to healthy controls. Furthermore, the immune cells and distinct cellular clusters of SPCO were disturbed in severe polycystic ovaries. The CD8+ T cell populations in ovarian of SPCOS group were strongly decreased (32.49% vs.22.35%, p &amp;lt; 0.001) and T cell activation signaling was downregulated by lowly expressed PTPRC, APBB1IP, LCP11 and MX12. Besides, the cytotoxicity-associated genes IFNG and TNF were highly expressed, especially in CD4+ T cells. The chemokines released by activated CD4+ T cells may increase the production and recruitment of CD8+ T cell and induce the compositional and functional alteration of ovarian, thereby prompting the progression of PCOS. Limitations, reasons for caution The study group is limited and transcriptome analysis covers much, but not enough. Although suggestive associations between immunological conditions and the severity of PCOS have concluded, additional animal models studies should be conducted to confirm our findings further. Wider implications of the findings The expression profiles of lymphoid cells provide deep insight into the molecular mechanisms of PCOS. Signaling receptors and gene data set will aid in future studies on the interorgan communication. It also facilitated discovery of novel biomarker for PCOS diagnosis and new immunological treatment. Trial registration number Not applicable

Aspalathus linearis (Rooibos) Targets Adipocytes and Obesity-Associated Inflammation

Excess weight and obesity are the fifth leading cause of death globally, and sustained efforts from health professionals and researchers are required to mitigate this pandemic-scale problem. Polyphenols and flavonoids found in Aspalathus linearis-a plant widely consumed as Rooibos tea-are increasingly being investigated for their positive effects on various health issues including inflammation. The aim of our study was to examine the effect of Rooibos extract on obesity and the associated low-grade chronic inflammatory state by testing antioxidant activity, cytokine secretions, macrophage polarization and the differentiation of human adipocytes through the development of adipospheroids. Rooibos extract significantly decreased ROS production and the secretion of pro-inflammatory cytokines (IFN-γ, IL-12, IL-2 and IL-17a) in human leukocytes. Additionally, Rooibos extract down-regulated LPS-induced macrophage M1 polarization, shown by a significant decrease in the expression of pro-inflammatory cytokines: TNFα, IL-8, IL-6, IL-1β and CXCL10. In addition, Rooibos inhibited intracellular lipid accumulation and reduced adipogenesis by decreasing the expression of PPARγ, Ap2 and HSL in adipospheroids. A significant decrease in leptin expression was noted and this, more interestingly, was accompanied by a significant increase in adiponectin expression. Using a co-culture system between macrophages and adipocytes, Rooibos extract significantly decreased the expression of all studied pro-inflammatory cytokines and particularly leptin, and increased adiponectin expression. Thus, adding Rooibos tea to the daily diet is likely to prevent the development of obesity associated with chronic low-level inflammation.

Relationship between Sleep Quality and Low Inflammation in Medical Students of Universitas Nusa Cendana

Sleep is one of the basic human physiological needs that can restore the body to its physiological functions after daily activities. Lack of sleep quality can significantly impact the body, one of the effects of which is related to chronic low-level inflammation and changes in the competence of the immune system. This research aims to knowing the relationship between sleep quality levels and Neutrophil Lymphocyte Ratio and Platelet Lymphocyte Ratio in medical students of Universitas Nusa Cendana. It is an observational analytical study using the cross-sectional method. The number of research samples was determined using a hypothesis test formula against relative risk, with a total sample of 54 people. The population of this study is the class of 2019, 2020, and 2021 using the proportionate stratified random sampling technique, which divides populations into sub-populations in a propositional and random manner. The relationship test used is the ETA test. Based on the results of relationship testing using the ETA test, sleep quality with Neutrophil Lymphocyte Ratio and Platelet Lymphocyte Ratio shows that sleep quality has no significant relationship with Neutrophil Lymphocyte Ratio (p-value = 0,324); however, it has a significant relationship with the Platelet Lymphocyte Ratio (p-value = 0,042). Sleep quality does not have a significant relationship with the Neutrophil Lymphocyte Ratio but has a significant relationship with the Platelet Lymphocyte Ratio. 228 kata.

Salivary cortisol awakening levels are reduced in human subjects with intermittent explosive disorder compared with controls

BackgroundThe role of the hypothalamic-pituitary-adrenal (HPA) axis in human aggressive behavior is poorly characterized, though some studies report that, unlike depression, circulating or salivary levels of cortisol are low compared with controls. MethodsIn this study, we collected three salivary cortisol levels (two in the morning and one in the evening) on three separate days in 78 adult study participants with (n = 28) and without (n = 52) prominent histories of impulsive aggressive behavior. Plasma C-Reactive Protein (CRP) and Interleukin-6 (IL-6) were also collected in most study participants. Aggressive study participants meet DSM-5 criteria for Intermittent Explosive Disorder (IED) while non-aggressive participants either had a history of a psychiatric disorder or no such history (Controls). ResultsMorning, but not evening, salivary cortisol levels were significantly lower in IED (p < 0.05), compared with control, study participants. In addition, salivary cortisol levels correlated with measures of trait anger (partial r = −0.26, p < 0.05) and aggression (partial r = −0.25, p < 0.05) but not with measures of impulsivity, psychopathy, depression, history of childhood maltreatment, or other tested variables that often differ in individuals with IED. Finally, plasma CRP levels correlated inversely with morning salivary cortisol levels (partial r = −0.28, p < 0.05); plasma IL-6 levels showed a similar, though not statistically significant (rp = −0.20, p = 0.12) relationship with morning salivary cortisol levels. ConclusionThe cortisol awakening response appears to be lower in individuals with IED compared with controls. In all study participants, morning salivary cortisol levels correlated inversely with trait anger, trait aggression, and plasma CRP, a marker of systemic inflammation. This suggests the present of a complex interaction between chronic-low level inflammation, the HPA axis, and IED that warrants further investigation.

Abstract B024: Deconvolution by scRNAseq, scATACseq and functional genomics of impact of a relevant high risk diet on stem cells and homeostasis

Abstract Dietary patterns are major determinants of sporadic colon cancer incidence, the vast majority of the disease. NWD1 is a unique purified rodent diet that establishes mouse exposure to key nutrients recapitulating levels linked to higher risk in human, and is the only mouse model that develops sporadic intestinal and colon tumors, reflecting the etiology, incidence, frequency and lag with developmental age of the human disease. NWD1 fed mice reflect human metabolic syndrome with chronic inflammation, exhibit elevated Wnt signaling throughout the small and large intestinal mucosa and altered lineage marker expression, but Lgr5hi cells are suppressed in their lineage tracing, accumulation of mutations, and efficiency in tumor initiation. Alternate cells are mobilized to maintain the mucosa with increased efficiency to cause tumors. Deconvolving impact of NWD1 using scRNAseq, scATACseq and functional genomics provided novel insight into mechanisms elevating risk for sporadic tumors. NWD1 extensively, rapidly, and reversibly reprogrammed Lgr5hi stem cells, down-regulating Ppargc1a expression that altered mitochondrial structure and function and suppressed Oxphos and the TCA cycle. Ppargc1a genetic knockout in Lgr5hi cells recapitulated the dietary effects, and NWD1 or Ppargc1a inactivation repressed developmental maturation of Lgr5hi cell progeny as cells progressed through progenitor cell compartments. In compensation, mobilized Bmi1+, Ascl2hi cells maintained and adapted the mucosa. In parallel, NWD1 altered Ppargc1a chromatin structure in stem cells, and also for genes adapting enterocytes to the diet, independently confirming NWD1 epigenetic reprogramming of stem and differentiated cells. Importantly, pathways of antigen processing and presentation were elevated, especially in mature enterocytes, a pathogenic mechanism causing human chronic low-level pro-tumorigenic inflammation in IBD, also present in NWD1 fed mice. Fundamental conclusions: 1) plasticity of cells to function as stem cells mediates physiological adaptation of the mucosa. Thus, the human mucosa is in constant flux in response to its environment, supporting historic concepts of homeostasis by Claude Bernard and Walter Cannon as a continual process of tissue adaptation to its environment, not a single optimized state. 2) our data and the literature suggest that failure to recapitulate key human nutritional exposures contributes to why human stem cells reach crypt clonality in 6 years, 50-fold longer than the 6 weeks in the mouse. Thus, better modeling of human nutritional exposures in the mouse more accurately reflects human mechanisms of homeostasis and pathogenesis. 3) Complexity of cell reprogramming reported for the earliest premalignant human colon tumors is already present in the mucosa at nutritional risk for tumor development. 4) Oncogenic mutations provide a competitive advantage to intestinal stem cells in tumorigenesis, but the competition takes place on a playing field sculpted by the nutritional environment, a major determinant of who wins. Citation Format: Jiahn Choi, Xusheng Zhang, Wenge Li, Michele Houston, Karina Peregrina, Robert Dubin, Kenny Ye, Leonard H. Augenlicht. Deconvolution by scRNAseq, scATACseq and functional genomics of impact of a relevant high risk diet on stem cells and homeostasis [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer; 2022 Oct 1-4; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_1):Abstract nr B024.

Ageing and Low-Level Chronic Inflammation: The Role of the Biological Clock.

Ageing is a multifactorial physiological manifestation that occurs inexorably and gradually in all forms of life. This process is linked to the decay of homeostasis due to the progressive decrease in the reparative and regenerative capacity of tissues and organs, with reduced physiological reserve in response to stress. Ageing is closely related to oxidative damage and involves immunosenescence and tissue impairment or metabolic imbalances that trigger inflammation and inflammasome formation. One of the main ageing-related alterations is the dysregulation of the immune response, which results in chronic low-level, systemic inflammation, termed "inflammaging". Genetic and epigenetic changes, as well as environmental factors, promote and/or modulate the mechanisms of ageing at the molecular, cellular, organ, and system levels. Most of these mechanisms are characterized by time-dependent patterns of variation driven by the biological clock. In this review, we describe the involvement of ageing-related processes with inflammation in relation to the functioning of the biological clock and the mechanisms operating this intricate interaction.

MicroRNA signature of leukocytes in the context of chronic systemic inflammation in vascular dementia

Chronic low-level inflammation during the aging process is a key risk factor for the activation of resident cells of the brain innate immune system of the (microglia and astrocytes). Such activation leads to the development of neuroinflammation and cognitive impairment which are typical to neurodegenerative diseases such as Alzheimers disease, vascular dementia, Parkinson disease etc. Currently, there is a lack of minimally invasive, affordable methods for diagnosing age-related neurodegenerative diseases and drugs that could slow down or prevent their progression. Hence, a search for new peripheral biomarkers is required, both for diagnostics and monitoring the efficiency of drug therapy. The option of using microRNAs as such biomarkers is under discussion. Our goal was to identify a leukocyte microRNA signature in vascular dementia as compared with healthy aging and reproductive age, in view of inflammation and cognitive deficits. We have examined 54 persons from young to senile age who were classified into the following groups: Vascular dementia, Healthy aging and Reproductive age. Expression of miRNAs known as regulators of communications between the immune and nervous systems (let-7d, let-7g, miR-21, miR-124, miR-146a, miR-155, miR-342-3p) was measured in peripheral blood leukocytes. The decision to study leukocytes was made, since these blood cells are responsible for immune functions, and, especially, cytokine production during aging. Total RNA was isolated by phenol-chloroform technique. The microRNA expression was determined by quantitative polymerase chain reaction with SYBRGreen. The U6 gene of small nuclear DNA was used as a reference housekeeping gene. The differences between groups were determined using the KruskalWallis test with post hoc pairwise comparisons according to ConoverInman. As a result of the study, it was found that the expression of microRNA-21 and microRNA-342 in leukocytes of elderly/senile people, both in healthy aging and in vascular dementia, was increased when compared to the persons in their reproductive age. In the persons with vascular dementia, the expression level of miRNA-124 and miRNA-342 in peripheral blood leukocytes was higher than in healthy aging group. Hence,, microRNA-124 and microRNA-342 may be informative biomarkers for the diagnostics of vascular dementia. However, large-scale studies of their biomarker potential are warranted.

Early onset of senescence and imbalanced epidermal homeostasis across the decades in photoexposed human skin: Fingerprints of inflammaging.

Inflammaging is a theory of ageing which purports that low-level chronic inflammation leads to cellular dysfunction and premature ageing of surrounding tissue. Skin is susceptible to inflammaging because it is the first line of defence from the environment, particularly solar radiation. To better understand the impact of ageing and photoexposure on epidermal biology, we performed a system biology-based analysis of photoexposed face and arm, and photoprotected buttock sites, from women between the ages of 20s to 70s. Biopsies were analysed by histology, transcriptomics, and proteomics and skin surface biomarkers collected from tape strips. We identified morphological changes with age of epidermal thinning, rete ridge pathlength loss and stratum corneum thickening. The SASP biomarkers IL-8 and IL-1RA/IL1-α were consistently elevated in face across age and cis/trans-urocanic acid were elevated in arms and face with age. In older arms, the DNA damage response biomarker 53BP1 showed higher puncti numbers in basal layers and epigenetic ageing were accelerated. Genes associated with differentiation and senescence showed increasing expression in the 30s whereas genes associated with hypoxia and glycolysis increased in the 50's. Proteomics comparing 60's vs 20's confirmed elevated levels of differentiation and glycolytic-related proteins. Representative immunostaining for proteins of differentiation, senescence and oxygen sensing/hypoxia showed similar relationships. This system biology-based analysis provides a body of evidence that young photoexposed skin is undergoing inflammaging. We propose the presence of chronic inflammation in young skin contributes to an imbalance of epidermal homeostasis that leads to a prematurely aged appearance during later life.

445 Oat components provide skin protection against exposomal-factor-induced damages, increase ceramide production and balance skin’s pH in vitro

Our skin is under continuous assault from damaging exposomal factors ultraviolet irradiation, heat and cold temperatures, air pollutants smoke and ozone which alter the skin barrier, affect skin sensitivity, and can increase chronic low-level inflammation accelerating the skin aging process (inflammaging) and exacerbate symptoms of compromised skin. Studies have shown anti-inflammatory properties of oat (Avena sativa). Furthermore, oat-containing topical treatments showed significant clinical improvements in a variety of skin concerns, including erythema, pruritus, and atopic dermatitis.