Proteostasis in T cell aging.

Aging leads to a decline in immune cell function, which leaves the organism vulnerable to infections and age-related multimorbidities. One major player of the adaptive immune response are T cells, and recent studies argue for a major role of disturbed proteostasis contributing to reduced function of these cells upon aging. Proteostasis refers to the state of a healthy, balanced proteome in the cell and is influenced by synthesis (translation), maintenance and quality control of proteins, as well as degradation of damaged or unwanted proteins by the proteasome, autophagy, lysosome and cytoplasmic enzymes. This review focuses on molecular processes impacting on proteostasis in T cells, and specifically functional or quantitative changes of each of these upon aging. Importantly, we describe the biological consequences of compromised proteostasis in T cells, which range from impaired T cell activation and function to enhancement of inflamm-aging by aged T cells. Finally, approaches to improve proteostasis and thus rejuvenate aged T cells through pharmacological or physical interventions are discussed.

Age-dependent inflammatory response is altered in an ex vivo model of bacterial pneumonia.

BACKGROUND: Aging is associated with an increased incidence and mortality of Pseudomonas aeruginosa-induced pneumonias. This might be partly due to age-dependent increases in inflammatory mediators, referred to as inflamm-aging and a decline in immune functions, known as immunosenescence. Still, the impact of dysregulated immune responses on lung infection during aging is poorly understood. Here, we aimed to mimic inflamm-aging using ex vivo precision-cut lung slices (PCLS) and neutrophils - as important effector cells of innate immunity - from young and old mice and investigated the influence of aging on inflammation upon infection with P. aeruginosa bacteria. METHODS: Murine PCLS were infected with the P. aeruginosa standard lab strain PAO1 and a clinical P. aeruginosa isolate D61. After infection, whole-transcriptome analysis of the tissue as well as cytokine expression in supernatants and tissue lysates were performed. Responses of isolated neutrophils towards the bacteria were investigated by quantifying neutrophil extracellular trap (NET) formation, cytokine secretion, and analyzing expression of surface activation markers using flow cytometry. RESULTS: Inflamm-aging was observed by transcriptome analysis, showing an enrichment of biological processes related to inflammation, innate immune response, and chemotaxis in uninfected PCLS of old compared with young mice. Upon P. aeruginosa infection, the age-dependent pro-inflammatory response was even further promoted as shown by increased production of cytokines and chemokines such as IL-1ß, IL-6, CXCL1, TNF-α, and IL-17A. In neutrophil cultures, aging did not influence NET formation or cytokine secretion during P. aeruginosa infection. However, expression of receptors associated with inflammatory responses such as complement, adhesion, phagocytosis, and degranulation was lower in neutrophils stimulated with bacteria from old mice as compared to young animals. CONCLUSIONS: By using PCLS and neutrophils from young and old mice as immunocompetent ex vivo test systems, we could mimic dysregulated immune responses upon aging on levels of gene expression, cytokine production, and receptor expression. The results furthermore reflect the exacerbation of inflammation upon P. aeruginosa lung infection as a result of inflamm-aging in old age.

Binge ethanol exposure in advanced age elevates neuroinflammation and early indicators of neurodegeneration and cognitive impairment in female mice.

Binge drinking is rising among aged adults (>65 years of age), however the contribution of alcohol misuse to neurodegenerative disease development is not well understood. Both advanced age and repeated binge ethanol exposure increase neuroinflammation, which is an important component of neurodegeneration and cognitive dysfunction. Surprisingly, the distinct effects of binge ethanol exposure on neuroinflammation and associated degeneration in the aged brain have not been well characterized. Here, we establish a model of intermittent binge ethanol exposure in young and aged female mice to investigate the effects of advanced age and binge ethanol on these outcomes. Following intermittent binge ethanol exposure, expression of pro-inflammatory mediators (tnf-α, il-1ß, ccl2) was distinctly increased in isolated hippocampal tissue by the combination of advanced age and ethanol. Binge ethanol exposure also increased measures of senescence, the nod like receptor pyrin domain containing 3 (NLRP3) inflammasome, and microglia reactivity in the brains of aged mice compared to young. Binge ethanol exposure also promoted neuropathology in the hippocampus of aged mice, including tau hyperphosphorylation and neuronal death. We further identified advanced age-related deficits in contextual memory that were further negatively impacted by ethanol exposure. These data suggest binge drinking superimposed with advanced age promotes early markers of neurodegenerative disease development and cognitive decline, which may be driven by heightened neuroinflammatory responses to ethanol. Taken together, we propose this novel exposure model of intermittent binge ethanol can be used to identify therapeutic targets to prevent advanced age- and ethanol-related neurodegeneration.

Exploring the emerging bidirectional association between inflamm-aging and cellular senescence in organismal aging and disease.

There is strong evidence that most individuals in the elderly population are characterized by inflamm-aging which refers to a subtle increase in the systemic pro-inflammatory environment and impaired innate immune activation. Although a variety of distinct factors are associated with the progression of inflamm-aging, emerging research is demonstrating a dynamic relationship between the processes of cellular senescence and inflamm-aging. Cellular senescence is a recognized factor governing organismal aging, and through a characteristic secretome, accumulating senescent cells can induce and augment a pro-inflammatory tissue environment that provides a rationale for immune system-independent activation of inflamm-aging and associated diseases. There is also accumulating evidence that inflamm-aging or its components can directly accelerate the development of senescent cells and ultimately senescent cell burden in tissues in a likely vicious inflammatory loop. The present review is intended to describe the emerging senescence-based molecular etiology of inflamm-aging as well as the dynamic reciprocal interactions between inflamm-aging and cellular senescence. Therapeutic interventions concurrently targeting cellular senescence and inflamm-aging are discussed and limitations as well as research opportunities have been deliberated. An effort has been made to provide a rationale for integrating inflamm-aging with cellular senescence both as an underlying cause and therapeutic target for further studies.

Monocyte-driven inflamm-aging reduces intestinal barrier function in females.

BACKGROUND: The intestinal barrier encompasses physical and immunological components that act to compartmentalize luminal contents, such as bacteria and endotoxins, from the host. It has been proposed that an age-related decline of intestinal barrier function may allow for the passage of luminal contents into the bloodstream, triggering a low-grade systemic inflammation termed inflamm-aging. Although there is mounting evidence to support this hypothesis in model species, it is unclear if this phenomenon occurs in humans. In addition, despite being well-established that biological sex impacts aging physiology, its influence on intestinal barrier function and inflamm-aging has not been explored. RESULTS: In this study, we observed sex differences in markers of intestinal barrier integrity, where females had increased epithelial permeability throughout life as compared to males. With age, females had an age-associated increase in circulating bacterial products and metabolites such as LPS and kynurenine, suggesting reduced barrier function. Females also had age-associated increases in established markers of inflamm-aging, including peripheral blood monocytes as well as TNF and CRP. To determine if impaired barrier function was driving inflamm-aging, we performed a mediation analysis. The results show that the loss of intestinal barrier integrity was not the mediator of inflamm-aging in humans. Instead, persistent, low-grade inflammation with age preceded the increase in circulating bacterial products, which we confirmed using animal models. We found, as in humans, that sex modified age-associated increases in circulating monocytes in mice, and that inflammation mediates the loss of intestinal barrier function. CONCLUSION: Taken together, our results suggest that higher basal intestinal permeability in combination with age-associated inflammation, increases circulating LPS in females. Thus, targeting barrier permeability in females may slow the progression of inflamm-aging, but is unlikely to prevent it.

Relationship between Hypoxia and Hypercapnia Tolerance and Life Expectancy.

The review discusses the potential relationship between hypoxia resistance and longevity, the influence of carbon dioxide on the mechanisms of aging of the mammalian organism, and intermittent hypercapnic-hypoxic effects on the signaling pathways of aging mechanisms. In the article, we focused on the potential mechanisms of the gero-protective efficacy of carbon dioxide when combined with hypoxia. The review summarizes the possible influence of intermittent hypoxia and hypercapnia on aging processes in the nervous system. We considered the perspective variants of the application of hypercapnic-hypoxic influences for achieving active longevity and the prospects for the possibilities of developing hypercapnic-hypoxic training methods.

Exploring the Pathophysiology of Long COVID: The Central Role of Low-Grade Inflammation and Multisystem Involvement.

Long COVID (LC), also referred to as Post COVID-19 Condition, Post-Acute Sequelae of SARS-CoV-2 Infection (PASC), and other terms, represents a complex multisystem disease persisting after the acute phase of COVID-19. Characterized by a myriad of symptoms across different organ systems, LC presents significant diagnostic and management challenges. Central to the disorder is the role of low-grade inflammation, a non-classical inflammatory response that contributes to the chronicity and diversity of symptoms observed. This review explores the pathophysiological underpinnings of LC, emphasizing the importance of low-grade inflammation as a core component. By delineating the pathogenetic relationships and clinical manifestations of LC, this article highlights the necessity for an integrated approach that employs both personalized medicine and standardized protocols aimed at mitigating long-term consequences. The insights gained not only enhance our understanding of LC but also inform the development of therapeutic strategies that could be applicable to other chronic conditions with similar pathophysiological features.

[Identification of Osteoarthritis Inflamm-Aging Biomarkers by Integrating Bioinformatic Analysis and Machine Learning Strategies and the Clinical Validation]. / ç”Ÿç‰©ä¿¡æ¯å­¦å’Œæœºå™¨å­¦ä¹ ç­–ç•¥è¯†åˆ«éª¨å ³èŠ‚ç‚Žç‚Žæ€§è¡°è€ç”Ÿç‰©æ ‡å¿—ç‰©ä¸Žä¸´åºŠéªŒè¯.

Objective: To identify inflamm-aging related biomarkers in osteoarthritis (OA). Methods: Microarray gene profiles of young and aging OA patients were obtained from the Gene Expression Omnibus (GEO) database and aging-related genes (ARGs) were obtained from the Human Aging Genome Resource (HAGR) database. The differentially expressed genes of young OA and older OA patients were screened and then intersected with ARGs to obtain the aging-related genes of OA. Enrichment analysis was performed to reveal the potential mechanisms of aging-related markers in OA. Three machine learning methods were used to identify core senescence markers of OA and the receiver operating characteristic (ROC) curve was used to assess their diagnostic performance. Peripheral blood mononuclear cells were collected from clinical OA patients to verify the expression of senescence-associated secretory phenotype (SASP) factors and senescence markers. Results: A total of 45 senescence-related markers were obtained, which were mainly involved in the regulation of cellular senescence, the cell cycle, inflammatory response, etc. Through the screening with the three machine learning methods, 5 core senescence biomarkers, including FOXO3, MCL1, SIRT3, STAG1, and S100A13, were obtained. A total of 20 cases of normal controls and 40 cases of OA patients, including 20 cases in the young patient group and 20 in the elderly patient group, were enrolled. Compared with those of the young patient group, C-reactive protein (CRP), interleukin (IL)-6, and IL-1ß levels increased and IL-4 levels decreased in the elderly OA patient group (P<0.01); FOXO3, MCL1, and SIRT3 mRNA expression decreased and STAG1 and S100A13 mRNA expression increased (P<0.01). Pearson correlation analysis demonstrated that the selected markers were associated with some indicators, including erythrocyte sedimentation rate (ESR), IL-1ß, IL-4, CRP, and IL-6. The area under the ROC curve of the 5 core aging genes was always greater than 0.8 and the C-index of the calibration curve in the nomogram prediction model was 0.755, which suggested the good calibration ability of the model. Conclusion: FOXO3, MCL1, SIRT3, STAG1, and S100A13 may serve as novel diagnostic biomolecular markers and potential therapeutic targets for OA inflamm-aging.

Short-chain fatty acids improve inflamm-aging and acute lung injury in old mice.

A chronic proinflammatory milieu (inflamm-aging) is observed in the elderly and associated with poorer prognosis in acute lung injury (ALI). Gut microbiome-derived short-chain fatty acids (SCFAs) are known to have immunomodulatory capabilities, but their function in the gut-lung axis in aging is poorly understood. Here, we analyzed the gut microbiome and its impact on inflammatory signaling in the aging lung and tested the effects of SCFAs in young (3 mo) and old (18 mo) mice that received either drinking water with a mixture of each 50 mM acetate, butyrate, and propionate for 2 wk or water alone. ALI was induced by intranasal lipopolysaccharide (LPS; n = 12/group) administration. Controls (n = 8/group) received saline. Fecal pellets were sampled for gut microbiome analysis before and after LPS/saline treatment. The left lung lobe was collected for stereology and right lung lobes for cytokine and gene expression analysis, inflammatory cell activation, and proteomics. Different gut microbial taxa, such as Bifidobacterium, Faecalibaculum, and Lactobacillus correlated positively with pulmonary inflammation in aging, suggesting an impact on inflamm-aging in the gut-lung axis. The supplementation of SCFAs reduced inflamm-aging, oxidative stress, metabolic alteration, and enhanced activation of myeloid cells in the lungs of old mice. The enhanced inflammatory signaling in ALI of old mice was also reduced by SCFA treatment. In summary, the study provides new evidence that SCFAs play a beneficial role in the gut-lung axis of the aging organism by reducing pulmonary inflamm-aging and ameliorating enhanced severity of ALI in old mice.

Unveiling the molecular basis of inflamm-aging induced by advanced glycation end products (AGEs)-modified human serum albumin (AGE-HSA) in patients with different immune-mediated diseases.

Increased serum advanced glycation end products (AGEs) are commonly found in the patients with Diabetes mellitus (DM), aging-related diseases, and immune-mediated diseases. These diseases are notorious for vasculopathy, immune dysfunctions, and low-grade inflammation mimicking inflamm-aging. However, the molecular basis of inflamm-aging related to AGEs remains elucidation. In this study, we incubated human serum albumin (HSA) and glucose at 37 °C in 5% CO2 incubator for 0-180 days to generate AGE-HSA. We found the mixture gradually changing the color from transparancy to brown color and increased molecular weight during incubation. The pH value also gradually decreased from 7.2 to 5.4 irrelevant to ionic charge or [Ca2+] concentration, but dependent on gradual glycation of the alkaline amino acids, lysine and arginine. Functionally, 40 µg/mL of AGE-HSA decreased IL-2 production from human Jurkat T cell line via suppressing p-STAT3, p-STAT4, and p-STAT6 with an increased tendency of senescence-associated ß-galactosidase (SA-ßgal) expression but irrelevant to change of Th1/Th2/Treg subpopulations. In contrast, AGE-HSA enhanced CC motif chemokine ligand 5 (CCL-5), IL-8, macrophage migration inhibitor factor (MIF), and interleukin 1 receptor antagonist (IL-1Ra) but suppressed SA-ßgal expression by human macrophage-like THP-1 cells. Interestingly, AGE-HSA abrogated the HSA-induced soluble intercellular adhesion molecules 1 (sICAM-1), sE-selectin and endothelin release from human coronary artery endothelial cells (HCAEC) and enhanced SA-ßgal expression. The accelerated and increased HSA glycations by individual inflammation-related cytokine such as IL-2, IL-6, IL-17, TGF-ß, or TNF-α in the in vitro study reflect increased serum AGE levels in patients with immune-mediated diseases. In conclusion, AGE-HSA can exert immunosuppresive, inflammatory and vasculopathic effects mimicking inflamm-aging in these patients.

Hyperglycaemia aggravates periodontal inflamm-aging by promoting SETDB1-mediated LINE-1 de-repression in macrophages.

AIM: To explore whether hyperglycaemia plays a role in periodontal inflamm-aging by inducing phenotypical transformation of macrophages, as well as the potential mechanism via SET domain-bifurcated histone lysine methyltransferase 1 (SETDB1). MATERIALS AND METHODS: A hyperglycaemic mouse model was established using streptozotocin injection. The alveolar bone was analysed using micro-computed tomography. Periodontal inflamm-aging was detected using western blotting, quantitative real-time PCR and immunohistochemical analysis. In vitro, RAW 264.7 macrophages were incubated with various doses of glucose. siRNA or overexpression plasmids were used to determine the regulatory mechanism of SETDB1 in macrophage senescence and inflamm-aging under hyperglycaemic conditions. Expression and distribution of SETDB1 and long interspersed element 1 (LINE-1) in gingival tissues of patients with or without diabetes were detected using immunofluorescent staining. RESULTS: SETDB1 expression in the periodontal tissues of patients and mice with diabetes was down-regulated compared with that in non-diabetic controls. SETDB1 deficiency induced senescence-like phenotypical changes in macrophages, which aggravated periodontal inflamm-aging in diabetic mice. Furthermore, metformin treatment rejuvenated SETDB1 activity and alleviated the hyperglycaemia-induced periodontal inflamm-aging. CONCLUSIONS: The findings of this study show that SETDB1 regulates senescence-like phenotypical switching of macrophages and is a potential candidate for the treatment of diabetes-induced periodontal inflamm-aging.

Changes in the Mitochondria in the Aging Process-Can α-Tocopherol Affect Them?

Aerobic organisms use molecular oxygen in several reactions, including those in which the oxidation of substrate molecules is coupled to oxygen reduction to produce large amounts of metabolic energy. The utilization of oxygen is associated with the production of ROS, which can damage biological macromolecules but also act as signaling molecules, regulating numerous cellular processes. Mitochondria are the cellular sites where most of the metabolic energy is produced and perform numerous physiological functions by acting as regulatory hubs of cellular metabolism. They retain the remnants of their bacterial ancestors, including an independent genome that encodes part of their protein equipment; they have an accurate quality control system; and control of cellular functions also depends on communication with the nucleus. During aging, mitochondria can undergo dysfunctions, some of which are mediated by ROS. In this review, after a description of how aging affects the mitochondrial quality and quality control system and the involvement of mitochondria in inflammation, we report information on how vitamin E, the main fat-soluble antioxidant, can protect mitochondria from age-related changes. The information in this regard is scarce and limited to some tissues and some aspects of mitochondrial alterations in aging. Improving knowledge of the effects of vitamin E on aging is essential to defining an optimal strategy for healthy aging.

Suppression of Inflamm-Aging by Moringa oleifera and Zingiber officinale Roscoe in the Prevention of Degenerative Diseases: A Review of Current Evidence.

Inflammation or inflamm-aging is a chronic low-grade inflammation that contributes to numerous types of degenerative diseases among the elderly and might be impeded by introducing an anti-inflammatory agent like Moringa oleifera Lam (moringa) and Zingiber officinale Roscoe (ginger). Therefore, this paper aims to review the role of moringa and ginger in suppressing inflamm-aging to prevent degenerative diseases. Various peer-reviewed publications were searched and downloaded using the reputed search engine "Pubmed" and "Google Scholar". These materials were reviewed and tabulated. A comparison between these previous findings was made based on the mechanism of action of moringa and ginger against degenerative diseases, focusing on their anti-inflammatory properties. Many studies have reported the efficacy of moringa and ginger in type 2 diabetes mellitus, neurodegenerative disease, cardiovascular disease, cancer, and kidney disease by reducing inflammatory cytokines activities, mainly of TNF-α and IL-6. They also enhanced the activity of antioxidant enzymes, including catalase, glutathione, and superoxide dismutase. The anti-inflammatory activities can be seen by inhibiting NF-κß activity. Thus, the anti-inflammatory potential of moringa and ginger in various types of degenerative diseases due to inflamm-aging has been shown in many recent types of research.

Renal inflamm-aging provokes intra-graft inflammation following experimental kidney transplantation.

Donor age is a major risk factor for allograft outcome in kidney transplantation. The underlying cellular mechanisms and the recipient's immune response within an aged allograft have yet not been analyzed. A comprehensive immunophenotyping of naïve and transplanted young versus aged kidneys revealed that naïve aged murine kidneys harbor significantly higher frequencies of effector/memory T cells, whereas regulatory T cells were reduced. Aged kidney-derived CD8+ T cells produced more IFNγ than their young counterparts. Senescent renal CD8+ T and NK cells upregulated the cytotoxicity receptor NKG2D and the enrichment of memory-like CD49a+ CXCR6+ NK cells was documented in aged naïve kidneys. In the C57BL/6 to BALB/c kidney transplantation model, recipient-derived T cells infiltrating an aged graft produced significantly more IFNγ, granzyme B and perforin on day 7 post-transplantation, indicating an enhanced inflammatory, cytotoxic response towards the graft. Pre-treatment of aged kidney donors with the senolytic drug ABT-263 changed the recipient-derived effector molecule profile to significantly reduced levels of IFNγ and IL-10 compared to controls. Graft function after ABT-263 pre-treatment was significantly improved 28 days post kidney transplantation. In conclusion, renal senescence also occurs at the immunological level (inflamm-aging) and aged organs provoke an altered recipient-dominated immune response in the graft.

Emerging cellular senescence-centric understanding of immunological aging and its potential modulation through dietary bioactive components.

Immunological aging is strongly associated with the observable deleterious effects of human aging. Our understanding of the causes, effects, and therapeutics of aging immune cells has long been considered within the sole purview of immunosenescence. However, it is being progressively realized that immunosenescence may not be the only determinant of immunological aging. The cellular senescence-centric theory of aging proposes a more fundamental and specific role of immune cells in regulating senescent cell (SC) burden in aging tissues that has augmented the notion of senescence immunotherapy. Now, in addition, several emerging studies are suggesting that cellular senescence itself may be prevalent in aging immune cells, and that senescent immune cells exhibiting characteristic markers of cellular senescence, similar to non-leucocyte cells, could be among the key drivers of various facets of physiological aging. The present review integrates the current knowledge related to immunosenescence and cellular senescence in immune cells per se, and aims at providing a cohesive overview of these two phenomena and their significance in immunity and aging. We present evidence and rationalize that understanding the extent and impact of cellular senescence in immune cells vis-à-vis immunosenescence is necessary for truly comprehending the notion of an 'aged immune cell'. In addition, we also discuss the emerging significance of dietary factors such as phytochemicals, probiotic bacteria, fatty acids, and micronutrients as possible modulators of immunosenescence and cellular senescence. Evidence and opportunities related to nutritional bioactive components and immunological aging have been deliberated to augment potential nutrition-oriented immunotherapy during aging.

Changes in the biochemical taste of cytoplasmic and cell-free DNA are major fuels for inflamm-aging.

Inflamm-aging depicts the progressive activation of the innate immune system that accompanies human aging. Its role as a disease-predisposing condition has been proposed, but its molecular basis is still poorly understood. A wealth of literature conveys that, particularly upon stress, nuclear and mitochondrial genomes are released into the cytoplasmic and extracellular compartments. Cytoplasmic (cy) and cell-free (cf) DNA pools trigger inflammation and innate immunity at local and systemic level. In particular, cyDNA plays a crucial role in the phenomenon of cell senescence and in the cognate pro-inflammatory secretome. Here we propose that changes in a variety of biochemical characteristics "tastes" of cy- and cf-DNA (e.g. the amount of 8-oxo-deoxy-guanosine and 5-methyl-deoxy-cytosine, the proportion of DNA hybridized with RNA) potentially affect the capability of these DNA pools to ignite the innate immune system. We also underpin that telomeric sequences are major components of the cy/cfDNA payload. Telomere shortening, a hallmark of aging, causes the depletion of telomeric sequences in cy/cfDNA pool, thus unleashing their potential to exert an age-related activation of the innate immune system. Finally, we posit that various sources of DNA (extracellular vesicles, the commensal metagenome and food) contribute to the cy/cfDNA payloads. We speculate that changes in the biochemical "taste" of cy/cfDNA are major modifiers of inflamm-aging.

Increasing Complexity of Molecular Landscapes in Human Hematopoietic Stem and Progenitor Cells during Development and Aging.

The past five decades have seen significant progress in our understanding of human hematopoiesis. This has in part been due to the unprecedented development of advanced technologies, which have allowed the identification and characterization of rare subsets of human hematopoietic stem and progenitor cells and their lineage trajectories from embryonic through to adult life. Additionally, surrogate in vitro and in vivo models, although not fully recapitulating human hematopoiesis, have spurred on these scientific advances. These approaches have heightened our knowledge of hematological disorders and diseases and have led to their improved diagnosis and therapies. Here, we review human hematopoiesis at each end of the age spectrum, during embryonic and fetal development and on aging, providing exemplars of recent progress in deciphering the increasingly complex cellular and molecular hematopoietic landscapes in health and disease. This review concludes by highlighting links between chronic inflammation and metabolic and epigenetic changes associated with aging and in the development of clonal hematopoiesis.

Hyperglycaemia-associated macrophage pyroptosis accelerates periodontal inflamm-aging.

AIM: Pyroptosis and inflamm-aging have been newly identified to be involved in diabetic periodontitis. This study aimed to elucidate whether macrophage pyroptosis plays a role in periodontal inflamm-aging by impacting the senescence of fibroblasts, as well as the potential mechanism via NLR family CARD domain-containing protein 4 (NLRC4) phosphorylation. MATERIALS AND METHODS: Diabetes was induced in mice using streptozotocin. Periodontal pyroptosis and senescence were detected using immunohistochemical analysis. Prior to evaluating senescence in human gingival fibroblasts cultured with conditioned medium derived from macrophages, RAW 264.7 macrophages were confirmed to undergo pyroptosis by scanning electron microscopy and gasdermin D (GSDMD) detection. The NLRC4-related pathway was examined under hyperglycaemic conditions. RESULTS: Our data showed that macrophage pyroptosis induced the expression of senescent markers in vivo and in vitro. Importantly, clearance of pyroptotic macrophages rescued senescence in fibroblasts. Furthermore, GSDMD activation and pyroptosis in hyperglycaemia were found to be mediated by NLRC4 phosphorylation. CONCLUSIONS: Hyperglycaemia could initially induce macrophage pyroptosis and lead to cellular senescence, thereby critically contributing to periodontal pathogenesis in diabetes. In particular, NLRC4 phosphorylation could be a potential therapeutic target for the inhibition of this process.

Environmental enrichment modulates inflammation during development in long-evans rats (Rattus norvegicus).

It is unknown whether increased production of pro-inflammatory mediators during the life span is caused by aging per se or via the combination of a cumulative allostatic load due to life challenges. This study aimed to investigate the long-term effects of stress and environmental enrichment on the inflammatory status associated with aging in rats. Animals were assigned to the following five treatment groups: chronic stress with and without environmental enrichment; acute stress with and without environmental enrichment; control animals. Enrichment was provided as an open field containing novel objects (30 min three times per week). Animals assigned to chronic stress groups were exposed to predator sound stressors (e.g., hawk sound) for 30 min daily, while animals assigned to acute stress groups were exposed once a week for 30 min. The interaction between the hypothalamic-pituitary-adrenal axis and the immune system was investigated by measuring metabolized dehydroepiandrosterone (DHEA) levels and peripheral levels of the cytokines IL-6 and IL-10. Results suggested that inflamm-aging was more pronounced in animals with low DHEA levels, which in turn were affected by exposure to environmental enrichment and acute stress. This study showed that environmental enrichment and acute stress can significantly attenuate disruptions in DHEA production, consequently contributing to improved neuroimmune function of aging animals.

Therapeutic Potential for Regulation of the Nuclear Factor Kappa-B Transcription Factor p65 to Prevent Cellular Senescence and Activation of Pro-Inflammatory in Mesenchymal Stem Cells.

Mesenchymal stem cells have an important potential in the treatment of age-related diseases. In the last years, small extracellular vesicles derived from these stem cells have been proposed as cell-free therapies. Cellular senescence and proinflammatory activation are involved in the loss of therapeutic capacity and in the phenomenon called inflamm-aging. The regulators of these two biological processes in mesenchymal stem cells are not well-known. In this study, we found that p65 is activated during cellular senescence and inflammatory activation in human umbilical cord-derived mesenchymal stem cell. To demonstrate the central role of p65 in these two processes, we used small-molecular inhibitors of p65, such as JSH-23, MG-132 and curcumin. We found that the inhibition of p65 prevents the cellular senescence phenotype in human umbilical cord-derived mesenchymal stem cells. Besides, p65 inhibition produced the inactivation of proinflammatory molecules as components of a senescence-associated secretory phenotype (SASP) (interleukin-6 and interleukin-8 (IL-6 and IL-8)). Additionally, we found that the inhibition of p65 prevents the transmission of paracrine senescence between mesenchymal stem cells and the proinflammatory message through small extracellular vesicles. Our work highlights the important role of p65 and its inhibition to restore the loss of functionality of small extracellular vesicles from senescent mesenchymal stem cells and their inflamm-aging signature.