Senescent Macrophages Research Articles

Quercetin Alleviates Pulmonary Fibrosis in Mice Exposed to Silica by Inhibiting Macrophage Senescence.

Quercetin exerts anti-inflammatory, anti-oxidant and other protective effects. Previous studies have shown that senescent cells, such as fibroblasts and type II airway epithelial cells, are strongly implicated in the development of pulmonary fibrosis pathology. However, the role of senescent macrophages during silicosis remains unclear. We investigated the effects of quercetin on macrophage senescence and pulmonary fibrosis, and explored underlying mechanisms. Mice were randomized to six model groups. Vitro model was also established by culturing RAW264.7 macrophages with silica (SiO2). We examined the effects of quercetin on fibrosis, senescence-associated β-galactosidase (SA-β-Gal) activity, and senescence-specific genes (p16, p21, and p53). We showed that quercetin reduced pulmonary fibrosis and inhibited extracellular matrix (ECM) formation. Quercetin also attenuated macrophage senescence induced by SiO2 both in vitro and in vivo. In addition, quercetin significantly decreased the expressions of the senescence-associated secretory phenotype (SASP), including proinflammatory factors (interleukin-1α (Il-1α), Il-6, tumor necrosis factor-α (TNF-α), and transforming growth factor-β1 (TGF-β1)) and matrix metalloproteinases (MMP2, MMP9, and MMP12). In conclusion, quercetin mediated its anti-fibrotic effects by inhibiting macrophage senescence, possibly via SASP.

Resveratrol promotes osteogenesis and angiogenesis through mediating immunology of senescent macrophages

Orthopedic implants have been used clinically to restore the functions of the compromised bone tissues, but there is still a relatively high risk of failure for elderly people. A critical reason is pro-inflammatory immune microenvironment created by senescent macrophages with homeostasis imbalance impairs osteogenesis and angiogenesis, two major processes involved in implant osseointegration. The present work proposes to use resveratrol as an autophagy inducing agent to upregulate the autophagy level of senescent macrophages to restore homeostasis, consequently generating a favorable immune microenvironment. The results show 0.1–1 μM of resveratrol can induce autophagy of senescent macrophages, promote cell viability and proliferation, reduce intracellular reactive oxygen species level, and polarize the cells to pro-healing M2 phenotype. The immune microenvironment created by senescent macrophages upon resveratrol stimulation can promote osteogenesis and angiogenesis, as manifested by upregulated proliferation, alkaline phosphatase activity, type I collagen secretion, and extracellular matrix mineralization of senescent osteoblasts as well as nitric oxide production, migration, and in vitro angiogenesis of senescent endothelial cells. In addition, resveratrol-loaded silk fibroin coatings can be fabricated on titanium surface through electrophoretic co-deposition and the coatings show beneficial effects on the functions of senescent macrophages. Our results suggest resveratrol can be used as surface additive of titanium implants to promote osseointegration of elderly people though regulating immunology of senescent macrophages.

Nrf2 driven macrophage responses in diverse pathophysiological contexts: Disparate pieces from a shared molecular puzzle.

The wide anatomical distribution of macrophages and their vast array of functions match various polarization states and their involvement in homeostasis and disease. The confluence of different cellular signaling networks, including direct involvement in inflammation, at the doorstep of the transcription factor Nuclear Factor- erythroid (NF-E2) p45-related factor 2 (Nrf2) activation raises the importance of deciphering the molecular circuitry at the background of multiple-discrete and antagonistic yet flexible and contextual pathways. While we primarily focus on wound healing and repair mechanisms that are affected in diabetic foot ulcers (DFUs), we strive to explore the striking similarities and differences in molecular events including inflammation, angiogenesis, and fibrosis during tissue injury and wound persistence that accumulates pro-inflammatory senescent macrophages, as a means to identify possible targets or cellular mediators to lessen DFU disease burden. In addition, the role of iron in the modulation of Nrf2 response in macrophages is crucial and reviewed here. Targeted approaches, unlike conventional treatments, in DFU management will require the review and re-assessment of mediators with relevance to other pathological conditions.

Senescent macrophages alter fibroblast fibrogenesis in response to SARS-CoV-2 infection.

SARS-CoV-2 has, since its emergence in 2019, become a global pandemic. Disease outcomes are worsened in older patients who are infected. The causes for this is multifactorial, but one potential cause for this disparity is increased rates of cellular senescence in older individuals, particularly in immune cells. Cellular senescence, the accumulation of factors resulting in cell growth arrest and apoptosis resistance, increases as individuals age. In immune cells, senescence is associated with increased inflammation, and alterations in immune response. We utilized a co-culture system consisting of senescent or non-senescent macrophages directly cultured with fibroblasts, and infected with SARS-CoV-2. We assessed the expression of collagen and fibronectin, important molecules in the extracellular matrix, as well as a number of fibrogenic factors. We observed that infection with SARS-CoV-2 induced collagen production in co-cultures with senescent, but not non-senescent macrophages. Fibronectin expression was decreased in both co-culture conditions. While significant results were not observed, concentrations of other fibrogenic molecules were consistent with the collagen results. These data demonstrate that senescence in macrophages alters the production of fibrotic molecules from fibroblasts in a SARS-CoV-2 infection model. As collagen and fibronectin expression are generally directly correlated, this suggests that senescence dysregulates fibrogenesis in response to infection with SARS-CoV-2. There is a need to further investigate the mechanisms for these changes.

Senescent macrophages in the human adipose tissue as a source of inflammaging

Obesity is a major risk factor for type 2 diabetes and a trigger of chronic and systemic inflammation. Recent evidence suggests that an increased burden of senescent cells (SCs) in the adipose tissue of obese/diabetic animal models might underlie such pro-inflammatory phenotype. However, the role of macrophages as candidate SCs, their phenotype, the distribution of SCs among fat depots, and clinical relevance are debated. The senescence marker β-galactosidase and the macrophage marker CD68 were scored in visceral (vWAT) and subcutaneous (scWAT) adipose tissue from obese patients (n=17) undergoing bariatric surgery and control patients (n=4) subjected to cholecystectomy. A correlation was made between the number of SCs and BMI, serum insulin, and the insulin resistance (IR) index HOMA. The monocyte cell line (THP-1) was cultured in vitro in high glucose milieu (60 mM D-glucose) and subsequently co-cultured with human adipocytes (hMADS) to investigate the reciprocal inflammatory activation. In obese patients, a significantly higher number of SCs was observed in vWAT compared to scWAT; about 70% of these cells expressed the macrophage marker CD68; and the number of SCs in vWAT, but not in scWAT, positively correlated with BMI, HOMA-IR, and insulin. THP-1 cultured in vitro in high glucose milieu acquired a senescent-like phenotype (HgSMs), characterized by a polarization toward a mixed M1/M2-like secretory phenotype. Co-culturing HgSMs with hMADS elicited pro-inflammatory cytokine expression in both cell types, and defective insulin signaling in hMADS. In morbid obesity, expansion of visceral adipose depots involves an increased burden of macrophages with senescent-like phenotype that may promote a pro-inflammatory profile and impair insulin signaling in adipocytes, supporting a framework where senescent macrophages fuel obesity-induced systemic inflammation and possibly contribute to the development of IR.

Obesity-induced senescent macrophages activate a fibrotic transcriptional program in adipocyte progenitors.

Adipose tissue fibrosis is regulated by the chronic and progressive metabolic imbalance caused by differences in caloric intake and energy expenditure. By exploring the cellular heterogeneity within fibrotic adipose tissue, we demonstrate that early adipocyte progenitor cells expressing both platelet-derived growth factor receptor (PDGFR) α and β are the major contributors to extracellular matrix deposition. We show that the fibrotic program is promoted by senescent macrophages. These macrophages were enriched in the fibrotic stroma and exhibit a distinct expression profile. Furthermore, we demonstrate that these cells display a blunted phagocytotic capacity and acquire a senescence-associated secretory phenotype. Finally, we determined that osteopontin, which was expressed by senescent macrophages in the fibrotic environment promoted progenitor cell proliferation, fibrotic gene expression, and inhibited adipogenesis. Our work reveals that obesity promotes macrophage senescence and provides a conceptual framework for the discovery of rational therapeutic targets for metabolic and inflammatory disease associated with obesity.

Radiation-Induced Macrophage Senescence Impairs Resolution Programs and Drives Cardiovascular Inflammation.

Radiation is associated with tissue damage and increased risk of atherosclerosis, but there are currently no treatments and a very limited mechanistic understanding of how radiation impacts tissue repair mechanisms. We uncovered that radiation significantly delayed temporal resolution programs that were associated with decreased efferocytosis in vivo. Resolvin D1 (RvD1), a known proresolving ligand, promoted swift resolution and restored efferocytosis in sublethally irradiated mice. Irradiated macrophages exhibited several features of senescence, including increased expression of p16INK4A and p21, heightened levels of SA-β-gal, COX-2, several proinflammatory cytokines/chemokines, and oxidative stress (OS) in vitro, and when transferred to mice, they exacerbated inflammation in vivo. Mechanistically, heightened OS in senescent macrophages led to impairment in their ability to carry out efficient efferocytosis, and treatment with RvD1 reduced OS and improved efferocytosis. Sublethally irradiated Ldlr -/- mice exhibited increased plaque necrosis, p16INK4A cells, and decreased lesional collagen compared with nonirradiated controls, and treatment with RvD1 significantly reduced necrosis and increased lesional collagen. Removal of p16INK4A hematopoietic cells during advanced atherosclerosis with p16-3MR mice reduced plaque necrosis and increased production of key intraplaque-resolving mediators. Our results demonstrate that sublethal radiation drives macrophage senescence and efferocytosis defects and suggest that RvD1 may be a new therapeutic strategy to limit radiation-induced tissue damage.

Perspectives on the dynamic implications of cellular senescence and immunosenescence on macrophage aging biology.

An intricate relationship between impaired immune functions and the age-related accumulation of tissue senescent cells is rapidly emerging. The immune system is unique as it undergoes mutually inclusive and deleterious processes of immunosenescence and cellular senescence with advancing age. While factors inducing immunosenescence and cellular senescence may be shared, however, both these processes are fundamentally different which holistically influence the aging immune system. Our understanding of the biological impact of immunosenescence is relatively well-understood, but such knowledge regarding cellular senescence in immune cells, especially in the innate immune cells such as macrophages, is only beginning to be elucidated. Tissue-resident macrophages are long-lived, and while functioning in tissue-specific and niche-specific microenvironments, senescence in macrophages can be directly influenced by senescent host cells which may impact organismal aging. In addition, evidence of age-associated immunometabolic changes as drivers of altered macrophage phenotype and functions such as inflamm-aging is also emerging. The present review describes the emerging impact of cellular senescence vis-à-vis immunosenescence in aging macrophages, its biological relevance with other senescent non-immune cells, and known immunometabolic regulators. Gaps in our present knowledge, as well as strategies aimed at understanding cellular senescence and its therapeutics in the context of macrophages, have been reviewed.

MO565M2 MACROPHAGES REGULATE MOUSE AORTIC SMOOTH MUSCLE CELL CALCIFICATION BY TRANSMITTING SENESCENCE INFORMATION

Abstract Background and Aims Vascular calcification is highly prevalent in chronic kidney disease (CKD)with high morbidity and mortality. Complex pathological mechanisms are involved in the development of vascular calcification, including aging. Previous work have indicated that M2-macrophage promote mouse aortic smooth muscle cells (MAoSMCs) calcification. The present study aimed to understand the contribution of M2-macrophage to MAoSMCs calcification by focusing on the mechanisms underlying the transmitting senescence information Method The expression of IFITM3 and P16, marker of aging, in aging macrophages were confimed by RT-qPCR, western blotting and immunofluorescence staining. Then, the MAoSMCs were co-cultured with the supernatant of M2 macrophages. The expression of IFITM3 and P16 in MAoSMCs also were detected. Alizarin red staining and calcium content assay were used to analyse MAoSMCs calcification. We modulated the expression of IFITM3 using siRNAs to study M2-macrophages function in regulating MAoSMCs calcification.We detected the expression of IFITM3 and P16 in co-cultivate MAoSMCs and validate intracellular calcium contents by calcium test kit. Results In the present study, we observed a significant increase in the expression of IFITM3 and P16 expression in M2 macrophages.Compared with M0 and M1 macrophages, the expression of IFITM3 and P16 at lowlevel. Alizarin red staining and calcium content assay revealed that M2 macrophage-mediated IFITM3 and P16 overexpression led to an apparent VSMC calcification in the presence of M2 macrophages medium.By contrast, inhibition of IFITM3 by siRNAs significantly blocked calcification of VSMCs in vitro. Moreover, we found that aging macrophages that overexpressed of IFITM3 and P16 increased in rats with CKD. Furthermore, pharmacological inhibition of aging signal was shown to block IFITM3-induced VSMC calcification. These findings demonstrate for the first time that M2 macrophage-mediated IFITM3 contributes to vascular calcification through a mechanism involving transmitting Senescence signalling. Conclusion Collectively, our present study demonstrated that the functional importance of M2 macrophage-IFITM3 dependent vascular calcification and provided a novel mechanistic insight to the macrophage senescence in CKD.

Potential role of senescent macrophages in radiation-induced pulmonary fibrosis

Radiation-induced pulmonary fibrosis (RIPF) is a late toxicity of therapeutic radiation in clinic with poor prognosis and limited therapeutic options. Previous results have shown that senescent cells, such as fibroblast and type II airway epithelial cell, are strongly implicated in pathology of RIPF. However, the role of senescent macrophages in the development RIPF is still unknown. In this study, we report that ionizing radiation (IR) increase cellular senescence with higher expression of senescence-associated β-galactosidase (SA-β-Gal) and senescence-specific genes (p16, p21, Bcl-2, and Bcl-xl) in irradiated bone marrow-derived monocytes/macrophages (BMMs). Besides, there’s a significant increase in the expression of pro-fibrogenic factors (TGF-β1 and Arg-1), senescence-associated secretory phenotype (SASP) proinflammatory factors (Il-1α, Il-6, and Tnf-α), SASP chemokines (Ccl2, Cxcl10, and Ccl17), and SASP matrix metalloproteinases (Mmp2, Mmp9 and Mmp12) in BMMs exposed to 10 Gy IR. In addition, the percentages of SA-β-Gal+ senescent macrophages are significantly increased in the macrophages of murine irradiated lung tissue. Moreover, robustly elevated expression of p16, SASP chemokines (Ccl2, Cxcl10, and Ccl17) and SASP matrix metalloproteinases (Mmp2, Mmp9, and Mmp12) is observed in the macrophages of irradiated lung, which might stimulate a fibrotic phenotype in pulmonary fibroblasts. In summary, irradiation can induce macrophage senescence, and increase the secretion of SASP in senescent macrophages. Our findings provide important evidence that senescent macrophages might be the target for prevention and treatment of RIPF.

Diabetes fuels periodontal lesions via GLUT1-driven macrophage inflammaging

Hyperglycemia induces chronic low-grade inflammation (inflammaging), which is a newly identified contributor to diabetes-related tissue lesions, including the inflammatory bone loss in periodontitis. It is also a secondary senescent pattern mediated by an increased burden of senescent cells and senescence-associated secretory phenotype (SASP). Macrophage is a key SASP-spreading cell and may contribute to the maintenance of SASP response in the periodontal microenvironment. Using a transgenic diabetic model (BLKS/J-Leprdb/leprdb mice) we identified striking senescence of the periodontium in young (18-wk)-diabetic mice accompanied by amassed p16+-macrophages and enhanced early SASP response. Exposed to high glucose in vitro, bone marrow-derived macrophage (BMDM) revealed a strong GLUT1 mRNA response driving the elevated-glucose uptake. GLUT1 is a representative and facilitative glucose transporter in macrophages with potential roles in hyperglycemia-induced inflammation. In this study, both GLUT1 and the downstream GTPase Rheb expression upregulated in the gingiva of diabetic mice with impaired condition. Furthermore, SASP release and p16/p21 signaling were proven to be triggered by mTOR phosphorylation in BMDM and antagonized by restricting glucose uptake in GLUT1−/− BMDM. Taken together, our findings suggest that elevated-GLUT1 sensor responded to high glucose is important for macrophage senescence and SASP response, generated as a result of hyperglycemia, and it is a potential molecular mechanism for the exacerbation of periodontitis in diabetes.

Activating transcription factor 3 involved in Pseudomonas aeruginosa PAO1-induced macrophage senescence

Pseudomonas aeruginosa (PA) is one of the most prevalent pathogens that cause nosocomial infection in critical patients. Previously, we reported PA induced macrophage to senescence under the circumstance of infection. As an oxidative stress responsiveness element, activating transcription factor 3 (ATF3) might be involved in the macrophage senescence process. To test this presumption, we manipulated the expression of ATF3 in macrophage by using a PAO1 infection system. In the present study, ATF3 expression in macrophage was increased, following the duration and colony counts of PAO1 infection. Knockdown of ATF3 in macrophage resulted in increased percentage of senescent macrophage under PAO1 infection, while overexpressing ATF3 partly blocked PAO1-induced macrophage senescence. In accordance with the senescent phenotype, elevated reactive oxygen species (ROS) production was shown in ATF3 knockdown macrophages. Also, capacity of phagocytosis was also affected by manipulation of ATF3 expression in macrophages, and increased phagocytosed fluorescent beads was found in ATF3 knockdown macrophage. ATF3 might regulate the senescence process through influence on NF-κB translocation. During infection, the overexpression or downregulation of ATF3 in macrophage negatively modulated the translocation of NF-κB p65 and its phosphorylation at Ser-536. As a result, IL-6 and TNFα was elevated, while IL-10 decreased in case of ATF3 knockdown. In conclusion, ATF3 negatively regulates NF-κB translocation and activation, and participates in PA-induced macrophage senescence. As oxidative stress and inflammation induced element, ATF3 may modulate macrophage-related host defense.

Obesity-Induced Senescent Macrophages Activate a Fibrotic Transcriptional Program Through Osteopontin Secretion

Adipose tissue fibrosis is regulated by the chronic and progressive metabolic imbalance caused by differences in caloric intake and energy expenditure. By exploring the cellular heterogeneity within fibrotic adipose tissue, we demonstrate that early adipocyte progenitor cells expressing both platelet derived growth factor receptor (PDGFR) α and β are the major contributors to extracellular matrix deposition. We show that the fibrotic program is promoted by senescent macrophages. These macrophages are highly enriched in the fibrotic stroma and exhibit a distinct expression profile . Furthermore, we demonstrate that these cells display a blunted phagocytotic capacity and acquire a senescence associated secretory phenotype. Finally, we determined that senescent macrophage-derived osteopontin in the fibrotic environment promoted progenitor cell proliferation, fibrotic gene expression, and inhibited adipogenesis. Our work reveals that obesity promotes macrophage senescence and provides a conceptual framework for the discovery of rational therapeutic targets for metabolic and inflammatory disease associated with obesity.

Similarities and interplay between senescent cells and macrophages.

Senescence is a cellular program that prevents the replication of old, damaged, or cancerous cells. Senescent cells become growth arrested and undergo changes in their morphology, chromatin organization, and metabolism, and produce a bioactive secretome. This secretome, the senescence-associated secretory phenotype (SASP), mediates many of the pathophysiological effects associated with senescent cells, for example, recruiting and activating immune cells such as macrophages. The relation between senescent cells and macrophages is intriguing: senescent cells recruit macrophages, can induce them to undergo senescence, or can influence their polarization. Senescent cells and macrophages share multiple phenotypic characteristics; both have a high secretory status, increased lysosome numbers, or the ability to activate the inflammasome. Senescent cells accumulate during aging and disease, and killing them results in widespread benefits. Here we discuss similarities between senescent cells and macrophages and interpret the latest developments in macrophage biology to understand the molecular mechanisms of cellular senescence. We describe evidence and effects of senescence in macrophages and speculate on the ontogeny of the senescent-like state in macrophages. Finally, we examine the macrophage-senescent cell interplay and its impact on macrophage effector functions during inflammatory conditions and in the tumor microenvironment.

The emerging role of cell senescence in atherosclerosis.

Cell senescence is a fundamental mechanism of aging and appears to play vital roles in the onset and prognosis of cardiovascular disease, fibrotic pulmonary disease, liver disease and tumor. Moreover, an increasing body of evidence shows that cell senescence plays an indispensable role in the formation and development of atherosclerosis. Multiple senescent cell types are associated with atherosclerosis, senescent human vascular endothelial cells participated in atherosclerosis via regulating the level of endothelin-1 (ET-1), nitric oxide (NO), angiotensin II and monocyte chemoattractant protein-1 (MCP-1), senescent human vascular smooth muscle cells-mediated plaque instability and vascular calcification via regulating the expression level of BMP-2, OPN, Runx-2 and inflammatory molecules, and senescent macrophages impaired cholesterol efflux and promoted the development of senescent-related cardiovascular diseases. This review summarizes the characteristics of cell senescence and updates the molecular mechanisms underlying cell senescence. Moreover, we also discuss the recent advances on the molecular mechanisms that can potentially regulate the development and progression of atherosclerosis.

P1201THE AGING OF THE IMMUNE SYSTEM AND FRAGILITY: TWO FEATURES IN PERITONEAL DIALYSIS AND END-STAGE RENAL DISEASE PATIENTS

Abstract Background and Aims Chronic kidney disease (CKD) is associated with premature immune aging and increased inflammatory activity leading into endothelial damage and macrophage senescence (CD14+CD16+). Objective. To evaluate the influence of CKD in senescent immune cells, and its relationship with fragility in patients with nondialysis CKD (ND-CKD) and Peritoneal Dialysis (PD). Method A descriptive transversal study analysing lymphocyte absolute counts and subpopulations in 74 CKD patients (36 DP, 38 ND-CKD) compared with 10 healthy subjects (HS). We also assessed immunoglobulin levels, C3 and C4 fragment complement, Edmonton fragility score and the percentage of proinflammatory blood monocytes with the CD14+CD16+ phenotype. Results PD patients presented more absolute lymphopenia compared with LCC and HS (PD 1194,2, 1589 ND-CKD and 1802 HS; p <0,001, respectively). This lymphopenia is also maintained in CD3, CD4, CD8 and NK cells. Lower CD4 lymphocytes levels were significantly correlated with higher fragility and incidence of peripheral vascular disease in uremic patients. Senescent macrophage was correlated with CD3 and CD4 lymphocytes all the cohorts (ND-CKD, PD and HS). Conclusion PD patients presented changes in immune system compared with healthy population, that could explain accelerated senescence. Accelerated senescence is associated with more fragility and endothelial damage. There are necessary more studies to identify the role premature aging in ND-CKD and to establish the differences between renal replacement modalities.

BRD4 contributes to LPS-induced macrophage senescence and promotes progression of atherosclerosis-associated lipid uptake.

Aging is closely associated with atherosclerosis. Macrophages accumulate in atherosclerotic lesions contributing to the development and progression of atherosclerosis. Although atherosclerotic lesions are known to contain senescent cells, the mechanism underlying the formation of senescent macrophages during atherosclerosis is still unclear. In this study, macrophages with different origins were collected, including THP-1 macrophages, telomerase reverse transcriptase knock out (Tert-/-) mouse peritoneal macrophages, and human peripheral blood mononuclear cells (PBMCs). We found Lipopolysaccharide (LPS) could induce the formation of senescent macrophages, which was typified by the morphological changes, senescence-associated secretory phenotype (SASP) secretory, and persistent DNA damage response. Mechanistically, bromodomain-containing protein 4 (BRD4), a chromosomal binding protein related to gene expression, was found to play a key role in the pathological process, which could offer new therapeutic perspectives. Inhibition of BRD4 by siBRD4 or inhibitors such as JQ-1 or I-BET762 prevented the aging of macrophages and lipid accumulation in the LPS-induced senescent macrophages by decreasing expression of SASP in autocrine and paracrine senescence. These findings have significant implications for the understanding of the pathobiology of age-associated diseases and may guide future studies on targeted clinical drug therapy.

Cellular senescence in recurrent tonsillitis and tonsillar hypertrophy in children

ObjectiveTo observe the difference in cellular senescence patterns between recurrent tonsillitis and tonsillar hypertrophy. Methods and materialsForty-three patients diagnosed with recurrent tonsillitis or tonsillar hypertrophy, based on medical history and symptoms, underwent tonsillectomy. The specimens were collected and examined using senescence β-galactosidase staining for cellular senescence. Macrophages were detected by immunochemistry. ResultsCellular senescence was found in both recurrent tonsillitis and tonsillar hypertrophy groups. The comparison of cellular senescence in microcompartments of tonsil tissue (germinal centre, mantle zone, subepithelial and intraepithelial) revealed a significant increase of senescent cells in germinal centres in tonsillar hypertrophy compared with that in tonsillar hypertrophy. The majority of senescent cells in both groups were CD68-positive. ConclusionsDifferent cellular senescence patterns were found between the two studied paediatric tonsillar diseases. Macrophage senescence may play a role in the pathogenesis of these diseases.

LncRNA-Triggered Macrophage Inflammaging Deteriorates Age-Related Diseases

Aging and age-related diseases (ARDs) share basic mechanisms largely involving inflammation. A chronic, low-grade, subclinical inflammation called inflammaging occurs during aging. Autophagy defects, oxidative stresses, senescence-associated secretory phenotypes (SASPs), and DNA damage generally contribute to inflammaging and are largely regulated by numerous lncRNA through two-level vicious cycles disrupting cellular homeostasis: (1) inflammaging and the cellular senescence cascade and (2) autophagy defects, oxidative stress, and the SASP cascade. SASPs and inflammasomes simultaneously cause inflammaging. This review discusses the involvement of macrophage inflammaging in various ARDs and its regulation via lncRNA. Among macrophages, this phenomenon potentially impairs its immunosurveillance and phagocytosis mechanisms, leading to decreased recognition and clearance of malignant and senescent cells. Moreover, SASPs extracellularly manifest to induce paracrine senescence. Macrophage senescence escalates to organ level malfunction, and the organism is more prone to ARDs. By targeting genes and proteins or functioning as competing endogenous RNA (ceRNA), lncRNA regulates different phenomena including inflammaging and ARDs. The detailed mechanism warrants further elucidation to obtain pathological evidence of ARDs and potential treatment approaches.

Bifidobacterium lactis BB-12 Attenuates Macrophage Aging Induced by D-Galactose and Promotes M2 Macrophage Polarization.

Immunosenescence comprises a set of dynamic changes occurring in innate and adaptive immune systems, and macrophage aging plays an important role in innate and adaptive immunosenescence. However, function and polarization changes in aging macrophages have not been fully evaluated, and no effective method for delaying macrophage senescence is currently available. The results of this study reveal that D-galactose (D-gal) can promote J774A.1 macrophage senescence and induce macrophage M1 polarization differentiation. Bifidobacterium lactis BB-12 can significantly inhibit J774A.1 macrophage senescence induced by D-gal. IL-6 and IL-12 levels in the BB-12 groups remarkably decreased compared with that in the D-gal group, and the M2 marker, IL-10, and Arg-1 mRNA levels increased in the BB-12 group. BB-12 inhibited the expression of p-signal transducer and activator of transcription 1 (STAT1) and promoted p-STAT6 expression. In summary, the present study indicates that BB-12 can attenuate the J774A.1 macrophage senescence and induce M2 macrophage polarization, thereby indicating the potential of BB-12 to slow down immunosenescence and inflamm-aging.