CHIP & HIPs: Clonal Hematopoiesis is Common in Hip Arthroplasty Patients and Associates with Autoimmune Disease

Blood ◽  
2021 ◽  
Author(s):  
Judith S. Hecker ◽  
Luise Hartmann ◽  
Jennifer Rivière ◽  
Michèle Constanze Buck ◽  
Mark van der Garde ◽  
...  
Keyword(s):  
Hip Arthroplasty ◽  
Inflammatory Diseases ◽  
Low Grade ◽  
Related Condition ◽  
Clonal Hematopoiesis ◽  
Mild Anemia ◽  
Age Related ◽  
Mutation Burden ◽  
Clinical Associations ◽  
Low Grade Inflammation

Clonal hematopoiesis (CH) is an age-related condition predisposing to blood cancer and cardiovascular disease (CVD). Murine models demonstrate CH-mediated altered immune function and proinflammation. Low-grade inflammation has been implicated in the pathogenesis of osteoarthritis (OA), the main indication for total hip arthroplasty (THA). THA-derived hip bones serve as a major source of 'healthy' hematopoietic cells in experimental hematology. We prospectively investigated frequency and clinical associations of CH in 200 patients without known hematologic disease undergoing THA. Prevalence of CH was 50%, including 77 patients with CH of indeterminate potential (CHIP, defined as somatic variants with allele frequencies [VAF] ≥2%), and 23 patients harboring CH with lower mutation burden (VAF 1-2%). Most commonly mutated genes were DNMT3A (29.5%), TET2 (15.0%) and ASXL1 (3.5%). CHIP significantly associated with lower hemoglobin, higher mean corpuscular volume, prior/present malignant disease, and CVD. Strikingly, we observed a previously unreported association of CHIP with autoimmune diseases (AID; multivariate adjusted odds ratio, 6.6; 95% confidence interval [1.7, 30]; p=0.0081). These findings underscore the association between CH and inflammatory diseases. Our results have considerable relevance for management of patients with OA and AID or mild anemia, and question use of hip bone-derived cells as 'healthy' experimental controls.

Hepatic macrophage accumulation with aging: cause for concern?

2021 ◽  
Author(s):  
Steven A. Bloomer ◽  
Eric Moyer
Keyword(s):  
Healthy Aging ◽  
Intercellular Adhesion Molecule ◽  
Low Grade ◽  
Intercellular Adhesion Molecule 1 ◽  
Age Related ◽  
Hepatic Macrophages ◽  
Liver Macrophage ◽  
Factor Α ◽  
Low Grade Inflammation ◽  
Hepatic Macrophage

Aging is associated with chronic, low-grade inflammation that adversely affects physiological function. The liver regulates systemic inflammation; it is a source of cytokine production and also scavenges bacteria from the portal circulation to prevent infection of other organs. The cells with primary roles in these functions, hepatic macrophages, become more numerous in the liver with "normal" aging (i.e. in the absence of disease). Here we demonstrate evidence and potential mechanisms for this phenomenon, which include augmented tumor necrosis factor-α (TNFα) and intercellular adhesion molecule-1 (ICAM-1) expression in the liver. Also, we discuss how an age-related impairment in autophagy within macrophages leads to a pro-oxidative state and ensuing production of pro-inflammatory cytokines, particularly interleukin 6 (IL-6). Given that the liver is a rich source of macrophages, we posit that it represents a major source of the elevated systemic IL-6 observed with aging, which is associated with physiological dysfunction. Testing a causal role for liver macrophage production of IL-6 during aging remains a challenge, yet interventions that have targeted macrophages and/or IL-6 have demonstrated promise in treating age-related diseases. These studies have demonstrated an age-related, deleterious reprogramming of macrophage function, which worsens pathology. Therefore, hepatic macrophage accrual is indeed a cause for concern, and therapies that attenuate the aged phenotype of macrophages will likely prove useful in promoting healthy aging.

scholarly journals Clonal Hematopoiesis of Indeterminate Potential: A Multidisciplinary Challenge in Personalized Hematology

2020 ◽  
Vol 10 (3) ◽  
pp. 94
Author(s):  
Gregor Hoermann ◽  
Georg Greiner ◽  
Andrea Griesmacher ◽  
Peter Valent
Keyword(s):  
Personalized Medicine ◽  
Clinical Medicine ◽  
Clinical Pathology ◽  
Causative Role ◽  
Related Condition ◽  
Clonal Hematopoiesis ◽  
Myeloid Neoplasm ◽  
Age Related

Clonal hematopoiesis of indeterminate potential (CHIP) is a common age-related condition that represents a potential pre-phase of hematologic neoplasm. Next-generation sequencing (NGS) is used to detect and monitor clonal hematopoiesis, and the spectrum of mutations substantially overlaps with that of myeloid neoplasms with DNMT3A, TET2, ASXL1, and JAK2 being the most frequently mutated. While, in general, the risk of progression to an overt myeloid neoplasm is only modest, the progression risk increases in patients with unexplained cytopenia or multiple mutations. In addition, CHIP represents a previously unrecognized major risk factor for atherosclerosis and cardiovascular disease (CVD), including coronary heart disease, degenerative aortic valve stenosis, and chronic heart failure; and a causative role of CHIP in the development of CVD has been demonstrated in vitro and in vivo. The management of patients with CHIP is a rapidly emerging topic in personalized medicine, as NGS has become widely available for clinical medicine. It requires a highly multidisciplinary setting, including hematology/oncology, cardiology, (clinical) pathology, and genetics for individualized guidance. Further research is urgently needed to provide robust evidence for future guidelines and recommendations on the management of patients with CHIP in the era of personalized medicine.

scholarly journals The Roles of the Gut Microbiota and Chronic Low-Grade Inflammation in Older Adults With Frailty

2021 ◽  
Vol 11 ◽  
Author(s):  
YuShuang Xu ◽  
XiangJie Liu ◽  
XiaoXia Liu ◽  
Di Chen ◽  
MengMeng Wang ◽  
...  
Keyword(s):  
Older Adults ◽  
Gut Microbiota ◽  
Chronic Inflammation ◽  
Healthy Aging ◽  
Low Grade ◽  
Age Related ◽  
Composition Structure ◽  
Low Grade Inflammation

Frailty is a major public issue that affects the physical health and quality of life of older adults, especially as the population ages. Chronic low-grade inflammation has been speculated to accelerate the aging process as well as the development of age-related diseases such as frailty. Intestinal homeostasis plays a crucial role in healthy aging. The interaction between the microbiome and the host regulates the inflammatory response. Emerging evidence indicates that in older adults with frailty, the diversity and composition structure of gut microbiota are altered. Age-associated changes in gut microbiota composition and in their metabolites contribute to increased gut permeability and imbalances in immune function. In this review, we aim to: identify gut microbiota changes in the aging and frail populations; summarize the role of chronic low-grade inflammation in the development of frailty; and outline how gut microbiota may be related to the pathogenesis of frailty, more specifically, in the regulation of gut-derived chronic inflammation. Although additional research is needed, the regulation of gut microbiota may represent a safe, easy, and inexpensive intervention to counteract the chronic inflammation leading to frailty.

scholarly journals Comprehensive expression patterns of inflammatory cytokines in aqueous humor of patients with neovascular age-related macular degeneration

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Tomohito Sato ◽  
Masaru Takeuchi ◽  
Yoko Karasawa ◽  
Kei Takayama ◽  
Toshio Enoki
Keyword(s):  
Macular Degeneration ◽  
Aqueous Humor ◽  
Expression Patterns ◽  
Principal Component ◽  
Age Related Macular Degeneration ◽  
Low Grade ◽  
Mutual Distance ◽  
Specific Expression ◽  
Age Related ◽  
Low Grade Inflammation

AbstractNeovascular age-related macular degeneration (nAMD) is a complex and multi-factorial disease, and low-grade inflammation is associated with pathogenesis of nAMD. Aqueous humor could reflect intraocular immune environments in various eye diseases. The research so far used aqueous humor samples and revealed that inflammation is involved in pathophysiology of nAMD, although immunological roles of cytokines were evaluated inadequately with aspect to individual effects. Here we used 27 kinds of cytokines covering general immunologic reactions, examined specific expression patterns of cytokines, and assessed relationships between inflammation and pathophysiology of nAMD by multivariate analyses. In nAMD eyes, principal component analysis showed that IL-7, MCP-1, MIP-1β and VEGF had high principal component loadings of over 0.6 in the first principal component constituting 32.6% of all variability of the data. In exploratory factor analysis, IL-6, MCP-1 and MIP-1β had high factor loadings (FL) of over 0.5 in Factor 1 constituting 32.6% of all variability, while VEGF had FL of over 1.0 in Factor 3 constituting 10.7% of all variability. In hierarchical cluster analysis, MCP-1 and VEGF were located in the cluster of first proximate mutual distance to central retinal thickness. These data could suggest that low-grade inflammation is a principal contributor in nAMD.

The Gut Microbiome, Metformin, and Aging

2021 ◽  
Vol 62 (1) ◽  
Author(s):  
Sri Nitya Reddy Induri ◽  
Payalben Kansara ◽  
Scott C. Thomas ◽  
Fangxi Xu ◽  
Deepak Saxena ◽  
...  
Keyword(s):  
Gut Microbiome ◽  
Healthy Aging ◽  
Bacterial Species ◽  
Annual Review ◽  
Publication Date ◽  
Low Grade ◽  
Host Interactions ◽  
Age Related ◽  
Low Grade Inflammation

Metformin has been extensively used for the treatment of type 2 diabetes, and it may also promote healthy aging. Despite its widespread use and versatility, metformin's mechanisms of action remain elusive. The gut typically harbors thousands of bacterial species, and as the concentration of metformin is much higher in the gut as compared to plasma, it is plausible that microbiome-drug-host interactions may influence the functions of metformin. Detrimental perturbations in the aging gut microbiome lead to the activation of the innate immune response concomitant with chronic low-grade inflammation. With the effectiveness of metformin in diabetes and antiaging varying among individuals, there is reason to believe that the gut microbiome plays a role in the efficacy of metformin. Metformin has been implicated in the promotion and maintenance of a healthy gut microbiome and reduces many age-related degenerative pathologies. Mechanistic understanding of metformin in the promotion of a healthy gut microbiome and aging will require a systems-level approach. Expected final online publication date for the Annual Review of Pharmacology and Toxicology, Volume 62 is January 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

scholarly journals The Role of Oxidative Stress and Inflammation in Cardiovascular Aging

2014 ◽  
Vol 2014 ◽  
pp. 1-13 ◽  
Author(s):  
Junzhen Wu ◽  
Shijin Xia ◽  
Bill Kalionis ◽  
Wenbin Wan ◽  
Tao Sun
Keyword(s):  
Oxidative Stress ◽  
Cardiovascular Disease ◽  
Ventricular Hypertrophy ◽  
Left Ventricular ◽  
Low Grade ◽  
Oxygen Species ◽  
Age Related ◽  
Vascular Elasticity ◽  
Low Grade Inflammation

Age is an independent risk factor of cardiovascular disease, even in the absence of other traditional factors. Emerging evidence in experimental animal and human models has emphasized a central role for two main mechanisms of age-related cardiovascular disease: oxidative stress and inflammation. Excess reactive oxygen species (ROS) and superoxide generated by oxidative stress and low-grade inflammation accompanying aging recapitulate age-related cardiovascular dysfunction, that is, left ventricular hypertrophy, fibrosis, and diastolic dysfunction in the heart as well as endothelial dysfunction, reduced vascular elasticity, and increased vascular stiffness. We describe the signaling involved in these two main mechanisms that include the factors NF-κB, JunD, p66Shc, and Nrf2. Potential therapeutic strategies to improve the cardiovascular function with aging are discussed, with a focus on calorie restriction, SIRT1, and resveratrol.

scholarly journals Insulin/IGF-1 signaling promotes immunosuppression via the STAT3 pathway: impact on the aging process and age-related diseases

2021 ◽  
Author(s):  
Antero Salminen ◽  
Kai Kaarniranta ◽  
Anu Kauppinen
Keyword(s):  
Aging Process ◽  
Mammalian Species ◽  
Low Grade ◽  
P53 Signaling ◽  
Stat3 Signaling ◽  
Age Related ◽  
Proliferation And Differentiation ◽  
Immunosuppressive Cells ◽  
Low Grade Inflammation ◽  
Adaptive Immune Systems

Abstract Background The insulin/IGF-1 signaling pathway has a major role in the regulation of longevity both in Caenorhabditis elegans and mammalian species, i.e., reduced activity of this pathway extends lifespan, whereas increased activity accelerates the aging process. The insulin/IGF-1 pathway controls protein and energy metabolism as well as the proliferation and differentiation of insulin/IGF-1-responsive cells. Insulin/IGF-1 signaling also regulates the functions of the innate and adaptive immune systems. The purpose of this review was to elucidate whether insulin/IGF-1 signaling is linked to immunosuppressive STAT3 signaling which is known to promote the aging process. Methods Original and review articles encompassing the connections between insulin/IGF-1 and STAT3 signaling were examined from major databases including Pubmed, Scopus, and Google Scholar. Results The activation of insulin/IGF-1 receptors stimulates STAT3 signaling through the JAK and AKT-driven signaling pathways. STAT3 signaling is a major activator of immunosuppressive cells which are able to counteract the chronic low-grade inflammation associated with the aging process. However, the activation of STAT3 signaling stimulates a negative feedback response through the induction of SOCS factors which not only inhibit the activity of insulin/IGF-1 receptors but also that of many cytokine receptors. The inhibition of insulin/IGF-1 signaling evokes insulin resistance, a condition known to be increased with aging. STAT3 signaling also triggers the senescence of both non-immune and immune cells, especially through the activation of p53 signaling. Conclusions Given that cellular senescence, inflammaging, and counteracting immune suppression increase with aging, this might explain why excessive insulin/IGF-1 signaling promotes the aging process.

scholarly journals Microbiota and age-related macular degeneration: where are we today?

ABOUTOPEN ◽  
2021 ◽  
Vol 8 (1) ◽  
pp. 23-28
Author(s):  
Angelo Maria Minnella ◽  
Francesca Albanesi ◽  
Martina Maceroni
Keyword(s):  
Macular Degeneration ◽  
Clinical Course ◽  
Retinal Disease ◽  
Age Related Macular Degeneration ◽  
Low Grade ◽  
Leaky Gut ◽  
Proinflammatory Mediators ◽  
Age Related ◽  
Simple Sugar ◽  
Low Grade Inflammation

Age-related macular degeneration (AMD) is a complex degenerative multifactorial retinal disease, representing a leading cause of legal blindness among elderly individuals. It is well known that age, family history, smoking, nutrition, and inflammation contribute to the development of AMD. Recent studies support the existence of a gut-retina axis involved in the pathogenesis of several ocular diseases, including AMD. High-fat and high simple sugar diets determine a derangement of the gut microbiota, with an increase of gut permeability and systemic low-grade inflammation. Leaky gut is correlated with higher levels of circulating microbial-associated pattern molecules, which trigger the systemic release of potent proinflammatory mediators and stimulate the specific immune cells of the retina, contributing to retinal damage. All these findings suggest that microbiota is closely related to AMD and that it may be targeted in order to influence AMD pathogenesis and/or its clinical course.

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