Mitochondrial Dysfunction and Inflammaging in Heart Failure: Novel Roles of CYP-Derived Epoxylipids

Age-associated changes leading to a decline in cardiac structure and function contribute to the increased susceptibility and incidence of cardiovascular diseases (CVD) in elderly individuals. Indeed, age is considered a risk factor for heart failure and serves as an important predictor for poor prognosis in elderly individuals. Effects stemming from chronic, low-grade inflammation, inflammaging, are considered important determinants in cardiac health; however, our understanding of the mechanisms involved remains unresolved. A steady decline in mitochondrial function is recognized as an important biological consequence found in the aging heart which contributes to the development of heart failure. Dysfunctional mitochondria contribute to increased cellular stress and an innate immune response by activating the NLRP-3 inflammasomes, which have a role in inflammaging and age-related CVD pathogenesis. Emerging evidence suggests a protective role for CYP450 epoxygenase metabolites of N-3 and N-6 polyunsaturated fatty acids (PUFA), epoxylipids, which modulate various aspects of the immune system and protect mitochondria. In this article, we provide insight into the potential roles N-3 and N-6 PUFA have modulating mitochondria, inflammaging and heart failure.

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Targeting Age-Related Pathways in Heart Failure

Circulation Research ◽

10.1161/circresaha.119.315889 ◽

2020 ◽

Vol 126 (4) ◽

pp. 533-551 ◽

Cited By ~ 7

Author(s):

Haobo Li ◽

Margaret H. Hastings ◽

James Rhee ◽

Lena E. Trager ◽

Jason D. Roh ◽

...

Keyword(s):

Heart Failure ◽

Elderly Population ◽

Molecular Mechanisms ◽

The Elderly ◽

Structure And Function ◽

Experimental Platform ◽

Age Related ◽

Cardiac Structure And Function ◽

And Function ◽

Increased Susceptibility

During aging, deterioration in cardiac structure and function leads to increased susceptibility to heart failure. The need for interventions to combat this age-related cardiac decline is becoming increasingly urgent as the elderly population continues to grow. Our understanding of cardiac aging, and aging in general, is limited. However, recent studies of age-related decline and its prevention through interventions like exercise have revealed novel pathological and cardioprotective pathways. In this review, we summarize recent findings concerning the molecular mechanisms of age-related heart failure and highlight exercise as a valuable experimental platform for the discovery of much-needed novel therapeutic targets in this chronic disease.

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Mitochondrial (Dys) Function in Inflammaging: Do MitomiRs Influence the Energetic, Oxidative, and Inflammatory Status of Senescent Cells?

Mediators of Inflammation ◽

10.1155/2017/2309034 ◽

2017 ◽

Vol 2017 ◽

pp. 1-11 ◽

Cited By ~ 16

Author(s):

Angelica Giuliani ◽

Francesco Prattichizzo ◽

Luigina Micolucci ◽

Antonio Ceriello ◽

Antonio Domenico Procopio ◽

...

Keyword(s):

Mitochondrial Gene ◽

Low Grade ◽

Master Regulators ◽

Inflammatory Status ◽

Age Related ◽

Secretory Phenotype ◽

And Function ◽

Low Grade Inflammation ◽

Proinflammatory Factors

A relevant feature of aging is chronic low-grade inflammation, termed inflammaging, a key process promoting the development of all major age-related diseases. Senescent cells can acquire the senescence-associated (SA) secretory phenotype (SASP), characterized by the secretion of proinflammatory factors fuelling inflammaging. Cellular senescence is also accompanied by a deep reshaping of microRNA expression and by the modulation of mitochondria activity, both master regulators of the SASP. Here, we synthesize novel findings regarding the role of mitochondria in the SASP and in the inflammaging process and propose a network linking nuclear-encoded SA-miRNAs to mitochondrial gene regulation and function in aging cells. In this conceptual structure, SA-miRNAs can translocate to mitochondria (SA-mitomiRs) and may affect the energetic, oxidative, and inflammatory status of senescent cells. We discuss the potential role of several of SA-mitomiRs (i.e., let-7b, miR-1, miR-130a-3p, miR-133a, miR-146a-5p, miR-181c-5p, and miR-378-5p), using miR-146a as a proof-of-principle model. Finally, we propose a comprehensive, metabolic, and epigenetic view of the senescence process, in order to amplify the range of possible approaches to target inflammaging, with the ultimate goal of decelerating the aging rate, postponing or blunting the development of age-related diseases.

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Consumption of Select Dietary Emulsifiers Exacerbates the Development of Spontaneous Intestinal Adenoma

International Journal of Molecular Sciences ◽

10.3390/ijms22052602 ◽

2021 ◽

Vol 22 (5) ◽

pp. 2602

Author(s):

Emilie Viennois ◽

Benoit Chassaing

Keyword(s):

Intestinal Inflammation ◽

Tumor Development ◽

Low Grade ◽

Gastrointestinal Cancers ◽

Cancer Initiation ◽

And Function ◽

The Impact ◽

Chronic Intestinal Inflammation ◽

Low Grade Inflammation ◽

Intestinal Adenoma

Inflammation is a well-characterized critical driver of gastrointestinal cancers. Previous findings have shown that intestinal low-grade inflammation can be promoted by the consumption of select dietary emulsifiers, ubiquitous component of processed foods which alter the composition and function of the gut microbiota. Using a model of colitis-associated cancer, we previously reported that consumption of the dietary emulsifiers carboxymethylcellulose or polysorbate-80 exacerbated colonic tumor development. Here, we investigate the impact of dietary emulsifiers consumption on cancer initiation and progression in a genetical model of intestinal adenomas. In APCmin mice, we observed that dietary emulsifiers consumption enhanced small-intestine tumor development in a way that appeared to be independent of chronic intestinal inflammation but rather associated with emulsifiers’ impact on the proliferative status of the intestinal epithelium as well as on intestinal microbiota composition in both male and female mice. Overall, our findings further support the hypothesis that emulsifier consumption may be a new modifiable risk factor for colorectal cancer (CRC) and that alterations in host–microbiota interactions can favor gastrointestinal carcinogenesis in individuals with a genetical predisposition to such disorders.

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Metabolic biomarker profiling for identification of susceptibility to severe pneumonia and COVID-19 in the general population

eLife ◽

10.7554/elife.63033 ◽

2021 ◽

Vol 10 ◽

Author(s):

◽

Heli Julkunen ◽

Anna Cichońska ◽

P Eline Slagboom ◽

Peter Würtz

Keyword(s):

General Population ◽

Disease Onset ◽

Severe Pneumonia ◽

Blood Sampling ◽

Low Grade ◽

Healthy Individuals ◽

Metabolic Biomarkers ◽

Low Grade Inflammation ◽

Increased Susceptibility

Biomarkers of low-grade inflammation have been associated with susceptibility to a severe infectious disease course, even when measured prior to disease onset. We investigated whether metabolic biomarkers measured by nuclear magnetic resonance (NMR) spectroscopy could be associated with susceptibility to severe pneumonia (2507 hospitalised or fatal cases) and severe COVID-19 (652 hospitalised cases) in 105,146 generally healthy individuals from UK Biobank, with blood samples collected 2007–2010. The overall signature of metabolic biomarker associations was similar for the risk of severe pneumonia and severe COVID-19. A multi-biomarker score, comprised of 25 proteins, fatty acids, amino acids and lipids, was associated equally strongly with enhanced susceptibility to severe COVID-19 (odds ratio 2.9 [95%CI 2.1–3.8] for highest vs lowest quintile) and severe pneumonia events occurring 7–11 years after blood sampling (2.6 [1.7–3.9]). However, the risk for severe pneumonia occurring during the first 2 years after blood sampling for people with elevated levels of the multi-biomarker score was over four times higher than for long-term risk (8.0 [4.1–15.6]). If these hypothesis generating findings on increased susceptibility to severe pneumonia during the first few years after blood sampling extend to severe COVID-19, metabolic biomarker profiling could potentially complement existing tools for identifying individuals at high risk. These results provide novel molecular understanding on how metabolic biomarkers reflect the susceptibility to severe COVID-19 and other infections in the general population.

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Hepatic macrophage accumulation with aging: cause for concern?

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00286.2020 ◽

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.

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

Blood ◽

10.1182/blood.2020010163 ◽

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.

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Glucocorticoid Receptor Gene, Low-Grade Inflammation, and Heart Failure: The Heart and Soul Study

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2009-2251 ◽

2010 ◽

Vol 95 (6) ◽

pp. 2885-2891 ◽

Cited By ~ 28

Author(s):

Christian Otte ◽

Stefan Wüst ◽

Shoujun Zhao ◽

Ludmila Pawlikowska ◽

Pui-Yan Kwok ◽

...

Keyword(s):

Heart Failure ◽

Glucocorticoid Receptor ◽

Systolic Dysfunction ◽

Left Ventricular ◽

Left Ventricular Ejection ◽

Low Grade ◽

C Reactive Protein ◽

Reactive Protein ◽

Glucocorticoid Receptor Gene ◽

Low Grade Inflammation

Abstract Context: A common haplotype of the glucocorticoid receptor (GR) gene has been associated with increased susceptibility to coronary heart disease (CHD). Whether this haplotype predisposes to heart failure (HF) is unknown. Objective: The objective of the study was to determine whether GR haplotype 3 is associated with HF and whether this association is explained by low-grade inflammation (C-reactive protein). Design: In a prospective cohort study, participants were genotyped for common GR gene polymorphisms (ER22/23EK, BclI C/G, N363S, 9β A/G). Haplotype analyses were conducted. Setting: The study was conducted at one university medical center, two Veterans Affairs medical centers, and nine public health clinics. Patients: Patients included 526 white outpatients with stable CHD. Main Outcome Measures: Echocardiographic evidence of ventricular dysfunction, self-reported heart failure, and subsequent hospitalization for heart failure were measured. Results: After adjusting for age, sex, smoking, and body mass index, participants with two copies of haplotype 3 were more likely than those with 0 or 1 copy to report heart failure [hazard ratio (HR) 4.15, 95% confidence interval (CI) 1.5–11.3, P < 0.01], have systolic dysfunction (left ventricular ejection fraction <50%) (HR 3.0, 95% CI 0.9–9.9, P = 0.07), and be hospitalized for HF during a mean follow-up of 6 yr (HR 3.0, 95% CI 1.3–7.0, P = 0.01). These associations were attenuated after adjustment for higher C-reactive protein levels in patients with two copies of haplotype 3. Conclusions: We found that the GR gene haplotype 3 was associated with prevalent HF, systolic dysfunction, and subsequent HF hospitalization in patients with CHD. This association was partly mediated by low-grade inflammation.

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Effects of External Loading on the Morphology of the Yielded Regions in Trabecular Bone Predicted by FEA

ASME 2008 Summer Bioengineering Conference, Parts A and B ◽

10.1115/sbc2008-193007 ◽

2008 ◽

Author(s):

Xiutao Shi ◽

Xiang Wang ◽

Glen L. Niebur

Keyword(s):

Trabecular Bone ◽

High Stress ◽

Tissue Level ◽

External Loading ◽

Trabecular Architecture ◽

Mineral Density ◽

Age Related ◽

Insight Into ◽

Increased Susceptibility

Osteoporosis is an age-related skeletal condition characterized by low bone mineral density and deterioration of the trabecular architecture leading to increased susceptibility to fracture [1]. Wolff hypothesized that trabecular architecture adapts to have its principal material axes aligned with the principal loading directions. Regions of experimentally labeled trabecular microdamage correspond to areas of high stress and strain calculated from FEA [2]. Studying the morphology of numerically predicted regions of tissue level yielding might provide insight into the role of trabecular architecture in the strength of trabecular bone.

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