bims-minfam Biomed News
on Inflammation and metabolism in ageing and cancer
Issue of 2022–06–26
fourteen papers selected by
Ayesh Seneviratne, Western University
  1. Therapy-Related Clonal Hematopoiesis: A New Link Between Cancer and Cardiovascular Disease.
  2. Biomarkers of Age-Related Frailty and Frailty Related to Diseases: An Exploratory, Cross-Sectional Analysis from the MAPT Study.
  3. Epigenetic aging: Biological age prediction and informing a mechanistic theory of aging.
  4. Blood pressure variability: a potential marker of aging.
  5. Editorial: A Golden Age of Aging Biomarker Discovery.
  6. Age-Related Lysosomal Dysfunctions.
  7. Clonal haematopoiesis is associated with higher mortality in patients with cardiogenic shock.
  8. Venetoclax in combination with FLAG-IDA-based protocol for patients with acute myeloid leukemia: a real-world analysis.
  9. Frailty in Aging and the Search for the Optimal Biomarker: A Review.
  10. Very Low-Calorie Ketogenic Diet: A Potential Application in the Treatment of Hypercortisolism Comorbidities.
  11. Resveratrol Analog 4-Bromo-Resveratrol Inhibits Gastric Cancer Stemness through the SIRT3-c-Jun N-Terminal Kinase Signaling Pathway.
  12. mRNA COVID-19 Vaccine Booster After Inactivated Vaccine Primary Series.
  13. IL-17A drives cognitive aging probably via inducing neuroinflammation and theta oscillation disruption in the hippocampus.
  14. Active Compounds in Fruits and Inflammation in the Body.
  1. Heart Fail Clin. 2022 Jul;pii: S1551-7136(22)00011-3. [Epub ahead of print]18(3): 349-359
    Therapy-Related Clonal Hematopoiesis: A New Link Between Cancer and Cardiovascular Disease.
    Yoshimitsu Yura, Jesse D Cochran, Kenneth Walsh.
      Clonal hematopoiesis is a precancerous state that is recognized as a new causal risk factor for cardiovascular disease. Therapy-related clonal hematopoiesis is a condition that is often found in cancer survivors. These clonal expansions are caused by mutations in DNA damage-response pathway genes that allow hematopoietic stem cells to undergo positive selection in response to the genotoxic stress. These mutant cells increasingly give rise to progeny leukocytes that display enhanced proinflammatory properties. Recent experimental studies suggest that therapy-related clonal hematopoiesis may contribute to the medium- to long-term risk of genotoxic therapies on the cardiovascular system.
    Keywords:  Cardio-oncology; Clonal hematopoiesis; Inflammation
    DOI:  https://doi.org/10.1016/j.hfc.2022.02.010
  2. J Nutr Health Aging. 2022 ;26(6): 545-551
    Biomarkers of Age-Related Frailty and Frailty Related to Diseases: An Exploratory, Cross-Sectional Analysis from the MAPT Study.
    D Angioni, W H Lu, S Sourdet, T Macaron, C Takeda, S Guyonnet, J F Mangin, Y Rolland, P de Souto Barreto, B Vellas.
       BACKGROUND: Frailty may in most cases result from two main causes: the aging process (age-related frailty) and diseases (evolving chronic conditions or acute medical illnesses - disease-related frailty). The biological determinants characterizing these two main causes of frailty may be different.
    OBJECTIVES: The aim of this study is to compare the biological and neuroimaging profile of people without frailty, those with age-related frailty, and subjects with disease-related frailty in community-dwelling older adults.
    MATERIAL AND METHODS: We performed a secondary, cross-sectional analysis from the Multidomain Alzheimer Preventive Trial (MAPT). We included 1199 subjects without frailty throughout the 5-year follow-up, 82 subjects with incident age-related frailty, and 53 with incident disease-related frailty. Available blood biomarkers involved nutritional (eg, vitamin D, omega-3 fatty acids), inflammatory-related (IL-6, TNFR1, GDF15), neurodegenerative (eg, beta-amyloid, neurofilament light chain) and neuroimaging markers (MRI, Amyloid-PET).
    RESULTS: Although not statistically significant, the results of the unadjusted model showed increasing gradients for inflammatory markers (GDF15, TNFR1) and decreasing gradients for nutritional and neuroimaging markers (omega 3 index, hippocampal volume) from age-related frailty participants to individuals with disease-related frailty. Considering the linear models we observed higher GDF15 values in disease-related frailty group compared to age-related frailty individuals [β = 242.8 (49.5, 436.2)]. We did not find any significant difference between subjects without frailty and those with age-related frailty. Subjects with disease-related frailty compared to subjects without frailty had lower values of DHA [β = -2.42 (-4.76, -0.08)], Omega 3 Index [β = -0.50 (-0.95, -0.06)] and hippocampal volume [β = -0.22 (-0.42,-0.02)]. They also had higher values of GDF15 [β = 246.1 (88.9, 403.4)] and TNFR1 [β = 157.5 (7.8, 307.2)].
    CONCLUSION: Age-related frailty and disease-related frailty may represent different degrees of frailty severity on a biological level. Further research is needed to identify biomarkers potentially able to distinguish these classifications of frailty.
    Keywords:  Frailty related to diseases; age-related frailty; biomarkers; geroscience
    DOI:  https://doi.org/10.1007/s12603-022-1793-9
  3. J Intern Med. 2022 Jun 20.
    Epigenetic aging: Biological age prediction and informing a mechanistic theory of aging.
    Adam Li, Zane Koch, Trey Ideker.
      Numerous studies have shown that epigenetic age-an individual's degree of aging based on patterns of DNA methylation-can be computed and is associated with an array of factors including diet, lifestyle, genetics, and disease. One can expect that still further associations will emerge with additional aging research, but to what end? Prediction of age was an important first step, but-in our view-the focus must shift from chasing increasingly accurate age computations to understanding the links between the epigenome and the mechanisms and physiological changes of aging. Here, we outline emerging areas of epigenetic aging research that prioritize biological understanding and clinical application. First, we survey recent progress in epigenetic clocks, which are beginning to predict not only chronological age but aging outcomes such as all-cause mortality and onset of disease, or which integrate aging signals across multiple biological processes. Second, we discuss research that exemplifies how investigation of the epigenome is building a mechanistic theory of aging and informing clinical practice. Such examples include identifying methylation sites and the genes most strongly predictive of aging-a subset of which have shown strong potential as biomarkers of neurodegenerative disease and cancer; relating epigenetic clock predictions to hallmarks of aging; and using longitudinal studies of DNA methylation to characterize human disease, resulting in the discovery of epigenetic indications of type 1 diabetes and the propensity for psychotic experiences.
    Keywords:  CpG; aging; epigenetics; longevity; methylation
    DOI:  https://doi.org/10.1111/joim.13533
  4. Ageing Res Rev. 2022 Jun 20. pii: S1568-1637(22)00119-2. [Epub ahead of print] 101677
    Blood pressure variability: a potential marker of aging.
    Leonardo Bencivenga, Philipe De Souto Barreto, Yves Rolland, Olivier Hanon, Jean-Sébastien Vidal, Philippe Cestac, Bruno Vellas, Laure Rouch.
      Aging is characterized by alterations in neuro-cardiovascular regulatory mechanisms, leading to impaired physiological variability patterns. Repeated evidence has shown that increased Blood Pressure Variability (BPV) is associated with organ damage and exerts independent predictive value on several health outcomes: cardiovascular events, neurocognitive impairment, metabolic disorders and typical geriatric syndromes such as sarcopenia and frailty. Accordingly, it may constitute the epiphenomenon of the alterations in homeostatic mechanisms, typical of late life. Aging and altered BPV share the same molecular mechanisms, in particular the clinical state of subclinical inflammation has been widely ascertained in advanced age and it is also related to BP dysregulation through altered endothelial function and increased production of ROS. Arterial stiffness and autonomic dysfunction have been associated to impairment in BPV and also represent key features in elderly patients. Furthermore, accumulating evidence in the field of Geroscience has reported that several molecular changes described in cardiovascular aging and altered BPV also relate with the majority of the 9 identified hallmarks of aging. Indeed, BPV may be linked to genomic instability, epigenetic modification and mitochondrial oxidative damage, which represent milestones of aging process. The aim of the present paper is to analyse the interplay between BPV and the pathophysiology of the ageing process, in order to stimulate discussion about the potential role of BPV as a new marker of aging.
    Keywords:  Blood Pressure Variability; Hallmarks; Hypertension; Marker; aging
    DOI:  https://doi.org/10.1016/j.arr.2022.101677
  5. J Nutr Health Aging. 2022 ;26(6): 543-544
    Editorial: A Golden Age of Aging Biomarker Discovery.
    T Tanaka, L Ferrucci.
      
    DOI:  https://doi.org/10.1007/s12603-022-1808-6
  6. Cells. 2022 Jun 20. pii: 1977. [Epub ahead of print]11(12):
    Age-Related Lysosomal Dysfunctions.
    Lena Guerrero-Navarro, Pidder Jansen-Dürr, Maria Cavinato.
      Organismal aging is normally accompanied by an increase in the number of senescent cells, growth-arrested metabolic active cells that affect normal tissue function. These cells present a series of characteristics that have been studied over the last few decades. The damage in cellular organelles disbalances the cellular homeostatic processes, altering the behavior of these cells. Lysosomal dysfunction is emerging as an important factor that could regulate the production of inflammatory molecules, metabolic cellular state, or mitochondrial function.
    Keywords:  aging; lysosome; senescence
    DOI:  https://doi.org/10.3390/cells11121977
  7. Eur J Heart Fail. 2022 Jun 21.
    Clonal haematopoiesis is associated with higher mortality in patients with cardiogenic shock.
    Fernando L Scolari, Sagi Abelson, Darshan H Brahmbhatt, Jessie J F Medeiros, Chun-Po S Fan, Nicole L Fung, Vesna Mihajlovic, Markus S Anker, Madison Otsuki, Patrick R Lawler, Heather J Ross, Adriana C Luk, Stefan Anker, John E Dick, Filio Billia.
       AIMS: Cardiogenic shock (CS) with variable systemic inflammation may be responsible for the patient heterogeneity and the exceedingly high mortality rate. Cardiovascular events have been associated with clonal haematopoiesis (CH) where specific gene mutations in hematopoietic stem cells lead to clonal expansion and the development of inflammation. This study aims to assess the prevalence of CH and its association with survival in a population of CS patients in a quaternary center.
    METHODS: We compared the frequency of CH mutations among 341 CS patients and 345 ambulatory heart failure (HF) matched for age, sex, ejection fraction, and HF aetiology. The association of CH with survival and levels of circulating inflammatory cytokines was analysed.
    RESULTS: We detected 266 CH mutations in 149 of 686 (22%) patients. CS patients had a higher prevalence of CH-related mutations than HF patients (OR 1.5; 95% CI 1.0-2.1, P=0.02) and was associated with decreased survival (30-days: HR 2.7; 95% CI 1.3-5.7, P=0.006; 90-days: HR 2.2; 95% CI 1.3-3.9, P=0.003; and 3-years: HR 1.7; 95% CI 1.1-2.8, P=0.01). TET2 or ASXL1 mutations were associated with lower survival in CS patients at all-time points (P≤0.03). CS patients with TET2 mutations had higher circulating levels of SCD40L, IFNγ, IL-4, and TNFα (P≤0.04), while those with ASXL1 mutations had decreased levels of CCL7 (P=0.03).
    CONCLUSIONS: CS patients have high frequency of CH, notably mutations in TET2 and ASXL1. This was associated with reduced survival and dysregulation of circulating inflammatory cytokines in those CS patients with CH. This article is protected by copyright. All rights reserved.
    Keywords:  cardiogenic shock; clonal haematopoiesis; cytokines; heart failure; inflammation; somatic mutations
    DOI:  https://doi.org/10.1002/ejhf.2588
  8. Ann Hematol. 2022 Jun 23.
    Venetoclax in combination with FLAG-IDA-based protocol for patients with acute myeloid leukemia: a real-world analysis.
    Ofir Wolach, Avraham Frisch, Liat Shargian, Moshe Yeshurun, Arie Apel, Vladimir Vainstein, Yakir Moshe, Shai Shimony, Odelia Amit, Yael Bar-On, Yishai Ofran, Pia Raanani, Boaz Nachmias, Ron Ram.
      Venetoclax in combination with intensive therapies is explored in both the upfront and relapse/refractory (R/R) setting, and available data suggest that such regimens are effective albeit with added hematological and infectious toxicity. We conducted a multicenter retrospective cohort study of patients with acute myeloid leukemia (AML) treated with venetoclax in combination with FLAG-IDA protocol. Twenty-five patients were included in this analysis (median age 53.4 years). Most patients were treated for R/R AML (n = 24, 96%) with a median of one (range 0-3) previous lines of therapy and 44% of patients (n = 11) having prior allogeneic hematopoietic cell transplantation (HCT). Median follow-up was 10 (range, 4-26) months. Platelet and neutrophil recovery were observed at a median of 31 (95% CI 17.6-38.3) and 23 (95% CI 20-28) days, respectively. The most common adverse events were infectious (blood stream infections, 48% and invasive fungal infections, 32%). Thirty-day mortality was 12%. Composite complete remission (CRc) was 72% for the entire cohort and 91% in patients treated for post-HCT relapse. Incidences of relapse-free and overall survival at 12 months were 67% (95% CI 58-76%) and 50% (95% CI 31-69%), respectively. Real-world data show that the addition of venetoclax to FLAG-IDA protocol is effective in patients with high-risk AML, most notably in the post-HCT relapse setting. Prophylaxis and surveillance for infections are crucial.
    Keywords:  High-risk AML; Intensive chemotherapy; Salvage; Venetoclax
    DOI:  https://doi.org/10.1007/s00277-022-04883-y
  9. Biomedicines. 2022 Jun 16. pii: 1426. [Epub ahead of print]10(6):
    Frailty in Aging and the Search for the Optimal Biomarker: A Review.
    Magdalena Sepúlveda, Diego Arauna, Francisco García, Cecilia Albala, Iván Palomo, Eduardo Fuentes.
      In the context of accelerated aging of the population worldwide, frailty has emerged as one of the main risk factors that can lead to loss of self-sufficiency in older people. This syndrome is defined as a reduced state of physiological reserve and functional capacity. The main diagnostic tools for frailty are based on scales that show deficits compared to their clinical application, such as the Fried frailty phenotype, among others. In this context, it is important to have one or more biomarkers with clinical applicability that can objectively and precisely determine the degree or risk of frailty in older people. The objective of this review was to analyze the biomarkers associated with frailty, classified according to the pathophysiological components of this syndrome (inflammation, coagulation, antioxidants, and liver function, among others). The evidence demonstrates that biomarkers associated with inflammation, oxidative stress, skeletal/cardiac muscle function, and platelet function represent the most promising markers of frailty due to their pathophysiological association with this syndrome. To a lesser extent but with the possibility of greater innovation, biomarkers associated with growth factors, vitamins, amino acids, and miRNAs represent alternatives as markers of this geriatric syndrome. Likewise, the incorporation of artificial intelligence represents an interesting approach to strengthening the diagnosis of frailty by biomarkers.
    Keywords:  aging; biomarkers; diagnosis; frailty; older people
    DOI:  https://doi.org/10.3390/biomedicines10061426
  10. Nutrients. 2022 Jun 09. pii: 2388. [Epub ahead of print]14(12):
    Very Low-Calorie Ketogenic Diet: A Potential Application in the Treatment of Hypercortisolism Comorbidities.
    Valentina Guarnotta, Fabrizio Emanuele, Roberta Amodei, Carla Giordano.
      A very low-calorie ketogenic diet (VLCKD) is characterized by low daily caloric intake (less than 800 kcal/day), low carbohydrate intake (<50 g/day) and normoproteic (1-1.5 g of protein/kg of ideal body weight) contents. It induces a significant weight loss and an improvement in lipid parameters, blood pressure, glycaemic indices and insulin sensitivity in patients with obesity and type 2 diabetes mellitus. Cushing's syndrome (CS) is characterized by an endogenous or exogenous excess of glucocorticoids and shows many comorbidities including cardiovascular disease, obesity, type 2 diabetes mellitus and lipid disorders. The aim of this speculative review is to provide an overview on nutrition in hypercortisolism and analyse the potential use of a VLCKD for the treatment of CS comorbidities, analysing the molecular mechanisms of ketogenesis.
    Keywords:  Cushing’s syndrome; cortisol; diabetes mellitus; glucocorticoid; obesity
    DOI:  https://doi.org/10.3390/nu14122388
  11. Curr Issues Mol Biol. 2021 Dec 22. 44(1): 63-72
    Resveratrol Analog 4-Bromo-Resveratrol Inhibits Gastric Cancer Stemness through the SIRT3-c-Jun N-Terminal Kinase Signaling Pathway.
    Yun-Shen Tai, Yi-Shih Ma, Chun-Lin Chen, Hsin-Yi Tsai, Chin-Chuan Tsai, Meng-Chieh Wu, Chih-Yi Chen, Ming-Wei Lin.
      Chemotherapy is the treatment of choice for gastric cancer, but the currently available therapeutic drugs have limited efficacy. Studies have suggested that gastric cancer stem cells may play a key role in drug resistance in chemotherapy. Therefore, new agents that selectively target gastric cancer stem cells in gastric tumors are urgently required. Sirtuin-3 (SIRT3) is a deacetylase that regulates mitochondrial metabolic homeostasis to maintain stemness in glioma stem cells. Targeting the mitochondrial protein SIRT3 may provide a novel therapeutic option for gastric cancer treatment. However, the mechanism by which stemness is regulated through SIRT3 inhibition in gastric cancer remains unknown. We evaluated the stemness inhibition ability of the SIRT3 inhibitor 4'-bromo-resveratrol (4-BR), an analog of resveratrol in human gastric cancer cells. Our results suggested that 4-BR inhibited gastric cancer cell stemness through the SIRT3-c-Jun N-terminal kinase pathway and may aid in gastric cancer stem-cell-targeted therapy.
    Keywords:  4-bromo-resveratrol; cancer stemness; chemosensitivity; gastric cancer
    DOI:  https://doi.org/10.3390/cimb44010005
  12. JAMA. 2022 06 21. 327(23): 2280
    mRNA COVID-19 Vaccine Booster After Inactivated Vaccine Primary Series.
    Howard D Larkin.
      
    DOI:  https://doi.org/10.1001/jama.2022.9408
  13. Int Immunopharmacol. 2022 Jul;pii: S1567-5769(22)00382-4. [Epub ahead of print]108 108898
    IL-17A drives cognitive aging probably via inducing neuroinflammation and theta oscillation disruption in the hippocampus.
    Yachun Li, Meng Mao, Lanyue Zhu, Qiang Sun, Jianhua Tong, Zhiqiang Zhou.
      Cognitive aging is a major risk factor for neurodegenerative diseases and has a great impact on the living quality of older individuals. However, the precise mechanisms underlying cognitive aging remain elusive. Accumulating evidence has demonstrated that interleukin 17A (IL-17A) is responsible for cognitive decline in the process of various neurological diseases. Thus, we conducted this study aiming to investigate the role of IL-17A in cognitive aging. In the present study, 31 aging (65-85 years) and 25 young (18-35 years) patients scheduled for elective removal of internal fixation surgery with spinal anesthesia were included for measurements of preoperative cognitive function, serum and cerebrospinal fluid (CSF) levels of IL-17A. For animal study, RNAseq and Kyoto Encyclopedia of Genes and Genomes pathways were used to identify differentially expressed genes between young and aging mice. For the treatment groups, young (2-3 months) and aging (16-18 months) mice received intraperitoneally with IL-17A and anti-IL-17A antibody, respectively. Twenty-four hours later, neurocognitive behavioral tests were conducted. Our results suggested that differentially expressed genes between young and aging mice were mainly enriched in IL-17 pathways. Serum and CSF levels of IL-17A increased significantly in aging patients and were negatively correlated with mini-mental state examination scores. Both young mice receiving IL-17A and aging mice showed impaired memory, increased blood-brain barrier permeability, overactivated microglia and increased inflammatory mediators in the hippocampus. Additionally, aging mice showed a significantly decreased θ power in the task-related neural oscillations. Notably, intraperitoneal injection of anti-IL-17A antibody alleviated increased blood-brain barrier permeability, microglial activation, neuroinflammation, θ oscillation disruption and cognitive decline of aging mice. In conclusion, our study demonstrated that IL-17A may be an initiating factor of cognitive aging.
    Keywords:  Aging; Blood-brain barrier; Cognition; IL-17A; Neural oscillation
    DOI:  https://doi.org/10.1016/j.intimp.2022.108898
  14. Nutrients. 2022 Jun 16. pii: 2496. [Epub ahead of print]14(12):
    Active Compounds in Fruits and Inflammation in the Body.
    Magdalena Majdan, Barbara Bobrowska-Korczak.
      Inflammation plays an important role in the pathogenesis of many diseases, including cardiovascular diseases, atherosclerosis, diabetes, asthma, and cancer. An appropriate diet and the active compounds contained in it can affect various stages of the inflammatory process and significantly affect the course of inflammatory diseases. Recent reports indicate that polyphenolic acids, vitamins, minerals, and other components of fruits may exhibit activity stimulating an anti-inflammatory response, which may be of importance in maintaining health and reducing the risk of disease. The article presents the latest data on the chemical composition of fruits and the health benefits arising from their anti-inflammatory and antioxidant effects. The chemical composition of fruits determines their anti-inflammatory and antioxidant properties, but the mechanisms of action are not fully understood.
    Keywords:  antioxidant; fruits; inflammation; phytochemical compounds
    DOI:  https://doi.org/10.3390/nu14122496
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