bims-minfam 2022-08-28 papers

bims-minfam

Biomed News

on Inflammation and metabolism in ageing and cancer

Issue of 2022–08–28
ten papers selected by
Ayesh Seneviratne, Western University

Molecular Pathways in Clonal Hematopoiesis: From the Acquisition of Somatic Mutations to Transformation into Hematologic Neoplasm.
Lipids and the cancer stemness regulatory system in acute myeloid leukemia.
Aryl hydrocarbon receptor (AhR) reveals evidence of antagonistic pleiotropy in the regulation of the aging process.
CHIPing away the progression potential of CHIP: A new reality in the making.
Lipid metabolism in sarcopenia.
Let-7 as a Promising Target in Aging and Aging-Related Diseases: A Promise or a Pledge.
Frailty and Associated Factors among the Elderly in Vietnam: A Cross-Sectional Study.
Old blood for young mice.
The dark side of Tregs during aging.
COVID vaccines slash risk of spreading Omicron - and so does prior infection.

Life (Basel). 2022 Jul 28. pii: 1135. [Epub ahead of print]12(8):

Molecular Pathways in Clonal Hematopoiesis: From the Acquisition of Somatic Mutations to Transformation into Hematologic Neoplasm.

Charles Gaulin, Katalin Kelemen, Cecilia Arana Yi.

  Hematopoietic stem cell aging, through the acquisition of somatic mutations, gives rise to clonal hematopoiesis (CH). While a high prevalence of CH has been described in otherwise healthy older adults, CH confers an increased risk of both hematologic and non-hematologic diseases. Classification of CH into clonal hematopoiesis of indeterminate potential (CHIP) and clonal cytopenia of undetermined significance (CCUS) further describes this neoplastic myeloid precursor state and stratifies individuals at risk of developing clinically significant complications. The sequential acquisition of driver mutations, such as DNMT3A, TET2, and ASXL1, provide a selective advantage and lead to clonal expansion. Inflammation, microbiome signatures, and external selective pressures also contribute to clonal evolution. Despite significant progress in recent years, the precise molecular mechanisms driving CH transformation to hematologic neoplasms are not well defined. Further understanding of these complex mechanisms may improve risk stratification and introduce therapeutic interventions in CH. Here we discuss the genetic drivers underpinning CH, mechanisms for clonal evolution, and transformation to hematologic neoplasm.

Keywords:  aging; clonal hematopoiesis; hematologic neoplasms; hematopoietic stem cell

DOI:  https://doi.org/10.3390/life12081135
Essays Biochem. 2022 Aug 23. pii: EBC20220028. [Epub ahead of print]

Lipids and the cancer stemness regulatory system in acute myeloid leukemia.

Isabel N X Lim, Murtaza S Nagree, Stephanie Z Xie.

  Acute myeloid leukemia (AML) is a heterogeneous disease of impaired myeloid differentiation and a caricature of normal hematopoiesis. Leukemic stem cells (LSCs) are responsible for long-term clonal propagation in AML just as hematopoietic stem cells (HSCs) sustain lifelong hematopoiesis. LSCs are often resistant to standard chemotherapy and are responsible for clinical relapse. Although AML is highly heterogeneous, determinants of stemness are prognostic for AML patient survival and can predict AML drug sensitivity. Therefore, one way to overcome challenges preventing efficacious treatment outcomes is to target LSC stemness. Metabolomic and lipidomic studies of serum and cells from AML patients are emerging to complement genomic, transcriptomic, epigenetic, and proteomic data sets to characterize and stratify AML. Recent studies have shown the value of fractionating LSCs versus blasts when characterizing metabolic pathways and implicate the importance of lipid balance to LSCs function. As more extensive metabolic studies coupled to functional in vivo assays are conducted on highly purified HSCs, bulk AML, and LSCs, the similarities and differences in lipid homeostasis in stem-like versus more mature AML subtypes as well as from normal HSCs are emerging. Here, we discuss the latest findings from studies of lipid function in LSCs, with a focus on sphingolipids (SLs) as stemness/lineage fate mediators in AML, and the balance of fatty acid anabolism and catabolism fueling metabolic flexibility and drug resistance in AML. We also discuss how designing successful strategies to target lipid vulnerabilities and improve AML patient survival should take into consideration the hierarchical nature of AML.

Keywords:  acute myeloid leukaemia; hematopoietic stem cells; leukemic stem cells; lipid metabolism; sphingolipids

DOI:  https://doi.org/10.1042/EBC20220028
Cell Mol Life Sci. 2022 Aug 20. 79(9): 489

Aryl hydrocarbon receptor (AhR) reveals evidence of antagonistic pleiotropy in the regulation of the aging process.

Antero Salminen.

  The antagonistic pleiotropy hypothesis is a well-known evolutionary theory to explain the aging process. It proposes that while a particular gene may possess beneficial effects during development, it can exert deleterious properties in the aging process. The aryl hydrocarbon receptor (AhR) has a significant role during embryogenesis, but later in life, it promotes several age-related degenerative processes. For instance, AhR factor (i) controls the pluripotency of stem cells and the stemness of cancer stem cells, (ii) it enhances the differentiation of embryonal stem cells, especially AhR signaling modulates the differentiation of hematopoietic stem cells and progenitor cells, (iii) it also stimulates the differentiation of immunosuppressive Tregs, Bregs, and M2 macrophages, and finally, (iv) AhR signaling participates in the differentiation of many peripheral tissues. On the other hand, AhR signaling is involved in many processes promoting cellular senescence and pathological processes, e.g., osteoporosis, vascular dysfunction, and the age-related remodeling of the immune system. Moreover, it inhibits autophagy and aggravates extracellular matrix degeneration. AhR signaling also stimulates oxidative stress, promotes excessive sphingolipid synthesis, and disturbs energy metabolism by catabolizing NAD+ degradation. The antagonistic pleiotropy of AhR signaling is based on the complex and diverse connections with major signaling pathways in a context-dependent manner. The major regulatory steps include, (i) a specific ligand-dependent activation, (ii) modulation of both genetic and non-genetic responses, (iii) a competition and crosstalk with several transcription factors, such as ARNT, HIF-1α, E2F1, and NF-κB, and (iv) the epigenetic regulation of target genes with binding partners. Thus, not only mTOR signaling but also the AhR factor demonstrates antagonistic pleiotropy in the regulation of the aging process.

Keywords:  Immunosuppression; Kynurenine; Lifespan; Longevity; RelB; Retrotransposon

DOI:  https://doi.org/10.1007/s00018-022-04520-x
Blood Rev. 2022 Aug 15. pii: S0268-960X(22)00075-3. [Epub ahead of print] 101001

CHIPing away the progression potential of CHIP: A new reality in the making.

Zhuoer Xie, Amer M Zeidan.

  Over the past few years, we have gained a deeper understanding of clonal hematopoiesis of indeterminate potential (CHIP), especially with regard to the epidemiology, clinical sequelae, and mechanical aspects. However, interventional strategies to prevent or delay the potential negative consequences of CHIP remain underdeveloped. In this review, we highlight the latest updates on clonal hematopoiesis research, including molecular mechanisms and clinical implications, with a particular focus on the evolving strategies for the interventions that are being evaluated in ongoing observational and interventional trials. There remains an urgent need to formulate standardized and evidence-based recommendations and guidelines for evaluating and managing individuals with clonal hematopoiesis. In addition, patient-centric endpoints must be defined for clinical trials, which will enable us to continue the robust development of effective preventive strategies and improve clinical outcomes.

Keywords:  Aging; CCUS; CHIP; Inflammation; Intervention; Prevention

DOI:  https://doi.org/10.1016/j.blre.2022.101001
Bone. 2022 Aug 22. pii: S8756-3282(22)00216-2. [Epub ahead of print] 116539

Lipid metabolism in sarcopenia.

Ahmed Al Saedi, Danielle A Debruin, Alan Hayes, Mark Hamrick.

  Sarcopenia is an age-related disease associated with loss of muscle mass and strength. This geriatric syndrome predisposes elderly individuals to a disability, falls, fractures, and death. Fat infiltration in muscle is one of the hallmarks of sarcopenia and aging. Alterations in fatty acid (FA) metabolism are evident in aging, type 2 diabetes, and obesity, with the accumulation of lipids inside muscle cells contributing to muscle insulin resistance and ceramide accumulation. These lipids include diacylglycerol, lipid droplets, intramyocellular lipids, intramuscular triglycerides, and polyunsaturated fatty acids (PUFAs). In this review, we examine the regulation of lipid metabolism in skeletal muscle, including lipid metabolization and storage, intervention, and the types of lipases expressed in skeletal muscle responsible for the breakdown of adipose triglyceride fats. In addition, we address the role of FAs in sarcopenia and the potential benefits of PUFAs.

Keywords:  Aging; Diacylglycerol; Fatty acids; Intramyocellular lipids; Lipid droplets

DOI:  https://doi.org/10.1016/j.bone.2022.116539
Biomolecules. 2022 Aug 02. pii: 1070. [Epub ahead of print]12(8):

Let-7 as a Promising Target in Aging and Aging-Related Diseases: A Promise or a Pledge.

Ya Wang, Juanjuan Zhao, Shipeng Chen, Dongmei Li, Jing Yang, Xu Zhao, Ming Qin, Mengmeng Guo, Chao Chen, Zhixu He, Ya Zhou, Lin Xu.

  The abnormal regulation and expression of microRNA (miRNA) are closely related to the aging process and the occurrence and development of aging-related diseases. Lethal-7 (let-7) was discovered in Caenorhabditis elegans (C. elegans) and plays an important role in development by regulating cell fate regulators. Accumulating evidence has shown that let-7 is elevated in aging tissues and participates in multiple pathways that regulate the aging process, including affecting tissue stem cell function, body metabolism, and various aging-related diseases (ARDs). Moreover, recent studies have found that let-7 plays an important role in the senescence of B cells, suggesting that let-7 may also participate in the aging process by regulating immune function. Therefore, these studies show the diversity and complexity of let-7 expression and regulatory functions during aging. In this review, we provide a detailed overview of let-7 expression regulation as well as its role in different tissue aging and aging-related diseases, which may provide new ideas for enriching the complex expression regulation mechanism and pathobiological function of let-7 in aging and related diseases and ultimately provide help for the development of new therapeutic strategies.

Keywords:  aging; aging-related diseases; let-7; miRNA; regulation

DOI:  https://doi.org/10.3390/biom12081070
Geriatrics (Basel). 2022 Aug 20. pii: 85. [Epub ahead of print]7(4):

Frailty and Associated Factors among the Elderly in Vietnam: A Cross-Sectional Study.

Trung Quoc Hieu Huynh, Thi Lan Anh Pham, Van Tam Vo, Ha Ngoc The Than, Tan Van Nguyen.

   BACKGROUND: Frailty syndrome is common among older people and can lead to various adverse consequences such as falls, cognitive decline, disability, dependent living, increased mortality, excessive drug use, and prolonged hospital stays.
OBJECTIVES: This research determined the prevalence of frailty and associated factors among older adults in Vietnam.
METHODS: A cross-sectional study was conducted on 584 older adults across five Ho Chi Minh City wards from November 2020 to January 2021. Based on the modified Fried frailty scale, the participants were divided into three categories: robust, pre-frail, and frail. A chi-square test (or Fisher's test) examined the relationship between frailty categories and other variables. Multivariable logistic regression used variates with a cut-off of p ≤ 0.05 in the univariate analysis.
RESULTS: The prevalence rates of frailty and pre-frailty were 19% and 64%, respectively. The most common frailty component was weak grip strength (63.9%), followed by slowness (36.1%), weight loss (21.6%), low physical activity (19.5%), and exhaustion (18.5%). In addition, the prevalence of frailty was significantly associated with age, BMI levels, living alone, and sarcopenia.
CONCLUSION: The community's prevalence of frailty among older adults is high. Frailty can lead to many adverse consequences for the elderly. As there were some modifiable factors associated with frailty, it should be assessed in older people through community-based healthcare programs for early diagnosis and management.

Keywords:  Vietnam; aging; community; frailty; functional decline; older adults

DOI:  https://doi.org/10.3390/geriatrics7040085
Lab Anim (NY). 2022 Sep;51(9): 238

Old blood for young mice.

Alexandra Le Bras.

DOI: https://doi.org/10.1038/s41684-022-01044-6
Front Immunol. 2022 ;13 940705

The dark side of Tregs during aging.

Martina Palatella, Stephane M Guillaume, Michelle A Linterman, Jochen Huehn.

  In the last century, we have seen a dramatic rise in the number of older persons globally, a trend known as the grey (or silver) tsunami. People live markedly longer than their predecessors worldwide, due to remarkable changes in their lifestyle and in progresses made by modern medicine. However, the older we become, the more susceptible we are to a series of age-related pathologies, including infections, cancers, autoimmune diseases, and multi-morbidities. Therefore, a key challenge for our modern societies is how to cope with this fragile portion of the population, so that everybody could have the opportunity to live a long and healthy life. From a holistic point of view, aging results from the progressive decline of various systems. Among them, the distinctive age-dependent changes in the immune system contribute to the enhanced frailty of the elderly. One of these affects a population of lymphocytes, known as regulatory T cells (Tregs), as accumulating evidence suggest that there is a significant increase in the frequency of these cells in secondary lymphoid organs (SLOs) of aged animals. Although there are still discrepancies in the literature about modifications to their functional properties during aging, mounting evidence suggests a detrimental role for Tregs in the elderly in the context of bacterial and viral infections by suppressing immune responses against non-self-antigens. Interestingly, Tregs seem to also contribute to the reduced effectiveness of immunizations against many pathogens by limiting the production of vaccine-induced protective antibodies. In this review, we will analyze the current state of understandings about the role of Tregs in acute and chronic infections as well as in vaccination response in both humans and mice. Lastly, we provide an overview of current strategies for Treg modulation with potential future applications to improve the effectiveness of vaccines in older individuals.

Keywords:  aging; germinal center reaction; pathogen-specific immune response; regulatory T cells; vaccination

DOI:  https://doi.org/10.3389/fimmu.2022.940705
Nature. 2022 Aug 26.

COVID vaccines slash risk of spreading Omicron - and so does prior infection.

Ruby Prosser Scully.



Keywords:  Infection; SARS-CoV-2; Vaccines

DOI:  https://doi.org/10.1038/d41586-022-02328-0