bims-minfam Biomed News
on Inflammation and metabolism in ageing and cancer
Issue of 2022–11–20
twelve papers selected by
Ayesh Seneviratne, Western University
  1. Aging drives Tet2+/- clonal hematopoiesis via IL-1 signaling.
  2. Editorial: Characteristics and behaviors of hematopoietic stem cells and leukemia stem cells in hematologic malignancies.
  3. Effects of lifespan-extending interventions on cognitive healthspan.
  4. Immunosenescence is a therapeutic target for frailty in older adults: a narrative review.
  5. Gut microbial evidence chain in high-salt diet exacerbates intestinal aging process.
  6. Aging of hair follicle stem cells and their niches.
  7. Quantum Healthy Longevity for healthy people, planet, and growth.
  8. Use of the DASH Diet and Coronary Artery Disease.
  9. Rapamycin not dietary restriction improves resilience against pathogens: a meta-analysis.
  10. Probing Clonal Hematopoiesis in Liquid Biopsy.
  11. How can Canada reduce surgical backlogs without expanding privatization?
  12. Mitochondrial Matrix Protease ClpP Agonists Inhibit Cancer Stem Cell Function in Breast Cancer Cells by Disrupting Mitochondrial Homeostasis.
  1. Blood. 2022 11 15. pii: blood.2022016835. [Epub ahead of print]
    Aging drives Tet2+/- clonal hematopoiesis via IL-1 signaling.
    Francisco Caiado, Larisa V Kovtonyuk, Nagihan G Gonullu, Jonas Fullin, Steffen Boettcher, Markus G Manz.
      Clonal hematopoiesis of indeterminate potential (CHIP), also referred to as aging-related clonal hematopoiesis (ARCH), is defined as an asymptomatic clonal expansion of mutant mature hematopoietic cells over 4% of blood leukocytes. CHIP associates with advanced age and increased risk for hematological malignancy, cardiovascular disease and all-cause mortality. Loss-of-function somatic mutations in TET2 are frequent drivers of CHIP. However, the contribution of aging-associated cooperating cell-extrinsic drivers, like inflammation, remains under-explored. Using bone marrow (BM) transplantation and newly developed genetic mosaicism (HSC-SCL-Cre-ERT; Tet2+/flox; R26+/tm6(CAG-ZsGreen1)Hze) mouse models of Tet2+/--driven CHIP, we observed an association between increased Tet2+/- clonal expansion and higher BM levels of the inflammatory cytokine IL-1 upon aging. Administration of IL-1 to mice carrying CHIP led to an IL-1R1-dependent expansion of Tet2+/- hematopoietic stem and progenitor cells (HSPCs) and mature blood cells. This expansion was caused by increased Tet2+/- HSPC cell-cycle progression, increased multilineage differentiation and higher repopulation capacity compared to their WT counterparts. In agreement, IL-1α-treated Tet2+/- HSCs showed increased DNA replication and repair transcriptomic signatures and reduced susceptibility to IL-1α-mediated downregulation of self-renewal genes. Importantly, genetic deletion of IL-1R1 in Tet2+/- HPSC or pharmacological inhibition of IL-1 signaling impaired Tet2+/- clonal expansion, establishing the IL-1 pathway as a relevant and therapeutically targetable driver of Tet2+/- CHIP progression during aging.
    DOI:  https://doi.org/10.1182/blood.2022016835
  2. Front Oncol. 2022 ;12 1037202
    Editorial: Characteristics and behaviors of hematopoietic stem cells and leukemia stem cells in hematologic malignancies.
    Haojian Zhang, Pengxu Qian.
      
    Keywords:  acute myeloid leukemia; chronic myeloid leukemia; drug resistance; hematopoietic malignancies; hematopoietic stem cell; leukemia stem cell
    DOI:  https://doi.org/10.3389/fonc.2022.1037202
  3. Expert Rev Mol Med. 2022 Nov 15. 1-83
    Effects of lifespan-extending interventions on cognitive healthspan.
    Luka Culig, Burcin Duan Sahbaz, Vilhelm A Bohr.
      
    DOI:  https://doi.org/10.1017/erm.2022.36
  4. Ann Transl Med. 2022 Oct;10(20): 1142
    Immunosenescence is a therapeutic target for frailty in older adults: a narrative review.
    Huanan Jia, Wei Huang, Chuanfeng Liu, Shiyu Tang, Jing Zhang, Chongli Chen, Yuan Tian, Wen Zhong.
       Background and Objective: Aging refers to a progressive decrease in functional performance, leading to increased mortality risk. At present, life expectancy is increasing worldwide and is expected to exceed 80 years by 2040. However, this increase in life expectancy also indicates a rise in the incidence and prevalence of diseases, such as cardiovascular, neurological, musculoskeletal, and oncological diseases, which are associated with aging. The exact underlying mechanisms of aging remain unknown, and whether it is a programmed process or the consequence of an accumulation of stress events remains unclear. Thus, more scientific research is needed to improve the management of complex and frail patients.
    Methods: Several databases were searched with the following key words: immunosenescence, inflamm-aging, frailty, sarcopenia and skeletal muscle, etc.
    Key Content and Findings: Skeletal muscle is the core phenotype of frailty and sarcopenia. Immune aging and skeletal muscle decline interplay with each other and form a vicious circle. Maintaining muscle health is beneficial for immune function and delays the onset of frailty. Particularly, in the context of the ongoing corona virus disease (COVID)-19 pandemic, studies have shown that the elderly are more prone to the consequences of the SARS-CoV-2 virus. It has been reported that the rates of hospitalization in the 65-74, 75-84, and ≥85 years old group were 5×, 8×, and 10× greater than the 18-29 years old group, with corresponding COVID-19-related deaths being 60×, 140×, and 330× that of the younger reference group, respectively. Considering the above, this review aims to discuss the relationship between immunosenescence, skeletal muscle, and frailty, and to explore immunosenescence as a potential therapeutic target to prevent frailty and extend healthspan, with some emphasis on the effects of the COVID-19 pandemic on the elderly.
    Conclusions: Immunosenescence is a promising potential therapeutic target for frailty and is worthy of further investigation.
    Keywords:  Immunosenescence; frailty; inflamm-aging; sarcopenia
    DOI:  https://doi.org/10.21037/atm-22-4405
  5. Front Nutr. 2022 ;9 1046833
    Gut microbial evidence chain in high-salt diet exacerbates intestinal aging process.
    Tian-Hao Liu, Lin Zhao, Chen-Yang Zhang, Xiao-Ya Li, Tie-Long Wu, Yuan-Yuan Dai, Ying-Yue Sheng, Yi-Lin Ren, Yu-Zheng Xue.
      Although excessive salt consumption appears to hasten intestinal aging and increases susceptibility to cardiovascular disease, the molecular mechanism is unknown. In this study, mutual validation of high salt (HS) and aging fecal microbiota transplantation (FMT) in C56BL/6 mice was used to clarify the molecular mechanism by which excessive salt consumption causes intestinal aging. Firstly, we observed HS causes vascular endothelial damage and can accelerate intestinal aging associated with decreased colon and serum expression of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and increased malondialdehyde (MDA); after transplantation with HS fecal microbiota in mice, vascular endothelial damage and intestinal aging can also occur. Secondly, we also found intestinal aging and vascular endothelial damage in older mice aged 14 months; and after transplantation of the older mice fecal microbiota, the same effect was observed in mice aged 6-8 weeks. Meanwhile, HS and aging significantly changed gut microbial diversity and composition, which was transferable by FMT. Eventually, based on the core genera both in HS and the aging gut microbiota network, a machine learning model was constructed which could predict HS susceptibility to intestinal aging. Further investigation revealed that the process of HS-related intestinal aging was highly linked to the signal transduction mediated by various bacteria. In conclusion, the present study provides an experimental basis of potential microbial evidence in the process of HS related intestinal aging. Even, avoiding excessive salt consumption and actively intervening in gut microbiota alteration may assist to delay the aging state that drives HS-related intestinal aging in clinical practice.
    Keywords:  gut microbiota; high-salt diet; intestinal aging; machine learning; signal transduction
    DOI:  https://doi.org/10.3389/fnut.2022.1046833
  6. BMB Rep. 2022 Nov 16. pii: 5791. [Epub ahead of print]
    Aging of hair follicle stem cells and their niches.
    Hansaem Jang, Yemin Jo, Jung Hyun Lee, Sekyu Choi.
      Hair follicles in the skin undergo cyclic rounds of regeneration, degeneration, and rest throughout life. Stem cells residing in hair follicles play a pivotal role in maintaining tissue homeostasis and hair growth cycles. Research on hair follicle aging and age-related hair loss has demonstrated that a decline in hair follicle stem cell (HFSC) activity with aging can decrease the regeneration capacity of hair follicles. This review summarizes our understanding of how age-associated HFSC intrinsic and extrinsic mechanisms can induce HFSC aging and hair loss. In addition, we discuss approaches developed to attenuate ageassociated changes in HFSCs and their niches, thereby promoting hair regrowth.
  7. Lancet Healthy Longev. 2022 Nov 11. pii: S2666-7568(22)00267-7. [Epub ahead of print]
    Quantum Healthy Longevity for healthy people, planet, and growth.
    Tina Woods, Nic Palmarini, Lynne Corner, Nir Barzilai, Lord James Bethell, Lynne S Cox, Harris Eyre, Luigi Ferrucci, Linda Fried, David Furman, Brian Kennedy, Andrew Roddam, Andrew Scott, Richard C Siow.
      
    DOI:  https://doi.org/10.1016/S2666-7568(22)00267-7
  8. Cardiol Rev. 2022 Oct 27.
    Use of the DASH Diet and Coronary Artery Disease.
    Matthew W McMaster, Dikshya Sharma, Paritosh Kafle, William H Frishman, Wilbert S Aronow.
      Initial dietary approach to stop hypertension (DASH) diet feeding trials showed blood pressure (BP)-lowering effects that corresponded to higher degrees of concordance with the diet. These results popularized the idea that adherence to a DASH diet could reduce coronary artery disease (CAD) risk for patients. Recent evidence shows that the impact of DASH on CAD incidence and risk is less clear. While many studies show that the DASH diet impacts CAD risk factors, others suggest that these effects do not remain when important confounders are controlled. Also, the evidence from meta-analyses that the DASH diet impacts incident CAD is still inconclusive. Reassessment of the DASH diet, and the search for an ideal diet to prevent CAD will require a better understanding of the mechanisms through which the DASH diet works. Proposed mechanisms for its benefit include preventing inflammation and atherosclerosis progression as well as providing a heathy balance of dietary sodium and potassium intake.
    DOI:  https://doi.org/10.1097/CRD.0000000000000482
  9. Geroscience. 2022 Nov 18.
    Rapamycin not dietary restriction improves resilience against pathogens: a meta-analysis.
    Eleanor J Phillips, Mirre J P Simons.
      Dietary restriction (DR) and rapamycin both increase lifespan across a number of taxa. Despite this positive effect on lifespan and other aspects of health, reductions in some physiological functions have been reported for DR, and rapamycin has been used as an immunosuppressant. Perhaps surprisingly, both interventions have been suggested to improve immune function and delay immunosenescence. The immune system is complex and consists of many components. Therefore, arguably, the most holistic measurement of immune function is survival from an acute pathogenic infection. We reanalysed published post-infection short-term survival data of mice (n = 1223 from 23 studies comprising 46 effect sizes involving DR (n = 17) and rapamycin treatment (n = 29) and analysed these results using meta-analysis. Rapamycin treatment significantly increased post infection survival rate (lnHR =  - 0.72; CI =  - 1.17, -0.28; p = 0.0015). In contrast, DR reduced post-infection survival (lnHR = 0.80; CI = 0.08, 1.52; p = 0.03). Importantly, the overall effect size of rapamycin treatment was significantly lower (p < 0.001) than the estimate from DR studies, suggesting opposite effects on immune function. Our results show that immunomodulation caused by rapamycin treatment is beneficial to the survival from acute infection. For DR, our results are based on a smaller number of studies, but do warrant caution as they indicate possible immune costs of DR. Our quantitative synthesis suggests that the geroprotective effects of rapamycin extend to the immune system and warrants further clinical trials of rapamycin to boost immunity in humans.
    Keywords:  Aging; Diet; Immunosenescence; Infection; Rapamycin; Restriction
    DOI:  https://doi.org/10.1007/s11357-022-00691-4
  10. Cancer Discov. 2022 Nov 12. OF1
    Probing Clonal Hematopoiesis in Liquid Biopsy.
      Increased use of liquid biopsy to pinpoint actionable genomic alterations in cancer has been accompanied by a rise in the incidental detection of clonal hematopoiesis. Its clinical significance remains unclear, however, as well as how best to risk-stratify patients for further evaluation and, if necessary, treatment.
    DOI:  https://doi.org/10.1158/2159-8290.CD-NB2022-0069
  11. CMAJ. 2022 Nov 15. 194(44): E1514-E1515
    How can Canada reduce surgical backlogs without expanding privatization?
    Diana Duong.
      
    DOI:  https://doi.org/10.1503/cmaj.1096025
  12. Cancer Res Commun. 2022 Oct 10. 2(10): 1144-1161
    Mitochondrial Matrix Protease ClpP Agonists Inhibit Cancer Stem Cell Function in Breast Cancer Cells by Disrupting Mitochondrial Homeostasis.
    Yoshimi Endo Greer, Lidia Hernandez, Emily M J Fennell, Manjari Kundu, Donna Voeller, Raj Chari, Samuel F Gilbert, Thomas S K Gilbert, Shashikala Ratnayake, Binwu Tang, Markus Hafner, Qingrong Chen, Daoud Meerzaman, Edwin Iwanowicz, Christina M Annunziata, Lee M Graves, Stanley Lipkowitz.
      Mitochondria are multifaceted organelles which are important for bioenergetics, biosynthesis and signaling in metazoans. Mitochondrial functions are frequently altered in cancer to promote both the energy and the necessary metabolic intermediates for biosynthesis required for tumor growth. Cancer stem cells (CSCs) contribute to chemotherapy resistance, relapse, and metastasis. Recent studies have shown that while non-stem, bulk cancer cells utilize glycolysis, breast CSCs are more dependent on oxidative phosphorylation (OxPhos) and therefore targeting mitochondria may inhibit CSC function. We previously reported that small molecule ONC201, which is an agonist for the mitochondrial caseinolytic protease (ClpP), induces mitochondrial dysfunction in breast cancer cells. In this study, we report that ClpP agonists inhibit breast cancer cell proliferation and CSC function in vitro and in vivo. Mechanistically, we found that OxPhos inhibition downregulates multiple pathways required for CSC function, such as the mevalonate pathway, YAP, Myc, and the HIF pathway. ClpP agonists showed significantly greater inhibitory effect on CSC functions compared with other mitochondria-targeting drugs. Further studies showed that ClpP agonists deplete NAD(P)+ and NAD(P)H, induce redox imbalance, dysregulate one-carbon metabolism and proline biosynthesis. Downregulation of these pathways by ClpP agonists further contribute to the inhibition of CSC function. In conclusion, ClpP agonists inhibit breast CSC functions by disrupting mitochondrial homeostasis in breast cancer cells and inhibiting multiple pathways critical to CSC function.
    Significance: ClpP agonists disrupt mitochondrial homeostasis by activating mitochondrial matrix protease ClpP. We report that ClpP agonists inhibit cell growth and cancer stem cell functions in breast cancer models by modulating multiple metabolic pathways essential to cancer stem cell function.
    DOI:  https://doi.org/10.1158/2767-9764.CRC-22-0142
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