bims-minfam Biomed News
on Inflammation and metabolism in ageing and cancer
Issue of 2024–01–14
nineteen papers selected by
Ayesh Seneviratne, Western University
  1. Targeting COPIng liabilities of senescent cells.
  2. A plasma proteome measure of organ aging.
  3. Emerging roles of mitochondrial functions and epigenetic changes in the modulation of stem cell fate.
  4. Early exposure to a systemic stressor confers protection later in life.
  5. Sluggish FUS: a key for HSC aging.
  6. Simultaneous assessment of mitochondrial DNA copy number and nuclear epigenetic age towards predictive models of development and aging.
  7. Slow and steady lives the longest.
  8. Can removal of zombie cells revitalize the aging cardiovascular system?
  9. Risk Factors for Clonal Hematopoiesis of Indeterminate Potential in People with HIV: a report from the REPRIEVE Trial.
  10. Augmented mitochondrial apoptotic signaling impairs C2C12 myoblast differentiation following cellular aging through sequential passaging.
  11. cGAS-STING, inflammasomes and pyroptosis: an overview of crosstalk mechanism of activation and regulation.
  12. GLP1 Receptor Agonists-Effects beyond Obesity and Diabetes.
  13. Geriatric Medicine as a Profession.
  14. Translating Science Into Clinical Practice for Your Emergency Department: How ENA's Clinical Practice Guidelines Can Help.
  15. Association Between Aortic Valve Sclerosis and Clonal Hematopoiesis of Indeterminate Potential.
  16. The current state of evidence for sodium and fluid restriction in heart failure.
  17. Hematopoietic stem cell quiescence and DNA replication dynamics maintained by the resilient β-catenin/Hoxa9/Prmt1 axis.
  18. PD-1 Checkmate and the 2-Edged Sword of the Immune System: What Next?
  19. Post-intensive Care Syndrome.
  1. Nat Aging. 2024 Jan 12.
    Targeting COPIng liabilities of senescent cells.
    Yahyah Aman.
      
    DOI:  https://doi.org/10.1038/s43587-024-00567-6
  2. Nat Aging. 2024 Jan 09.
    A plasma proteome measure of organ aging.
    Anna Kriebs.
      
    DOI:  https://doi.org/10.1038/s43587-024-00568-5
  3. Cell Mol Life Sci. 2024 Jan 12. 81(1): 26
    Emerging roles of mitochondrial functions and epigenetic changes in the modulation of stem cell fate.
    Chensong Zhang, Yang Meng, Junhong Han.
      Mitochondria serve as essential organelles that play a key role in regulating stem cell fate. Mitochondrial dysfunction and stem cell exhaustion are two of the nine distinct hallmarks of aging. Emerging research suggests that epigenetic modification of mitochondria-encoded genes and the regulation of epigenetics by mitochondrial metabolites have an impact on stem cell aging or differentiation. Here, we review how key mitochondrial metabolites and behaviors regulate stem cell fate through an epigenetic approach. Gaining insight into how mitochondria regulate stem cell fate will help us manufacture and preserve clinical-grade stem cells under strict quality control standards, contributing to the development of aging-associated organ dysfunction and disease.
    Keywords:  Epigenetic modifications; Mitochondria; Mitochondria metabolites; Senescence; Stem cell fate
    DOI:  https://doi.org/10.1007/s00018-023-05070-6
  4. Nat Aging. 2024 Jan 09.
    Early exposure to a systemic stressor confers protection later in life.
    Supriya Srinivasan.
      
    DOI:  https://doi.org/10.1038/s43587-023-00553-4
  5. Blood. 2024 Jan 11. 143(2): 99-100
    Sluggish FUS: a key for HSC aging.
    Motohiko Oshima, Atsushi Iwama.
      
    DOI:  https://doi.org/10.1182/blood.2023022532
  6. BMC Res Notes. 2024 Jan 11. 17(1): 21
    Simultaneous assessment of mitochondrial DNA copy number and nuclear epigenetic age towards predictive models of development and aging.
    Phyo W Win, Julia Nyugen, Amanda L Morin, Charles E Newcomb, Shiva M Singh, Noha Gomaa, Christina A Castellani.
       OBJECTIVE: Mitochondrial dysfunction and nuclear epigenetic alterations, two hallmarks of aging, are associated with aberrant development and complex disease risk. Here, we report a method for the simultaneous assessment of mitochondrial DNA copy number (mtDNA-CN) and DNA methylation age (DNAm age) from the same DNA extraction using quantitative polymerase chain reaction (qPCR) and array data, respectively.
    RESULT: We present methods for the concurrent estimation of mtDNA-CN and DNAm age from the same DNA samples. This includes qPCR to estimate mtDNA-CN, representing the number of circular mitochondrial genomes in a cell, and DNA methylation microarray data to estimate the epigenetic age of an individual. Further, we provide a method for the combination of these metrics into a shared metric termed 'mtEpiAge'. This approach provides a valuable tool for exploring the interplay between mitochondrial dysfunction and nuclear epigenetic alterations, and their associations with disease and aging.
    Keywords:  DNA methylation; Epigenetic age; Mitochondrial DNA; Mitochondrial DNA copy number; qPCR
    DOI:  https://doi.org/10.1186/s13104-023-06673-9
  7. Nat Aging. 2024 Jan 08.
    Slow and steady lives the longest.
    Francesco Morandini, Andrei Seluanov, Vera Gorbunova.
      
    DOI:  https://doi.org/10.1038/s43587-023-00554-3
  8. Eur Heart J. 2024 Jan 08. pii: ehad849. [Epub ahead of print]
    Can removal of zombie cells revitalize the aging cardiovascular system?
    Seyed Soheil Saeedi Saravi, Mark W Feinberg.
      
    DOI:  https://doi.org/10.1093/eurheartj/ehad849
  9. Blood Adv. 2024 Jan 10. pii: bloodadvances.2023011324. [Epub ahead of print]
    Risk Factors for Clonal Hematopoiesis of Indeterminate Potential in People with HIV: a report from the REPRIEVE Trial.
    Romit Bhattacharya, Md Mesbah Uddin, Aniruddh P Patel, Abhishek Niroula, Phoebe Finneran, Rachel Bernardo, Kathleen V Fitch, Michael T Lu, Gerald S Bloomfield, Carlos Malvestutto, Judith A Aberg, Carl J Fichtenbaum, Whitney Hornsby, Heather Ribaudo, Peter Libby, Benjamin L Ebert, Markella Zanni, Pamela Douglas, Steven Grinspoon, Pradeep Natarajan.
      Clonal hematopoiesis of Indeterminate Potential (CHIP), the clonal expansion of myeloid cells with leukemogenic mutations, results in increased coronary artery disease (CAD) risk. CHIP is more prevalent among people with HIV (PWH) but the risk factors are unknown. CHIP was identified among PWH in REPRIEVE (Randomized Trial to Prevent Vascular Events in HIV) using whole exome sequencing (WES). Logistic regression was used to associate sociodemographic factors and HIV-specific factors with CHIP adjusting for age, sex, and smoking status. In the studied global cohort of 4,486 PWH, mean (SD) age was 49.9 (6.4) years, 1650 (36.8%) were female, and 3418 (76.2%) were non-White. CHIP was identified in 223/4486 (4.97%), and in 38/373 (10.2%) among those 60 years of age or older. Age (OR 1.07, 95%CI 1.05-1.09, p<0.0001) and smoking (OR 1.37, 95%CI 1.14-1.66, p<0.001) associated with increased odds of CHIP. Globally, participants outside of North America had lower odds of CHIP including Sub-Saharan Africa (OR 0.57, 95%CI 0.4-0.81, p=0.0019), South Asia (OR 0.45, 95%CI 0.23-0.80, p=0.01), and Latin America/Caribbean (OR 0.56, 95%CI 0.34-0.87, p=0.014). Hispanic/Latino ethnicity (OR 0.38, 95%CI 0.23-0.54, p=0.002) associated with significantly lower odds of CHIP. Among HIV-specific factors, CD4 nadir <50 cells/mm3 associated with a 1.9-fold (95%CI 1.21-3.05, p=0.006) increased odds of CHIP, with the effect being significantly stronger among individuals with short duration of antiretroviral therapy (ART) (OR 4.15, 95%CI 1.51-11.1, p=0.005) (pinteraction=0.0492). Among PWH at low-to-moderate CAD risk on stable ART, smoking, CD4 nadir, North American origin, and non-Hispanic ethnicity associated with increased odds of CHIP. Clinical Trials Registration: NCT02344290.
    DOI:  https://doi.org/10.1182/bloodadvances.2023011324
  10. J Cell Physiol. 2024 Jan 11.
    Augmented mitochondrial apoptotic signaling impairs C2C12 myoblast differentiation following cellular aging through sequential passaging.
    Fasih A Rahman, Dylan J Hian-Cheong, Kristen Boonstra, Andrew Ma, James P Thoms, Anderson S Zago, Joe Quadrilatero.
      Aging is associated with the steady decline of several cellular processes. The loss of skeletal muscle mass, termed sarcopenia, is one of the major hallmarks of aging. Aged skeletal muscle exhibits a robust reduction in its regenerative capacity due to dysfunction (i.e., senescence, lack of self-renewal, and impaired differentiation) of resident muscle stem cells, called satellite cells. To replicate aging in vitro, immortalized skeletal muscle cells (myoblasts) can be treated with various agents to mimic age-related dysfunction; however, these come with their own set of limitations. In the present study, we used sequential passaging of mouse myoblasts to mimic impaired differentiation that is observed in aged skeletal muscle. Further, we investigated mitochondrial apoptotic mechanisms to better understand the impaired differentiation in these "aged" cells. Our data shows that sequential passaging (>20 passages) of myoblasts is accompanied with significant reductions in differentiation and elevated cell death. Furthermore, high-passage (HP) myoblasts exhibit greater mitochondrial-mediated apoptotic signaling through mitochondrial BAX translocation, CYCS and AIFM1 release, and caspase-9 activation. Finally, we show that inhibition of mitochondrial outer membrane permeability partly recovered differentiation in HP myoblasts. Together, our findings suggests that mitochondrial apoptotic signaling is a contributing factor to the diminished differentiation that is observed in aged myoblasts.
    Keywords:  aging; apoptotic signaling; differentiation; high-passage; mitochondria; skeletal muscle
    DOI:  https://doi.org/10.1002/jcp.31155
  11. Cell Commun Signal. 2024 Jan 09. 22(1): 22
    cGAS-STING, inflammasomes and pyroptosis: an overview of crosstalk mechanism of activation and regulation.
    Jingwen Liu, Jing Zhou, Yuling Luan, Xiaoying Li, Xiangrui Meng, Wenhao Liao, Jianyuan Tang, Zheilei Wang.
       BACKGROUND: Intracellular DNA-sensing pathway cGAS-STING, inflammasomes and pyroptosis act as critical natural immune signaling axes for microbial infection, chronic inflammation, cancer progression and organ degeneration, but the mechanism and regulation of the crosstalk network remain unclear. Cellular stress disrupts mitochondrial homeostasis, facilitates the opening of mitochondrial permeability transition pore and the leakage of mitochondrial DNA to cell membrane, triggers inflammatory responses by activating cGAS-STING signaling, and subsequently induces inflammasomes activation and the onset of pyroptosis. Meanwhile, the inflammasome-associated protein caspase-1, Gasdermin D, the CARD domain of ASC and the potassium channel are involved in regulating cGAS-STING pathway. Importantly, this crosstalk network has a cascade amplification effect that exacerbates the immuno-inflammatory response, worsening the pathological process of inflammatory and autoimmune diseases. Given the importance of this crosstalk network of cGAS-STING, inflammasomes and pyroptosis in the regulation of innate immunity, it is emerging as a new avenue to explore the mechanisms of multiple disease pathogenesis. Therefore, efforts to define strategies to selectively modulate cGAS-STING, inflammasomes and pyroptosis in different disease settings have been or are ongoing. In this review, we will describe how this mechanistic understanding is driving possible therapeutics targeting this crosstalk network, focusing on the interacting or regulatory proteins, pathways, and a regulatory mitochondrial hub between cGAS-STING, inflammasomes, and pyroptosis.
    SHORT CONCLUSION: This review aims to provide insight into the critical roles and regulatory mechanisms of the crosstalk network of cGAS-STING, inflammasomes and pyroptosis, and to highlight some promising directions for future research and intervention.
    Keywords:  Crosstalk network; Diseases; Inflammasome; Inflammation; Pyroptosis; cGAS-STING
    DOI:  https://doi.org/10.1186/s12964-023-01466-w
  12. Cells. 2023 Dec 28. pii: 65. [Epub ahead of print]13(1):
    GLP1 Receptor Agonists-Effects beyond Obesity and Diabetes.
    Sydney S Wilbon, Mikhail G Kolonin.
      Glucagon-like peptide-1 receptor agonists (GLP1RA) have been transformative for patients and clinicians in treating type-2 diabetes and obesity. Drugs of this class, the bioavailability of which is continuously improving, enable weight loss and control blood glucose with minimal unwanted side effects. Since adopting GLP1RA for treating metabolic diseases, animal and clinical studies have revealed their beneficial effects on several other pathologies, including cardiovascular diseases, neurodegeneration, kidney disease, and cancer. A notable commonality between these diseases is their association with older age. Clinical trials and preclinical data suggest that GLP1RA may improve outcomes in these aging-related diseases. Some of the benefits of GLP1RA may be indirect due to their effects on obesity and glucose metabolism. However, there is building evidence that GLP1RA may also act directly on multiple organs implicated in aging-related pathology. This review aims to compile the studies reporting the effects of GLP1RA on aging-related diseases and discuss potential underlying mechanisms.
    Keywords:  GLP-1 receptor agonist; aging; cancer; cardiovascular disease; diabetes; incretin; neurodegenerative disease; obesity
    DOI:  https://doi.org/10.3390/cells13010065
  13. JAMA. 2024 01 09. 331(2): 166
    Geriatric Medicine as a Profession.
    Robert S Crupi, Melissa Patterson, Cynthia X Pan.
      
    DOI:  https://doi.org/10.1001/jama.2023.22484
  14. J Emerg Nurs. 2024 Jan;pii: S0099-1767(23)00304-5. [Epub ahead of print]50(1): 3-6
    Translating Science Into Clinical Practice for Your Emergency Department: How ENA's Clinical Practice Guidelines Can Help.
    Andrea Slivinski, Altair M Delao.
      
    DOI:  https://doi.org/10.1016/j.jen.2023.10.012
  15. Ann Lab Med. 2024 Jan 11.
    Association Between Aortic Valve Sclerosis and Clonal Hematopoiesis of Indeterminate Potential.
    Minkwan Kim, Jin Ju Kim, Seung-Tae Lee, Yeeun Shim, Hyeonah Lee, SungA Bae, Nak-Hoon Son, Saeam Shin, In Hyun Jung.
       Background: The mechanism and medical treatment target for degenerative aortic valve disease, including aortic stenosis, is not well studied. In this study, we investigated the effect of clonal hematopoiesis of indeterminate potential (CHIP) on the development of aortic valve sclerosis (AVS), a calcified aortic valve without significant stenosis.
    Methods: Participants with AVS (valves ≥2 mm thick, high echogenicity, and a peak transaortic velocity of <2.5 m/sec) and an age- and sex-matched control group were enrolled. Twenty-four CHIP genes with common variants in cardiovascular disease were used to generate a next-generation sequencing panel. The primary endpoint was the CHIP detection rate between the AVS and control groups. Inverse-probability treatment weighting (IPTW) analysis was performed to adjust for differences in baseline characteristics.
    Results: From April 2020 to April 2022, 187 participants (125 with AVS and 62 controls) were enrolled; the mean age was 72.6±8.5 yrs, and 54.5% were male. An average of 1.3 CHIP variants was observed. CHIP detection, defined by a variant allele frequency (VAF) of ≥0.5%, was similar between the groups. However, the AVS group had larger CHIP clones: 49 (39.2%) participants had a VAF of ≥1% (vs. 13 [21.0%] in the control group; P=0.020), and 25 (20.0%) had a VAF of ≥2% (vs. 4 [6.5%]; P=0.028). AVS is independently associated with a VAF of ≥1% (adjusted odds ratio: 2.44, 95% confidence interval: 1.11-5.36; P=0.027). This trend was concordant and clearer in the IPTW cohort.
    Conclusions: Participants with AVS more commonly had larger CHIP clones than age- and sex-matched controls. Further studies are warranted to identify causality between AVS and CHIP.
    Keywords:  Aortic valve sclerosis; Clonal hematopoiesis; High-throughput nucleotide sequencing; Inflammation; Variant allele frequency
    DOI:  https://doi.org/10.3343/alm.2023.0268
  16. Prog Cardiovasc Dis. 2024 Jan 10. pii: S0033-0620(24)00004-5. [Epub ahead of print]
    The current state of evidence for sodium and fluid restriction in heart failure.
    Eloisa Colin-Ramirez, Joanne Arcand, Clara Saldarriaga, Justin A Ezekowitz.
      The field of heart failure has evolved in terms of the therapies that are available including pharmaceutical and device therapies. There is now substantial randomized trial data to indicate that dietary sodium restriction does not provide the reduction in clinical events with accepted heterogeneity in the clinical trial results. Dietary sodium restriction should be considered for some but not all patients and with different objectives than clinical outcomes but instead for potential quality of life benefit. In addition, fluid restriction, once the mainstay of clinical practice, has not shown to be of any additional benefit for patients in hospital or in the ambulatory care setting and therefore should be considered to be used cautiously (if at all) in clinical practice. Further developments and clinical trials are needed in this area to better identify patients who may benefit or have harm from these lower cost interventions and future research should focus on large scale, high quality, clinical trials rather than observational data to drive clinical practice.
    Keywords:  Dietary sodium; Fluid restriction; Heart failure
    DOI:  https://doi.org/10.1016/j.pcad.2024.01.004
  17. Blood. 2024 Jan 11. pii: blood.2023022082. [Epub ahead of print]
    Hematopoietic stem cell quiescence and DNA replication dynamics maintained by the resilient β-catenin/Hoxa9/Prmt1 axis.
    Jennifer Lynch, Estelle Troadec, Tsz Kan Fung, Kornelia Gladysz, Clemence Virely, Priscilla Nga Ieng Lau, Ngai Cheung, Bernd Zeisig, Jason Wing Hon Wong, Massimo Lopes, Suming Huang, Chi Wai Eric So.
      Maintenance of quiescence and DNA replication dynamics are two paradoxical requirements for the distinct states of dormant and active hematopoietic stem cells (HSCs), which are required to preserve the stem cell reservoir and replenish the blood cell system in response to hematopoietic stress respectively. Here, we show that key self-renewal factors, β-catenin or Hoxa9, largely dispensable for HSC integrity in fact have dual functions in maintaining quiescence and enabling efficient DNA replication fork dynamics to preserve the functionality of hematopoietic stem and progenitor cells (HSPCs). While β-catenin or Hoxa9 single knockout (KO) exhibited mostly normal hematopoiesis, their co-inactivation led to severe hematopoietic defects stemmed from aberrant cell cycle, DNA replication and damage in HSPCs. Mechanistically, β-catenin and Hoxa9 function in a compensatory manner to sustain key transcriptional programs that converge on the pivotal downstream target and epigenetic modifying enzyme, Prmt1, which protects the quiescent state and ensures an adequate supply of DNA replication and repair factors to maintain robust replication fork dynamics. Inactivation of Prmt1 phenocopied both cellular and molecular phenotypes of β-catenin/Hoxa9 combined KO, which at the same time could also be partially rescued by Prmt1 expression. The discovery of the highly resilient β-catenin/Hoxa9/Prmt1 axis in protecting both quiescence and DNA replication dynamics essential for HSCs at different key states provides not only novel mechanistic insights into their intricate regulation but also a potential tractable target for therapeutic intervention.
    DOI:  https://doi.org/10.1182/blood.2023022082
  18. JACC Basic Transl Sci. 2023 Dec;8(12): 1518-1520
    PD-1 Checkmate and the 2-Edged Sword of the Immune System: What Next?
    Madeleine W Cunningham, Leslie T Cooper.
      
    Keywords:  immune checkpoints; inflammation; myocarditis; tissue injury
    DOI:  https://doi.org/10.1016/j.jacbts.2023.10.006
  19. ATS Sch. 2023 Dec;4(4): 569-570
    Post-intensive Care Syndrome.
    Hugo Carmona, Rania Esteitie, Diana J Kelm.
      
    DOI:  https://doi.org/10.34197/ats-scholar.2023-0004OT
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