bims-minfam Biomed News
on Inflammation and metabolism in ageing and cancer
Issue of 2023–03–12
fiveteen papers selected by
Ayesh Seneviratne, Western University
  1. Defining clonal hematopoiesis of indeterminate potential: evolutionary dynamics and detection under aging and inflammation.
  2. Editorial: Intrinsic capacity and resilience vs. frailty: On the way to healthy aging.
  3. Expanding HSCs without cytokines.
  4. The Role of the National Institute on Aging in the Development of the Field of Geroscience.
  5. Assessing tolerability and physiological responses to 17α-estradiol administration in male rhesus macaques.
  6. Optogenetic rejuvenation of mitochondrial membrane potential extends C. elegans lifespan.
  7. Mitochondrial molecule controls inflammation.
  8. Influence of the Mediterranean Diet on Healthy Aging.
  9. Vitamin D as a Shield against Aging.
  10. Rejuvenating muscle stem cells with the glutathione system.
  11. Mitochondrial Dysfunction in Cardiac Arrhythmias.
  12. Putting aging on ICE.
  13. Polarized Anti-Inflammatory Mesenchymal Stem Cells Increase Hippocampal Neurogenesis and Improve Cognitive Function in Aged Mice.
  14. Inulin: properties and health benefits.
  15. Gut microbiota, an additional hallmark of human aging and neurodegeneration.
  1. Cold Spring Harb Mol Case Stud. 2023 Mar 08. pii: mcs.a006251. [Epub ahead of print]
    Defining clonal hematopoiesis of indeterminate potential: evolutionary dynamics and detection under aging and inflammation.
    Elisabeth Aline Goldman, Paul T Spellman, Anupriya Agarwal.
      Clonal hematopoiesis (CH), where hematopoietic stem and progenitor cell (HSPC) clones and their progeny expand in the circulating blood cell population, occurs following the acquisition of somatic driver mutations. Individuals diagnosed with clonal hematopoiesis of indeterminate potential (CHIP) carry somatic mutations in hematological malignancy-associated driver genes, historically at or above a variant allele frequency of 2%, but do not exhibit abnormal blood cell counts or any other symptoms of hematologic disease. However, CHIP is associated with moderately increased risk of hematological cancer, and a greater likelihood of cardiovascular and pulmonary disease. Recent advances in the resolution of high-throughput sequencing experiments suggest CHIP is much more prevalent in the population than once thought, particularly among those aged 60 and over. While CHIP does elevate the risk of eventual hematological malignancy, only one in ten individuals with CHIP will receive such a diagnosis; the problem lies in the continued difficulty in accurately separating the 10% of CHIP patients who are most likely to be in a pre-malignant state from those who are not, given the heterogeneity of this condition and the etiology of the associated hematological cancers. Concerns over the risk of eventual malignancies must be balanced with growing recognition of CH as common age-dependent occurrence, and efforts to better characterize and differentiate oncogenic clonal expansion from that which is much more benign. In this review, we discuss evolutionary dynamics of CH and CHIP, the relationship of CH to aging and inflammation, and the role of the epigenome in promoting potentially pathogenic or benign cellular trajectories. We outline molecular mechanisms that may contribute to heterogeneity in the etiology of CHIP and incidence of malignant disease among individuals. Finally, we discuss epigenetic markers and modifications for CHIP detection and monitoring with potential for translational applications and clinical utility in the near future.
    Keywords:  Acute myeloid leukemia; Hematological neoplasm
    DOI:  https://doi.org/10.1101/mcs.a006251
  2. Front Med (Lausanne). 2023 ;10 1155648
    Editorial: Intrinsic capacity and resilience vs. frailty: On the way to healthy aging.
    Elena Frolova, Beatrice Arosio, Wee Shiong Lim.
      
    Keywords:  biomarkers; frailty; geroprotective; healthy aging; interventions; intrinsic capacity; psychosocial aspects; sarcopenia
    DOI:  https://doi.org/10.3389/fmed.2023.1155648
  3. Nat Rev Drug Discov. 2023 Mar 07.
    Expanding HSCs without cytokines.
    Sarah Crunkhorn.
      
    DOI:  https://doi.org/10.1038/d41573-023-00038-4
  4. Cold Spring Harb Perspect Med. 2023 Mar 06. pii: a041211. [Epub ahead of print]
    The Role of the National Institute on Aging in the Development of the Field of Geroscience.
    Felipe Sierra, Ronald A Kohanski.
      The conceptualization of the field of geroscience, which began about 10 years ago, marks, together with the publication of "The hallmarks of aging" (see López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G. Cell 153: 1194-1217, 2013), a significant watershed in the development of aging research. Based on a very simple and commonly accepted premise, namely, that aging biology is at the core the most significant risk factor for all chronic diseases affecting the elderly, geroscience became possible because of earlier significant developments in the field of aging biology. Here we describe the origins of the concept, as well as its current status in the field. The principles of geroscience provide an important new biomedical perspective and have spawned a significantly increased interest in aging biology within the larger biomedical scientific community.
    DOI:  https://doi.org/10.1101/cshperspect.a041211
  5. Geroscience. 2023 Mar 10.
    Assessing tolerability and physiological responses to 17α-estradiol administration in male rhesus macaques.
    Michael B Stout, Kelli L Vaughan, Jose V V Isola, Shivani N Mann, Bayli Wellman, Jessica M Hoffman, Hunter L Porter, Willard M Freeman, Julie A Mattison.
      17α-estradiol has recently been shown to extend healthspan and lifespan in male mice through multiple mechanisms. These benefits occur in the absence of significant feminization or deleterious effects on reproductive function, which makes 17α-estradiol a candidate for translation into humans. However, human dosing paradigms for the treatment of aging and chronic disease are yet to be established. Therefore, the goals of the current studies were to assess tolerability of 17α-estradiol treatment, in addition to evaluating metabolic and endocrine responses in male rhesus macaque monkeys during a relatively short treatment period. We found that our dosing regimens (0.30 and 0.20 mg/kg/day) were tolerable as evidenced by a lack of GI distress, changes in blood chemistry or complete blood counts, and unaffected vital signs. We also found that the higher dose did elicit mild benefits on metabolic parameters including body mass, adiposity, and glycosylated hemoglobin. However, both of our 17α-estradiol trial doses elicited significant feminization to include testicular atrophy, increased circulating estrogens, and suppressed circulating androgens and gonadotropins. We suspect that the observed level of feminization results from a saturation of the endogenous conjugation enzymes, thereby promoting a greater concentration of unconjugated 17α-estradiol in serum, which has more biological activity. We also surmise that the elevated level of unconjugated 17α-estradiol was subjected to a greater degree of isomerization to 17β-estradiol, which is aligned with the sevenfold increase in serum 17β-estradiol in 17α-estradiol treated animals in our first trial. Future studies in monkeys, and certainly humans, would likely benefit from the development and implementation of 17α-estradiol transdermal patches, which are commonly prescribed in humans and would circumvent potential issues with bolus dosing effects.
    Keywords:  Aging; Dihydrotestosterone; Endocrinology; Follicle stimulating hormone; Luteinizing hormone; Testosterone
    DOI:  https://doi.org/10.1007/s11357-023-00767-9
  6. Nat Aging. 2023 Feb;3(2): 157-161
    Optogenetic rejuvenation of mitochondrial membrane potential extends C. elegans lifespan.
    Brandon J Berry, Anežka Vodičková, Annika Müller-Eigner, Chen Meng, Christina Ludwig, Matt Kaeberlein, Shahaf Peleg, Andrew P Wojtovich.
      Mitochondrial dysfunction plays a central role in aging but the exact biological causes are still being determined. Here, we show that optogenetically increasing mitochondrial membrane potential during adulthood using a light-activated proton pump improves age-associated phenotypes and extends lifespan in C. elegans. Our findings provide direct causal evidence that rescuing the age-related decline in mitochondrial membrane potential is sufficient to slow the rate of aging and extend healthspan and lifespan.
    DOI:  https://doi.org/10.1038/s43587-022-00340-7
  7. Nature. 2023 Mar 08.
    Mitochondrial molecule controls inflammation.
    Taylor A Poor, Navdeep S Chandel.
      
    Keywords:  Cell biology; Immunology; Metabolism
    DOI:  https://doi.org/10.1038/d41586-023-00596-y
  8. Int J Mol Sci. 2023 Feb 24. pii: 4491. [Epub ahead of print]24(5):
    Influence of the Mediterranean Diet on Healthy Aging.
    Maria Carmen Andreo-López, Victoria Contreras-Bolívar, Manuel Muñoz-Torres, Beatriz García-Fontana, Cristina García-Fontana.
      The life expectancy of the global population has increased. Aging is a natural physiological process that poses major challenges in an increasingly long-lived and frail population. Several molecular mechanisms are involved in aging. Likewise, the gut microbiota, which is influenced by environmental factors such as diet, plays a crucial role in the modulation of these mechanisms. The Mediterranean diet, as well as the components present in it, offer some proof of this. Achieving healthy aging should be focused on the promotion of healthy lifestyle habits that reduce the development of pathologies that are associated with aging, in order to increase the quality of life of the aging population. In this review we analyze the influence of the Mediterranean diet on the molecular pathways and the microbiota associated with more favorable aging patterns, as well as its possible role as an anti-aging treatment.
    Keywords:  Mediterranean diet; aging; microbiome; molecular pathways
    DOI:  https://doi.org/10.3390/ijms24054491
  9. Int J Mol Sci. 2023 Feb 25. pii: 4546. [Epub ahead of print]24(5):
    Vitamin D as a Shield against Aging.
    Cristina Fantini, Clarissa Corinaldesi, Andrea Lenzi, Silvia Migliaccio, Clara Crescioli.
      Aging can be seen as a physiological progression of biomolecular damage and the accumulation of defective cellular components, which trigger and amplify the process, toward whole-body function weakening. Senescence initiates at the cellular level and consists in an inability to maintain homeostasis, characterized by the overexpression/aberrant expression of inflammatory/immune/stress responses. Aging is associated with significant modifications in immune system cells, toward a decline in immunosurveillance, which, in turn, leads to chronic elevation of inflammation/oxidative stress, increasing the risk of (co)morbidities. Albeit aging is a natural and unavoidable process, it can be regulated by some factors, like lifestyle and diet. Nutrition, indeed, tackles the mechanisms underlying molecular/cellular aging. Many micronutrients, i.e., vitamins and elements, can impact cell function. This review focuses on the role exerted by vitamin D in geroprotection, based on its ability to shape cellular/intracellular processes and drive the immune response toward immune protection against infections and age-related diseases. To this aim, the main biomolecular paths underlying immunosenescence and inflammaging are identified as biotargets of vitamin D. Topics such as heart and skeletal muscle cell function/dysfunction, depending on vitamin D status, are addressed, with comments on hypovitaminosis D correction by food and supplementation. Albeit research has progressed, still limitations exist in translating knowledge into clinical practice, making it necessary to focus attention on the role of vitamin D in aging, especially considering the growing number of older individuals.
    Keywords:  cardiomyocytes; immunocytes; immunosenescence; inflammaging; molecular mechanisms; skeletal muscle cells; vitamin D
    DOI:  https://doi.org/10.3390/ijms24054546
  10. Cell Metab. 2023 Mar 07. pii: S1550-4131(23)00045-1. [Epub ahead of print]35(3): 379-381
    Rejuvenating muscle stem cells with the glutathione system.
    Laura Forcina, Antonio Musarò.
      Aging results from the combination of complex processes still largely undefined. In this issue, Benjamin et al. use multiomic analysis to reveal a causative role of altered glutathione (GSH) synthesis and metabolism in age-dependent muscle stem cell (MuSC) dysfunction, casting light on novel mechanisms regulating stem cell function and on therapeutic approaches to improve defective regeneration in the aged muscle.
    DOI:  https://doi.org/10.1016/j.cmet.2023.02.009
  11. Cells. 2023 Feb 21. pii: 679. [Epub ahead of print]12(5):
    Mitochondrial Dysfunction in Cardiac Arrhythmias.
    Jielin Deng, Yunqiu Jiang, Zhen Bouman Chen, June-Wha Rhee, Yingfeng Deng, Zhao V Wang.
      Electrophysiological and structural disruptions in cardiac arrhythmias are closely related to mitochondrial dysfunction. Mitochondria are an organelle generating ATP, thereby satisfying the energy demand of the incessant electrical activity in the heart. In arrhythmias, the homeostatic supply-demand relationship is impaired, which is often accompanied by progressive mitochondrial dysfunction leading to reduced ATP production and elevated reactive oxidative species generation. Furthermore, ion homeostasis, membrane excitability, and cardiac structure can be disrupted through pathological changes in gap junctions and inflammatory signaling, which results in impaired cardiac electrical homeostasis. Herein, we review the electrical and molecular mechanisms of cardiac arrhythmias, with a particular focus on mitochondrial dysfunction in ionic regulation and gap junction action. We provide an update on inherited and acquired mitochondrial dysfunction to explore the pathophysiology of different types of arrhythmias. In addition, we highlight the role of mitochondria in bradyarrhythmia, including sinus node dysfunction and atrioventricular node dysfunction. Finally, we discuss how confounding factors, such as aging, gut microbiome, cardiac reperfusion injury, and electrical stimulation, modulate mitochondrial function and cause tachyarrhythmia.
    Keywords:  ATP supply; arrhythmia; mitochondrial dysfunction; reactive oxygen species
    DOI:  https://doi.org/10.3390/cells12050679
  12. Cell Metab. 2023 Mar 07. pii: S1550-4131(23)00048-7. [Epub ahead of print]35(3): 383-385
    Putting aging on ICE.
    Bryan B Teefy, Bérénice A Benayoun.
      A recent report by Yang et al. in Cell demonstrates that faithful DNA double-strand breaks and repair cycles phenocopy many aspects of aging in mice. Whether this progeroid phenotype is caused by a loss of epigenetic information remains to be conclusively determined.
    DOI:  https://doi.org/10.1016/j.cmet.2023.02.012
  13. Int J Mol Sci. 2023 Feb 24. pii: 4490. [Epub ahead of print]24(5):
    Polarized Anti-Inflammatory Mesenchymal Stem Cells Increase Hippocampal Neurogenesis and Improve Cognitive Function in Aged Mice.
    Matanel Tfilin, Nikolai Gobshtis, David Fozailoff, Vadim E Fraifeld, Gadi Turgeman.
      Age-related decline in cognitive functions is associated with reduced hippocampal neurogenesis caused by changes in the systemic inflammatory milieu. Mesenchymal stem cells (MSC) are known for their immunomodulatory properties. Accordingly, MSC are a leading candidate for cell therapy and can be applied to alleviate inflammatory diseases as well as aging frailty via systemic delivery. Akin to immune cells, MSC can also polarize into pro-inflammatory MSC (MSC1) and anti-inflammatory MSC (MSC2) following activation of Toll-like receptor 4 (TLR4) and TLR3, respectively. In the present study, we apply pituitary adenylate cyclase-activating peptide (PACAP) to polarize bone-marrow-derived MSC towards an MSC2 phenotype. Indeed, we found that polarized anti-inflammatory MSC were able to reduce the plasma levels of aging related chemokines in aged mice (18-months old) and increased hippocampal neurogenesis following systemic administration. Similarly, aged mice treated with polarized MSC displayed improved cognitive function in the Morris water maze and Y-maze assays compared with vehicle- and naïve-MSC-treated mice. Changes in neurogenesis and Y-maze performance were negatively and significantly correlated with sICAM, CCL2 and CCL12 serum levels. We conclude that polarized PACAP-treated MSC present anti-inflammatory properties that can mitigate age-related changes in the systemic inflammatory milieu and, as a result, ameliorate age related cognitive decline.
    Keywords:  MSC2; aging; cognitive decline; hippocampal neurogenesis; mesenchymal stem cells (MSC); pituitary adenylate cyclase-activating peptide (PACAP); systemic inflammation
    DOI:  https://doi.org/10.3390/ijms24054490
  14. Food Funct. 2023 Mar 06.
    Inulin: properties and health benefits.
    Yu-Qing Qin, Liu-Yan Wang, Xin-Yu Yang, Yi-Jie Xu, Gang Fan, Yan-Ge Fan, Jing-Nan Ren, Qi An, Xiao Li.
      Inulin, a soluble dietary fiber, is widely found in more than 36 000 plant species as a reserve polysaccharide. The primary sources of inulin, include Jerusalem artichoke, chicory, onion, garlic, barley, and dahlia, among which Jerusalem artichoke tubers and chicory roots are often used as raw materials for inulin production in the food industry. It is universally acknowledged that inulin as a prebiotic has an outstanding effect on the regulation of intestinal microbiota via stimulating the growth of beneficial bacteria. In addition, inulin also exhibits excellent health benefits in regulating lipid metabolism, weight loss, lowering blood sugar, inhibiting the expression of inflammatory factors, reducing the risk of colon cancer, enhancing mineral absorption, improving constipation, and relieving depression. In this review paper, we attempt to present an exhaustive overview of the function and health benefits of inulin.
    DOI:  https://doi.org/10.1039/d2fo01096h
  15. Neuroscience. 2023 Mar 07. pii: S0306-4522(23)00092-1. [Epub ahead of print]
    Gut microbiota, an additional hallmark of human aging and neurodegeneration.
    Natalia Molinero, Alejandro Antón, Félix Hernández, Jesús Ávila, Begoña Bartolomé, M Victoria Moreno-Arribas.
      Gut microbiota represents a diverse and dynamic population of microorganisms harbouring the gastrointestinal tract, which influences host health and disease. Bacterial colonization of the gastrointestinal tract begins at birth and changes throughout life, with age being one of the conditioning factors for its vitality. Aging is also a primary risk factor for most neurodegenerative diseases. Among them, Alzheimeŕs disease (AD) is probably the one where its association with a state of dysbiosis of the gut microbiota has been most studied. In particular, intestinal microbial-derived metabolites have been associated with β-amyloid formation and brain amyloid deposition, tau phosphorylation, as well as neuroinflammation in AD patients. Moreover, it has been suggested that some oral bacteria increase the risk of developing AD. However, the causal connections among microbiome, amyloid-tau interaction, and neurodegeneration need to be addressed. This paper summarizes the emerging evidence in the literature regarding the link between the oral and gut microbiome and neurodegeneration with a focus on AD. Taxonomic features of bacteria as well as microbial functional alterations associated with AD biomarkers are the main points reviewed. Data from clinical studies as well as the link between microbiome and clinical determinants of AD are particularly emphasized. Further, relationships between gut microbiota and age-dependent epigenetic changes and other neurological disorders are also described. Together, all this evidence suggests that, in some sense, gut microbiota can be seen as an additional hallmark of human aging and neurodegeneration.
    Keywords:  Alzheimer’s disease; aging; epigenetic alterations; gut microbiome; neurodegeneration; oral-gut-brain axis
    DOI:  https://doi.org/10.1016/j.neuroscience.2023.02.014
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