bims-minfam Biomed News
on Inflammation and metabolism in ageing and cancer
Issue of 2021–10–31
twenty-six papers selected by
Ayesh Seneviratne, University of Toronto
  1. Lineage-Specific Clonal Hematopoiesis Predicts Hematologic Malignancy.
  2. Ex vivo expansion of hematopoietic stem cells: Finally transitioning from the lab to the clinic.
  3. Strategies for late phase preclinical and early clinical trials of senolytics.
  4. Low-Glycemic Diets Restrict Tumor Growth through Altered Lipid Metabolism.
  5. [THE CHALLENGE OF HEALTHY AGING WITH DIABETES: THE ISRAELI NATIONAL DIABETES COUNCIL GUIDELINES FOR TREATING OLDER PEOPLE].
  6. The State of frailty in research: a mapping review of its clinical applicability to practice.
  7. Dnmt3a-mutated clonal hematopoiesis promotes osteoporosis.
  8. Research progress of gut microbiota and frailty syndrome.
  9. Whole-body vibration combined with exercise may be more effective in lowering blood pressure and arterial stiffness than exercise alone in older adults with hypertension.
  10. Modulating Sirtuin Biology and Nicotinamide Adenine Diphosphate Metabolism in Cardiovascular Disease-From Bench to Bedside.
  11. Daily caloric restriction limits tumor growth more effectively than caloric cycling regardless of dietary composition.
  12. Multilayer omics analysis reveals a non-classical retinoic acid signaling axis that regulates hematopoietic stem cell identity.
  13. Reevaluation of the effect of dietary restriction on different recombinant inbred lines of male and female mice.
  14. Characterizing the Heterogeneity of Aging: A Vision for a Staging System for Aging.
  15. Targeting mitochondrial metabolism in acute myeloid leukemia.
  16. Frailty, an Imperfect ICU Rationing Criterion.
  17. Understanding T cell aging to improve anti-viral immunity.
  18. Chronic viral infections persistently alter marrow stroma and impair hematopoietic stem cell fitness.
  19. The many roles mitochondria play in mammalian aging.
  20. Sirtuin 1 in Endothelial Dysfunction and Cardiovascular Aging.
  21. Canada's health system is at a breaking point, say medical leaders.
  22. Clearing stressed cells.
  23. Role of senescence in the chronic health consequences of COVID-19.
  24. The Frailty of Disability: A Controversial Triage Criterion.
  25. Frailty but not sarcopenia nor malnutrition increases the risk of developing COVID-19 in older community-dwelling adults.
  26. The Fragility Index Should Not Be Used For Sample Size Calculations in Clinical Trials.
  1. Cancer Discov. 2021 Oct 29.
    Lineage-Specific Clonal Hematopoiesis Predicts Hematologic Malignancy.
      Genetic drivers of clonal hematopoiesis (CH) predict risk of myeloid and lymphoid malignancies.
    DOI:  https://doi.org/10.1158/2159-8290.CD-RW2021-156
  2. Blood Rev. 2021 Nov;pii: S0268-960X(21)00059-X. [Epub ahead of print]50 100853
    Ex vivo expansion of hematopoietic stem cells: Finally transitioning from the lab to the clinic.
    Eran Zimran, Luena Papa, Ronald Hoffman.
      Hematopoietic stem cells (HSCs) have been used for therapeutic purposes for decades in the form of autologous and allogeneic transplantation and are currently emerging as an attractive target for gene therapy. A low stem cell dose is a major barrier to the application of HSC therapy in several situations, primarily umbilical cord blood transplantation and gene modification. Strategies that promote ex vivo expansion of the numbers of functional HSCs could overcome this barrier, hence have been the subject of intense and prolonged research. Several ex vivo expansion strategies have advanced to evaluation clinical trials, which are showing favorable outcomes along with convincing safety signals. Preclinical studies have recently confirmed beneficial incorporation of ex vivo expansion into HSC gene modification protocols. Collectively, ex vivo HSC expansion holds promise for significantly broadening the availability of cord blood units for transplantation, and for optimizing gene therapy protocols to enable their clinical application.
    Keywords:  Gene editing; Gene therapy; Hematopoietic stem cell transplantation; Hematopoietic stem cells; Umbilical cord blood; ex vivo expansion
    DOI:  https://doi.org/10.1016/j.blre.2021.100853
  3. Mech Ageing Dev. 2021 Oct 23. pii: S0047-6374(21)00163-9. [Epub ahead of print]200 111591
    Strategies for late phase preclinical and early clinical trials of senolytics.
    Erin O Wissler Gerdes, Avanish Misra, Jair Machado Espindola Netto, Tamar Tchkonia, James L Kirkland.
      Cellular senescence and the hallmarks of aging contribute to age-related disease and dysfunction. The Unitary Theory of Fundamental Aging Mechanisms highlights the interdependence among the hallmarks of aging and suggests that by intervening in one fundamental aging process, most or all of the other processes could be impacted. Accumulation of senescent cells is associated with frailty, cardiovascular disease, obesity, diabetes, cognitive decline, and other age- and/or chronic disease-related disorders, suggesting that senescent cells are a target for intervention. Early preclinical data using senolytics, agents that target senescent cells, show promising results in several aging and disease models. The first in-human trials using the senolytic combination of Dasatinib and Quercetin indicated reduced senescent cell burden in adipose tissue of diabetic kidney disease patients and improved physical function in patients with idiopathic pulmonary fibrosis. Clinical trials with other senolytics, including the flavonoid Fisetin and BCL-xL inhibitors, are underway. These results from preclinical and early clinical trials illustrate the potential of senolytics to alleviate age-related dysfunction and diseases. However, multiple clinical trials across different aging and disease models are desperately needed. Parallel trials across institutions through the Translational Geroscience Network are facilitating testing to determine whether senolytics can be translated into clinical application.
    Keywords:  Dasatinib; Fisetin; Quercetin; Senolytics; Translational Geroscience Network; Unitary Theory of Fundamental Aging Processes
    DOI:  https://doi.org/10.1016/j.mad.2021.111591
  4. Cancer Discov. 2021 Oct 29.
    Low-Glycemic Diets Restrict Tumor Growth through Altered Lipid Metabolism.
      Low-glycemic diets that decrease circulating lipids limit tumor growth.
    DOI:  https://doi.org/10.1158/2159-8290.CD-RW2021-157
  5. Harefuah. 2021 Oct;160(10): 693-697
    [THE CHALLENGE OF HEALTHY AGING WITH DIABETES: THE ISRAELI NATIONAL DIABETES COUNCIL GUIDELINES FOR TREATING OLDER PEOPLE].
    Michal Azmon, Tali Cukierman-Yaffe, Amnon Lahad, Joshua Ben Israel, Diane Levin-Zamir, Julio Wainstein, Ofri Mosenzon, Itamar Raz.
       INTRODUCTION: The prevalence of diabetes increases with age. Diabetes is a risk factor for many complications such as cardiovascular disease, kidney failure, stroke, neuropathy, and retinopathy. Data from recent years indicate that it is also a risk factor for cognitive impairment, dementia, functional disability and frailty. Diabetes is a disease that requires complex self-care capabilities; the individuals with diabetes are required to take medications on time, examine their feet, exercise, maintain a balance diet, preform daily glucose monitoring, cope with hypoglycemia and understand how differing life situations may effect glucose levels. All of these require intact cognitive and functional abilities. Thus, treatment plans should take into consideration the person's cognitive/functional state. Indeed, in the last several years many professional organizations such as the American Diabetes Association, the International Diabetes Federation, and the American Endocrinology Society have published guidelines for treating older people with diabetes. The Israeli National Diabetes Council, headed by Prof. Itamar Raz, in collaboration with other physician unions and other national councils, have recently authorized the Israeli guidelines for treating older people with diabetes. The Israeli guidelines include categorization of older adults with diabetes in relation to their functional status in order to reach determined treatment targets. According to the Israeli guidelines and in accordance with international guidelines, the treatment targets of the elderly person with diabetes should not be determined by the chronological age of the individuals but rather by their risk for functional deterioration. Older people with diabetes are categorized into three groups according to their risk for functional deterioration. Each category has unique glucose, blood pressure and lipid targets. The guidelines offer valid and reliable tools that, in addition to personal acquaintance with the patient, can help determine the level of risk of functional decline.
  6. Ageing Res Rev. 2021 Oct 25. pii: S1568-1637(21)00240-3. [Epub ahead of print] 101493
    The State of frailty in research: a mapping review of its clinical applicability to practice.
    Quoc Dinh Nguyen, Erica M Moodie, Philippe Desmarais, Marie-France Forget, Han Ting Wang, Mark R Keezer, Christina Wolfson.
      Research on frailty has expanded in the last decade, but direct evidence supporting its implementation in clinical practice may be limited. This mapping review synthesizes the contexts-of-use and overall clinical applicability of recent pre-COVID frailty research. We sampled 476 articles from articles published on frailty in PubMed and EMBASE in 2017-2018, of which 150 articles were fully appraised for the contexts-of-use, definitions, and interventions. A clinical applicability framework was used to classify articles as practice-changing, practice-informing, or not practice-informing. Of the 476 sampled articles, 31% (n = 150) used frailty in functions that could inform a clinical indication: predictor or mediator (26%, n = 125), selection criterion (3%, n = 15), and effect modifier (2%, n = 10). Articles spanned all health disciplines, and cohort studies comprised 91% (n =137) of studies and trials 9% (n = 13). Thirty-eight frailty definitions using varied cut-offs and a wide range of interventions were identified. Among all articles, 13% (n = 63) of articles were practice-informing, 2% (n = 11) potentially practice-changing, and 0.2% (n = 1) clearly practice-changing. Lack of well-defined intervention and identifiable effect (96%) or originality (83%) were predominant reasons reducing applicability. Only a minority of recent frailty research provides direct evidence of applicability to practice. Future research on frailty should focus on translating frailty, as a risk factor, into a clinical indication and address definition ambiguity.
    Keywords:  Frailty; clinical practice; epidemiology; interventions; risk factor
    DOI:  https://doi.org/10.1016/j.arr.2021.101493
  7. J Exp Med. 2021 Dec 06. pii: e20211872. [Epub ahead of print]218(12):
    Dnmt3a-mutated clonal hematopoiesis promotes osteoporosis.
    Peter Geon Kim, Abhishek Niroula, Veronica Shkolnik, Marie McConkey, Amy E Lin, Mikołaj Słabicki, John P Kemp, Alexander Bick, Christopher J Gibson, Gabriel Griffin, Aswin Sekar, Daniel J Brooks, Waihay J Wong, Drew N Cohen, Md Mesbah Uddin, Wesley J Shin, James Pirruccello, Jonathan M Tsai, Mridul Agrawal, Douglas P Kiel, Mary L Bouxsein, J Brent Richards, David M Evans, Marc N Wein, Julia F Charles, Siddhartha Jaiswal, Pradeep Natarajan, Benjamin L Ebert.
      Osteoporosis is caused by an imbalance of osteoclasts and osteoblasts, occurring in close proximity to hematopoietic cells in the bone marrow. Recurrent somatic mutations that lead to an expanded population of mutant blood cells is termed clonal hematopoiesis of indeterminate potential (CHIP). Analyzing exome sequencing data from the UK Biobank, we found CHIP to be associated with increased incident osteoporosis diagnoses and decreased bone mineral density. In murine models, hematopoietic-specific mutations in Dnmt3a, the most commonly mutated gene in CHIP, decreased bone mass via increased osteoclastogenesis. Dnmt3a-/- demethylation opened chromatin and altered activity of inflammatory transcription factors. Bone loss was driven by proinflammatory cytokines, including Irf3-NF-κB-mediated IL-20 expression from Dnmt3a mutant macrophages. Increased osteoclastogenesis due to the Dnmt3a mutations was ameliorated by alendronate or IL-20 neutralization. These results demonstrate a novel source of osteoporosis-inducing inflammation.
    DOI:  https://doi.org/10.1084/jem.20211872
  8. Open Med (Wars). 2021 ;16(1): 1525-1536
    Research progress of gut microbiota and frailty syndrome.
    Xiao Wang, Min Wu.
      Frailty is a clinical syndrome caused by homeostasis imbalance. It is characterized by marked vulnerability to endogenous or exogenous stressors, reduced self-care ability, and increased mortality risk. This aging-related syndrome is common in individuals older than 65 years and carries an increased risk for poor health outcomes. These include falls, incident disability, incapacity, and mortality. In addition, it can result in a poor prognosis for other comorbidities. With the aging population, frailty increases the burden of adverse health outcomes. Studies on frailty are at their infancy. In addition, there is a lack of thorough understanding of its pathogenesis. Several studies have suggested that frailty is caused by chronic inflammation due to enhanced intestinal permeability following gut microbiota imbalance as well as pathogen-related antibodies entering the circulation system. These result in musculoskeletal system disorders and neurodegenerative diseases. However, this assumption has not been validated in large cohort-based studies. Several studies have suggested that inflammation is not the only cause of frailty. Hence, further studies are necessary to extend our understanding of its pathogenesis. This review summarizes the research findings in the field and expands on the possible role of the gut microbiota in frailty syndrome.
    Keywords:  chronic inflammation; frailty; gut microbiota; inflammatory factors; neurodegenerative diseases
    DOI:  https://doi.org/10.1515/med-2021-0364
  9. Med Hypotheses. 2021 Oct 19. pii: S0306-9877(21)00233-4. [Epub ahead of print]157 110714
    Whole-body vibration combined with exercise may be more effective in lowering blood pressure and arterial stiffness than exercise alone in older adults with hypertension.
    Chidiebere Emmanuel Okechukwu.
      
    Keywords:  Aging; Exercise; High blood pressure; Vibrations
    DOI:  https://doi.org/10.1016/j.mehy.2021.110714
  10. Front Physiol. 2021 ;12 755060
    Modulating Sirtuin Biology and Nicotinamide Adenine Diphosphate Metabolism in Cardiovascular Disease-From Bench to Bedside.
    Yu-Jen Wang, Francesco Paneni, Sokrates Stein, Christian M Matter.
      Sirtuins (SIRT1-7) comprise a family of highly conserved deacetylases with distribution in different subcellular compartments. Sirtuins deacetylate target proteins depending on one common substrate, nicotinamide adenine diphosphate (NAD+), thus linking their activities to the status of cellular energy metabolism. Sirtuins had been linked to extending life span and confer beneficial effects in a wide array of immune-metabolic and cardiovascular diseases. SIRT1, SIRT3, and SIRT6 have been shown to provide protective effects in various cardiovascular disease models, by decreasing inflammation, improving metabolic profiles or scavenging oxidative stress. Sirtuins may be activated collectively by increasing their co-substrate NAD+. By supplementing NAD+ precursors, NAD+ boosters confer pan-sirtuin activation with protective cardiometabolic effects in the experimental setting: they improve endothelial dysfunction, protect from experimental heart failure, hypertension and decrease progression of liver steatosis. Different precursor molecules were applied ranging from nicotinamide (NAM), nicotinamide mononucleotide (NMN) to nicotinamide riboside (NR). Notably, not all experimental results showed protective effects. Moreover, the results are not as striking in clinical studies as in the controlled experimental setting. Species differences, (lack of) genetic heterogeneity, different metabolic pathways, dosing, administration routes and disease contexts may account for these challenges in clinical translation. At the clinical scale, caloric restriction can reduce the risks of cardiovascular disease and raise NAD+ concentration and sirtuin expression. In addition, antidiabetic drugs such as metformin or SGLT2 inhibitors may confer cardiovascular protection, indirectly via sirtuin activation. Overall, additional mechanistic insight and clinical studies are needed to better understand the beneficial effects of sirtuin activation and NAD+ boosters from bench to bedside.
    Keywords:  NAD+ boosters; caloric restriction; cardiovascular diseases; sirtuins; translational studies
    DOI:  https://doi.org/10.3389/fphys.2021.755060
  11. Nat Commun. 2021 Oct 27. 12(1): 6201
    Daily caloric restriction limits tumor growth more effectively than caloric cycling regardless of dietary composition.
    Laura C D Pomatto-Watson, Monica Bodogai, Oye Bosompra, Jonathan Kato, Sarah Wong, Melissa Carpenter, Eleonora Duregon, Dolly Chowdhury, Priya Krishna, Sandy Ng, Emeline Ragonnaud, Roberto Salgado, Paula Gonzalez Ericsson, Alberto Diaz-Ruiz, Michel Bernier, Nathan L Price, Arya Biragyn, Valter D Longo, Rafael de Cabo.
      Cancer incidence increases with age and is a leading cause of death. Caloric restriction (CR) confers benefits on health and survival and delays cancer. However, due to CR's stringency, dietary alternatives offering the same cancer protection have become increasingly attractive. Short cycles of a plant-based diet designed to mimic fasting (FMD) are protective against tumorigenesis without the chronic restriction of calories. Yet, it is unclear whether the fasting time, level of dietary restriction, or nutrient composition is the primary driver behind cancer protection. Using a breast cancer model in mice, we compare the potency of daily CR to that of periodic caloric cycling on FMD or an isocaloric standard laboratory chow against primary tumor growth and metastatic burden. Here, we report that daily CR provides greater protection against tumor growth and metastasis to the lung, which may be in part due to the unique immune signature observed with daily CR.
    DOI:  https://doi.org/10.1038/s41467-021-26431-4
  12. Cell Stem Cell. 2021 Oct 20. pii: S1934-5909(21)00414-8. [Epub ahead of print]
    Multilayer omics analysis reveals a non-classical retinoic acid signaling axis that regulates hematopoietic stem cell identity.
    Katharina Schönberger, Nadine Obier, Mari Carmen Romero-Mulero, Pierre Cauchy, Julian Mess, Polina V Pavlovich, Yu Wei Zhang, Michael Mitterer, Jasmin Rettkowski, Maria-Eleni Lalioti, Karin Jäcklein, Jonathan D Curtis, Betty Féret, Pia Sommerkamp, Claudia Morganti, Keisuke Ito, Norbert B Ghyselinck, Eirini Trompouki, Joerg M Buescher, Erika L Pearce, Nina Cabezas-Wallscheid.
      Hematopoietic stem cells (HSCs) rely on complex regulatory networks to preserve stemness. Due to the scarcity of HSCs, technical challenges have limited our insights into the interplay between metabolites, transcription, and the epigenome. In this study, we generated low-input metabolomics, transcriptomics, chromatin accessibility, and chromatin immunoprecipitation data , revealing distinct metabolic hubs that are enriched in HSCs and their downstream multipotent progenitors. Mechanistically, we uncover a non-classical retinoic acid (RA) signaling axis that regulates HSC function. We show that HSCs rely on Cyp26b1, an enzyme conventionally considered to limit RA effects in the cell. In contrast to the traditional view, we demonstrate that Cyp26b1 is indispensable for production of the active metabolite 4-oxo-RA. Further, RA receptor beta (Rarb) is required for complete transmission of 4-oxo-RA-mediated signaling to maintain stem cells. Our findings emphasize that a single metabolite controls stem cell fate by instructing epigenetic and transcriptional attributes.
    Keywords:  4-oxo-RA; Cyp26b1; Rarb; at-RA; epigenetics; hematopoietic stem cells; metabolites; self-renewal; vitamin A
    DOI:  https://doi.org/10.1016/j.stem.2021.10.002
  13. Aging Cell. 2021 Oct 29. e13500
    Reevaluation of the effect of dietary restriction on different recombinant inbred lines of male and female mice.
    Archana Unnikrishnan, Stephanie Matyi, Karla Garrett, Michelle Ranjo-Bishop, David B Allison, Keisuke Ejima, Xiwei Chen, Stephanie Dickinson, Arlan Richardson.
      Dietary restriction (DR) was reported to either have no effect or reduce the lifespan of the majority of the 41-recombinant inbred (RI) lines studied by Liao et al. (Aging Cell, 2010, 9, 92). In an appropriately power longevity study (n > 30 mice/group), we measured the lifespan of the four RI lines (115-RI, 97-RI, 98-RI, and 107-RI) that were reported to have the greatest decrease in lifespan when fed 40% DR. DR increased the median lifespan of female RI-115, 97-RI, and 107-RI mice and male 115-RI mice. DR had little effect (<4%) on the median lifespan of female and male 98-RI mice and male 97-RI mice and reduced the lifespan of male 107-RI mice over 20%. While our study was unable to replicate the effect of DR on the lifespan of the RI mice (except male 107-RI mice) reported by Liao et al. (Aging Cell, 2010, 9, 92), we found that the genotype of a mouse had a major impact on the effect of DR on lifespan, with the effect of DR ranging from a 50% increase to a 22% decrease in median lifespan. No correlation was observed between the changes in either body composition or glucose tolerance induced by DR and the changes observed in lifespan of the four RI lines of male and female mice. These four RI lines of mice give the research community a unique resource where investigators for the first time can study the anti-aging mechanism of DR by comparing mice in which DR increases lifespan to mice where DR has either no effect or reduces lifespan.
    Keywords:  adiposity; dietary restriction; glucose tolerance; lifespan; recombinant inbred lines
    DOI:  https://doi.org/10.1111/acel.13500
  14. Front Public Health. 2021 ;9 513557
    Characterizing the Heterogeneity of Aging: A Vision for a Staging System for Aging.
    Efraim Jaul, Jeremy Barron.
      Introduction: Older adulthood encompasses several decades of change and heterogeneity. Primary care providers need a geriatric comprehensive vision for defining older adult subpopulations. Methods: Using PubMed and Google searches, we reviewed the literature on epidemiology of age-related physiological changes, age-related diseases and geriatric syndromes, functional state, and emotional and social changes. We divided old age into strata based on chronological age and strata based on functional state, disease burden, and geriatric syndromes. Results: We describe 4 chronological-age strata beginning at age 60, and 4 functional-age strata based on frailty according to a modified clinical frailty scale. We provide clinical considerations and anticipatory guidance topics for each of the age strata and functional strata. Conclusion: Chronological age, functional status, chronic disease burden and geriatric syndromes, and life expectancy are all important domains that impact clinical care and appropriate anticipatory guidance for individual older adults. Better knowledge for differentiating subpopulations of older adults may improve clinical care, reduce medical overuse, improve personalized anticipatory guidance, and focus on the impact of functional state on the quality of life.
    Keywords:  aging; anticipatory guidance; chronologic age; functional status; life expectancy
    DOI:  https://doi.org/10.3389/fpubh.2021.513557
  15. Leuk Lymphoma. 2021 Oct 27. 1-8
    Targeting mitochondrial metabolism in acute myeloid leukemia.
    Madison Rush Rex, Robert Williams, Kivanç Birsoy, Martin S Ta Llman, Maximillian Stahl.
      Cancer cells reprogram their metabolism to maintain sustained proliferation, which creates unique metabolic dependencies between malignant and healthy cells that can be exploited for therapy. In acute myeloid leukemia (AML), mitochondrial inhibitors that block tricarboxylic acid cycle enzymes or electron transport chain complexes have recently shown clinical promise. The isocitrate dehydrogenase 1 inhibitor ivosidenib, the isocitrate dehydrogenase 2 inhibitor enasidenib, and the BH3 mimetic venetoclax received FDA approval for treatment of AML in the last few years. Other mitochondrial inhibitors including CPI-613, CB-839, dihydroorotate dehydrogenase inhibitors, IACS-010759, and mubritinib, have shown encouraging preclinical efficacy and are currently being evaluated in clinical trials. In this review, we summarize recent metabolism-based therapies and their ability to target altered cancer metabolism in AML.
    Keywords:  Targeted therapy; acute myeloid leukemia; mitochondrial metabolism
    DOI:  https://doi.org/10.1080/10428194.2021.1992759
  16. Am J Bioeth. 2021 Nov;21(11): 69-71
    Frailty, an Imperfect ICU Rationing Criterion.
    Ramesh K Batra, Stephen R Latham.
      
    DOI:  https://doi.org/10.1080/15265161.2021.1980142
  17. Curr Opin Virol. 2021 Oct 21. pii: S1879-6257(21)00122-X. [Epub ahead of print]51 127-133
    Understanding T cell aging to improve anti-viral immunity.
    Huimin Zhang, Cornelia M Weyand, Jörg J Goronzy, Claire E Gustafson.
      T cells are a critical component of the immune system and required for protection against viral and bacterial infections. However, the capacity of these cells to provide sufficient protection declines with age, leading to an increased susceptibility to and mortality from infection in older individuals. In many cases, it also contributes to poor vaccine-induced immunity. Understanding the basic biology behind T cell aging is key to unraveling these defects and, in turn, designing more effective vaccines and therapeutics for the older population. Here, we will discuss recent studies that have provided significant insight into the features of T cell aging, how these features may contribute to poor immune responses with advancing age and newer avenues of research that may further enhance anti-viral immunity in older individuals.
    DOI:  https://doi.org/10.1016/j.coviro.2021.09.017
  18. J Exp Med. 2021 Dec 06. pii: e20192070. [Epub ahead of print]218(12):
    Chronic viral infections persistently alter marrow stroma and impair hematopoietic stem cell fitness.
    Stephan Isringhausen, YeVin Mun, Larisa Kovtonyuk, Nike J Kräutler, Ute Suessbier, Alvaro Gomariz, Gianluca Spaltro, Patrick M Helbling, Hui Chyn Wong, Takashi Nagasawa, Markus G Manz, Annette Oxenius, César Nombela-Arrieta.
      Chronic viral infections are associated with hematopoietic suppression, bone marrow (BM) failure, and hematopoietic stem cell (HSC) exhaustion. However, how persistent viral challenge and inflammatory responses target BM tissues and perturb hematopoietic competence remains poorly understood. Here, we combine functional analyses with advanced 3D microscopy to demonstrate that chronic infection with lymphocytic choriomeningitis virus leads to (1) long-lasting decimation of the BM stromal network of mesenchymal CXCL12-abundant reticular cells, (2) proinflammatory transcriptional remodeling of remaining components of this key niche subset, and (3) durable functional defects and decreased competitive fitness in HSCs. Mechanistically, BM immunopathology is elicited by virus-specific, activated CD8 T cells, which accumulate in the BM via interferon-dependent mechanisms. Combined antibody-mediated inhibition of type I and II IFN pathways completely preempts degeneration of CARc and protects HSCs from chronic dysfunction. Hence, viral infections and ensuing immune reactions durably impact BM homeostasis by persistently decreasing the competitive fitness of HSCs and disrupting essential stromal-derived, hematopoietic-supporting cues.
    DOI:  https://doi.org/10.1084/jem.20192070
  19. Antioxid Redox Signal. 2021 Oct 29.
    The many roles mitochondria play in mammalian aging.
    Caio M P F Batalha, Anibal Eugênio Vercesi, Nadja C Souza-Pinto.
       SIGNIFICANCE: Aging is a natural process that affects most living organisms, resulting in increased mortality. As the world population ages, the prevalence of age-associated diseases, and their associated healthcare costs, has increased sharply. A better understanding of the molecular mechanisms that lead to cellular dysfunction may provide important targets for interventions to prevent or treat these diseases. Recent Advances: Although the mitochondrial theory of aging has been proposed over 40 years ago, recent new data has given stronger support for a central role for mitochondrial dysfunction in several pathways that are deregulated during normal aging and age-associated disease.
    CRITICAL ISSUES: Several of the experimental evidence linking mitochondrial alterations to age-associated loss of function are correlative and mechanistic insight are still elusive. Here, we review how mitochondrial dysfunction may be involved in many of the known hallmarks of aging, and how these pathways interact in an intricate net of molecular relationships.
    FUTURE DIRECTIONS: As it has become clear that mitochondrial dysfunction plays causative roles in normal aging and age-associated diseases, it is necessary to better define the molecular interactions and the temporal and causal relations between these changes and the relevant phenotypes seen during the aging process.
    DOI:  https://doi.org/10.1089/ars.2021.0074
  20. Front Physiol. 2021 ;12 733696
    Sirtuin 1 in Endothelial Dysfunction and Cardiovascular Aging.
    Stefano Ministrini, Yustina M Puspitasari, Georgia Beer, Luca Liberale, Fabrizio Montecucco, Giovanni G Camici.
      Sirtuin 1 (SIRT1) is a histone deacetylase belonging to the family of Sirtuins, a class of nicotinamide adenine dinucleotide (NAD+)-dependent enzymes with multiple metabolic functions. SIRT1 localizes in the nucleus and cytoplasm, and is implicated in the regulation of cell survival in response to several stimuli, including metabolic ones. The expression of SIRT1 is associated with lifespan and is reduced with aging both in animal models and in humans, where the lack of SIRT1 is regarded as a potential mediator of age-related cardiovascular diseases. In this review, we will summarize the extensive evidence linking SIRT1 functional and quantitative defects to cellular senescence and aging, with particular regard to their role in determining endothelial dysfunction and consequent cardiovascular diseases. Ultimately, we outline the translational perspectives for this topic, in order to highlight the missing evidence and the future research steps.
    Keywords:  aging–old age–seniors; atherosclerosis; cardiovascular disease; eNOS (endothelial nitric oxide synthase); endothelial (dys)function; inflammaging; sirtuin (SIRT1)
    DOI:  https://doi.org/10.3389/fphys.2021.733696
  21. CMAJ. 2021 Oct 25. 193(42): E1638
    Canada's health system is at a breaking point, say medical leaders.
    Diana Duong.
      
    DOI:  https://doi.org/10.1503/cmaj.1095965
  22. Science. 2021 Oct 29. 374(6567): 534-535
    Clearing stressed cells.
    Virinder Reen, Jesús Gil.
      [Figure: see text].
    DOI:  https://doi.org/10.1126/science.abm3229
  23. Transl Res. 2021 Oct 22. pii: S1931-5244(21)00259-0. [Epub ahead of print]
    Role of senescence in the chronic health consequences of COVID-19.
    Erin O Wissler Gerdes, Greg Vanichkachorn, Brandon P Verdoorn, Gregory J Hanson, Avni Y Joshi, M Hassan Murad, Stacey A Rizza, Ryan T Hurt, Tamar Tchkonia, James L Kirkland.
      While the full impact of COVID-19 is not yet clear, early studies have indicated that upwards of 10% of patients experience COVID-19 symptoms longer than 3 weeks, known as Long-Hauler's Syndrome or PACS (post-acute sequelae of SARS-CoV-2 infection). There is little known about risk factors or predictors of susceptibility for Long-Hauler's Syndrome, but older adults are at greater risk for severe outcomes and mortality from COVID-19. The pillars of aging (including cellular senescence, telomere dysfunction, impaired proteostasis, mitochondrial dysfunction, deregulated nutrient sensing, genomic instability, progenitor cell exhaustion, altered intercellular communication, and epigenetic alterations) that contribute to age-related dysfunction and chronic diseases (the "Geroscience Hypothesis") may interfere with defenses against viral infection and consequences of these infections. Heightening of the low-grade inflammation that is associated with aging may generate an exaggerated response to an acute COVID-19 infection. Innate immune system dysfunction that leads to decreased senescent cell removal and/or increased senescent cell formation could contribute to accumulation of senescent cells with both aging and viral infections. These processes may contribute to increased risk for long-term COVID-19 sequelae in older or chronically ill patients. Hence, senolytics and other geroscience interventions that may prolong healthspan and alleviate chronic diseases and multi-morbidity linked to fundamental aging processes might be an option for delaying, preventing, or alleviating Long-Hauler's syndrome.
    DOI:  https://doi.org/10.1016/j.trsl.2021.10.003
  24. Am J Bioeth. 2021 Nov;21(11): 82-84
    The Frailty of Disability: A Controversial Triage Criterion.
    Joaquín Hortal-Carmona, Belén Liedo, Jon Rueda, Rosana Triviño-Caballero.
      
    DOI:  https://doi.org/10.1080/15265161.2021.1980140
  25. Aging Clin Exp Res. 2021 Oct 23.
    Frailty but not sarcopenia nor malnutrition increases the risk of developing COVID-19 in older community-dwelling adults.
    Laetitia Lengelé, Médéa Locquet, Michel Moutschen, Charlotte Beaudart, Jean-François Kaux, Sophie Gillain, Jean-Yves Reginster, Olivier Bruyère.
       BACKGROUND: The identification of coronavirus disease 2019 (COVID-19) risk factors is requested to implement prevention strategies.
    AIM: To explore the associations between the COVID-19 incidence and malnutrition, sarcopenia, and frailty, identified as potential risk factors in previous cross-sectional studies.
    METHODS: Malnutrition, sarcopenia, and frailty were assessed at the last available follow-up from the Sarcopenia and Physical Impairments with Advancing Age (SarcoPhAge) cohort (i.e., the fifth year that ended in 2019) according to the Mini-Nutritional Assessment short-form, the European Working Group on Sarcopenia in Older People (EWGSOP2), and the Fried criteria, respectively. Information regarding the COVID-19 was gathered by phone calls interviews in April 2021 to measure its self-declared incidence. Adjusted Cox regressions and Kaplan-Meier curves were performed.
    RESULTS: The present study included 241 participants [median age 75.6 (73.0-80.6) years, 63.1% women]. Among them, 27 participants (11.2%) developed the non-fatal Covid-19. No significant increased risks of COVID-19 were observed in patients with malnutrition [adjusted HR 1.14 (0.26-5.07)] and sarcopenia [adjusted HR 1.25 (0.35-4.42)]. Nevertheless, the incidence of COVID-19 was significantly higher in frail (44.4%) than in robust participants (8.5%) [Adjusted HR 7.01 (2.69-18.25)], which was confirmed by the Kaplan-Meier curves (p < 0.001). Among the frailty syndrome components, a low physical activity level was the only one significantly associated with an increased risk of COVID-19 [adjusted HR 5.18 (1.37-19.54)].
    CONCLUSION: Despite some limitations in the methodology of this study (i.e., limited sample size, COVID-19 incidence self-reported and not assessed systematically using objective measurements) requiring careful  consideration, an increased risk to develop COVID-19 was observed in the presence of the frailty syndrome. Further investigations are needed to elaborate on our findings.
    Keywords:  COVID-19; Frailty; Malnutrition; SarcoPhAge; Sarcopenia
    DOI:  https://doi.org/10.1007/s40520-021-01991-z
  26. J Clin Epidemiol. 2021 Oct 21. pii: S0895-4356(21)00333-4. [Epub ahead of print]
    The Fragility Index Should Not Be Used For Sample Size Calculations in Clinical Trials.
    Gail E Potter.
      
    DOI:  https://doi.org/10.1016/j.jclinepi.2021.10.009
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