bims-minfam Biomed News
on Inflammation and metabolism in ageing and cancer
Issue of 2022–02–06
33 papers selected by
Ayesh Seneviratne, University of Toronto
  1. Clonal hematopoiesis and vascular disease.
  2. Hotspot DNMT3A mutations in clonal hematopoiesis and acute myeloid leukemia sensitize cells to azacytidine via viral mimicry response.
  3. Mechanisms of Musculoskeletal Frailty in People Living with HIV.
  4. Clinical experience with venetoclax in patients with newly diagnosed, relapsed, or refractory acute myeloid leukemia.
  5. Prevalence of Physical Frailty: Results from the DO-HEALTH Study.
  6. Immune system aging and the aging-related diseases in the COVID-19 era.
  7. Rapamycin, Acarbose and 17α-estradiol share common mechanisms regulating the MAPK pathways involved in intracellular signaling and inflammation.
  8. A venetoclax bench-to-bedside story.
  9. Nutritional Deficiencies in Vegetarian, Gluten-Free, and Ketogenic Diets.
  10. Mitochondrial inhibitors circumvent adaptive resistance to venetoclax and cytarabine combination therapy in acute myeloid leukemia.
  11. Calm before the Storm.
  12. Adaptation of Arterial Wall Viscosity to the Short-Term Reduction of Heart Rate: Impact of Aging.
  13. A microbiome-macrophage-iron axis guides stressed hematopoietic stem cell fate.
  14. Less intensive antileukemic therapies (monotherapy and/or combination) for older adults with acute myeloid leukemia who are not candidates for intensive antileukemic therapy: A systematic review and meta-analysis.
  15. Tryptophan metabolism drives dynamic immunosuppressive myeloid states in IDH-mutant gliomas.
  16. Multi-Omics Analysis of Lipid Metabolism for a Marine Probiotic Meyerozyma guilliermondii GXDK6 Under High NaCl Stress.
  17. Perspective: Vegan Diets for Older Adults? A Perspective On the Potential Impact On Muscle Mass and Strength.
  18. Passing on the exercise baton: what can endocrine patients learn from elite athletes?
  19. The mouse metallomic landscape of aging and metabolism.
  20. Frailty and dementia in long-term care: An analysis of the InterRAI data over the past decade.
  21. Last-resort cancer therapy holds back disease for more than a decade.
  22. What long-term care interventions have been published between 2010 and 2020? Results of a WHO scoping review identifying long-term care interventions for older people around the world.
  23. A 2D and 3D cell culture protocol to study O-GlcNAc in sphingosine-1-phosphate mediated fibroblast contraction.
  24. Mitochondria, a Missing Link in COVID-19 Heart Failure and Arrest?
  25. Are you more impulsive with age? Examining age, marital status, and gender on cognitive ageing.
  26. Deleterious effect of bone marrow-resident macrophages on hematopoietic stem cells in response to total body irradiation.
  27. How well can Omicron evade immunity from COVID vaccines?
  28. Association between diabetes, obesity, aging, and cancer: review of recent literature.
  29. Epigenetic Achilles' heel of AML.
  30. The selection force weakens with age because ageing evolves and not vice versa.
  31. Mitochondrial protein import determines lifespan through metabolic reprogramming and de novo serine biosynthesis.
  32. From surviving to thriving: the current status of the behavioral, social, and psychological issues of aging with HIV.
  33. The Effects of Exercise on Aging-Induced Exaggerated Cytokine Responses: An Interdisciplinary Discussion.
  1. Semin Immunopathol. 2022 Feb 04.
    Clonal hematopoiesis and vascular disease.
    Kaushik Amancherla, John A Wells, Alexander G Bick.
      Somatic mutations in hematopoietic stem cells are common with aging and can result in expansion of clones harboring mutations, termed clonal hematopoiesis. This results in an increased risk of blood cancers but has also been linked with chronic inflammatory disease states. In recent years, clonal hematopoiesis has been established to have a causative role in atherogenesis and cardiovascular disease. Additionally, as the effector cells have been identified to be immune cells, there is ongoing interest in assessing whether dysregulated immune function plays a role in other chronic inflammatory conditions such as rheumatologic disease. Here, we summarize current understanding of clonal hematopoiesis with a focus on cardiovascular disease and inflammation while outlining the potential, yet unexplored, relationship between clonal hematopoiesis and autoimmune disease. Hematopoietic stem cells (HSCs) continually regenerate blood cells. Acquisition of a somatic mutation that provides a selective advantage, a driver mutation, can result in clonal expansion. Clonal hematopoiesis of indeterminate potential, where somatic mutations in certain cancer-associated genes result in clonal expansion in the absence of overt malignancy, can result in atherosclerotic cardiovascular disease in multiple vascular beds, inflammation, and may also contribute to the pathogenesis of autoimmune disease. Many questions remain unanswered regarding the relationship between clonal hematopoiesis and inflammatory disorders.
    Keywords:  ASCVD; Atherosclerosis; CHIP; Clonal hematopoiesis; Vascular disease
    DOI:  https://doi.org/10.1007/s00281-022-00913-z
  2. Nat Cancer. 2021 May;2(5): 527-544
    Hotspot DNMT3A mutations in clonal hematopoiesis and acute myeloid leukemia sensitize cells to azacytidine via viral mimicry response.
    Marina Scheller, Anne Kathrin Ludwig, Stefanie Göllner, Christian Rohde, Stephen Krämer, Sina Stäble, Maike Janssen, James-Arne Müller, Lixiazi He, Nicole Bäumer, Christian Arnold, Joachim Gerß, Maximilian Schönung, Christian Thiede, Christian Niederwieser, Dietger Niederwieser, Hubert Serve, Wolfgang E Berdel, Ulrich Thiem, Inga Hemmerling, Florian Leuschner, Christoph Plass, Matthias Schlesner, Judith Zaugg, Michael D Milsom, Andreas Trumpp, Caroline Pabst, Daniel B Lipka, Carsten Müller-Tidow.
      Somatic mutations in DNA methyltransferase 3A (DNMT3A) are among the most frequent alterations in clonal hematopoiesis (CH) and acute myeloid leukemia (AML), with a hotspot in exon 23 at arginine 882 (DNMT3AR882). Here, we demonstrate that DNMT3AR882H-dependent CH and AML cells are specifically susceptible to the hypomethylating agent azacytidine (AZA). Addition of AZA to chemotherapy prolonged AML survival solely in individuals with DNMT3AR882 mutations, suggesting its potential as a predictive marker for AZA response. AML and CH mouse models confirmed AZA susceptibility specifically in DNMT3AR882H-expressing cells. Hematopoietic stem cells (HSCs) and progenitor cells expressing DNMT3AR882H exhibited cell autonomous viral mimicry response as a result of focal DNA hypomethylation at retrotransposon sequences. Administration of AZA boosted hypomethylation of retrotransposons specifically in DNMT3AR882H-expressing cells and maintained elevated levels of canonical interferon-stimulated genes (ISGs), thus leading to suppressed protein translation and increased apoptosis.
    DOI:  https://doi.org/10.1038/s43018-021-00213-9
  3. J Frailty Aging. 2022 ;11(1): 83-90
    Mechanisms of Musculoskeletal Frailty in People Living with HIV.
    A K Nelson, G Fiskum, C Renn, S Zhu, S Kottilil, N J Klinedinst.
      People over age 50 living with HIV experience frailty including functional declines and illnesses usually attributed to aging, more frequently and ten years earlier than people without HIV. As the number of people living with HIV over age 50 is expected to triple by the year 2040, those experiencing early frailty will continue to grow. This review synthesizes the known correlates and contributors to musculoskeletal frailty in people living with HIV. A conceptual model of musculoskeletal frailty in HIV that outlines chronic inflammation, altered energy metabolism, immune activation, and endocrine alterations as mechanisms associated with frailty development is presented. Additionally, the potential ability of aerobic exercise to modify the risk of frailty is highlighted as an important intervention.
    Keywords:  Mitochondria; aerobic exercise; endocrine alterations; immune activation; inflammation
    DOI:  https://doi.org/10.14283/jfa.2021.44
  4. J Cancer Res Clin Oncol. 2022 Jan 31.
    Clinical experience with venetoclax in patients with newly diagnosed, relapsed, or refractory acute myeloid leukemia.
    Maximilian Fleischmann, Sebastian Scholl, Jochen J Frietsch, Inken Hilgendorf, Karin Schrenk, Jakob Hammersen, Florian Prims, Christian Thiede, Andreas Hochhaus, Ulf Schnetzke.
       BACKGROUND: Diagnosis of acute myeloid leukemia (AML) is associated with poor outcome in elderly and unfit patients. Recently, approval of the BCL-2 inhibitor venetoclax (VEN) in combination with hypo-methylating agents (HMA) led to a significant improvement of response rates and survival. Further, application in the relapsed or refractory (r/r) AML setting or in context of allogeneic stem cell transplantation (alloHSCT) seems feasible.
    METHODS AND PATIENTS: Fifty-six consecutive adult AML patients on VEN from January 2019 to June 2021 were analyzed retrospectively. Patients received VEN either as first-line treatment, as subsequent therapy (r/r AML excluding prior alloHSCT), or at relapse after alloHSCT. VEN was administered orally in 28-day cycles either combined with HMA or low-dose cytarabine (LDAC).
    RESULTS: After a median follow-up of 11.5 (range 6.1-22.3) months, median overall survival (OS) from start of VEN treatment was 13.3 (2.2-20.5) months, 5.0 (0.8-24.3) months and 4.0 (1.5-22.1) months for first-line, subsequent line treatment and at relapse post-alloHSCT, respectively. Median OS was 11.5 (10-22.3) months from start of VEN when subsequent alloHSCT was carried out. Relapse-free survival (RFS) for the total cohort was 10.2 (2.2 - 24.3) months. Overall response rate (composite complete remission + partial remission) was 51.8% for the total cohort (61.1% for VEN first-line treatment, 52.2% for subsequent line and 42.8% at relapse post-alloHSCT). Subgroup analysis revealed a significantly reduced median OS in FLT3-ITD mutated AML with 3.4 (1.9-4.9) months versus 10.4 (0.8-24.3) months for non-mutated cases, (HR 4.45, 95% CI 0.89-22.13, p = 0.0002). Patients harboring NPM1 or IDH1/2 mutations lacking co-occurrence of FLT3-ITD showed a survival advantage over patients without those mutations (11.2 (5-24.3) months versus 5.0 (0.8-22.1) months, respectively, (HR 0.53, 95% CI 0.23 - 1.21, p = 0.131). Multivariate analysis revealed mutated NPM1 as a significant prognostic variable for achieving complete remission (CR) (HR 19.14, 95% CI 2.30 - 436.2, p < 0.05). The most common adverse events were hematological, with grade 3 and 4 neutropenia and thrombocytopenia reported in 44.6% and 14.5% of patients, respectively.
    CONCLUSION: Detailed analyses on efficacy for common clinical scenarios, such as first-line treatment, subsequent therapy (r/r AML), and application prior to and post-alloHSCT, are presented. The findings suggest VEN treatment combinations efficacious not only in first-line setting but also in r/r AML. Furthermore, VEN might play a role in a subgroup of patients with failure to conventional chemotherapy as a salvage regimen aiming for potential curative alloHSCT.
    Keywords:  AML; Hypo-methylating agents; Refractory; Relapse; Salvage therapy; Venetoclax
    DOI:  https://doi.org/10.1007/s00432-022-03930-5
  5. J Frailty Aging. 2022 ;11(1): 18-25
    Prevalence of Physical Frailty: Results from the DO-HEALTH Study.
    M Gagesch, P O Chocano-Bedoya, L A Abderhalden, G Freystaetter, A Sadlon, J A Kanis, R W Kressig, S Guyonnet, J A P DaSilva, D Felsenberg, R Rizzoli, M Blauth, E J Orav, A Egli, H A Bischoff-Ferrari.
       BACKGROUND: Frailty is a geriatric syndrome associated with multiple negative health outcomes. However, its prevalence varies by population and instrument used. We investigated frailty and pre-frailty prevalence by 5 instruments in community-dwelling older adults enrolled to a randomized-controlled trial in 5 European countries.
    METHODS: Cross-sectional baseline analysis in 2,144 DO-HEALTH participants recruited from Switzerland, Austria, France, Germany, and Portugal with complete data for frailty. Frailty status was assessed by the Physical Frailty Phenotype [PFP], SOF-Frailty Index [SOF-FI], FRAIL-Scale, SHARE-Frailty Instrument [SHARE-FI], and a modified SHARE-FI, and compared by country, age, and gender. Logistic regression was used to determine relevant factors associated with frailty and pre-frailty.
    RESULTS: Mean age was 74.9 (±4.4) years, 61.6% were women. Based on the PFP, overall frailty and pre-frailty prevalence was 3.0% and 43.0%. By country, frailty prevalence was highest in Portugal (13.7%) and lowest in Austria (0%), and pre-frailty prevalence was highest in Portugal (57.3%) and lowest in Germany (37.1%). By instrument and overall, frailty and pre-frailty prevalence was highest based on SHARE-FI (7.0% / 43.7%) and lowest based on SOF-FI (1.0% / 25.9%). Frailty associated factors were residing in Coimbra (Portugal) [OR 12.0, CI 5.30-27.21], age above 75 years [OR 2.0, CI 1.17-3.45], and female gender [OR 2.8, CI 1.48-5.44]. The same three factors predicted pre-frailty.
    CONCLUSIONS: Among relatively healthy adults age 70 and older enroled to DO-HEALTH, prevalence of frailty and pre-frailty differed significantly by instrument, country, gender, and age. Among instruments, the highest prevalence of frailty and pre-frailty was documented by the SHARE-FI and the lowest by the SOF-FI.
    Keywords:  Frailty; clinical trials; community-dwelling; epidemiology; prevalence
    DOI:  https://doi.org/10.14283/jfa.2021.18
  6. Immunol Lett. 2022 Jan 31. pii: S0165-2478(22)00019-0. [Epub ahead of print]243 19-27
    Immune system aging and the aging-related diseases in the COVID-19 era.
    Jacek M Witkowski.
      The interest in the process of aging, and specifically in how aging affects the working of our immune system, has recently enormously grown among both specialists (immunologists and gerontologists) and representatives of other disciplines of health sciences. An obvious reason for this interest is the current pandemics of COVID-19, known to affect the elderly more than younger people. In this paper current knowledge about mechanisms and complex facets of human immune system aging is presented, stemming from the knowledge about the working of various parts of the immune system, and leading to understanding of immunological mechanisms of chronic, inflammatory, aging-related diseases and of COVID-19.
    Keywords:  Adaptive immune system; Aging-related diseases; COVID-19; Immune system aging; Immunosenescence; Inflammaging; Innate immune system
    DOI:  https://doi.org/10.1016/j.imlet.2022.01.005
  7. Immun Ageing. 2022 Feb 01. 19(1): 8
    Rapamycin, Acarbose and 17α-estradiol share common mechanisms regulating the MAPK pathways involved in intracellular signaling and inflammation.
    Lily Wink, Richard A Miller, Gonzalo G Garcia.
       BACKGROUND: Rapamycin (Rapa), acarbose (ACA), and 17α-estradiol (17aE2, males only) have health benefits that increase lifespan of mice. Little is known about how these three agents alter the network of pathways downstream of insulin/IGF1 signals as well as inflammatory/stress responses.
    RESULTS: ACA, Rapa, and 17aE2 (in males, but not in females) oppose age-related increases in the MEK1- ERK1/2-MNK1/2 cascade, and thus reduce phosphorylation of eIF4E, a key component of cap-dependent translation. In parallel, these treatments (in both sexes) reduce age-related increases in the MEK3-p38MAPK-MK2 pathway, to decrease levels of the acute phase response proteins involved in inflammation.
    CONCLUSION: Each of three drugs converges on the regulation of both the ERK1/2 signaling pathway and the p38-MAPK pathway. The changes induced by treatments in ERK1/2 signaling are seen in both sexes, but the 17aE2 effects are male-specific, consistent with the effects on lifespan. However, the inhibition of age-dependent p38MAPK pathways and acute phase responses is triggered in both sexes by all three drugs, suggesting new approaches to prevention or reversal of age-related inflammatory changes in a clinical setting independent of lifespan effects.
    Keywords:  17-alpha-estradiol; Acarbose; Acute phase proteins; Aging; Diets; Inflammation; Liver and kidneys; Rapamycin; Signal transduction
    DOI:  https://doi.org/10.1186/s12979-022-00264-1
  8. Nat Cancer. 2021 Jan;2(1): 3-5
    A venetoclax bench-to-bedside story.
    Courtney D DiNardo, Marina Y Konopleva.
      
    DOI:  https://doi.org/10.1038/s43018-020-00165-6
  9. Pediatr Rev. 2022 Feb 01. 43(2): 61-70
    Nutritional Deficiencies in Vegetarian, Gluten-Free, and Ketogenic Diets.
    Erik Andrewski, Katherine Cheng, Charles Vanderpool.
      Previously, medical diets, including the ketogenic and gluten-free diets, were rare outside of their target population. Subspecialists more familiar with risks and benefits often managed nutrition and any associated shortcomings. With more patients electively following a gluten-free or ketogenic diet for nonmedical needs, as well as the increasing prevalence of vegetarian diets, general pediatricians are seeing more followers of restrictive diets with general well-child care. Increasingly, general pediatricians can be the first provider to witness presenting signs or symptoms of associated nutritional deficiencies. This article reviews signs and symptoms of possible nutrient deficiencies seen with the vegetarian, ketogenic, and gluten-free diets.
    DOI:  https://doi.org/10.1542/pir.2020-004275
  10. Nat Cancer. 2021 Nov;2(11): 1204-1223
    Mitochondrial inhibitors circumvent adaptive resistance to venetoclax and cytarabine combination therapy in acute myeloid leukemia.
    Claudie Bosc, Estelle Saland, Aurélie Bousard, Noémie Gadaud, Marie Sabatier, Guillaume Cognet, Thomas Farge, Emeline Boet, Mathilde Gotanègre, Nesrine Aroua, Pierre-Luc Mouchel, Nathaniel Polley, Clément Larrue, Eléonore Kaphan, Muriel Picard, Ambrine Sahal, Latifa Jarrou, Marie Tosolini, Florian Rambow, Florence Cabon, Nathalie Nicot, Laura Poillet-Perez, Yujue Wang, Xiaoyang Su, Quentin Fovez, Jérôme Kluza, Rafael José Argüello, Céline Mazzotti, Hervé Avet-Loiseau, François Vergez, Jérôme Tamburini, Jean-Jacques Fournié, Ing S Tiong, Andrew H Wei, Tony Kaoma, Jean-Christophe Marine, Christian Récher, Lucille Stuani, Carine Joffre, Jean-Emmanuel Sarry.
      Therapy resistance represents a major clinical challenge in acute myeloid leukemia (AML). Here we define a 'MitoScore' signature, which identifies high mitochondrial oxidative phosphorylation in vivo and in patients with AML. Primary AML cells with cytarabine (AraC) resistance and a high MitoScore relied on mitochondrial Bcl2 and were highly sensitive to venetoclax (VEN) + AraC (but not to VEN + azacytidine). Single-cell transcriptomics of VEN + AraC-residual cell populations revealed adaptive resistance associated with changes in oxidative phosphorylation, electron transport chain complex and the TP53 pathway. Accordingly, treatment of VEN + AraC-resistant AML cells with electron transport chain complex inhibitors, pyruvate dehydrogenase inhibitors or mitochondrial ClpP protease agonists substantially delayed relapse following VEN + AraC. These findings highlight the central role of mitochondrial adaptation during AML therapy and provide a scientific rationale for alternating VEN + azacytidine with VEN + AraC in patients with a high MitoScore and to target mitochondrial metabolism to enhance the sensitivity of AML cells to currently approved therapies.
    DOI:  https://doi.org/10.1038/s43018-021-00264-y
  11. N Engl J Med. 2022 Feb 03. 386(5): 479-485
    Calm before the Storm.
    Manuel B Braga Neto, Andrew D Badley, Sameer A Parikh, Rondell P Graham, Patrick S Kamath.
      
    DOI:  https://doi.org/10.1056/NEJMcps2111163
  12. J Am Heart Assoc. 2022 Feb 03. e023409
    Adaptation of Arterial Wall Viscosity to the Short-Term Reduction of Heart Rate: Impact of Aging.
    Frédéric Roca, Michèle Iacob, Thomas Duflot, Nathalie Donnadieu, Caroline Thill, Jérémy Bellien, Robinson Joannides.
      Background Changes in arterial wall viscosity, which dissipates the energy stored within the arterial wall, may contribute to the beneficial effect of heart rate (HR) reduction on arterial stiffness and cardiovascular coupling. However, it has never been assessed in humans and could be altered by aging. We evaluated the effect of a selective HR-lowering agent on carotid arterial wall viscosity and the impact of aging on this effect. Methods and Results This randomized, placebo-controlled, double-blind, crossover study performed in 19 healthy volunteers evaluated the effects of ivabradine (5 mg BID, 1-week) on carotid arterial wall viscosity, mechanics, hemodynamics, and cardiovascular coupling. Arterial wall viscosity was evaluated by the area of the hysteresis loop of the pressure-lumen cross-sectional area relationship, representing the energy dissipated (WV), and by the relative viscosity (WV/WE), with WE representing the elastic energy stored. HR reduction by ivabradine increased WV and WE whereas WV/WE remained stable. In middle-aged subjects (n=11), baseline arterial stiffness and cardiovascular coupling were less favorable, and WE was similar but WV and therefore WV/WE were lower than in youth (n=8). HR reduction increased WV/WE in middle-aged but not in young subjects, owing to a larger increase in WV than WE. These results were supported by the age-related linear increase in WV/WE after HR reduction (P=0.009), explained by a linear increase in WV. Conclusion HR reduction increases arterial wall energy dissipation proportionally to the increase in WE, suggesting an adaptive process to bradycardia. This mechanism is altered during aging resulting in a larger than expected energy dissipation, the impact of which should be assessed. Registration URL: https://www.clinicaltrials.gov; Unique identifier: 2015/077/HP. URL: https://www. eudract.ema.europa.eu; Unique identifier: 2015-002060-17.
    Keywords:  aging; artery; heart rate; stiffness; wall viscosity
    DOI:  https://doi.org/10.1161/JAHA.121.023409
  13. Cell Stem Cell. 2022 Feb 03. pii: S1934-5909(22)00009-1. [Epub ahead of print]29(2): 177-179
    A microbiome-macrophage-iron axis guides stressed hematopoietic stem cell fate.
    Francisco Caiado, Markus G Manz.
      The mammalian microbiota is a recently recognized regulator of hematopoiesis. In this issue of Cell Stem Cell, Zhang et al. (2022) show in mice that microbiota-derived butyrate enhances bone marrow macrophage erythrophagocytosis-dependent iron availability, which supports stress-induced hematopoietic stem cell differentiation and blood regeneration.
    DOI:  https://doi.org/10.1016/j.stem.2022.01.009
  14. PLoS One. 2022 ;17(2): e0263240
    Less intensive antileukemic therapies (monotherapy and/or combination) for older adults with acute myeloid leukemia who are not candidates for intensive antileukemic therapy: A systematic review and meta-analysis.
    Luis Enrique Colunga-Lozano, Fernando Kenji Nampo, Arnav Agarwal, Pinkal Desai, Mark Litzow, Mikkael A Sekeres, Gordon H Guyatt, Romina Brignardello-Petersen.
       INTRODUCTION: Elderly patients with acute myeloid leukemia not eligible for intensive antileukemic therapy are treated with less intensive therapies, uncertainty remains regarding their relative merits.
    OBJECTIVES: To compare the effectiveness and safety of less intensive antileukemic therapies for older adults with newly diagnosed AML not candidates for intensive therapies.
    METHODS: We included randomized controlled trials (RCTs) and non-randomized studies (NRS) comparing less intensive therapies in adults over 55 years with newly diagnosed AML. We searched MEDLINE and EMBASE from inception to August 2021. We assessed risk of bias of RCTs with a modified Cochrane Risk of Bias tool, and NRS with the Non-Randomized Studies of Interventions tool (ROBINS-I). We calculated pooled hazard ratios (HRs), risk ratios (RRs), mean differences (MD) and their 95% confidence intervals (CIs) using a random-effects pairwise meta-analyses and assessed the certainty of evidence using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach.
    RESULTS: We included 27 studies (17 RCTs, 10 NRS; n = 5,698), which reported 9 comparisons. Patients were treated with azacitidine, decitabine, and low-dose cytarabine (LDAC), as monotherapies or in combination with other agents. Moderate certainty of evidence suggests no convincing difference in overall survival of patients who receive azacitidine monotherapy compared to LDAC monotherapy (HR 0.69; 95% CI, 0.31-1.53), fewer febrile neutropenia events occurred between azacitidine monotherapy to azacitidine combination (RR 0.45; 95% CI, 0.31-0.65), and, fewer neutropenia events occurred between LDAC monotherapy to decitabine monotherapy (RR 0.62; 95% CI 0.44-0.86). All other comparisons and outcomes had low or very low certainty of evidence.
    CONCLUSION: There is no convincing superiority in OS when comparing less intensive therapies. Azacitidine monotherapy is likely to have fewer adverse events than azacitidine combination (febrile neutropenia), and LDAC monotherapy is likely to have fewer adverse events than decitabine monotherapy (neutropenia).
    DOI:  https://doi.org/10.1371/journal.pone.0263240
  15. Nat Cancer. 2021 Jul;2(7): 723-740
    Tryptophan metabolism drives dynamic immunosuppressive myeloid states in IDH-mutant gliomas.
    Mirco Friedrich, Roman Sankowski, Lukas Bunse, Michael Kilian, Edward Green, Carina Ramallo Guevara, Stefan Pusch, Gernot Poschet, Khwab Sanghvi, Markus Hahn, Theresa Bunse, Philipp Münch, Hagen M Gegner, Jana K Sonner, Anna von Landenberg, Frederik Cichon, Katrin Aslan, Tim Trobisch, Lucas Schirmer, Denis Abu-Sammour, Tobias Kessler, Miriam Ratliff, Daniel Schrimpf, Felix Sahm, Carsten Hopf, Dieter H Heiland, Oliver Schnell, Jürgen Beck, Chotima Böttcher, Camila Fernandez-Zapata, Josef Priller, Sabine Heiland, Ilona Gutcher, Francisco J Quintana, Andreas von Deimling, Wolfgang Wick, Marco Prinz, Michael Platten.
      The dynamics and phenotypes of intratumoral myeloid cells during tumor progression are poorly understood. Here we define myeloid cellular states in gliomas by longitudinal single-cell profiling and demonstrate their strict control by the tumor genotype: in isocitrate dehydrogenase (IDH)-mutant tumors, differentiation of infiltrating myeloid cells is blocked, resulting in an immature phenotype. In late-stage gliomas, monocyte-derived macrophages drive tolerogenic alignment of the microenvironment, thus preventing T cell response. We define the IDH-dependent tumor education of infiltrating macrophages to be causally related to a complex re-orchestration of tryptophan metabolism, resulting in activation of the aryl hydrocarbon receptor. We further show that the altered metabolism of IDH-mutant gliomas maintains this axis in bystander cells and that pharmacological inhibition of tryptophan metabolism can reverse immunosuppression. In conclusion, we provide evidence of a glioma genotype-dependent intratumoral network of resident and recruited myeloid cells and identify tryptophan metabolism as a target for immunotherapy of IDH-mutant tumors.
    DOI:  https://doi.org/10.1038/s43018-021-00201-z
  16. Front Genet. 2021 ;12 798535
    Multi-Omics Analysis of Lipid Metabolism for a Marine Probiotic Meyerozyma guilliermondii GXDK6 Under High NaCl Stress.
    Huijie Sun, Xinghua Cai, Bing Yan, Huashan Bai, Duotao Meng, Xueyan Mo, Sheng He, Guijiao Su, Chengjian Jiang.
      Investigating microbial lipid regulation contributes to understanding the lipid-dependent signal transduction process of cells and helps to improve the sensitivity of microorganisms to environmental factors by interfering with lipid metabolism, thus beneficial for constructing advanced cell factories of novel molecular drugs. Integrated omics technology was used to systematically reveal the lipid metabolism mechanism of a marine Meyerozyma guilliermondii GXDK6 under high NaCl stress and test the sensitivity of GXDK6 to antibiotics when its lipid metabolism transformed. The omics data showed that when GXDK6 perceived 10% NaCl stress, the expression of AYR1 and NADPH-dependent 1-acyldihydroxyacetone phosphate reductase was inhibited, which weaken the budding and proliferation of cell membranes. This finding was further validated by decreased 64.39% of OD600 under 10% NaCl stress when compared with salt-free stress. In addition, salt stress promoted a large intracellular accumulation of glycerol, which was also verified by exogenous addition of glycerol. Moreover, NaCl stress remarkably inhibited the expression of drug target proteins (such as lanosterol 14-alpha demethylase), thereby increasing sensitivity to fluconazole. This study provided new insights into the molecular mechanism involved in the regulation of lipid metabolism in Meyerozyma guilliermondii strain and contributed to developing new methods to improve the effectiveness of killing fungi with lower antibiotics.
    Keywords:  Meyerozyma guilliermondii; antibiotics; integrated omics technology; lipid metabolism; signal transduction
    DOI:  https://doi.org/10.3389/fgene.2021.798535
  17. Adv Nutr. 2022 Feb 02. pii: nmac009. [Epub ahead of print]
    Perspective: Vegan Diets for Older Adults? A Perspective On the Potential Impact On Muscle Mass and Strength.
    Jacintha Domić, Pol Grootswagers, Luc J C van Loon, Lisette C P G M de Groot.
      Consumers are increasingly encouraged to consume more plant-based foods and lower their consumption of foods from animal origin. Concurrently, older adults are recommended to consume an adequate amount of high-quality dietary protein for the prevention of age-related muscle loss. In the current perspective, we discuss why it may not be preferred to consume a vegan diet at an older age. Our perspective is based on the proposed lower bioavailability and functionality of proteins in a vegan diet due to the matrix of the whole-food protein sources, the lower essential amino acid (EAA) content, and specific EAA deficiencies in proteins derived from plant-based foods. We propose that a vegan diet increases the risk of an inadequate protein intake at an older age and that current strategies to improve the anabolic properties of plant-based foods are not feasible for many older adults. We provide recommendations for further research to substantiate the remaining knowledge gaps regarding the consequences of a vegan diet on skeletal muscle mass and strength at an older age.
    Keywords:  ageing; animal-based food; plant-based diet; plant-based food; protein; sustainable food
    DOI:  https://doi.org/10.1093/advances/nmac009
  18. Clin Endocrinol (Oxf). 2022 Feb 04.
    Passing on the exercise baton: what can endocrine patients learn from elite athletes?
    Olivia McCarthy, Jason P Pitt, Nicky Keay, Esben Thyssen Vestergaard, Abbigail Sy Tan, Rachel Churm, D Aled Rees, Richard M Bracken.
      As elite athletes demonstrate through the Olympic motto 'citius, altius, fortius', new performance records are driven forward by favourable skeletal muscle bioenergetics, cardiorespiratory, and endocrine system adaptations. At a recreational level, regular physical activity is an effective non-pharmacological therapy in the treatment of many endocrine conditions. However, the impact of physical exercise on endocrine function and how best to incorporate exercise therapy into clinical care are not well understood. Beyond the pursuit of an Olympic medal, elite athletes may therefore serve as role models for showcasing how exercise can help in the management of endocrine disorders and improve metabolic dysfunction. This review summarises research evidence for clinicians who wish to understand endocrine changes in athletes who already perform high levels of activity as well as to encourage patients to exercise more safely. Herein, we detail the upper limits of athleticism to showcase the adaptability of human endocrine-metabolic-physiological systems. Then, we describe the growing research base that advocates the importance of understanding maladaptation to physical training and nutrition in males and females; especially the young. Finally, we explore the impact of physical activity in improving some endocrine disorders with guidance on how lessons can be taken from athletes training and incorporated into strategies to move more people more often. This article is protected by copyright. All rights reserved.
    Keywords:  Exercise; athletes; endocrine disorders; endocrinology; energy metabolism; exercise physiology
    DOI:  https://doi.org/10.1111/cen.14683
  19. Nat Commun. 2022 Feb 01. 13(1): 607
    The mouse metallomic landscape of aging and metabolism.
    Jean-David Morel, Lucie Sauzéat, Ludger J E Goeminne, Pooja Jha, Evan Williams, Riekelt H Houtkooper, Ruedi Aebersold, Johan Auwerx, Vincent Balter.
      Organic elements make up 99% of an organism but without the remaining inorganic bioessential elements, termed the metallome, no life could be possible. The metallome is involved in all aspects of life, including charge balance and electrolytic activity, structure and conformation, signaling, acid-base buffering, electron and chemical group transfer, redox catalysis energy storage and biomineralization. Here, we report the evolution with age of the metallome and copper and zinc isotope compositions in five mouse organs. The aging metallome shows a conserved and reproducible fingerprint. By analyzing the metallome in tandem with the phenome, metabolome and proteome, we show networks of interactions that are organ-specific, age-dependent, isotopically-typified and that are associated with a wealth of clinical and molecular traits. We report that the copper isotope composition in liver is age-dependent, extending the existence of aging isotopic clocks beyond bulk organic elements. Furthermore, iron concentration and copper isotope composition relate to predictors of metabolic health, such as body fat percentage and maximum running capacity at the physiological level, and adipogenesis and OXPHOS at the biochemical level. Our results shed light on the metallome as an overlooked omic layer and open perspectives for potentially modulating cellular processes using careful and selective metallome manipulation.
    DOI:  https://doi.org/10.1038/s41467-022-28060-x
  20. Alzheimers Dement. 2021 Dec;17 Suppl 3 e049471
    Frailty and dementia in long-term care: An analysis of the InterRAI data over the past decade.
    Xiaowei Song, Hilary Low, Ronald Kelly, Robert McDermid.
       BACKGROUND: Older adults in long-term care are typically frail with multiple health problems and functional impairments; many have dementias of Alzheimer's disease (AD) or other types. Frailty and dementia have a complex relationship; deterioration in one can make people more susceptible to the other. The association between frailty and dementia in long-term care is not well understood. We conducted this study to investigate 1) how frailty differed by AD and dementia diagnoses in long-term care residents, and 2) whether the relationship between frailty and dementia changes over time.
    METHODS: Data were retrieved from the InterRAI Residential Care assessments conducted in Fraser Health, Canada. Participants aged 65 years and over at the time of admission to one of the 83 long-term care facilities between 2010 and 2019 (number of participants n=25,744; mean age=84.7±7.7 (85-111) years; 63.2% females) were included in the study. Diagnosis of AD (n=4,055) and other dementias (n=11,882) were recorded during the assessment. A frailty index (FI) was calculated for each participant using 36 variables from their first full MDS2.0 assessment. Deficits included diseases, symptoms, functions, nutrition and other health conditions. The FI was presented as the ratio of deficits present over the total number of deficits considered (i.e., 36 here; higher FI indicating more deficits). Group mean differences of the FI were examined using ANOVA. Relations of the FI with AD and dementia diagnoses were examined using multivariate regressions, adjusted for year of assessment and demographics.
    RESULTS: The FI of the individuals increased exponentially with age (r=0.127, p<0.001) and differed significantly among diagnoses (no dementia=0.369±0.137, AD=0.394±0.144, other dementias=0.422±0.144, F=370.15, p<0.001). The 99% limits of the FI ranged 0.686 - 0.736, depending on assessment year. Frailty increased dementia risks: a 1% increase of the FI was associated with 2.7% (95% confidence interval CI=2.4-2.9) higher risk for other dementias and 1.4% (1.1-1.6) for AD, independent of the effects of age, sex, and the year of admission.
    CONCLUSION: Data demonstrate the robust characteristics of the frailty index. The consistent association between frailty and dementia in long-term care over the decade has implications for integrated management strategies to delay frailty and dementia trajectories among at-risk residents.
    DOI:  https://doi.org/10.1002/alz.049471
  21. Nature. 2022 Feb 02.
    Last-resort cancer therapy holds back disease for more than a decade.
    Heidi Ledford.
      
    Keywords:  Cancer; Immunology; Medical research; Synthetic biology
    DOI:  https://doi.org/10.1038/d41586-022-00241-0
  22. BMJ Open. 2022 Jan 31. 12(1): e054492
    What long-term care interventions have been published between 2010 and 2020? Results of a WHO scoping review identifying long-term care interventions for older people around the world.
    Natalia Arias-Casais, Jotheeswaran Amuthavalli Thiyagarajan, Monica Rodrigues Perracini, Eunok Park, Lieve Van den Block, Yuka Sumi, Ritu Sadana, Anshu Banerjee, Zee-A Han.
       OBJECTIVE: The global population is rapidly ageing. To tackle the increasing prevalence of older adults' chronic conditions, loss of intrinsic capacity and functional ability, long-term care interventions are required. The study aim was to identify long-term care interventions reported in scientific literature from 2010 to 2020 and categorise them in relation to WHO's public health framework of healthy ageing.
    DESIGN: Scoping review conducted on PubMed, CINHAL, Cochrane and Google Advanced targeting studies reporting on long-term care interventions for older and frail adults. An internal validated Excel matrix was used for charting.Setting nursing homes, assisted care homes, long-term care facilities, home, residential houses for the elderly and at the community.
    INCLUSION CRITERIA: Studies published in peer-reviewed journals between 1 January 2010 to 1 February 2020 on implemented interventions with outcome measures provided in the settings mentioned above for subjects older than 60 years old in English, Spanish, German, Portuguese or French.
    RESULTS: 305 studies were included. Fifty clustered interventions were identified and organised into four WHO Healthy Ageing domains and 20 subdomains. All interventions delved from high-income settings; no interventions from low-resource settings were identified. The most frequently reported interventions were multimodal exercise (n=68 reports, person-centred assessment and care plan development (n=22), case management for continuum care (n=16), multicomponent interventions (n=15), psychoeducational interventions for caregivers (n=13) and interventions mitigating cognitive decline (n=13).
    CONCLUSION: The identified interventions are diverse overarching multiple settings and areas seeking to prevent, treat and improve loss of functional ability and intrinsic capacity. Interventions from low-resource settings were not identified.
    Keywords:  geriatric medicine; health services administration & management; public health
    DOI:  https://doi.org/10.1136/bmjopen-2021-054492
  23. STAR Protoc. 2022 Mar 18. 3(1): 101113
    A 2D and 3D cell culture protocol to study O-GlcNAc in sphingosine-1-phosphate mediated fibroblast contraction.
    Murielle M Morales, Nichole J Pedowitz, Matthew R Pratt.
      O-linked β-N-acetylglucosamine (O-GlcNAc) is an abundant posttranslational modification involved in a wide range of signaling pathways, but its specific role in regulating biological processes remains unclear. This protocol describes approaches to understand O-GlcNAc's role in fibroblast contraction. Specifically, cellular O-GlcNAc levels are controlled through treatment of fibroblasts with inhibitors in both 2D and 3D cultures. We then describe 2D contraction assay and 3D collagen gel contraction assay to analyze the effect of the modification on sphingosine-1-phosphate signaling for contraction. For complete details on the use and execution of this protocol, please refer to Pedowitz et al. (2021).
    Keywords:  Biophysics; Cell Biology; Cell culture; Cell-based Assays; Microscopy; Molecular/Chemical Probes
    DOI:  https://doi.org/10.1016/j.xpro.2021.101113
  24. Front Cardiovasc Med. 2021 ;8 830024
    Mitochondria, a Missing Link in COVID-19 Heart Failure and Arrest?
    Ralph Ryback, Alfonso Eirin.
      
    Keywords:  ATP; COVID-19; cardiovascular disease; heart failure; mitochondria
    DOI:  https://doi.org/10.3389/fcvm.2021.830024
  25. Appl Neuropsychol Adult. 2022 Feb 02. 1-13
    Are you more impulsive with age? Examining age, marital status, and gender on cognitive ageing.
    Katerine-Ann MacKinnon-Lee, Mark Bahr.
      Understanding non-pathological cognitive aging processes remains a public health goal and research priority. Age-associated cognitive aging is a normal human process, however, individual differences may aid in the mitigation of cognitive aging. Assessing the role of certain protective factors (i.e., age, marital status, and gender) that influence age-related cognitive aging is imperative to slow down the progression of unwarranted cognitive aging. Participants aged over 18 (N = 123; 97 females and 26 males) recruited from Sydney, New South Wales, and Gold Coast, Queensland, completed an online neuropsychological test battery with computer-administered tasks, assessing impulsivity and working memory, which were entered as dependent variables. A 3(Age Group: 18-27 years; 28-61 years; 62+ years) x2(Marital Status: married; single) x2(Gender: male; female) Multivariate Analysis of Covariance (MANCOVA) design was used to examine the relationship between age, marital status, and gender (entered as independent variables) on cognitive aging. Participants' total scores from psychometrically sound measures assessing depressive symptomology, personal wellbeing, resilience, and social network engagement, were entered as covariates. No significant effects were found from the independent variables included in the MANCOVA. A significant covariate effect for resilience and depressive symptomology on impulsivity was found. A multiple regression analysis was performed on the significant covariates, and revealed increased resilience and depressive symptomology to significantly predict greater impulsivity.
    Keywords:  Cognitive aging; cognitive reserve; depressive symptomology; impulsivity; resilience
    DOI:  https://doi.org/10.1080/23279095.2022.2029741
  26. Blood Adv. 2022 Jan 31. pii: bloodadvances.2021005983. [Epub ahead of print]
    Deleterious effect of bone marrow-resident macrophages on hematopoietic stem cells in response to total body irradiation.
    Marion Chalot, Vilma Barroca, Saiyirami Devanand, Françoise Hoffschir, Paul-Henri Roméo, Stephanie G Moreno.
      Bone marrow resident macrophages interact with a population of long-term hematopoietic stem cell (LT-HSC) but their role on LT-HSC properties after stress is not well defined. Here, we show that a 2 Gy total body irradiation (TBI)-mediated death of LT-HSC is associated with increased percentages of LT-HSC with reactive oxygen species (ROS) and of bone marrow resident macrophages producing nitric oxide (NO), resulting in an increased percentage of LT-HSC with endogenous cytotoxic peroxynitrites. Pharmacological or genetic depletion of bone marrow resident macrophages impairs the radio-induced increases in the percentage of both ROS+ LT-HSC and peroxynitrite+ LT-HSC and results in a complete recovery of a functional pool of LT-HSC. Finally, we show that after a 2 Gy-TBI, a specific decrease of NO production by bone marrow resident macrophages improves the LT-HSC recovery, whereas an exogenous NO delivery decreases the LT-HSC compartment. Altogether, these results show that bone marrow resident macrophages are involved in the response of LT-HSC to a 2 Gy-TBI and suggest that regulation of NO production can be used to modulate some deleterious effects of a TBI on LT-HSC.
    DOI:  https://doi.org/10.1182/bloodadvances.2021005983
  27. Nature. 2022 Feb 02.
    How well can Omicron evade immunity from COVID vaccines?
    Sara Reardon.
      
    Keywords:  Epidemiology; Medical research; Public health; SARS-CoV-2; Vaccines
    DOI:  https://doi.org/10.1038/d41586-022-00283-4
  28. Transl Cancer Res. 2020 Sep;9(9): 5743-5759
    Association between diabetes, obesity, aging, and cancer: review of recent literature.
    Judy K Qiang, Lorraine L Lipscombe, Iliana C Lega.
      Rates of obesity and diabetes have risen significantly in recent years and are projected to increase even further in the coming decades. Obesity and diabetes are associated with increased risk of certain tumours, with the strongest relationships demonstrated for colorectal, post-menopausal breast, and endometrial cancer. Another important risk factor for cancer development is aging. Aging is characterized by chronic inflammation and immunosenescence, and accelerated by obesity, which may further stimulate the development of cancer. In this review, we summarize recent literature on the complex interactions between obesity, diabetes, aging, and cancer risk and mortality. We will also provide an overview of both epidemiological as well as pathophysiologic data and their clinical implications. In the context of an aging population and anticipated rise in rates of obesity and diabetes, a better understanding of how these factors interact and impact on cancer risk and prognosis will be important in helping to guide therapeutic interventions.
    Keywords:  Cancer; aging; diabetes mellitus; obesity
    DOI:  https://doi.org/10.21037/tcr.2020.03.14
  29. Nat Cancer. 2021 May;2(5): 481-483
    Epigenetic Achilles' heel of AML.
    Koki Ueda, Ulrich Steidl.
      
    DOI:  https://doi.org/10.1038/s43018-021-00212-w
  30. Nat Commun. 2022 Feb 03. 13(1): 686
    The selection force weakens with age because ageing evolves and not vice versa.
    Stefano Giaimo, Arne Traulsen.
      According to the classic theory of life history evolution, ageing evolves because selection on traits necessarily weakens throughout reproductive life. But this inexorable decline of the selection force with adult age was shown to crucially depend on specific assumptions that are not necessarily fulfilled. Whether ageing still evolves upon their relaxation remains an open problem. Here, we propose a fully dynamical model of life history evolution that does not presuppose any specific pattern the force of selection should follow. The model shows: (i) ageing can stably evolve, but negative ageing cannot; (ii) when ageing is a stable equilibrium, the associated selection force decreases with reproductive age; (iii) non-decreasing selection is either a transient or an unstable phenomenon. Thus, we generalize the classic theory of the evolution of ageing while overturning its logic: the decline of selection with age evolves dynamically, and is not an implicit consequence of certain assumptions.
    DOI:  https://doi.org/10.1038/s41467-022-28254-3
  31. Nat Commun. 2022 Feb 03. 13(1): 651
    Mitochondrial protein import determines lifespan through metabolic reprogramming and de novo serine biosynthesis.
    Eirini Lionaki, Ilias Gkikas, Ioanna Daskalaki, Maria-Konstantina Ioannidi, Maria I Klapa, Nektarios Tavernarakis.
      Sustained mitochondrial fitness relies on coordinated biogenesis and clearance. Both processes are regulated by constant targeting of proteins into the organelle. Thus, mitochondrial protein import sets the pace for mitochondrial abundance and function. However, our understanding of mitochondrial protein translocation as a regulator of longevity remains enigmatic. Here, we targeted the main protein import translocases and assessed their contribution to mitochondrial abundance and organismal physiology. We find that reduction in cellular mitochondrial load through mitochondrial protein import system suppression, referred to as MitoMISS, elicits a distinct longevity paradigm. We show that MitoMISS triggers the mitochondrial unfolded protein response, orchestrating an adaptive reprogramming of metabolism. Glycolysis and de novo serine biosynthesis are causatively linked to longevity, whilst mitochondrial chaperone induction is dispensable for lifespan extension. Our findings extent the pro-longevity role of UPRmt and provide insight, relevant to the metabolic alterations that promote or undermine survival and longevity.
    DOI:  https://doi.org/10.1038/s41467-022-28272-1
  32. Curr Opin HIV AIDS. 2022 Jan 31.
    From surviving to thriving: the current status of the behavioral, social, and psychological issues of aging with HIV.
    Erik L Ruiz, Karah Y Greene, Jerome T Galea, Brandon Brown.
       PURPOSE OF REVIEW: Despite significant advances in knowledge regarding the biological and clinical issues related to aging with HIV, significantly less research has centered on related psychological, behavioral, and social issues, which are increasingly recognized as important for successfully aging with HIV.
    RECENT FINDINGS: Barriers to successful aging include physical challenges from a sociobehavioral perspective, psychosocial challenges, and system-level challenges. In contrast, several resiliencies and interventions that help facilitate healthy aging with HIV are also emerging. Comprehensive interventions to address the physical, mental, and psychosocial needs of older people living with HIV (OPLWH) are necessary.
    CONCLUSION: To promote healthy aging with HIV, we must utilize both clinical and biopsychosocial interventions. The lack of data on the needs of OPLWH is an important barrier to healthy aging in this population.
    DOI:  https://doi.org/10.1097/COH.0000000000000725
  33. Scientifica (Cairo). 2022 ;2022 3619362
    The Effects of Exercise on Aging-Induced Exaggerated Cytokine Responses: An Interdisciplinary Discussion.
    Soontaraporn Huntula, Laddawan Lalert, Chuchard Punsawad.
      Aging is generally known to be associated with dynamic biological changes, physiological dysfunction, and environmental and psychological decline. Several studies have suggested that aging is associated with increased inflammatory cytokines, causing several diseases. However, the effect of exercise on aging has been less delineated, and the relationships between cytokine activation, aging, and exercise also need further study. Here, we discuss some ideas about the effect of exercise on aging-induced exaggerated cytokine responses and discuss the possible roles of the aging-induced exaggerated cytokine response following exercise. Evidence from these findings suggests that exercise is a beneficially applicable model to use in studies on the mechanisms underlying the age-associated gradated cytokine response, and these results may provide guidelines for health professionals with diverse backgrounds.
    DOI:  https://doi.org/10.1155/2022/3619362
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