bims-minfam Biomed News
on Inflammation and metabolism in ageing and cancer
Issue of 2022–01–23
27 papers selected by
Ayesh Seneviratne, University of Toronto
  1. Acute Myeloid Leukemia Stem Cells: Origin, Characteristics, and Clinical Implications.
  2. Immune Aging and How It Works for Inflammation and Fibrosis.
  3. Ageing.
  4. Does the human lifespan have a limit?
  5. Association Between Neutrophil-Lymphocyte Ratio and Frailty: The Chinese Longitudinal Healthy Longevity Survey.
  6. Ageing exacerbates ribosome pausing to disrupt cotranslational proteostasis.
  7. Calorie Restriction for Cancer Prevention and Therapy: Mechanisms, Expectations, and Efficacy.
  8. Canada's public health system is stretched "dangerously thin".
  9. Role of herbal medicines in the management of patients with COVID-19: A systematic review and meta-analysis of randomized controlled trials.
  10. The Danaid Theory of Aging.
  11. To Analyze the Influencing Factors of Senile Coronary Heart Disease Patients Complicated with Frailty Syndrome.
  12. BNT162b2 Covid-19 Vaccine in Children 5 to 11 Years of Age.
  13. NAD supplementation improves mitochondrial performance of cardiolipin mutants.
  14. The Elephant in The Room: AML Relapse Post Allogeneic Hematopoietic Cell Transplantation.
  15. Safe and efficient in vivo hematopoietic stem cell transduction in nonhuman primates using HDAd5/35++ vectors.
  16. Geroscience: the need to address some issues.
  17. Clinician-scientists: how to reverse their declining numbers.
  18. Considerations for assessing frail older adults requesting medical assistance in dying.
  19. Role of Cannabinoids in Inflammation.
  20. Metabolomic Profiles of Mouse Tissues Reveal an Interplay between Aging and Energy Metabolism.
  21. TLR4 downregulation by the RNA-binding protein PUM1 alleviates cellular aging and osteoarthritis.
  22. Low free testosterone is associated with increased mortality in frail surgical patients.
  23. Changing paradigms in the treatment of acute myeloid leukemia in older patients.
  24. Diet-derived small molecules (nutraceuticals) inhibit cellular proliferation by interfering with key oncogenic pathways: an overview of experimental evidence in cancer chemoprevention.
  25. Dapagliflozin reduces uric acid concentration, an independent predictor of adverse outcomes in DAPA-HF.
  26. Association of zinc intake with risk of impaired physical function and frailty among older adults.
  27. The Introduction of Direct Oral Anticoagulants Has Not Resolved Treatment Gaps for Frail Patients With Nonvalvular Atrial Fibrillation.
  1. Stem Cell Rev Rep. 2022 Jan 20.
    Acute Myeloid Leukemia Stem Cells: Origin, Characteristics, and Clinical Implications.
    Nathaniel A Long, Upendarrao Golla, Arati Sharma, David F Claxton.
      The stem cells of acute myeloid leukemia (AML) are the malignancy initiating cells whose survival ultimately drives growth of these lethal diseases. Here we review leukemia stem cell (LSC) biology, particularly as it relates to the very heterogeneous nature of AML and to its high disease relapse rate. Leukemia ontogeny is presented, and the defining functional and phenotypic features of LSCs are explored. Surface and metabolic phenotypes of these cells are described, particularly those that allow distinction from features of normal hematopoietic stem cells (HSCs). Opportunities for use of this information for improving therapy for this challenging group of diseases is highlighted, and we explore the clinical needs which may be addressed by emerging LSC data. Finally, we discuss current gaps in the scientific understanding of LSCs.
    Keywords:  Acute Myeloid Leukemia; Hematopoiesis; Leukemia; Leukemia Stem Cell
    DOI:  https://doi.org/10.1007/s12015-021-10308-6
  2. Front Physiol. 2021 ;12 795508
    Immune Aging and How It Works for Inflammation and Fibrosis.
    Hiroshi Nishiura, Mai Imasaka, Koji Yamanegi, Jiro Fujimoto, Masaki Ohmuraya.
      Almost all mature cells that undergo apoptosis in an age-dependent or an accidental manner are completely recovered in tissue-specific microenvironments without any physiological changes. After peripheral blood leukocytes are released into the local region, fibroblast cells and new blood vessels commonly proliferate during wound healing. Inducible repair tools mainly supplied from blood vessels are cleared by peripheral blood phagocytic macrophages. Finally, hematopoietic stem cell (HSC)-derived precursor cells migrate from bone marrow (BM) to the microenvironment to rebuild damaged tissues (the mature immune system). In contrast to the mature immune system, the effects of aging on HSCs (long-term HSCs) and peripheral blood lymphocytes (long-term PBLs) are not clearly understood in the BM and thymus niches with tissue-specific microenvironments with some physiological changes (the aged BM niche) for incomplete rebuilding of damaged tissues (the aged immune system). In this review, the roles of the aged immune system in both a delay of acute inflammation and the development of chronic inflammation or fibrosis are discussed.
    Keywords:  aging; immune system; inflammation; niche; stem cell
    DOI:  https://doi.org/10.3389/fphys.2021.795508
  3. Nature. 2022 Jan;601(7893): S1
    Ageing.
      
    Keywords:  Ageing; Society
    DOI:  https://doi.org/10.1038/d41586-022-00069-8
  4. Nature. 2022 Jan;601(7893): S2-S4
    Does the human lifespan have a limit?
    Michael Eisenstein.
      
    Keywords:  Ageing; Society
    DOI:  https://doi.org/10.1038/d41586-022-00070-1
  5. Front Med (Lausanne). 2021 ;8 783077
    Association Between Neutrophil-Lymphocyte Ratio and Frailty: The Chinese Longitudinal Healthy Longevity Survey.
    Weihao Xu, Yuanfeng Liang, Zhanyi Lin.
      Background: Inflammation has been reported to play an important role in frailty syndrome. The neutrophil-lymphocyte ratio (NLR) has recently emerged as an informative marker for systematic inflammation. However, few studies have examined the association between NLR and frailty. This study aims to examine the association between NLR and frailty in community-dwelling older adults. Methods: Community-dwelling older adults aged ≥ 65 years in the 2011 (n = 2,354) and 2014 (n = 2,458) waves of the Chinese Longitudinal Healthy Longevity Survey (CLHLS) were included. Frailty status was determined using the 38-item frailty index (FI) and categorized into "robust" (FI ≤ 0.1), "pre-frail" (0.1 < FI ≤ 0.21), or "frail" (FI > 0.21). NLR was calculated using a derived formula: NLR = (white blood cell-lymphocyte)/lymphocyte. Results: A total of 3,267 participants were finally included. In cross-sectional analyses, participants with higher NLR levels had increased likelihood of frailty [the 3rd quartile: adjusted odds ratio (OR) = 1.29; 95% confidence interval (CI): 1.02-1.63; the 4th quartile: OR = 1.59; 95% CI: 1.23-2.02) compared with those in the 1st quartile group. During the 3-year follow-up, 164 of the 1,206 participants, robust or pre-frail at baseline, developed frailty, and 197 of the 562 participants, robust at baseline, developed pre-frailty or frailty. Among the robust and pre-frail participants in 2011, after multivariate adjustment, those in the 4th quartile group had a higher frailty incidence than those in the 1st quartile group (OR = 2.06; 95% CI: 1.18-3.59). Among the robust participants in 2011, those in the 4th quartile group also had a higher pre-frailty or frailty incidence than those in the 1st quartile group (OR = 1.95; 95% CI: 1.07-3.55). Conclusion: Among community-dwelling older adults, higher NLR levels were found to be associated with increased odds of prevalent and incident frailty.
    Keywords:  frailty; frailty index; inflammatory marker; neutrophil-lymphocyte ratio; old age
    DOI:  https://doi.org/10.3389/fmed.2021.783077
  6. Nature. 2022 Jan 19.
    Ageing exacerbates ribosome pausing to disrupt cotranslational proteostasis.
    Kevin C Stein, Fabián Morales-Polanco, Joris van der Lienden, T Kelly Rainbolt, Judith Frydman.
      Ageing is accompanied by a decline in cellular proteostasis, which underlies many age-related protein misfolding diseases1,2. Yet, how ageing impairs proteostasis remains unclear. As nascent polypeptides represent a substantial burden on the proteostasis network3, we hypothesized that altered translational efficiency during ageing could help to drive the collapse of proteostasis. Here we show that ageing alters the kinetics of translation elongation in both Caenorhabditis elegans and Saccharomyces cerevisiae. Ribosome pausing was exacerbated at specific positions in aged yeast and worms, including polybasic stretches, leading to increased ribosome collisions known to trigger ribosome-associated quality control (RQC)4-6. Notably, aged yeast cells exhibited impaired clearance and increased aggregation of RQC substrates, indicating that ageing overwhelms this pathway. Indeed, long-lived yeast mutants reduced age-dependent ribosome pausing, and extended lifespan correlated with greater flux through the RQC pathway. Further linking altered translation to proteostasis collapse, we found that nascent polypeptides exhibiting age-dependent ribosome pausing in C. elegans were strongly enriched among age-dependent protein aggregates. Notably, ageing increased the pausing and aggregation of many components of proteostasis, which could initiate a cycle of proteostasis collapse. We propose that increased ribosome pausing, leading to RQC overload and nascent polypeptide aggregation, critically contributes to proteostasis impairment and systemic decline during ageing.
    DOI:  https://doi.org/10.1038/s41586-021-04295-4
  7. J Cancer Prev. 2021 Dec 30. 26(4): 224-236
    Calorie Restriction for Cancer Prevention and Therapy: Mechanisms, Expectations, and Efficacy.
    Chiara Vidoni, Alessandra Ferraresi, Andrea Esposito, Chinmay Maheshwari, Danny N Dhanasekaran, Vincenzo Mollace, Ciro Isidoro.
      Cancer is one of the most frequently diagnosed diseases, and despite the continuous efforts in searching for new and more effective treatments, its morbidity and mortality remain a significant health problem worldwide. Calorie restriction, a dietary manipulation that consists in a reduction of the calorie intake, is gaining attention as a potential adjuvant intervention for preventing and/or fighting cancer. Several forms of energy reduction intake, which includes caloric restriction tout-court, dietary restrictions, and intermittent fasting, are being explored for their ability to prevent or slow down cancer progression. Additionally, another anti-cancer approach being under investigation relies on the use of nutraceuticals known as "Caloric Restriction Mimetics" that can provide caloric restriction-mediated benefits without subjecting the patients to a strict diet. Preclinical in vitro and in vivo studies consistently show that diet modifiers reducing the calorie have impact on tumor microenvironment and cancer metabolism, resulting in reduced growth and progression of cancer. Preliminary clinical studies show that patients subjected to a reduced nutrient/energy intake experience improved outcomes from chemo- and radiotherapy while better tolerating the side effects. Here, we review the state of the art on the therapeutic potential of calorie restriction and of caloric restriction mimetics in preventing or retarding tumor development by modulating a subset of cellular processes. The most recent clinical progresses with caloric restriction mimetics in the clinical practice are also discussed.
    Keywords:  Caloric restriction mimetics; Drug therapy; Ketogenic diet; Tumor microenvironment; Warburg effect
    DOI:  https://doi.org/10.15430/JCP.2021.26.4.224
  8. CMAJ. 2022 Jan 17. 194(2): E57
    Canada's public health system is stretched "dangerously thin".
    Diana Duong, Lauren Vogel.
      
    DOI:  https://doi.org/10.1503/cmaj.1095983
  9. J Tradit Complement Med. 2022 Jan 11.
    Role of herbal medicines in the management of patients with COVID-19: A systematic review and meta-analysis of randomized controlled trials.
    Ansul Kumar, Arpita Rai, Mohd Saif Khan, Amit Kumar, Zeya Ul Haque, Mohammad Fazil, Gulam Rabbani.
       Background and aim: The management of the worldwide spreading COVID-19 consists of amelioration of its symptoms but no cure is yet available. Herbal medicines supplemented with the Western medicine have been applied for COVID-19 treatment in India, China, Iran, and other countries. This systematic review and meta-analysis of RCTs evaluates the effect and safety of herbal intervention in the management of COVID-19.
    Experimental procedure: RCTs from databases like PubMed, Cochrane Library, ScienceDirect, Google Scholar, Science Direct, CTRI, AYUSH Research Portal, India, were reviewed and the data were extracted for study sample demographics, intervention details, clinical effect, inflammatory markers and safety monitoring. Outcomes were expressed as Risk-ratio (RR) with 95% CI for dichotomous data, and Mean-Difference (MD) with 95% CI for continuous data.
    Result and conclusion: From the 32 eligible studies, a total of 3177 COVID-19 patients were included in the review. Herbal intervention as an adjuvant to Western medicine causes significantly higher improvement compared to Western medicine alone [Fever (RR = 1.09 CI 1.03, 1.15), Cough (Risk-Ratio = 1.22 CI 1.08, 1.37), Fatigue (Risk-Ratio = 1.27 CI 1.11, 1.44), Chest CT Improvement (Risk-Ratio = 1.15 CI 1.08, 1.23)]. The laboratory parameters were also better in the herbal medicine group compared to standard care group only WBC (MD = 0.36 CI 0.16, 0.55), Lymphocyte percentage (MD = 5.48 CI 3.05, 7.92), Absolute lymphocyte count (MD = 0.23 CI 0.07, 0.39), CRP (MD = -5.66 CI -7.96, -3.37). However, duration of hospital stays (MD = -1.82 CI -3.84, 0.21); IL-6 (MD = -3.67 CI -8.76, 1.43), ESR Level (MD = -10.38 CI -25.96, 5.21) were statistically insignificant. No significant adverse events for herbal medications were noted in the included RCTs, during the time of the studies. (n = 665, RR 0.93; 95% CI 0.76, 1.14).
    Keywords:  COVID-19; Herbal medicine; Meta-analysis; Systematic review
    DOI:  https://doi.org/10.1016/j.jtcme.2022.01.002
  10. Front Cell Dev Biol. 2021 ;9 671208
    The Danaid Theory of Aging.
    Maarten J Wensink, Alan A Cohen.
      The classical evolutionary theories of aging suggest that aging evolves due to insufficient selective pressure against it. In these theories, declining selection pressure with age leads to aging through genes or resource allocations, implying that aging could potentially be stalled were genes, resource allocation, or selection pressure somewhat different. While these classical evolutionary theories are undeniably part of a description of the evolution of aging, they do not explain the diversity of aging patterns, and they do not constitute the only possible evolutionary explanation. Without denying selection pressure a role in the evolution of aging, we argue that the origin and diversity of aging should also be sought in the nature and evolution of organisms that are, from their very physiological make up, unmaintainable. Drawing on advances in developmental biology, genetics, biochemistry, and complex systems theory since the classical theories emerged, we propose a fresh evolutionary-mechanistic theory of aging, the Danaid theory. We argue that, in complex forms of life like humans, various restrictions on maintenance and repair may be inherent, and we show how such restrictions are laid out during development. We further argue that there is systematic variation in these constraints across taxa, and that this is a crucial factor determining variation in aging and lifespan across the tree of life. Accordingly, the core challenge for the field going forward is to map and understand the mosaic of constraints, trade-offs, chance events, and selective pressures that shape aging in diverse ways across diverse taxa.
    Keywords:  aging; constraint; development; evolution; maintenance; senescence; theory
    DOI:  https://doi.org/10.3389/fcell.2021.671208
  11. J Healthc Eng. 2022 ;2022 7619438
    To Analyze the Influencing Factors of Senile Coronary Heart Disease Patients Complicated with Frailty Syndrome.
    Tian Qin, Wang Sheng, Guoheng Hu.
      To analyze the influencing factors of senile coronary heart disease patients complicated with frailty syndrome. A total of 80 elderly patients with coronary heart disease admitted to our hospital from March 2020 to March 2021 were selected as the research subjects. The Fried Frailty Symptom Scale was used to evaluate whether the 80 patients were complicated with frailty syndrome. According to the evaluation results, the patients were divided into a nonfrailty syndrome group (52 cases in total) and frailty syndrome group (28 cases in total). Clinical data of two groups of patients were collected, and multivariate logistic regression was used to analyze the influencing factors of senile coronary heart disease patients complicated with frailty syndrome. Among 80 patients, the incidence of frailty syndrome was 35.00% (28/80), including 18 cases in early frailty and 10 cases in frailty stage. Univariate analysis showed that age, body mass (BMI), diabetes mellitus, congestive heart failure, chronic renal insufficiency, chronic obstructive pulmonary disease (COPD), tumor, high uric acid hematic disease, arrhythmia, interleukin-6 (IL-6), c-reactive protein (CRP), fibrinogen (FIB), brain natriuretic peptide (BNP), uric acid (UA), serum creatinine (Scr), serum protein (ALB), white blood cell count (WBC), and neutrophil count were the possible risk factors for senile coronary heart disease complicated with frailty syndrome (P < 0.05). Multivariate logistic regression analysis showed that combined COPD, combined tumor, IL-6, BNP, UA, SCR, ALB, and neutrophil count were independent risk factors for senile CHD complicated with frailty syndrome (P < 0.05). Combined with COPD, combined with tumor, IL-6, BNP, UA, SCR, ALB, and neutron cell count are the influencing factors for senile coronary heart disease patients complicated with frailty syndrome. These factors can be used as the basis for the diagnosis of frailty syndrome and guide the clinical development of targeted diagnosis and treatment plan.
    DOI:  https://doi.org/10.1155/2022/7619438
  12. N Engl J Med. 2022 Jan 19. pii: 10.1056/NEJMc2118775#sa2. [Epub ahead of print]386(6):
    BNT162b2 Covid-19 Vaccine in Children 5 to 11 Years of Age.
    Yishai Mintzker.
      
    DOI:  https://doi.org/10.1056/NEJMc2118775
  13. Biochim Biophys Acta Mol Cell Biol Lipids. 2022 Jan 17. pii: S1388-1981(21)00222-5. [Epub ahead of print] 159094
    NAD supplementation improves mitochondrial performance of cardiolipin mutants.
    Jiajia Ji, Deena Damschroder, Denise Bessert, Pablo Lazcano, Robert Wessells, Christian A Reynolds, Miriam L Greenberg.
      Cardiolipin (CL) deficiency causes mitochondrial dysfunction and aberrant metabolism that are associated in humans with the severe disease Barth syndrome (BTHS). Several metabolic abnormalities are observed in BTHS patients and model systems, including decreased oxidative phosphorylation, reduced tricarboxylic acid (TCA) cycle flux, and accumulated lactate and D-β-hydroxybutyrate, which strongly suggests that nicotinamide adenine dinucleotide (NAD) redox metabolism may be altered in CL-deficient cells. In this study, we identified abnormal NAD+ metabolism in multiple BTHS model systems and demonstrate that supplementation of NAD+ precursors such as nicotinamide mononucleotide (NMN) improves mitochondrial function. Improved mitochondrial function in the Drosophila model was associated with restored exercise endurance, which suggests a potential therapeutic benefit of NAD+ precursor supplementation in the management of BTHS patients.
    Keywords:  Barth syndrome; Cardiolipin deficiency; Mitochondrial function; NAD(+) precursors; NAD(+) redox; Nicotinamide mononucleotide
    DOI:  https://doi.org/10.1016/j.bbalip.2021.159094
  14. Front Oncol. 2021 ;11 793274
    The Elephant in The Room: AML Relapse Post Allogeneic Hematopoietic Cell Transplantation.
    Iman Abou Dalle, Ali Atoui, Ali Bazarbachi.
      Relapsed acute myeloid leukemia (AML) following allogeneic hematopoietic cell transplantation (allo-HCT) is an unfavorable event associated with a poor prognosis, particularly for patients with early relapses. It usually arises from resistant leukemic blasts that escaped both preparative chemotherapy regimen and the graft-versus-leukemia (GVL) effect. Independent from the choice of salvage treatment, only minority of patients can achieve durable remissions. In recent years, better understanding of the disease relapse biology post allo-HCT allowed the application of newer strategies that could induce higher rates of remission, and potential longer survival. Those strategies aim at optimizing drugs that have a direct anti-leukemia activity by targeting different oncogenic mutations, metabolism pathways or surface antigens, and concurrently enhancing the immune microenvironment to promote GVL effect. This review discusses the current treatment landscape of AML relapse post allo-HCT.
    Keywords:   immunotherapy; AML; Graft versus leukaemia (GVL); allotransplant; relapse
    DOI:  https://doi.org/10.3389/fonc.2021.793274
  15. Mol Ther Methods Clin Dev. 2022 Mar 10. 24 127-141
    Safe and efficient in vivo hematopoietic stem cell transduction in nonhuman primates using HDAd5/35++ vectors.
    Chang Li, Hongjie Wang, Sucheol Gil, Audrey Germond, Connie Fountain, Audrey Baldessari, Jiho Kim, Zhinan Liu, Aphrodite Georgakopoulou, Stefan Radtke, Tamás Raskó, Amit Pande, Christina Chiang, Eli Chin, Evangelia Yannaki, Zsuzsanna Izsvák, Thalia Papayannopoulou, Hans-Peter Kiem, André Lieber.
      We tested a new in vivo hematopoietic stem cell (HSC) transduction/selection approach in rhesus macaques using HSC-tropic, integrating, helper-dependent adenovirus vectors (HDAd5/35++) designed for the expression of human γ-globin in red blood cells (RBCs) to treat hemoglobinopathies. We show that HDAd5/35++ vectors preferentially transduce HSCs in vivo after intravenous injection into granulocyte colony-stimulating factor (G-CSF)/AMD3100-mobilized animals and that transduced cells return to the bone marrow and spleen. The approach was well tolerated, and the activation of proinflammatory cytokines that are usually associated with intravenous adenovirus vector injection was successfully blunted by pre-treatment with dexamethasone in combination with interleukin (IL)-1 and IL-6 receptor blockers. Using our MGMTP140K-based in vivo selection approach, γ-globin+ RBCs increased in all animals with levels up to 90%. After selection, the percentage of γ-globin+ RBCs declined, most likely due to an immune response against human transgene products. Our biodistribution data indicate that γ-globin+ RBCs in the periphery were mostly derived from mobilized HSCs that homed to the spleen. Integration site analysis revealed a polyclonal pattern and no genotoxicity related to transgene integrations. This is the first proof-of-concept study in nonhuman primates to show that in vivo HSC gene therapy could be feasible in humans without the need for high-dose chemotherapy conditioning and HSC transplantation.
    Keywords:  adenovirus vector; gamma globin; hematopoietic stem cells; hemoglobinopathies; in vivo; nonhuman primates
    DOI:  https://doi.org/10.1016/j.omtm.2021.12.003
  16. Biogerontology. 2022 Jan 20.
    Geroscience: the need to address some issues.
    Eric Le Bourg.
      The geroscience field hypothesises that it could be possible to delay all age-related diseases by delaying the ageing process itself, and not by curing each age-related disease individually. While this perspective is attracting, some issues provisionally prohibit to fully adhere to it, such as the risk for some over-enthusiasm or scientism and the tendency to accept that results observed in animal models can be easily translated in human beings. Particularly, it is not clear whether geroscience plans to delay or suppress ageing, or if healthspan could become very close to lifespan. This article lists some of these issues, in the hope that supporters of geroscience will grasp them to allow a full development of the field, and argues that geroscience should avoid reductionist approaches not taking into account social and behavioural complex aspects of human ageing.
    Keywords:  Geroscience; Healthspan; Lifespan
    DOI:  https://doi.org/10.1007/s10522-022-09951-4
  17. Nature. 2022 Jan;601(7893): 318
    Clinician-scientists: how to reverse their declining numbers.
    Farah R W Kools, Berent Prakken.
      
    Keywords:  Careers; Medical research; Research management
    DOI:  https://doi.org/10.1038/d41586-022-00095-6
  18. CMAJ. 2022 Jan 17. 194(2): E51-E53
    Considerations for assessing frail older adults requesting medical assistance in dying.
    Sarah Engelhart, Nathan M Stall, Kieran L Quinn.
      
    DOI:  https://doi.org/10.1503/cmaj.210729
  19. Molecules. 2022 Jan 12. pii: 478. [Epub ahead of print]27(2):
    Role of Cannabinoids in Inflammation.
    Eric J Downer.
      This Special Issue brings an update on some of the advances in research in the cannabinoid field, with focus on the impact of cannabinoids on inflammation [...].
    DOI:  https://doi.org/10.3390/molecules27020478
  20. Metabolites. 2021 Dec 26. pii: 17. [Epub ahead of print]12(1):
    Metabolomic Profiles of Mouse Tissues Reveal an Interplay between Aging and Energy Metabolism.
    Qishun Zhou, Jakob Kerbl-Knapp, Fangrong Zhang, Melanie Korbelius, Katharina Barbara Kuentzel, Nemanja Vujić, Alena Akhmetshina, Gerd Hörl, Margret Paar, Ernst Steyrer, Dagmar Kratky, Tobias Madl.
      Energy metabolism, including alterations in energy intake and expenditure, is closely related to aging and longevity. Metabolomics studies have recently unraveled changes in metabolite composition in plasma and tissues during aging and have provided critical information to elucidate the molecular basis of the aging process. However, the metabolic changes in tissues responsible for food intake and lipid storage have remained unexplored. In this study, we aimed to investigate aging-related metabolic alterations in these tissues. To fill this gap, we employed NMR-based metabolomics in several tissues, including different parts of the intestine (duodenum, jejunum, ileum) and brown/white adipose tissues (BAT, WAT), of young (9-10 weeks) and old (96-104 weeks) wild-type (mixed genetic background of 129/J and C57BL/6) mice. We, further, included plasma and skeletal muscle of the same mice to verify previous results. Strikingly, we found that duodenum, jejunum, ileum, and WAT do not metabolically age. In contrast, plasma, skeletal muscle, and BAT show a strong metabolic aging phenotype. Overall, we provide first insights into the metabolic changes of tissues essential for nutrient uptake and lipid storage and have identified biomarkers for metabolites that could be further explored, to study the molecular mechanisms of aging.
    Keywords:  NMR spectroscopy; aging; energy metabolism; fat; intestine; metabolomics; mice
    DOI:  https://doi.org/10.3390/metabo12010017
  21. Cell Death Differ. 2022 Jan 16.
    TLR4 downregulation by the RNA-binding protein PUM1 alleviates cellular aging and osteoarthritis.
    Dong Suk Yoon, Kyoung-Mi Lee, Yoorim Choi, Eun Ae Ko, Na-Hyun Lee, Sehee Cho, Kwang Hwan Park, Jung-Hwan Lee, Hae-Won Kim, Jin Woo Lee.
      Dysfunction of mRNA or RNA-binding proteins (RBPs) causes cellular aging and age-related degenerative diseases; however, information regarding the mechanism through which RBP-mediated posttranscriptional regulation affects cellular aging and related disease processes is limited. In this study, PUM1 was found to be associated with the self-renewal capacity and aging process of human mesenchymal stem cells (MSC). PUM1 interacted with the 3'-untranslated region of Toll-like receptor 4 (TLR4) to suppress TLR4 mRNA translation and regulate the activity of nuclear factor-κB (NF-κB), a master regulator of the aging process in MSCs. PUM1 overexpression protected MSCs against H2O2-induced cellular senescence by suppressing TLR4-mediated NF-κB activity. TLR4-mediated NF-κB activation is a key regulator in osteoarthritis (OA) pathogenesis. PUM1 overexpression enhanced the chondrogenic potential of MSCs even under the influence of inflammation-inducing factors, such as lipopolysaccharide (LPS) or interleukin-1β (IL-1β), whereas the chondrogenic potential was reduced following the PUM1 knockdown-mediated TLR4 activation. PUM1 levels decreased under inflammatory conditions in vitro and during OA progression in human and mouse disease models. PUM1 knockdown in human chondrocytes promoted chondrogenic phenotype loss, whereas PUM1 overexpression protected the cells from inflammation-mediated disruption of the chondrogenic phenotype. Gene therapy using a lentiviral vector encoding mouse PUM1 showed promise in preserving articular cartilage integrity in OA mouse models. In conclusion, PUM1 is a novel suppressor of MSC aging, and the PUM1-TLR4 regulatory axis represents a potential therapeutic target for OA.
    DOI:  https://doi.org/10.1038/s41418-021-00925-6
  22. Surg Open Sci. 2022 Jan;7 36-41
    Low free testosterone is associated with increased mortality in frail surgical patients.
    Fangyi Lin, Gordon Hong, Frances Kwon, Farha Pirani, Salima Makhani, Mark Henry, Ian Cooke, Reza Nabavizadeh, Eric Midenberg, Akanksha Mehta, Chad Ritenour, Viraj A Master, Kenneth Ogan.
       Background: Preoperative frailty has been associated with adverse postoperative outcomes. Additionally, low testosterone has been associated with physical frailty and cognitive decline. However, the impact of simultaneous frailty and low testosterone on surgical outcomes is understudied.
    Methods: Preoperative frailty status and testosterone levels were obtained in patients undergoing a diverse range of surgical procedures. Preoperative frailty was evaluated independently and in combination with testosterone through the creation of composite risk groups. Relationships between preoperative frailty and composite risk groups with overall survival were determined using Kaplan-Meier and logistic regression analyses. Bivariate analysis was used to determine the associations between frailty and testosterone status on postoperative complications, length of hospital stay, and readmission rates.
    Results: Median age of the cohort was 63 years, and the median follow-up time was 105 weeks. Thirty-one patients (23%) were frail, and 36 (27%) had low free testosterone. Bivariate analysis demonstrated a statistically significant relationship between preoperative frailty and overall survival (P = .044). In multivariate analysis, coexisting frailty and low free testosterone were significantly associated with decreased overall survival (hazard ratio 4.93, 95% confidence interval, 1.68-14.46, P = .004).
    Conclusion: We observed preoperative frailty, both independently and in combination with low free testosterone levels, to be significantly associated with decreased overall survival across various surgical procedures. Personalizing the surgical risk assessment through the incorporation of preoperative frailty and testosterone status may serve to improve the prognostication of patients undergoing major surgery.
    Keywords:  ASA, American Society of Anesthesiologists; BMI, body mass index; CCI, Charlson Comorbidity Index; CI, confidence interval; ECOG, Eastern COoperative Oncology Group; HR, hazard ratio; IQR, interquartile range; OS, overall survival; T, testosterone; eGFR, estimated Glomerular Filtration Rate
    DOI:  https://doi.org/10.1016/j.sopen.2021.11.002
  23. Clin Adv Hematol Oncol. 2022 Jan;20(1): 37-46
    Changing paradigms in the treatment of acute myeloid leukemia in older patients.
    Alexandre Bazinet, Tapan M Kadia.
      Standard therapy for acute myeloid leukemia (AML) has long consisted of intensive chemotherapy followed by allogeneic hematopoietic stem cell transplant. Older individuals (≥60 years), who constitute the majority of patients with AML, may not always benefit from such intensive approaches owing to increasing frailty, comorbidities, and a higher incidence of adverse-risk disease features. Recent years have seen major advances in the development of effective low-intensity therapies for AML. Low-intensity induction regimens based on hypomethylating agents, venetoclax, and nucleoside analogues are highly effective and safe. A greater emphasis is being placed on the importance of an accurate genetic classification of AML to identify patients who may benefit from novel targeted therapies, such as FLT3 and IDH inhibitors. Genomic classification also highlights a group of patients with high-risk disease (TP53-mutated), for whom improved treatments are urgently needed. Finally, given that relapse is the major cause of treatment failure in elderly patients with AML, innovative maintenance strategies incorporating targeted therapy are being investigated to delay or prevent relapse. In this article, we provide an updated review of the treatment of AML in older patients.
  24. Biol Futur. 2022 Jan 17.
    Diet-derived small molecules (nutraceuticals) inhibit cellular proliferation by interfering with key oncogenic pathways: an overview of experimental evidence in cancer chemoprevention.
    Mohammad Fahad Ullah, Aamir Ahmad, Showket H Bhat, Faisel M Abuduhier, Syed Khalid Mustafa, Shazia Usmani.
      Discouraging statistics of cancer disease has projected an increase in the global cancer burden from 19.3 to 28.4 million incidences annually within the next two decades. Currently, there has been a revival of interest in nutraceuticals with evidence of pharmacological properties against human diseases including cancer. Diet is an integral part of lifestyle, and it has been proposed that an estimated one-third of human cancers can be prevented through appropriate lifestyle modification including dietary habits; hence, it is considered significant to explore the pharmacological benefits of these agents, which are easily accessible and have higher safety index. Accordingly, an impressive embodiment of evidence supports the concept that the dietary factors are critical modulators to prevent, retard, block, or reverse carcinogenesis. Such an action reflects the ability of these molecules to interfere with multitude of pathways to subdue and neutralize several oncogenic factors and thereby keep a restraint on neoplastic transformations. This review provides a series of experimental evidence based on the current literature to highlight the translational potential of nutraceuticals for the prevention of the disease through consumption of enriched diets and its efficacious management by means of novel interventions. Specifically, this review provides the current understanding of the chemopreventive pharmacology of nutraceuticals such as cucurbitacins, morin, fisetin, curcumin, luteolin and garcinol toward their potential as anticancer agents.
    Keywords:  Apoptosis; Cancer; Chemoprevention; Nutraceuticals; Signaling pathways
    DOI:  https://doi.org/10.1007/s42977-022-00110-x
  25. Eur J Heart Fail. 2022 Jan 22.
    Dapagliflozin reduces uric acid concentration, an independent predictor of adverse outcomes in DAPA-HF.
    Kirsty McDowell, Paul Welsh, Kieran F Docherty, David A Morrow, Pardeep S Jhund, Rudolf A De Boer, Eileen O'Meara, Silvio E Inzucchi, Lars Køber, Mikhail N Kosiborod, Felipe A Martinez, Piotr Ponikowski, Ann Hammarstedt, Anna Maria Langkilde, Mikaela Sjöstrand, Daniel Lindholm, Scott D Solomon, Naveed Sattar, Marc S Sabatine, John J V McMurray.
       BACKGROUND: Blood uric acid (UA) levels are frequently elevated in patients with HFrEF, may lead to gout and are associated with worse outcomes. Reduction in UA is desirable in HFrEF and sodium-glucose cotransporter 2 (SGLT2) inhibitors may have this effect.
    OBJECTIVES: To examine the association between UA and outcomes, the effect of dapagliflozin according to baseline UA level, and the effect of dapagliflozin on UA in patients with HFrEF in the DAPA-HF trial.
    METHODS AND RESULTS: The association between UA and the primary composite outcome of cardiovascular death or worsening HF, its components, and all-cause mortality was examined using Cox regression analyses among 3119 patients using tertiles of UA, after adjustment for other prognostic variables. Change in UA from baseline over 12 months was also evaluated. Patients in tertile 3 (UA ≥6.8 mg/dL) versus tertile 1 (<5.4 mg/dL) were younger (66.3 ± 10.8 vs 68 ± 10.2 years), more often male (83.1% vs 71.5%), had lower eGFR (58.2 ± 17.4 vs 70.6 ± 18.7 mL/min/1.73m2 ), and more often treated with diuretics. Higher UA was associated with a greater risk of the primary outcome (adjusted HR tertile 3 vs. tertile 1 = 1.32 [95%CI 1.06, 1.66; P = 0.01). The risk of HF hospitalization and CV death increased by 7% and 6% respectively per 1 mg/dL unit increase of UA. (P = 0.04, 0.07) Spline analysis revealed a linear increase in risk above a cut off UA value of 7.09 mg/dL. Compared with placebo, dapagliflozin reduced UA by 0.84 mg/dL (95% CI -0.93, -0.74) over 12 months (P < 0.001). Dapagliflozin improved outcomes, irrespective of baseline UA concentration.
    CONCLUSION: UA remains an independent predictor of worse outcomes in a well-treated contemporary HFrEF population. Compared with placebo, dapagliflozin reduced UA and improved outcomes irrespective of UA concentration.
    Keywords:  Heart failure; SGLT2; diabetes; mortality; uric acid
    DOI:  https://doi.org/10.1002/ejhf.2433
  26. J Gerontol A Biol Sci Med Sci. 2022 Jan 16. pii: glac014. [Epub ahead of print]
    Association of zinc intake with risk of impaired physical function and frailty among older adults.
    Veronica Vega-Cabello, Francisco Félix Caballero, Alberto Lana, Lucia Arias-Fernandez, José R Banegas, Fernando Rodriguez-Artalejo, Esther Lopez-Garcia, Ellen A Struijk.
       BACKGROUND: Zinc could be a target nutrient in the prevention of physical impairment and frailty in older adults due to its anti-inflammatory/antioxidant properties. However, prospective studies evaluating this inquiry are scarce. Thus, we aimed to assess the association between zinc intake and impaired lower-extremity function (ILEF) and frailty among community-dwelling older adults.
    METHODS: We examined 2,963 adults aged ≥60 years from the Seniors-ENRICA cohort. At baseline (2008-2010) and subsequent follow-up (2012), zinc intake (mg/d) was estimated with a validated computerized face-to-face diet history and adjusted for total energy intake. From 2012 to 2017, the occurrence of ILEF was ascertained with the Short Physical Performance Battery, and of frailty according to the Fried phenotype criteria. Analyses were conducted using Cox proportional hazard models adjusted for relevant confounders, including lifestyle, comorbidity, and dietary factors.
    RESULTS: During follow-up, we identified 515 incident cases of ILEF and 241 of frailty. Compared to participants in the lowest tertile of zinc intake (3.99-8.36 mg/d), those in the highest tertile (9.51-21.2 mg/d) had a lower risk of ILEF [fully-adjusted hazard ratio (95% confidence interval): 0.75 (0.58-0.97); p for trend: 0.03] and of frailty [0.63 (0.44-0.92); p for trend: 0.02]. No differences in the association were seen by strata of socio-demographic and lifestyle factors.
    CONCLUSIONS: Higher zinc intake was prospectively associated with a lower risk of ILEF and frailty among older adults, suggesting that adequate zinc intake, that can be achieved through a healthy diet, may help preserve physical function and reduce the progression to frailty.
    Keywords:  Cohort study; Frailty; Physical impairment; Short Physical Performance Battery; Zinc intake
    DOI:  https://doi.org/10.1093/gerona/glac014
  27. Can J Cardiol. 2022 Jan;pii: S0828-282X(21)00742-X. [Epub ahead of print]38(1): 77-84
    The Introduction of Direct Oral Anticoagulants Has Not Resolved Treatment Gaps for Frail Patients With Nonvalvular Atrial Fibrillation.
    Michela Orlandi, Douglas C Dover, Roopinder K Sandhu, Nathaniel M Hawkins, Padma Kaul, Finlay A McAlister.
       BACKGROUND: The extent to which the introduction of direct oral anticoagulants (DOACs) influenced treatment patterns in frail and nonfrail patients with nonvalvular atrial fibrillation (NVAF) is unclear.
    METHODS: This was a retrospective cohort study of all Albertans 20 years or older who were discharged from an emergency department or hospital with a new diagnosis of NVAF between April 1, 2009, and March 31, 2019. The Hospital Frailty Risk Score was used to define frailty and the CHA2DS2-VASc and CHADS-65 scores were used to identify if anticoagulation was indicated.
    RESULTS: Among 75,796 patients (median age, 75 years; 45% female) with a new diagnosis of NVAF, 17,143 (22.6%) were frail. Although guideline criteria for anticoagulation were more commonly met by frail patients than nonfrail patients (92.1% vs 74.2%, for CHA2DS2-VASc, and 96.8% vs 85.8% for CHADS-65; both P < 0.0001), frail patients were less likely to receive any anticoagulant, even after those with contraindications to anticoagulation were excluded (adjusted odds ratio, 0.61; 95% confidence interval, 0.58-0.64). After DOACs became available, anticoagulant prescribing for patients with guideline indications increased more in nonfrail patients (from 42.4% to 68.2%) than in frail patients (from 29.0% to 52.2%) and frail patients were less likely to receive a DOAC than warfarin (adjusted odds ratio, 0.66; 95% confidence interval, 0.54-0.81).
    CONCLUSIONS: Although they stand to potentially derive greater benefits from anticoagulation, frail patients were less likely to receive an anticoagulant and, if anticoagulated, they were more likely to receive warfarin than a DOAC. The introduction of DOACs has increased anticoagulation rates but not resolved treatment gaps for frail patients with NVAF.
    DOI:  https://doi.org/10.1016/j.cjca.2021.09.021
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