bims-minfam Biomed News
on Inflammation and metabolism in ageing and cancer
Issue of 2021‒04‒04
thirty-one papers selected by
Ayesh Seneviratne
University of Toronto
  1. Lipid Metabolism and Ferroptosis.
  2. Stem Cell Metabolism and Diet.
  3. Lifelong restriction of dietary branched-chain amino acids has sex-specific benefits for frailty and lifespan in mice.
  4. Changes in the National Cancer Institute's R01 workforce: growth, aging, retention, and policy implications.
  5. The DASH Diet and Cardiometabolic Health and Chronic Kidney Disease: A Narrative Review of the Evidence in East Asian Countries.
  6. Diabetes, inflammation, and the adiponectin paradox: therapeutic targets in SARS-CoV-2.
  7. Therapeutic Potential for Regulation of the Nuclear Factor Kappa-B Transcription Factor p65 to Prevent Cellular Senescence and Activation of Pro-Inflammatory in Mesenchymal Stem Cells.
  8. A decrease in NAD+ contributes to the loss of osteoprogenitors and bone mass with aging.
  9. Selenium supplementation inhibits IGF-1 signaling and confers methionine restriction-like healthspan benefits to mice.
  10. Dietary influence on adiponectin in patients with type 2 diabetes.
  11. Resistance to venetoclax and hypomethylating agents in acute myeloid leukemia.
  12. Azacitidine maintenance therapy post-allogeneic stem cell transplantation in poor-risk acute myeloid leukemia.
  13. Vedolizumab for Steroid Refractory Lower Gastrointestinal Tract Graft-Versus-Host Disease.
  14. Expanding Roles of De Novo Lipogenesis in Breast Cancer.
  15. Cancer and Aging: Two Tightly Interconnected Biological Processes.
  16. The Role of Chloroplast Membrane Lipid Metabolism in Plant Environmental Responses.
  17. Fatty Acid Metabolism and Cancer.
  18. The Role of Cancer Stem Cells in Colorectal Cancer: From the Basics to Novel Clinical Trials.
  19. Targeting the Mitochondria-Proteostasis Axis to Delay Aging.
  20. A plateful of medicine.
  21. The role of heme oxygenase-1 in hematopoietic system and its microenvironment.
  22. Energy Metabolism in IDH1 Wild-Type and IDH1-Mutated Glioblastoma Stem Cells: A Novel Target for Therapy?
  23. The TRAIL in the Treatment of Human Cancer: An Update on Clinical Trials.
  24. Molecular Mechanisms of Obesity-Linked Cardiac Dysfunction: An Up-Date on Current Knowledge.
  25. Oral Azacitidine Maintenance for Acute Myeloid Leukemia. Reply.
  26. Adherence to Ketogenic and Mediterranean Study Diets in a Crossover Trial: The Keto-Med Randomized Trial.
  27. Spicy Herb Extracts as a Potential Improver of the Antioxidant Properties and Inhibitor of Enzymatic Browning and Endogenous Microbiota Growth in Stored Mung Bean Sprouts.
  28. Fecal microbiota transplant boosts cancer immunotherapy in patients.
  29. Taking aim at IDH in fitter patients with AML.
  30. Flavonoids Alleviate Peripheral Neuropathy Induced by Anticancer Drugs.
  31. Glycine and N-acetylcysteine (GlyNAC) supplementation in older adults improves glutathione deficiency, oxidative stress, mitochondrial dysfunction, inflammation, insulin resistance, endothelial dysfunction, genotoxicity, muscle strength, and cognition: Results of a pilot clinical trial.
  1. Biology (Basel). 2021 Mar 02. pii: 184. [Epub ahead of print]10(3):
    Lipid Metabolism and Ferroptosis.
    Ji-Yoon Lee, Won Kon Kim, Kwang-Hee Bae, Sang Chul Lee, Eun-Woo Lee.
      Ferroptosis is a type of iron-dependent regulated necrosis induced by lipid peroxidation that occurs in cellular membranes. Among the various lipids, polyunsaturated fatty acids (PUFAs) associated with several phospholipids, such as phosphatidylethanolamine (PE) and phosphatidylcholine (PC), are responsible for ferroptosis-inducing lipid peroxidation. Since the de novo synthesis of PUFAs is strongly restricted in mammals, cells take up essential fatty acids from the blood and lymph to produce a variety of PUFAs via PUFA biosynthesis pathways. Free PUFAs can be incorporated into the cellular membrane by several enzymes, such as ACLS4 and LPCAT3, and undergo lipid peroxidation through enzymatic and non-enzymatic mechanisms. These pathways are tightly regulated by various metabolic and signaling pathways. In this review, we summarize our current knowledge of how various lipid metabolic pathways are associated with lipid peroxidation and ferroptosis. Our review will provide insight into treatment strategies for ferroptosis-related diseases.
    Keywords:  GPX4; ferroptosis; lipid peroxidation; lipoxygenase; polyunsaturated fatty acids
    DOI:  https://doi.org/10.3390/biology10030184
  2. Curr Stem Cell Rep. 2020 Dec;6(4): 119-125
    Stem Cell Metabolism and Diet.
    Marine Barthez, Zehan Song, Chih Ling Wang, Danica Chen.
      Purpose of Review: Diet has profound impacts on health and longevity. Evidence is emerging to suggest that diet impinges upon the metabolic pathways in tissue-specific stem cells to influence health and disease. Here, we review the similarities and differences in the metabolism of stem cells from several tissues, and highlight the mitochondrial metabolic checkpoint in stem cell maintenance and aging. We discuss how diet engages the nutrient sensing metabolic pathways and impacts stem cell maintenance. Finally, we explore the therapeutic implications of dietary and metabolic regulation of stem cells.Recent findings: Stem Cell transition from quiescence to proliferation is associated with a metabolic switch from glycolysis to mitochondrial OXPHOS and the mitochondrial metabolic checkpoint is critically controlled by the nutrient sensors SIRT2, SIRT3, and SIRT7 in hematopoietic stem cells. Intestine stem cell homeostasis during aging and in response to diet is critically dependent on fatty acid metabolism and ketone bodies and is influenced by the niche mediated by the nutrient sensor mTOR.
    Summary: Nutrient sensing metabolic pathways critically regulate stem cell maintenance during aging and in response to diet. Elucidating the molecular mechanisms underlying dietary and metabolic regulation of stem cells provides novel insights for stem cell biology and may be targeted therapeutically to reverse stem cell aging and tissue degeneration.
    Keywords:  SIRT2; SIRT3; SIRT7; calorie restriction; mTOR; stem cell metabolism
    DOI:  https://doi.org/10.1007/s40778-020-00180-4
  3. Nat Aging. 2021 Jan;1(1): 73-86
    Lifelong restriction of dietary branched-chain amino acids has sex-specific benefits for frailty and lifespan in mice.
    Nicole E Richardson, Elizabeth N Konon, Haley S Schuster, Alexis T Mitchell, Colin Boyle, Allison C Rodgers, Megan Finke, Lexington R Haider, Deyang Yu, Victoria Flores, Heidi H Pak, Soha Ahmad, Sareyah Ahmed, Abigail Radcliff, Jessica Wu, Elizabeth M Williams, Lovina Abdi, Dawn S Sherman, Timothy Hacker, Dudley W Lamming.
      Protein restricted (PR) diets promote health and longevity in many species. While the precise components of a PR diet that mediate the beneficial effects to longevity have not been defined, we recently showed that many metabolic effects of PR can be attributed to reduced dietary levels of the branched-chain amino acids (BCAAs) leucine, isoleucine, and valine. Here, we demonstrate that restricting dietary BCAAs increases the survival of two different progeroid mouse models, delays frailty and promotes the metabolic health of wild-type C57BL/6J mice when started in midlife, and leads to a 30% increase in lifespan and a reduction in frailty in male, but not female, wild-type mice when fed lifelong. Our results demonstrate that restricting dietary BCAAs can increase healthspan and longevity in mice, and suggest that reducing dietary BCAAs may hold potential as a translatable intervention to promote healthy aging.
    Keywords:  branched-chain amino acids; healthspan; lifespan; mTOR; mTORC1; progeria; protein restriction; rapamycin
    DOI:  https://doi.org/10.1038/s43587-020-00006-2
  4. J Clin Invest. 2021 Apr 01. pii: 146925. [Epub ahead of print]131(7):
    Changes in the National Cancer Institute's R01 workforce: growth, aging, retention, and policy implications.
    Melissa D Antman, Roman Gorelik, Amy Kennedy, Grace F Liou, Eddie N Billingslea, James G Corrigan, L Michelle Bennett.
      Scientific progress and discovery of preventions and cures for life-threatening diseases depend on the vitality of the biomedical research workforce. We analyzed the workforce of cancer researchers applying for and receiving R01 awards from the National Cancer Institute (NCI) from fiscal years 1990 to 2016, the last year prior to implementation of the Next Generation Researchers Initiative. Here we report that the NCI R01 Principal Investigator (PI) workforce expanded 1.4-fold and aged over this time frame. We tracked 9 age groups and found that the number of PIs in the 3 oldest groups increased dramatically, in contrast with the younger groups. Sustained increases in the number of funded older PIs stemmed from increases in the number of older PIs submitting applications, rather than higher funding rates for older PIs. The decline in the number of funded younger PIs was driven in part by (a) a marked increase in time from PhD degree to first R01 application and award, as well as (b) a decrease in retention of PIs in the funded R01 workforce beyond their first R01 award. The NCI is using these and other analyses to inform strategies and policies for attracting, supporting, and retaining meritorious early-career researchers.
    DOI:  https://doi.org/10.1172/JCI146925
  5. Nutrients. 2021 Mar 18. pii: 984. [Epub ahead of print]13(3):
    The DASH Diet and Cardiometabolic Health and Chronic Kidney Disease: A Narrative Review of the Evidence in East Asian Countries.
    Yazhen Song, Andrea J Lobene, Yanfang Wang, Kathleen M Hill Gallant.
      The rising incidence of cardiometabolic diseases and chronic kidney disease (CKD) is a leading public health problem in East Asia. Diet is an important modifiable risk factor; thus, adopting a healthy diet such as the Dietary Approaches to Stop Hypertension (DASH) diet may help combat these chronic diseases. The DASH diet was originally developed in a U.S. population, and East Asia is demographically and culturally different from the U.S. Therefore, it is important to examine the evidence regarding the DASH diet and chronic disease in this unique population. This narrative review summarizes the evidence on the DASH diet and cardiometabolic health and CKD in East Asia. Culturally-modified DASH diets have been developed in some East Asian countries. Studies suggest the DASH diet is effective at lowering blood pressure in this population, though the long-term benefits remain unclear. Evidence also suggests the DASH diet may reduce the risk of type 2 diabetes and metabolic syndrome. Further research indicates the DASH diet and its components may reduce CKD risk. However, recommending the DASH diet in those who already have CKD is controversial, as it conflicts with current CKD dietary guidelines, especially in advanced CKD. Notably, current intakes in the general population differ from the DASH dietary pattern, suggesting public health efforts would be needed to encourage adoption of the DASH diet.
    Keywords:  China; DASH diet; East Asia; Japan; South Korea; cardiometabolic health; cardiovascular disease; chronic kidney disease; type 2 diabetes
    DOI:  https://doi.org/10.3390/nu13030984
  6. Drug Discov Today. 2021 Mar 25. pii: S1359-6446(21)00149-5. [Epub ahead of print]
    Diabetes, inflammation, and the adiponectin paradox: therapeutic targets in SARS-CoV-2.
    Gilbert Ho, Alysha Ali, Yoshiki Takamatsu, Ryoko Wada, Eliezer Masliah, Makoto Hashimoto.
      Aging and pre-existing conditions in older patients increase severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) severity and its complications, although the causes remain unclear. Apart from acute pulmonary syndrome, Coronavirus 2019 (COVID-19) can increasingly induce chronic conditions. Importantly, SARS-CoV-2 triggers de novo type 2 diabetes mellitus (T2DM) linked to age-associated cardiovascular disease (CVD), cancers, and neurodegeneration. Mechanistically, SARS-CoV-2 induces inflammation, possibly through damage-associated molecular pattern (DAMP) signaling and 'cytokine storm', causing insulin resistance and the adiponectin (APN) paradox, a phenomenon linking metabolic dysfunction to chronic disease. Accordingly, preventing the APN paradox by suppressing APN-related inflammatory signaling might prove beneficial. A better understanding could uncover novel therapies for SARS-CoV-2 and its chronic disorders.
    Keywords:  COVID-19; SARS-CoV-2; adiponectin paradox; antagonistic pleiotropy; diabetes mellitus; inflammation
    DOI:  https://doi.org/10.1016/j.drudis.2021.03.013
  7. Int J Mol Sci. 2021 Mar 25. pii: 3367. [Epub ahead of print]22(7):
    Therapeutic Potential for Regulation of the Nuclear Factor Kappa-B Transcription Factor p65 to Prevent Cellular Senescence and Activation of Pro-Inflammatory in Mesenchymal Stem Cells.
    Rocío Mato-Basalo, Miriam Morente-López, Onno J Arntz, Fons A J van de Loo, Juan Fafián-Labora, María C Arufe.
      Mesenchymal stem cells have an important potential in the treatment of age-related diseases. In the last years, small extracellular vesicles derived from these stem cells have been proposed as cell-free therapies. Cellular senescence and proinflammatory activation are involved in the loss of therapeutic capacity and in the phenomenon called inflamm-aging. The regulators of these two biological processes in mesenchymal stem cells are not well-known. In this study, we found that p65 is activated during cellular senescence and inflammatory activation in human umbilical cord-derived mesenchymal stem cell. To demonstrate the central role of p65 in these two processes, we used small-molecular inhibitors of p65, such as JSH-23, MG-132 and curcumin. We found that the inhibition of p65 prevents the cellular senescence phenotype in human umbilical cord-derived mesenchymal stem cells. Besides, p65 inhibition produced the inactivation of proinflammatory molecules as components of a senescence-associated secretory phenotype (SASP) (interleukin-6 and interleukin-8 (IL-6 and IL-8)). Additionally, we found that the inhibition of p65 prevents the transmission of paracrine senescence between mesenchymal stem cells and the proinflammatory message through small extracellular vesicles. Our work highlights the important role of p65 and its inhibition to restore the loss of functionality of small extracellular vesicles from senescent mesenchymal stem cells and their inflamm-aging signature.
    Keywords:  SASP; cellular senescence; inflamm-aging; mesenchymal stem cells; sEV
    DOI:  https://doi.org/10.3390/ijms22073367
  8. NPJ Aging Mech Dis. 2021 Apr 01. 7(1): 8
    A decrease in NAD+ contributes to the loss of osteoprogenitors and bone mass with aging.
    Ha-Neui Kim, Filipa Ponte, Aaron Warren, Rebecca Ring, Srividhya Iyer, Li Han, Maria Almeida.
      Age-related osteoporosis is caused by a deficit in osteoblasts, the cells that secrete bone matrix. The number of osteoblast progenitors also declines with age associated with increased markers of cell senescence. The forkhead box O (FoxO) transcription factors attenuate Wnt/β-catenin signaling and the proliferation of osteoprogenitors, thereby decreasing bone formation. The NAD+-dependent Sirtuin1 (Sirt1) deacetylates FoxOs and β-catenin in osteoblast progenitors and, thereby, increases bone mass. However, it remains unknown whether the Sirt1/FoxO/β-catenin pathway is dysregulated with age in osteoblast progenitors. We found decreased levels of NAD+ in osteoblast progenitor cultures from old mice, associated with increased acetylation of FoxO1 and markers of cell senescence. The NAD+ precursor nicotinamide riboside (NR) abrogated FoxO1 and β-catenin acetylation and several marker of cellular senescence, and increased the osteoblastogenic capacity of cells from old mice. Consistent with these effects, NR administration to C57BL/6 mice counteracted the loss of bone mass with aging. Attenuation of NAD+ levels in osteoprogenitor cultures from young mice inhibited osteoblastogenesis in a FoxO-dependent manner. In addition, mice with decreased NAD+ in cells of the osteoblast lineage lost bone mass at a young age. Together, these findings suggest that the decrease in bone formation with old age is due, at least in part, to a decrease in NAD+ and dysregulated Sirt1/FoxO/β-catenin pathway in osteoblast progenitors. NAD+ repletion, therefore, represents a rational therapeutic approach to skeletal involution.
    DOI:  https://doi.org/10.1038/s41514-021-00058-7
  9. Elife. 2021 Mar 30. pii: e62483. [Epub ahead of print]10
    Selenium supplementation inhibits IGF-1 signaling and confers methionine restriction-like healthspan benefits to mice.
    Jason D Plummer, Spike Dl Postnikoff, Jessica K Tyler, Jay E Johnson.
      Methionine restriction (MR) dramatically extends the healthspan of several organisms. Methionine-restricted rodents have less age-related pathology and increased longevity as compared with controls, and recent studies suggest that humans might benefit similarly. Mechanistically, it is likely that the decreased IGF-1 signaling that results from MR underlies the benefits of this regimen. Thus, we hypothesized that interventions that decrease IGF-1 signaling would also produce MR-like healthspan benefits. Selenium supplementation inhibits IGF-1 signaling in rats and has been studied for its putative healthspan benefits. Indeed, we show that feeding mice a diet supplemented with sodium selenite results in an MR-like phenotype, marked by protection against diet-induced obesity, as well as altered plasma levels of IGF-1, FGF-21, adiponectin, and leptin. Selenomethionine supplementation results in a similar, albeit less robust response, and also extends budding yeast lifespan. Our results indicate that selenium supplementation is sufficient to produce MR-like healthspan benefits for yeast and mammals.
    Keywords:  S. cerevisiae; aging; biochemistry; chemical biology; genetics; genomics; histone deacetylase; lifespan; metabolism; mitophagy; mouse; selenomethionine
    DOI:  https://doi.org/10.7554/eLife.62483
  10. Eur J Clin Invest. 2021 Apr 02. e13548
    Dietary influence on adiponectin in patients with type 2 diabetes.
    Lutgarda Bozzetto, Rita Polito, Ersilia Nigro, Anna Prinster, Giuseppe Della Pepa, Giuseppina Costabile, Claudia Vetrani, Marilena Vitale, Aurora Daniele, Angela Albarosa Rivellese, Giovanni Annuzzi.
      BACKGROUND: Here, we evaluate the effects of a diet rich in low-glycaemic index carbohydrates and fibre (CHO/Fibre diet) or monounsaturated fatty acids (MUFA diet), on fasting and postprandial adiponectin concentrations and their relationship with the beneficial effects of the experimental diets on postprandial glucose metabolism and liver fat in type 2 diabetes (T2D).METHODS: Fasting and postprandial adiponectin plasma concentrations were measured before and after dietary interventions in the participants to a randomized controlled trial (NCT01025856), wherein 37 men and 8 women with T2D, aged 35-70 years, followed a CHO/Fibre diet or a MUFA diet for an 8-week period. Hepatic fat content by 1 H NMR and fasting and postprandial plasma glucose and insulin measurements were also available.
    RESULTS: Fasting adiponectin plasma levels did not change after both diets. Postprandial adiponectin significantly increased after the CHO/fibre diet (9.9 ± 1.6 μg/mL vs. 10.8 ± 2.3 μg/mL; P = .033) but not after the MUFA diet (10.6 ± 1.8 μg/mL vs. 10.6 ± 1.6 μg/mL; P = .935) with a significant difference between changes (P = .035). In the combined CHO/Fibre and MUFA groups, fasting and postprandial adiponectin significantly and inversely correlated with postprandial insulin iAUC at baseline and after intervention, and with liver fat content after intervention.
    CONCLUSIONS: A diet rich in CHO/Fibre increased postprandial plasma adiponectin significantly more than a MUFA diet in patients with T2D. Independently of diet, adiponectin levels associated with postprandial insulin concentrations. The dietary interventions modulated the relationship between adiponectin and liver fat.
    Keywords:  adiponectin; dietary fibres; glycaemic index; liver fat; monounsaturated fatty acids; type 2 diabetes
    DOI:  https://doi.org/10.1111/eci.13548
  11. Cancer Drug Resist. 2021 ;4 125-142
    Resistance to venetoclax and hypomethylating agents in acute myeloid leukemia.
    Antoine N Saliba, August J John, Scott H Kaufmann.
      Despite the success of the combination of venetoclax with the hypomethylating agents (HMA) decitabine or azacitidine in inducing remission in older, previously untreated patients with acute myeloid leukemia (AML), resistance - primary or secondary - still constitutes a significant roadblock in the quest to prolong the duration of response. Here we review the proposed and proven mechanisms of resistance to venetoclax monotherapy, HMA monotherapy, and the doublet of venetoclax and HMA for the treatment of AML. We approach the mechanisms of resistance to HMAs and venetoclax in the light of the agents' mechanisms of action. We briefly describe potential therapeutic strategies to circumvent resistance to this promising combination, including alternative scheduling or the addition of other agents to the HMA and venetoclax backbone. Understanding the mechanisms of action and evolving resistance in AML remains a priority in order to maximize the benefit from novel drugs and combinations, identify new therapeutic targets, define potential prognostic markers, and avoid treatment failure.
    Keywords:  Venetoclax; acute myeloid leukemia; azacitidine; decitabine; hypomethylating agents; resistance
    DOI:  https://doi.org/10.20517/cdr.2020.95
  12. Hematol Oncol Stem Cell Ther. 2021 Mar 19. pii: S1658-3876(21)00030-3. [Epub ahead of print]
    Azacitidine maintenance therapy post-allogeneic stem cell transplantation in poor-risk acute myeloid leukemia.
    Amany R Keruakous, Jennifer Holter Chakrabarty, Sarah A Schmidt, Mohamad O Khawandanah, George Selby, Carrie Yuen.
      OBJECTIVE/BACKGROUND: Allogeneic hematopoietic stem cell transplant (HSCT) is the potential curative modality for poor-risk acute myeloid leukemia (AML), relapse remains the main reason for transplant failure. Early-phase studies showed azacitidine is safe for post-transplant maintenance therapy in AML.METHODS: We performed a single institutional prospective cohort study to evaluate the benefit of azacitidine maintenance therapy following allogeneic HSCT in poor-risk AML. The main objective of this study is to generate a hypothesis aiming to optimize post-transplantation outcomes in poor-risk AML. Forty-nine adults with poor-risk AML who underwent allogeneic HSCT were evaluated in a nonrandomized prospective cohort fashion. Thirty-one participants received post-transplant azacitidine (32 mg/m2) on Days 1-5 for a 28-day treatment cycle beginning approximately 40 days after transplantation. The study was controlled using 18 matched individuals who were on a noninterventional surveillance protocol.
    RESULTS: The relapse rate was significantly higher in the control cohort (66.67%) versus (25.81%) in the azacitidine maintenance cohort (p < .005). Time to relapse was significantly prolonged by azacitidine maintenance, not reached versus 4.1 months in the control arm (p < .0001). In addition, median overall survival was lower in the control cohort at 7.6 versus 27.4 months in the interventional cohort (p < .0001). At a median follow-up of 24 months, incidence of graft-versus-host disease (GVHD) did not differ between study groups (p = .325). In both cohorts, minimal residual disease was correlated with higher hazard of relapse (95% confidence interval, 2.31-13.74; p < .001).
    CONCLUSION: We conclude that low dose azacitidine maintenance following allogeneic HSCT in poor-risk AML, decreased relapse rate, and increased both the time to relapse and overall survival without increased risk of GVHD.
    Keywords:  Clinical research; Poor-risk AML; Post-HSCT low dose azacitidine; Post-transplantation maintenance; Stem cell transplantation
    DOI:  https://doi.org/10.1016/j.hemonc.2021.03.001
  13. Transplant Cell Ther. 2021 Mar;pii: S2666-6367(20)30057-9. [Epub ahead of print]27(3): 272.e1-272.e5
    Vedolizumab for Steroid Refractory Lower Gastrointestinal Tract Graft-Versus-Host Disease.
    Rohtesh S Mehta, Rima M Saliba, Anna Jan, Terri Lynn Shigle, Emily Wang, Yago Nieto, Stefan O Ciurea, Betul Oran, Jin Im, Amanda Olson, David Marin, Muzaffar Qazilbash, Issa Khouri, Gabriela Rondon, Paolo Anderlini, Katayoun Rezvani, Uday Popat, Partow Kebriaei, Elizabeth Shpall, Richard Champlin, Amin Alousi.
      Steroid-refractory (SR) lower gastrointestinal (LGI) acute graft-versus-host disease (aGVHD) has poor prognosis, and novel drugs are needed. We describe outcomes of patients with SR-LGI aGVHD treated with vedolizumab. The primary objective was to determine overall response rate (ORR) at days 14, 28, and 56. Secondary outcomes included overall survival (OS), non-relapse mortality and toxicities. Twenty patients, median age 46 years (range, 23-71), were included. All but 2 patients (90%) had grade 3 to 4 aGVHD (45% stage 4, 40% stage 3 LGI). Median time to vedolizumab was 21 days (range, 5-1031) and 13 days (range, 0-533) after diagnosis of LGI aGVHD and SR-LGI aGVHD, respectively. It was given as ≥3rd line (median 3; range 2-6) in 75% after failure of steroids, and additional treatments including ruxolitinib (n = 12) and others. Median follow-up was 17 months (range, 10-34). The days 14, 28 and 56 ORRs were 45% (9/20; complete response [CR] 25%), 35% (7/20; CR 20%), and 25% (5/20; CR 20%), respectively. Among ruxolitinib failures, it was 50% (6/12; CR 25%), 50% (6/12; CR 25%) and 25% (3/12; CR 16.7%), respectively. Fifteen patients died (14 GVHD, 1 leukemia relapse). The actuarial 6-month OS was 35% (95% confidence interval 16-55). No progressive multifocal leukoencephalopathy or infusion reaction occurred. Forty-four infection events (22 viral, 18 bacterial, and 4 fungal) were noted in 16 patients. Vedolizumab was well tolerated and demonstrated potential efficacy even after ruxolitinib failure for SR-LGI aGVHD. Yet the responses were suboptimal, and its use requires further investigation.
    Keywords:  Allogeneic hematopoietic stem cell transplantation; GVHD; Gastrointestinal tract; Ruxolitinib; Steroid-refractory GVHD; Vedolizumab
    DOI:  https://doi.org/10.1016/j.jtct.2020.12.011
  14. Int J Environ Res Public Health. 2021 Mar 30. pii: 3575. [Epub ahead of print]18(7):
    Expanding Roles of De Novo Lipogenesis in Breast Cancer.
    Pasquale Simeone, Stefano Tacconi, Serena Longo, Paola Lanuti, Sara Bravaccini, Francesca Pirini, Sara Ravaioli, Luciana Dini, Anna M Giudetti.
      In recent years, lipid metabolism has gained greater attention in several diseases including cancer. Dysregulation of fatty acid metabolism is a key component in breast cancer malignant transformation. In particular, de novo lipogenesis provides the substrate required by the proliferating tumor cells to maintain their membrane composition and energetic functions during enhanced growth. However, it appears that not all breast cancer subtypes depend on de novo lipogenesis for fatty acid replenishment. Indeed, while breast cancer luminal subtypes rely on de novo lipogenesis, the basal-like receptor-negative subtype overexpresses genes involved in the utilization of exogenous-derived fatty acids, in the synthesis of triacylglycerols and lipid droplets, and fatty acid oxidation. These metabolic differences are specifically associated with genomic and proteomic changes that can perturb lipogenic enzymes and related pathways. This behavior is further supported by the observation that breast cancer patients can be stratified according to their molecular profiles. Moreover, the discovery that extracellular vesicles act as a vehicle of metabolic enzymes and oncometabolites may provide the opportunity to noninvasively define tumor metabolic signature. Here, we focus on de novo lipogenesis and the specific differences exhibited by breast cancer subtypes and examine the functional contribution of lipogenic enzymes and associated transcription factors in the regulation of tumorigenic processes.
    Keywords:  breast cancer; de novo lipogenesis; extracellular vesicles; metabolism
    DOI:  https://doi.org/10.3390/ijerph18073575
  15. Cancers (Basel). 2021 Mar 19. pii: 1400. [Epub ahead of print]13(6):
    Cancer and Aging: Two Tightly Interconnected Biological Processes.
    Lieze Berben, Giuseppe Floris, Hans Wildiers, Sigrid Hatse.
      Age is one of the main risk factors of cancer; several biological changes linked with the aging process can explain this. As our population is progressively aging, the proportion of older patients with cancer is increasing significantly. Due to the heterogeneity of general health and functional status amongst older persons, treatment of cancer is a major challenge in this vulnerable population. Older patients often experience more side effects of anticancer treatments. Over-treatment should be avoided to ensure an optimal quality of life. On the other hand, under-treatment due to fear of toxicity is a frequent problem and can lead to an increased risk of relapse and worse survival. There is a delicate balance between benefits of therapy and risk of toxicity. Robust biomarkers that reflect the body's biological age may aid in outlining optimal individual treatment regimens for older patients with cancer. In particular, the impact of age on systemic immunity and the tumor immune infiltrate should be considered, given the expanding role of immunotherapy in cancer treatment. In this review, we summarize current knowledge concerning the mechanistic connections between aging and cancer, as well as aging biomarkers that could be helpful in the field of geriatric oncology.
    Keywords:  aging; biomarkers; cancer
    DOI:  https://doi.org/10.3390/cancers13061400
  16. Cells. 2021 Mar 23. pii: 706. [Epub ahead of print]10(3):
    The Role of Chloroplast Membrane Lipid Metabolism in Plant Environmental Responses.
    Ron Cook, Josselin Lupette, Christoph Benning.
      Plants are nonmotile life forms that are constantly exposed to changing environmental conditions during the course of their life cycle. Fluctuations in environmental conditions can be drastic during both day-night and seasonal cycles, as well as in the long term as the climate changes. Plants are naturally adapted to face these environmental challenges, and it has become increasingly apparent that membranes and their lipid composition are an important component of this adaptive response. Plants can remodel their membranes to change the abundance of different lipid classes, and they can release fatty acids that give rise to signaling compounds in response to environmental cues. Chloroplasts harbor the photosynthetic apparatus of plants embedded into one of the most extensive membrane systems found in nature. In part one of this review, we focus on changes in chloroplast membrane lipid class composition in response to environmental changes, and in part two, we will detail chloroplast lipid-derived signals.
    Keywords:  fatty acids; galactolipids; glycerolipids; jasmonate; oxylipin; phospholipids; plant stress
    DOI:  https://doi.org/10.3390/cells10030706
  17. Adv Exp Med Biol. 2021 ;1280 231-241
    Fatty Acid Metabolism and Cancer.
    Zhenning Jin, Yang D Chai, Shen Hu.
      Although normal cells depend on exogenous lipids to function and survive, excessive amount of body fat has been associated with increased risk for certain human cancers. Cancer cells can redirect metabolic pathways to meet energy demands through the regulation of fatty acid metabolism. The importance of de novo fatty acid synthesis and fatty acid oxidation in cancer cells suggests fatty acid metabolism may be targeted for anticancer treatment through the use of pharmacological blockade to limit cell proliferation, growth, and transformation. However, our current knowledge about fatty acid metabolism in cancer cells remains limited, and the investigations of such processes and related pathways are certainly warranted to reveal the clinical relevance of fatty acid metabolism in cancer diagnosis and therapy.
    Keywords:  Cancer metabolism; Fatty acid oxidation; Fatty acid synthesis
    DOI:  https://doi.org/10.1007/978-3-030-51652-9_16
  18. Cancers (Basel). 2021 Mar 04. pii: 1092. [Epub ahead of print]13(5):
    The Role of Cancer Stem Cells in Colorectal Cancer: From the Basics to Novel Clinical Trials.
    Céline Hervieu, Niki Christou, Serge Battu, Muriel Mathonnet.
      The treatment options available for colorectal cancer (CRC) have increased over the years and have significantly improved the overall survival of CRC patients. However, the response rate for CRC patients with metastatic disease remains low and decreases with subsequent lines of therapy. The clinical management of patients with metastatic CRC (mCRC) presents a unique challenge in balancing the benefits and harms while considering disease progression, treatment-related toxicities, drug resistance and the patient's overall quality of life. Despite the initial success of therapy, the development of drug resistance can lead to therapy failure and relapse in cancer patients, which can be attributed to the cancer stem cells (CSCs). Thus, colorectal CSCs (CCSCs) contribute to therapy resistance but also to tumor initiation and metastasis development, making them attractive potential targets for the treatment of CRC. This review presents the available CCSC isolation methods, the clinical relevance of these CCSCs, the mechanisms of drug resistance associated with CCSCs and the ongoing clinical trials targeting these CCSCs. Novel therapeutic strategies are needed to effectively eradicate both tumor growth and metastasis, while taking into account the tumor microenvironment (TME) which plays a key role in tumor cell plasticity.
    Keywords:  cancer stem cells; clinical trials; colorectal cancer; drug resistance
    DOI:  https://doi.org/10.3390/cancers13051092
  19. Front Cell Dev Biol. 2021 ;9 656201
    Targeting the Mitochondria-Proteostasis Axis to Delay Aging.
    Andreas Zimmermann, Corina Madreiter-Sokolowski, Sarah Stryeck, Mahmoud Abdellatif.
      Human life expectancy continues to grow globally, and so does the prevalence of age-related chronic diseases, causing a huge medical and economic burden on society. Effective therapeutic options for these disorders are scarce, and even if available, are typically limited to a single comorbidity in a multifaceted dysfunction that inevitably affects all organ systems. Thus, novel therapies that target fundamental processes of aging itself are desperately needed. In this article, we summarize current strategies that successfully delay aging and related diseases by targeting mitochondria and protein homeostasis. In particular, we focus on autophagy, as a fundamental proteostatic process that is intimately linked to mitochondrial quality control. We present genetic and pharmacological interventions that effectively extend health- and life-span by acting on specific mitochondrial and pro-autophagic molecular targets. In the end, we delve into the crosstalk between autophagy and mitochondria, in what we refer to as the mitochondria-proteostasis axis, and explore the prospect of targeting this crosstalk to harness maximal therapeutic potential of anti-aging interventions.
    Keywords:  aging; anti-aging targets; autophagy; mitochondria; proteostasis
    DOI:  https://doi.org/10.3389/fcell.2021.656201
  20. Science. 2021 Apr 02. 372(6537): 20-23
    A plateful of medicine.
    Jocelyn Kaiser.
      
    DOI:  https://doi.org/10.1126/science.372.6537.20
  21. Cell Mol Life Sci. 2021 Mar 31.
    The role of heme oxygenase-1 in hematopoietic system and its microenvironment.
    Agata Szade, Krzysztof Szade, Mahdi Mahdi, Alicja Józkowicz.
      Hematopoietic system transports all necessary nutrients to the whole organism and provides the immunological protection. Blood cells have high turnover, therefore, this system must be dynamically controlled and must have broad regeneration potential. In this review, we summarize how this complex system is regulated by the heme oxygenase-1 (HO-1)-an enzyme, which degrades heme to biliverdin, ferrous ion and carbon monoxide. First, we discuss how HO-1 influences hematopoietic stem cells (HSC) self-renewal, aging and differentiation. We also describe a critical role of HO-1 in endothelial cells and mesenchymal stromal cells that constitute the specialized bone marrow niche of HSC. We further discuss the molecular and cellular mechanisms by which HO-1 modulates innate and adaptive immune responses. Finally, we highlight how modulation of HO-1 activity regulates the mobilization of bone marrow hematopoietic cells to peripheral blood. We critically discuss the issue of metalloporphyrins, commonly used pharmacological modulators of HO-1 activity, and raise the issue of their important HO-1-independent activities.
    Keywords:  HO-1; HSPC; Hematopoiesis; Hmox1; Niche
    DOI:  https://doi.org/10.1007/s00018-021-03803-z
  22. Cells. 2021 Mar 22. pii: 705. [Epub ahead of print]10(3):
    Energy Metabolism in IDH1 Wild-Type and IDH1-Mutated Glioblastoma Stem Cells: A Novel Target for Therapy?
    Cornelis J F van Noorden, Vashendriya V V Hira, Amber J van Dijck, Metka Novak, Barbara Breznik, Remco J Molenaar.
      Cancer is a redox disease. Low levels of reactive oxygen species (ROS) are beneficial for cells and have anti-cancer effects. ROS are produced in the mitochondria during ATP production by oxidative phosphorylation (OXPHOS). In the present review, we describe ATP production in primary brain tumors, glioblastoma, in relation to ROS production. Differentiated glioblastoma cells mainly use glycolysis for ATP production (aerobic glycolysis) without ROS production, whereas glioblastoma stem cells (GSCs) in hypoxic periarteriolar niches use OXPHOS for ATP and ROS production, which is modest because of the hypoxia and quiescence of GSCs. In a significant proportion of glioblastoma, isocitrate dehydrogenase 1 (IDH1) is mutated, causing metabolic rewiring, and all cancer cells use OXPHOS for ATP and ROS production. Systemic therapeutic inhibition of glycolysis is not an option as clinical trials have shown ineffectiveness or unwanted side effects. We argue that systemic therapeutic inhibition of OXPHOS is not an option either because the anti-cancer effects of ROS production in healthy cells is inhibited as well. Therefore, we advocate to remove GSCs out of their hypoxic niches by the inhibition of their binding to niches to enable their differentiation and thus increase their sensitivity to radiotherapy and/or chemotherapy.
    Keywords:  IDH1-mutation; energy metabolism; glioblastoma stem cells
    DOI:  https://doi.org/10.3390/cells10030705
  23. Front Mol Biosci. 2021 ;8 628332
    The TRAIL in the Treatment of Human Cancer: An Update on Clinical Trials.
    Martin Snajdauf, Klara Havlova, Jiri Vachtenheim, Andrej Ozaniak, Robert Lischke, Jirina Bartunkova, Daniel Smrz, Zuzana Strizova.
      TRAIL (tumor-necrosis factor related apoptosis-inducing ligand, CD253) and its death receptors TRAIL-R1 and TRAIL-R2 selectively trigger the apoptotic cell death in tumor cells. For that reason, TRAIL has been extensively studied as a target of cancer therapy. In spite of the promising preclinical observations, the TRAIL-based therapies in humans have certain limitations. The two main therapeutic approaches are based on either an administration of TRAIL-receptor (TRAIL-R) agonists or a recombinant TRAIL. These approaches, however, seem to elicit a limited therapeutic efficacy, and only a few drugs have entered the phase II clinical trials. To deliver TRAIL-based therapies with higher anti-tumor potential several novel TRAIL-derivates and modifications have been designed. These novel drugs are, however, mostly preclinical, and many problems continue to be unraveled. We have reviewed the current status of all TRAIL-based monotherapies and combination therapies that have reached phase II and phase III clinical trials in humans. We have also aimed to introduce all novel approaches of TRAIL utilization in cancer treatment and discussed the most promising drugs which are likely to enter clinical trials in humans. To date, different strategies were introduced in order to activate anti-tumor immune responses with the aim of achieving the highest efficacy and minimal toxicity.In this review, we discuss the most promising TRAIL-based clinical trials and their therapeutic strategies.
    Keywords:  TRAIL clinical trials; TRAIL-receptor agonists; cancer; dulanermin; mapatumumab; recombinant TRAIL
    DOI:  https://doi.org/10.3389/fmolb.2021.628332
  24. Cells. 2021 Mar 12. pii: 629. [Epub ahead of print]10(3):
    Molecular Mechanisms of Obesity-Linked Cardiac Dysfunction: An Up-Date on Current Knowledge.
    Jorge Gutiérrez-Cuevas, Ana Sandoval-Rodriguez, Alejandra Meza-Rios, Hugo Christian Monroy-Ramírez, Marina Galicia-Moreno, Jesús García-Bañuelos, Arturo Santos, Juan Armendariz-Borunda.
      Obesity is defined as excessive body fat accumulation, and worldwide obesity has nearly tripled since 1975. Excess of free fatty acids (FFAs) and triglycerides in obese individuals promote ectopic lipid accumulation in the liver, skeletal muscle tissue, and heart, among others, inducing insulin resistance, hypertension, metabolic syndrome, type 2 diabetes (T2D), atherosclerosis, and cardiovascular disease (CVD). These diseases are promoted by visceral white adipocyte tissue (WAT) dysfunction through an increase in pro-inflammatory adipokines, oxidative stress, activation of the renin-angiotensin-aldosterone system (RAAS), and adverse changes in the gut microbiome. In the heart, obesity and T2D induce changes in substrate utilization, tissue metabolism, oxidative stress, and inflammation, leading to myocardial fibrosis and ultimately cardiac dysfunction. Peroxisome proliferator-activated receptors (PPARs) are involved in the regulation of carbohydrate and lipid metabolism, also improve insulin sensitivity, triglyceride levels, inflammation, and oxidative stress. The purpose of this review is to provide an update on the molecular mechanisms involved in obesity-linked CVD pathophysiology, considering pro-inflammatory cytokines, adipokines, and hormones, as well as the role of oxidative stress, inflammation, and PPARs. In addition, cell lines and animal models, biomarkers, gut microbiota dysbiosis, epigenetic modifications, and current therapeutic treatments in CVD associated with obesity are outlined in this paper.
    Keywords:  PPARs; animal models; biomarkers; cardiovascular diseases; epigenetic modifications; gut microbiota dysbiosis; obesity; pathophysiology; therapeutic treatments
    DOI:  https://doi.org/10.3390/cells10030629
  25. N Engl J Med. 2021 Apr 01. pii: 10.1056/NEJMc2101283#sa2. [Epub ahead of print]384(13): e51
    Oral Azacitidine Maintenance for Acute Myeloid Leukemia. Reply.
    Andrew H Wei, Hartmut Döhner, Gail J Roboz.
      
    DOI:  https://doi.org/10.1056/NEJMc2101283
  26. Nutrients. 2021 Mar 17. pii: 967. [Epub ahead of print]13(3):
    Adherence to Ketogenic and Mediterranean Study Diets in a Crossover Trial: The Keto-Med Randomized Trial.
    Matthew J Landry, Anthony Crimarco, Dalia Perelman, Lindsay R Durand, Christina Petlura, Lucia Aronica, Jennifer L Robinson, Sun H Kim, Christopher D Gardner.
      Adherence is a critical factor to consider when interpreting study results from randomized clinical trials (RCTs) comparing one diet to another, but it is frequently not reported by researchers. The purpose of this secondary analysis of the Keto-Med randomized trial was to provide a detailed examination and comparison of the adherence to the two study diets (Well Formulated Ketogenic Diet (WFKD) and Mediterranean Plus (Med-Plus)) under the two conditions: all food being provided (delivered) and all food being obtained by individual participants (self-provided). Diet was assessed at six time points including baseline (×1), week 4 of each phase when participants were receiving food deliveries (×2), week 12 of each phase when participants were preparing and providing food on their own (×2), and 12 weeks after participants completed both diet phases and were free to choose their own diet pattern (×1). The adherence scores for WFKD and Med-Plus were developed specifically for this study. Average adherence to the two diet patterns was very similar during both on-study time points of the intervention. Throughout the study, a wide range of adherence was observed among participants-for both diet types and during both the delivery phase and self-provided phase. Insight from this assessment of adherence may aid other researchers when answering the important question of how to improve behavioral adherence during dietary trials. This study is registered at clinicaltrials.gov NCT03810378.
    Keywords:  Mediterranean; crossover trial; diet adherence; dietary trial; ketogenic
    DOI:  https://doi.org/10.3390/nu13030967
  27. Antioxidants (Basel). 2021 Mar 10. pii: 425. [Epub ahead of print]10(3):
    Spicy Herb Extracts as a Potential Improver of the Antioxidant Properties and Inhibitor of Enzymatic Browning and Endogenous Microbiota Growth in Stored Mung Bean Sprouts.
    Małgorzata Sikora, Urszula Złotek, Monika Kordowska-Wiater, Michał Świeca.
      The quality and shelf life of sprouts can be improved by postharvest application of water herb extracts. The effect of water infusions of marjoram, oregano, basil, and thyme on the phenolic content, antioxidant potential, and the microbiological and consumer quality of stored mung bean sprouts was studied. Compared to the control, the treatments increased total phenolic content. The highest amounts were determined in sprouts soaked in the thyme extract (6.8 mg/g d.m.). The infusions also inhibited the activity of enzymes utilizing phenolics, and marjoram and oregano were found to be the most effective. The increase in the level of phenolics was reflected in enhanced antioxidant properties (ability to quench cation radical ABTS•+, reducing and chelating power). Both total phenolics and flavonoids, as well as antioxidant capacities, were highly bioaccessible in vitro. All the natural extracts effectively reduced the growth of total mesophilic bacteria, coliforms, and molds (they were more effective than ascorbic and kojic acids). The treatments did not exert a negative influence on the sensory properties or nutritional value of the sprouts, and even improved starch and protein digestibility. These results are very promising and may suggest a wider used of natural extracts as preservatives of minimally processed food.
    Keywords:  antioxidant capacity; bioaccessibility; consumer quality; enzymatic browning; herbs; infusion; microbiological purity; phenolic compounds; storage
    DOI:  https://doi.org/10.3390/antiox10030425
  28. Am J Transplant. 2021 Apr;21(4): 1355
    Fecal microbiota transplant boosts cancer immunotherapy in patients.
    Xian C Li.
      
    DOI:  https://doi.org/10.1111/ajt.16559
  29. Blood. 2021 Apr 01. 137(13): 1706-1707
    Taking aim at IDH in fitter patients with AML.
    Andrew H Wei, Naval Daver.
      
    DOI:  https://doi.org/10.1182/blood.2020009361
  30. Cancers (Basel). 2021 Mar 29. pii: 1576. [Epub ahead of print]13(7):
    Flavonoids Alleviate Peripheral Neuropathy Induced by Anticancer Drugs.
    Manaal Siddiqui, Basma Abdellatif, Kevin Zhai, Alena Liskova, Peter Kubatka, Dietrich Büsselberg.
      PURPOSE: This study aimed to assess the potential of flavonoids in combating CIPN.METHODS: PubMed and Google Scholar were used, and studies that investigated flavonoids in models of CIPN and models of neuropathic pain similar to CIPN were included. Only studies investigating peripheral mechanisms of CIPN were used.
    RESULTS: Flavonoids inhibit several essential mechanisms of CIPN, such as proinflammatory cytokine release, astrocyte and microglial activation, oxidative stress, neuronal damage and apoptosis, mitochondrial damage, ectopic discharge, and ion channel activation. They decreased the severity of certain CIPN symptoms, such as thermal hyperalgesia and mechanical, tactile, and cold allodynia.
    CONCLUSIONS: Flavonoids hold immense promise in treating CIPN; thus, future research should investigate their effects in humans. Specifically, precise pharmacological mechanisms and side effects need to be elucidated in human models before clinical benefits can be achieved.
    Keywords:  CIPN; chemotherapy; flavonoids; peripheral neuropathy
    DOI:  https://doi.org/10.3390/cancers13071576
  31. Clin Transl Med. 2021 Mar;11(3): e372
    Glycine and N-acetylcysteine (GlyNAC) supplementation in older adults improves glutathione deficiency, oxidative stress, mitochondrial dysfunction, inflammation, insulin resistance, endothelial dysfunction, genotoxicity, muscle strength, and cognition: Results of a pilot clinical trial.
    Premranjan Kumar, Chun Liu, Jean W Hsu, Shaji Chacko, Charles Minard, Farook Jahoor, Rajagopal V Sekhar.
      BACKGROUND: Oxidative stress (OxS) and mitochondrial dysfunction are implicated as causative factors for aging. Older adults (OAs) have an increased prevalence of elevated OxS, impaired mitochondrial fuel-oxidation (MFO), elevated inflammation, endothelial dysfunction, insulin resistance, cognitive decline, muscle weakness, and sarcopenia, but contributing mechanisms are unknown, and interventions are limited/lacking. We previously reported that inducing deficiency of the antioxidant tripeptide glutathione (GSH) in young mice results in mitochondrial dysfunction, and that supplementing GlyNAC (combination of glycine and N-acetylcysteine [NAC]) in aged mice improves naturally-occurring GSH deficiency, mitochondrial impairment, OxS, and insulin resistance. This pilot trial in OA was conducted to test the effect of GlyNAC supplementation and withdrawal on intracellular GSH concentrations, OxS, MFO, inflammation, endothelial function, genotoxicity, muscle and glucose metabolism, body composition, strength, and cognition.METHODS: A 36-week open-label clinical trial was conducted in eight OAs and eight young adults (YAs). After all the participants underwent an initial (pre-supplementation) study, the YAs were released from the study. OAs were studied again after GlyNAC supplementation for 24 weeks, and GlyNAC withdrawal for 12 weeks. Measurements included red-blood cell (RBC) GSH, MFO; plasma biomarkers of OxS, inflammation, endothelial function, glucose, and insulin; gait-speed, grip-strength, 6-min walk test; cognitive tests; genomic-damage; glucose-production and muscle-protein breakdown rates; and body-composition.
    RESULTS: GlyNAC supplementation for 24 weeks in OA corrected RBC-GSH deficiency, OxS, and mitochondrial dysfunction; and improved inflammation, endothelial dysfunction, insulin-resistance, genomic-damage, cognition, strength, gait-speed, and exercise capacity; and lowered body-fat and waist-circumference. However, benefits declined after stopping GlyNAC supplementation for 12 weeks.
    CONCLUSIONS: GlyNAC supplementation for 24-weeks in OA was well tolerated and lowered OxS, corrected intracellular GSH deficiency and mitochondrial dysfunction, decreased inflammation, insulin-resistance and endothelial dysfunction, and genomic-damage, and improved strength, gait-speed, cognition, and body composition. Supplementing GlyNAC in aging humans could be a simple and viable method to promote health and warrants additional investigation.
    Keywords:  aging; cognition; inflammation; insulin resistance; mitochondria; oxidative stress; strength
    DOI:  https://doi.org/10.1002/ctm2.372
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