bims-minfam Biomed News
on Inflammation and metabolism in ageing and cancer
Issue of 2021–10–10
38 papers selected by
Ayesh Seneviratne, University of Toronto
  1. Iron: an underrated factor in aging.
  2. Mild mitochondrial impairment enhances inn3ate immunity and longevity through ATFS-1 and p38 signaling.
  3. The Science of Frailty: Sex Differences.
  4. Targeting cholesterol homeostasis in hematopoietic malignancies.
  5. Role of Intra- and Extracellular Lipid Signals in Cancer Stemness and Potential Therapeutic Strategy.
  6. Clonal hematopoiesis in CIN.
  7. Aging Matters Through the Years: A Retrospective.
  8. Frailty as a Clinically Relevant Measure of Human Aging.
  9. Inflammatory Modulation of Hematopoiesis: Linking Trained Immunity and Clonal Hematopoiesis with Chronic Disorders.
  10. Dietary Restriction Extends Lifespan through Metabolic Regulation of Innate Immunity.
  11. The Contribution of Physiological and Accelerated Aging to Cancer Progression Through Senescence-Induced Inflammation.
  12. Genetic repression of the antioxidant enzymes reduces the lifespan in Drosophila melanogaster.
  13. Better the cure you know: why patients with AML ≥60 years of age should be offered early allogeneic stem cell transplantation.
  14. Current and Emerging Therapies for Acute Myeloid Leukemia.
  15. An integrated network analysis approach to identify potential key genes, transcription factors, and microRNAs regulating human hematopoietic stem cell aging.
  16. Respiratory Symptoms Are Associated With Frailty in Older Adults With Normal Spirometry, Independent of Smoking, in the Canadian Longitudinal Study of Aging.
  17. Aging and Women's Health: An Update from the National Institute on Aging.
  18. All patients with AML over 60 years of age should not be offered early allogeneic stem cell transplantation.
  19. The role of frailty and functional impairment in healthy ageing.
  20. A comprehensive overview of the complex relationship between epigenetics, bioactive components, cancer, and aging.
  21. Type-1 Interferon to Prevent Leukemia Relapse after Allogeneic Transplantation.
  22. Caught in the antiviral crossfire: Ganciclovir-associated mutagenesis in HSC transplant recipients.
  23. The Aging Study of Pyeongchang Rural Area (ASPRA): Findings and Perspectives for Human Aging, Frailty, and Disability.
  24. Social vulnerability and aging of elderly people in the United States.
  25. A Mediterranean lifestyle and frailty incidence in older adults: the Seniors-ENRICA-1 cohort.
  26. Senescent immune cells release grancalcin to promote skeletal aging.
  27. Mesenchymal stromal cells: Putative microenvironmental modulators become cell therapy.
  28. CRISPR screens identify cholesterol biosynthesis as a therapeutic target on stemness and drug resistance of colon cancer.
  29. PHDs/CPT1B/VDAC1 axis regulates long-chain fatty acid oxidation in cardiomyocytes.
  30. Haematopoietic stem-cell transplantation in older adults: geriatric assessment, donor considerations, and optimisation of care.
  31. Cardiovascular Aging and Physical Activity: Insights From Metabolomics.
  32. Optimizing care for critically ill older adults.
  33. Orchestrating and sharing large multimodal data for transparent and reproducible research.
  34. Therapeutic Potential of Nutraceuticals and Dietary Supplements in the Prevention of Viral Diseases: A Review.
  35. Oklahoma Nathan Shock Aging Center - assessing the basic biology of aging from genetics to protein and function.
  36. Editorial: Coronavirus Disease (COVID-19): Diet, Inflammation and Nutritional Status.
  37. COVID-19 and metabolic disease: mechanisms and clinical management.
  38. THE PRESENT AND FUTURE OF PERSONALIZED NUTRITION.
  1. Aging (Albany NY). 2021 Oct 06. 13(undefined):
    Iron: an underrated factor in aging.
    Dennis Mangan.
      Iron is an essential element for virtually all living organisms, but its reactivity also makes it potentially harmful. Iron accumulates with aging, and is associated with many age-related diseases; it also shortens the lifespans of several model organisms. Blocking iron absorption through drugs or natural products extends lifespan. Many life-extending interventions, such as rapamycin, calorie restriction, and old plasma dilution can be explained by the effects they have on iron absorption, excretion, and metabolism. Control of body iron stores so that they remain in a low normal range may be an important, lifespan- and healthspan-extending intervention.
    Keywords:  aging; calorie restriction; iron; oxidative stress; plasma dilution
    DOI:  https://doi.org/10.18632/aging.203612
  2. EMBO Rep. 2021 Oct 07. e52964
    Mild mitochondrial impairment enhances inn3ate immunity and longevity through ATFS-1 and p38 signaling.
    Juliane C Campos, Ziyun Wu, Paige D Rudich, Sonja K Soo, Meeta Mistry, Julio Cb Ferreira, T Keith Blackwell, Jeremy M Van Raamsdonk.
      While mitochondrial function is essential for life in all multicellular organisms, a mild impairment of mitochondrial function can extend longevity in model organisms. By understanding the molecular mechanisms involved, these pathways might be targeted to promote healthy aging. In studying two long-lived mitochondrial mutants in C. elegans, we found that disrupting subunits of the mitochondrial electron transport chain results in upregulation of genes involved in innate immunity, which is driven by the mitochondrial unfolded protein response (mitoUPR) but also dependent on the canonical p38-mediated innate immune signaling pathway. Both of these pathways are required for the increased resistance to bacterial pathogens and extended longevity of the long-lived mitochondrial mutants, as is the FOXO transcription factor DAF-16. This work demonstrates that both the p38-mediated innate immune signaling pathway and the mitoUPR act in concert on the same innate immunity genes to promote pathogen resistance and longevity and that input from the mitochondria can extend longevity by signaling through these pathways. This indicates that multiple evolutionarily conserved genetic pathways controlling innate immunity also function to modulate lifespan.
    Keywords:   C. elegans ; aging; innate immunity; mitochondria; mitochondrial unfolded protein response
    DOI:  https://doi.org/10.15252/embr.202152964
  3. Clin Geriatr Med. 2021 Nov;pii: S0749-0690(21)00042-2. [Epub ahead of print]37(4): 625-638
    The Science of Frailty: Sex Differences.
    Caroline Park, Fred C Ko.
      Frailty is an important clinical syndrome of age-related decline in physiologic reserve and increased vulnerability. In older adults, frailty leads to progressive multisystem decline and increased adverse clinical outcomes. The pathophysiology of frailty is hypothesized to be driven by dysregulation of neuroendocrine, inflammatory, and metabolic pathways. Sex-specific differences in the prevalence of frailty have been observed. Treatment interventions of geriatric care can be applied to the care of frail older women with these differences in mind. As additional evidence regarding sex-specific differences in frailty emerges, research efforts should encompass the development of screening tools and therapeutic interventions that optimize outcomes.
    Keywords:  5 Ms; Frailty; Sex differences; Sex-frailty paradox
    DOI:  https://doi.org/10.1016/j.cger.2021.05.008
  4. Blood. 2021 Oct 05. pii: blood.2021012788. [Epub ahead of print]
    Targeting cholesterol homeostasis in hematopoietic malignancies.
    Andrea Brendolan, Vincenzo Russo.
      Cholesterol is a vital lipid for cellular functions. It is necessary for membrane biogenesis, cell proliferation and differentiation. In addition to maintaining cell integrity and permeability, increasing evidence indicates a strict link between cholesterol homeostasis, inflammation and haematological tumors. This makes cholesterol homeostasis an optimal therapeutic target for hematopoietic malignancies. Manipulating cholesterol homeostasis either interfering with its synthesis or activating the reverse cholesterol transport via the engagement of liver X receptors (LXRs), affects the integrity of tumor cells both in vitro and in vivo. Cholesterol homeostasis has also been manipulated to restore antitumor immune responses in preclinical models. These observations have prompted clinical trials in acute myeloid leukemia (AML) to test the combination of chemotherapy with drugs interfering with cholesterol synthesis, i.e. statins. We review the role of cholesterol homeostasis in hematopoietic malignancies, as well as in cells of the tumor microenvironment, and discuss the potential use of lipid modulators for therapeutic purposes.
    DOI:  https://doi.org/10.1182/blood.2021012788
  5. Front Pharmacol. 2021 ;12 730751
    Role of Intra- and Extracellular Lipid Signals in Cancer Stemness and Potential Therapeutic Strategy.
    Jianming Hu, Leyi Zhang, Wuzhen Chen, Lesang Shen, Jingxin Jiang, Shanshan Sun, Zhigang Chen.
      Accumulating evidence showed that cancer stem cells (CSCs) play significant roles in cancer initiation, resistance to therapy, recurrence and metastasis. Cancer stem cells possess the ability of self-renewal and can initiate tumor growth and avoid lethal factors through flexible metabolic reprogramming. Abnormal lipid metabolism has been reported to be involved in the cancer stemness and promote the development of cancer. Lipid metabolism includes lipid uptake, lipolysis, fatty acid oxidation, de novo lipogenesis, and lipid desaturation. Abnormal lipid metabolism leads to ferroptosis of CSCs. In this review, we comprehensively summarized the role of intra- and extracellular lipid signals in cancer stemness, and explored the feasibility of using lipid metabolism-related treatment strategies for future cancer.
    Keywords:  cancer stem cell; ferroptosis; lipid metabolism; therapeutic target; tumor environment
    DOI:  https://doi.org/10.3389/fphar.2021.730751
  6. Blood. 2021 Oct 07. 138(14): 1204-1206
    Clonal hematopoiesis in CIN.
    Laura G Schuettpelz.
      
    DOI:  https://doi.org/10.1182/blood.2021012877
  7. J Psychosoc Nurs Ment Health Serv. 2021 Oct;59(10): 7-11
    Aging Matters Through the Years: A Retrospective.
    Jeanne M Sorrell.
      The goal of the Aging Matters column is to address important issues related to geropsychiatry and the well-being of older adults. This article offers reflections on columns from the past 15 years and how the aging process has changed in issues related to aging and technology, aging healthfully, end-of-life issues, caregivers for older adults, and growing old in American society. To promote successful aging, we need to hear stories of what it is like to grow old in America. We also need research to better understand the aging process and what is needed for successful aging. In addition, we need policies and resources that help ensure well-trained caregivers who can protect vulnerable older adults and help them age healthfully. Stories of individuals, research, and health care policies need to be connected to create meaningful changes within the health care system. [Journal of Psychosocial Nursing and Mental Health Services, 59(10), 7-11.].
    DOI:  https://doi.org/10.3928/02793695-20210908-01
  8. Ann Geriatr Med Res. 2021 Sep;25(3): 139-140
    Frailty as a Clinically Relevant Measure of Human Aging.
    Hee-Won Jung.
      
    DOI:  https://doi.org/10.4235/agmr.21.0106
  9. Annu Rev Physiol. 2021 Oct 06.
    Inflammatory Modulation of Hematopoiesis: Linking Trained Immunity and Clonal Hematopoiesis with Chronic Disorders.
    Triantafyllos Chavakis, Ben Wielockx, George Hajishengallis.
      Inflammation-adapted hematopoietic stem and progenitor cells (HSPCs) have long been appreciated as key drivers of emergency myelopoiesis, thereby enabling the bone marrow to meet the elevated demand for myeloid cell generation under various stress conditions, such as systemic infection, inflammation, or myelosuppressive insults. In recent years, HSPC adaptations were associated with potential involvement in the induction of long-lived trained immunity and the emergence of clonal hematopoiesis of indeterminate potential (CHIP). Whereas trained immunity has context-dependent effects, protective in infections and tumors but potentially detrimental in chronic inflammatory diseases, CHIP increases the risk for hematological neoplastic disorders and cardiometabolic pathologies. This review focuses on the inflammatory regulation of HSPCs in the aforementioned processes and discusses how modulation of HSPC function could lead to novel therapeutic interventions. Expected final online publication date for the Annual Review of Physiology, Volume 84 is February 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
    DOI:  https://doi.org/10.1146/annurev-physiol-052521-013627
  10. Cell Metab. 2021 Oct 05. pii: S1550-4131(21)00379-X. [Epub ahead of print]33(10): 2090
    Dietary Restriction Extends Lifespan through Metabolic Regulation of Innate Immunity.
    Ziyun Wu, Meltem Isik, Natalie Moroz, Michael J Steinbaugh, Peng Zhang, T Keith Blackwell.
      
    DOI:  https://doi.org/10.1016/j.cmet.2021.08.016
  11. Front Oncol. 2021 ;11 747822
    The Contribution of Physiological and Accelerated Aging to Cancer Progression Through Senescence-Induced Inflammation.
    Jorge Morales-Valencia, Gregory David.
      Senescent cells are found to accumulate in aged individuals, as well as in cancer patients that receive chemotherapeutic treatment. Although originally believed to halt cancer progression due to their characteristic growth arrest, senescent cells remain metabolically active and secrete a combination of inflammatory agents, growth factors and proteases, collectively known as the senescence-associated secretory phenotype (SASP). In this review, we discuss the contribution of senescent cells to cancer progression through their ability to alter cancer cells' properties and to generate a microenvironment that promotes tumor growth. Furthermore, recent evidence suggests that senescent cells are able resume proliferation and drive cancer relapse, pointing to the use of senolytics and SASP modulators as a potential approach to prevent tumor resurgence following treatment cessation. Thus, a better understanding of the hallmarks of senescence and the impact of the SASP will allow the development of improved targeted therapeutic strategies to leverage vulnerabilities associated with this cellular state.
    Keywords:  SASP; aging; cancer; inflammation; senescence
    DOI:  https://doi.org/10.3389/fonc.2021.747822
  12. J Comp Physiol B. 2021 Oct 08.
    Genetic repression of the antioxidant enzymes reduces the lifespan in Drosophila melanogaster.
    S Deepashree, T Shivanandappa, Saraf R Ramesh.
      Aging is a biological process associated with gradual loss of function caused by cellular and molecular damages ultimately leading to mortality. Free radicals are implicated in oxidative damage which affects the longevity of organisms. Natural cellular defenses involving antioxidant enzymes delay or prevent oxidative damage and, therefore, influence the aging process and longevity has been shown in many species including Drosophila. We and others have shown that oxidative resistance is an important mechanism in the aging process in Drosophila. Therefore, we hypothesized that repressing endogenous antioxidant defenses shortens longevity in Drosophila. To study the influence of natural defense mechanisms against oxidative stress in aging, we have investigated the effect of genetic repression of the antioxidant enzymes, superoxide dismutase (SOD) and catalase (CAT), on longevity in Drosophila using transgenic RNAi flies and in vivo inhibition of the enzymes with chemical inhibitors. RNAi lines of Drosophila viz., UAS-sod1-IR and UAS-cat-IR, are driven ubiquitously using Act5C-Gal4 and Tubulin-Gal4 to achieve the suppression of SOD1 and CAT activities, respectively. We show that genetic repression of SOD1 and CAT by RNAi in transgenic flies led to drastically reduced longevity (SOD1, 77%; CAT, 83%), presenting the evidence for the role of endogenous antioxidant defenses in lifespan extension in Drosophila. Further, our study shows that the enzyme inhibitors, diethyldithiocarbamate and 3-amino-1,2,4-triazole, although lower the enzyme activities in vivo in flies, but did not affect longevity, which could be attributed to the factors such as bioavailability and metabolism of the inhibitors and adaptive mechanisms involving de novo synthesis of the enzymes. Our study of genetic repression using transgenic RNAi provides experimental evidence that extended longevity is associated with endogenous antioxidant defenses and aging is correlated with oxidative stress resistance.
    Keywords:  Chemical inhibitors; Longevity; RNAi
    DOI:  https://doi.org/10.1007/s00360-021-01412-7
  13. Blood Adv. 2021 Oct 04. pii: bloodadvances.2021004829. [Epub ahead of print]
    Better the cure you know: why patients with AML ≥60 years of age should be offered early allogeneic stem cell transplantation.
    Siok-Keen Tey, Steven W Lane.
      
    DOI:  https://doi.org/10.1182/bloodadvances.2021004829
  14. Cancer Treat Res. 2021 ;181 57-73
    Current and Emerging Therapies for Acute Myeloid Leukemia.
    Brian Ball, Matthew Mei, Salman Otoukesh, Anthony Stein.
      Acute myeloid leukemia (AML) is predominantly a disease of older adults and the majority of affected patients succumb to the disease. After decades of slow progress, the last 5 years have witnessed remarkable progress in AML therapy with the approval of multiple highly active and well-tolerated novel therapies. Notable among these are agents targeting driver mutations including FLT3, IDH1/2 as well as the Bcl-2 inhibitor venetoclax. The combination of hypomethylating agents with venetoclax is highly active in AML and has become the standard of care for older patients as well as those with comorbidities. As a result of these advances, a larger proportion of AML patients now achieve complete remissions enabling them to undergo allogeneic hematopoietic cell transplantation with curative intent. Progress is also being made in the field of monoclonal antibodies targeting leukemia antigens and other immunotherapies and many such agents are currently under active investigation.
    Keywords:  Acute myeloid leukemia; Bcl-2; FLT3; IDH; Mutation; Treatment
    DOI:  https://doi.org/10.1007/978-3-030-78311-2_4
  15. Mol Omics. 2021 Oct 04.
    An integrated network analysis approach to identify potential key genes, transcription factors, and microRNAs regulating human hematopoietic stem cell aging.
    Vinay Randhawa, Manoj Kumar.
      Hematopoietic stem cells (HSCs) undergo functional deterioration with increasing age that causes loss of their self-renewal and regenerative potential. Despite various efforts, significant success in identifying molecular regulators of HSC aging has not been achieved, one prime reason being the non-availability of appropriate human HSC samples. To demonstrate the scope of integrating and re-analyzing the HSC transcriptomics data available, we used existing tools and databases to structure a sequential data analysis pipeline to predict potential candidate genes, transcription factors, and microRNAs simultaneously. This sequential approach comprises (i) collecting matched young and aged mice HSC sample datasets, (ii) identifying differentially expressed genes, (iii) identifying human homologs of differentially expressed genes, (iv) inferring gene co-expression network modules, and (v) inferring the microRNA-transcription factor-gene regulatory network. Systems-level analyses of HSC interaction networks provided various insights based on which several candidates were predicted. For example, 16 HSC aging-related candidate genes were predicted (e.g., CD38, BRCA1, AGTR1, GSTM1, etc.) from GCN analysis. Following this, the shortest path distance-based analyses of the regulatory network predicted several novel candidate miRNAs and TFs. Among these, miR-124-3p was a common regulator in candidate gene modules, while TFs MYC and SP1 were identified to regulate various candidate genes. Based on the regulatory interactions among candidate genes, TFs, and miRNAs, a potential regulation model of biological processes in each of the candidate modules was predicted, which provided systems-level insights into the molecular complexity of each module to regulate HSC aging.
    DOI:  https://doi.org/10.1039/d1mo00199j
  16. Respir Care. 2021 Oct 05. pii: respcare.09225. [Epub ahead of print]
    Respiratory Symptoms Are Associated With Frailty in Older Adults With Normal Spirometry, Independent of Smoking, in the Canadian Longitudinal Study of Aging.
    Chris P Verschoor, Robert E Dales, MyLinh Duong, Caitlyn Bourque, Oxana Mian, Jinhui Ma, Lauren E Griffith.
       BACKGROUND: Recent studies have demonstrated that even in the absence of lung impairment as determined by spirometry, smoking and respiratory symptoms are associated with poor overall health and well-being. However, this relationship is not well defined; and it remains unclear the degree to which symptoms are related to poor health, independent of smoking. This is of particular importance to older adults, as they are more likely to exhibit respiratory symptoms and are, therefore, at risk of not receiving appropriate treatment if they have never smoked and have normal spirometry.
    METHODS: We performed a cross-sectional analysis of data from the Canadian Longitudinal Study on Aging to delineate the associations of respiratory symptoms and smoking on the health of participants age 45-86 who exhibited normal spirometry. Participant health was estimated using a frailty index, a multidimensional measure of vulnerability to adverse outcomes that has been validated in numerous health settings.
    RESULTS: Of the 21,293 participants included in our analysis, 87% exhibited a normal FEV1, FVC, and FEV1/FVC; of those, 45% reported at least one respiratory symptom, and 50% were former or current smokers. Both respiratory symptoms and smoking were independently associated with frailty (median interquartile range [IQR] = 0.11 [0.07-0.15]), the most substantial associations observed for those having at least one respiratory symptom (adjusted β 0.023, 95% CI 0.022-0.025) and current smokers with > 10 pack-year exposure (adjusted β 0.014, 95% CI [0.010-0.019). Not only was the association between symptoms and frailty evident in never smokers, a significant proportion of the total effect of smoking on frailty was observed to be mediated by symptoms.
    CONCLUSIONS: Our data show that respiratory symptoms, regardless of smoking history, were a significant correlate of frailty in older adults with normal spirometry. Hence, they should not be simply regarded as a benign by-product of aging.
    Keywords:  Canadian Longitudinal Study on Aging; frailty; lung function; smoking; symptoms
    DOI:  https://doi.org/10.4187/respcare.09225
  17. Clin Geriatr Med. 2021 Nov;pii: S0749-0690(21)00036-7. [Epub ahead of print]37(4): 533-541
    Aging and Women's Health: An Update from the National Institute on Aging.
    Catherine Nagy, Patricia Jones, Marie A Bernard.
      Older women outnumber older men in the United States and may experience a range of physical, cognitive, social, and emotional challenges. The "Geriatric 5 Ms"-Multicomplexity, Mind, Mobility, Medications, and What Matters Most-provide a useful framework for understanding and addressing the health and wellness needs of older women in the clinic. The National Institute on Aging, a component of the US National Institutes of Health, supports a vibrant program of aging research with many immediately implementable findings and useful resources for the busy clinician.
    Keywords:  Aging; Clinical care; Women’s health
    DOI:  https://doi.org/10.1016/j.cger.2021.05.002
  18. Blood Adv. 2021 Oct 04. pii: bloodadvances.2021004799. [Epub ahead of print]
    All patients with AML over 60 years of age should not be offered early allogeneic stem cell transplantation.
    H Joachim Deeg.
      
    DOI:  https://doi.org/10.1182/bloodadvances.2021004799
  19. Int Psychogeriatr. 2021 Oct 08. 1-7
    The role of frailty and functional impairment in healthy ageing.
    Simone Reppermund.
      
    DOI:  https://doi.org/10.1017/S1041610221002593
  20. Crit Rev Food Sci Nutr. 2021 Oct 08. 1-13
    A comprehensive overview of the complex relationship between epigenetics, bioactive components, cancer, and aging.
    Şule Kocabas, Nevin Sanlier.
      Among age-related diseases, the incidence of cancer increases significantly due to the overlap of some molecular pathways between cancer and aging. While the genetic influence on the human lifespan is estimated to be about 20-25%, epigenetic changes play an important role in modulating individual health status, aging. Aging and age-related conditions are processes that can be modified by both genetic, environmental factors, including dietary habits. Epigenetics is a new discipline has significant potential to be applied for the prevention, management of certain carcinomas and diseases. Epigenetic modifications may play an important role in disease occurrence and pathogenesis. Some nutritional components can be significantly effective in the prevention of breast, skin, esophagus, colorectal, prostate, pancreatic, lung cancers. It contains minerals, vitamins, and some bioactive components (curcumin, indole 3 carbinol, di-indolylmethane, sulforaphane, epigallocatechin-3-gallate, genistein, resveratrol, pterostilbene, apigenin, etc.) regulatory processes. However, compelling evidence suggests that dietary habits can manipulate the aging process and/or its consequences, have health benefits. Aging processes become complex when combined with the relational role of bioactive nutritional components on gene expression. In this review, the relationship between epigenetic processes caused by DNA methylylation, histone modification, non-coding m-RNA, and telomerase activity, the risk of aging and cancer is discussed.
    Keywords:  aging; bioactive components; cancer; epigenetics; nutrition
    DOI:  https://doi.org/10.1080/10408398.2021.1986803
  21. Blood Adv. 2021 Oct 04. pii: bloodadvances.2021004908. [Epub ahead of print]
    Type-1 Interferon to Prevent Leukemia Relapse after Allogeneic Transplantation.
    John M Magenau, Daniel C Peltier, Mary Riwes, Attaphol Pawarode, Brian Parkin, Thomas M Braun, Sarah Anand, Monalisa Ghosh, John Maciejewski, Gregory A Yanik, Sung Won Choi, Moshe Talpaz, Pavan Reddy.
      A potent graft-versus-leukemia (GVL) response is crucial in preventing relapse, the major impediment to successful allogeneic hematopoietic cell transplantation (HCT). In preclinical studies, Type-1 interferon (IFNα) enhanced cross-presentation of leukemia specific antigens by CD8α dendritic cells (DCs) and amplified GVL. This observation was translated into a proof-of-concept phase I/II clinical trial with long-acting IFNα (pegIFNα) in patients undergoing HCT for high-risk acute myeloid leukemia (AML). Patients with treatment resistant AML not in remission or poor risk leukemia were administered four dosages of pegIFNα every 14 days beginning at day -1 before HCT. Dose selection was established by adaptive design that continuously assessed the probability of dose limiting toxicities throughout the trial. Efficacy was evaluated by determining the six-month incidence of relapse at the maximum tolerated dose (MTD). Thirty-six patients (median age of 60 years) received pegIFNα treatment. Grade 3 or greater SAEs occurred in 25% of patients establishing 180mcg as the MTD. In phase II, the incidence of relapse was 39% at six-months, which was sustained through one-year post HCT. The incidence of transplant-related mortality was 13% and severe grade III-IV acute GVHD occurred in 11%. Paired blood samples from donors and recipients after HCT indicated elevated levels of Type-1 IFN with cellular response, persistence of cross-presenting DCs and circulating leukemia antigen specific T cells. These data suggest that prophylactic administration of pegIFNα is feasible in the peri-HCT period. In high-risk AML, increased toxicity was not observed with preliminary evidence for reduction in leukemia relapse after HCT.
    DOI:  https://doi.org/10.1182/bloodadvances.2021004908
  22. Cell Stem Cell. 2021 Oct 07. pii: S1934-5909(21)00387-8. [Epub ahead of print]28(10): 1683-1685
    Caught in the antiviral crossfire: Ganciclovir-associated mutagenesis in HSC transplant recipients.
    Michael Spencer Chapman, Jyoti Nangalia.
      In this issue of Cell Stem Cell, de Kanter et al. (2021) show that most allogeneic hematopoietic stem cells do not acquire additional somatic mutations following transplantation. However, they observe somatic mutagenesis associated with the antiviral drug ganciclovir and find plausible evidence that it may contribute to some post-transplant malignancies.
    DOI:  https://doi.org/10.1016/j.stem.2021.09.011
  23. Ann Geriatr Med Res. 2021 Sep;25(3): 160-169
    The Aging Study of Pyeongchang Rural Area (ASPRA): Findings and Perspectives for Human Aging, Frailty, and Disability.
    Ji Yeon Baek, Eunju Lee, Gahee Oh, Yu Rang Park, Heayon Lee, Jihye Lim, Hyungchul Park, Chan Mi Park, Chang Ki Lee, Hee-Won Jung, Il-Young Jang, Dae Hyun Kim.
      The Aging Study of Pyeongchang Rural Area (ASPRA) is a population-based, prospective cohort study of older adults in Pyeongchang, South Korea. Since the initial enrollment of 382 participants, the ASPRA has been maintained and has conducted comprehensive geriatric assessments annually, gradually expanding its population and coverage area. As a cohort study of aging-related conditions and their functional consequences, the ASPRA leveraged Pyeongchang's relatively low annual population movement rate and its healthcare delivery system, which was largely maintained by community health posts. Since its establishment, the ASPRA has reported numerous observational and multicomponent intervention studies on functional decline, geriatric syndrome, and frailty. Here, we discuss the findings and perspectives of ASPRA studies. We hope that the ASPRA enables the further implementation of a longitudinal study design on geriatric parameters and the development of public health strategies targeting aging-related conditions, especially in resource-limited community settings.
    Keywords:  Aging phenotype; Cohort; Frailty; Intervention
    DOI:  https://doi.org/10.4235/agmr.21.0100
  24. SSM Popul Health. 2021 Dec;16 100924
    Social vulnerability and aging of elderly people in the United States.
    Ana Lucia Abeliansky, Devin Erel, Holger Strulik.
      We use 7 waves of the Health and Retirement Study and construct a social vulnerability index (SVI) for elderly U.S. Americans (born 1913-1966). We show that the SVI is mildly larger for men than for women and increases in age from above age 60 onwards for both genders. Social vulnerability of men (but not of women) is lower in the West and Midwest than in other regions and higher income mildly reduces the SVI for men (but not for women). In cohort analysis we find an increase of the SVI for individuals born in the late 1940s or later, which is, however, statistically significant only for women. In order to investigate the nexus between social vulnerability and aging, we construct a frailty index from the same data. We find that socially vulnerable persons display more health deficits at any age. Using the initial SVI (at first interview) we find that social vulnerability exerts a significant impact on subsequent accumulation of health deficits, which is of about the same size for men and women. A one standard deviation increase in the initial SVI leads to a 20 percent increase of the frailty index at any age.
    Keywords:  Aging; Frailty index; Health; Social capital; Social vulnerability; United States
    DOI:  https://doi.org/10.1016/j.ssmph.2021.100924
  25. J Gerontol A Biol Sci Med Sci. 2021 Oct 06. pii: glab292. [Epub ahead of print]
    A Mediterranean lifestyle and frailty incidence in older adults: the Seniors-ENRICA-1 cohort.
    Javier Maroto-Rodriguez, Mario Delgado-Velandia, Rosario Ortolá, Esther García-Esquinas, David Martinez-Gomez, Ellen A Struijk, Esther Lopez-Garcia, Fernando Rodriguez-Artalejo, Mercedes Sotos-Prieto.
       BACKGROUND: Frailty is a geriatric syndrome that entails high risk of hospitalization, disability, and death. While adherence to Mediterranean diet has been associated with lower risk of frailty, the joint effect of diet and lifestyle is uncertain. This study examined the association between a Mediterranean lifestyle (diet, customs, and traditions) and frailty incidence in older adults.
    METHODS: We analyzed data from 1,880 individuals aged ≥ 60 from the prospective Seniors-ENRICA-1 cohort. Adherence to the Mediterranean lifestyle was assessed at baseline with the 27-item MEDLIFE index (higher scores representing better adherence), divided into three blocks: 1) "Mediterranean food consumption", 2) "Mediterranean dietary habits" (practices around meals)" and 3) "Physical activity, rest, social habits and conviviality". Frailty was ascertained as the presence of ≥ 3 of the 5 Fried criteria: a) Exhaustion; b) Muscle weakness; c) Low physical activity; d) Slow walking speed; e) Unintentional weight loss. Main statistical analyses were performed using logistic regression models, adjusting for the main confounders.
    RESULTS: After a 3.3-y follow-up, 136 incident frailty cases were ascertained. Compared with participants in the lowest tertile of the MEDLIFE score, the OR (95% CI) for frailty was 0.88 (0.58-1.34) for the second tertile, and 0.38 (0.21-0.69) for the third tertile (p-trend = 0.003). Blocks 1 and 3 of the MEDLIFE score were independently associated with lower frailty risk. Most items within these blocks showed a tendency to reduced frailty.
    CONCLUSIONS: Higher adherence to a Mediterranean lifestyle was associated with lower risk of frailty.
    Keywords:  Mediterranean lifestyle; Spanish population; diet index; lifestyle index
    DOI:  https://doi.org/10.1093/gerona/glab292
  26. Cell Metab. 2021 Oct 05. pii: S1550-4131(21)00372-7. [Epub ahead of print]33(10): 1957-1973.e6
    Senescent immune cells release grancalcin to promote skeletal aging.
    Chang-Jun Li, Ye Xiao, Yu-Chen Sun, Wen-Zhen He, Ling Liu, Mei Huang, Chen He, Min Huang, Kai-Xuan Chen, Jing Hou, Xu Feng, Tian Su, Qi Guo, Yan Huang, Hui Peng, Mi Yang, Guang-Hui Liu, Xiang-Hang Luo.
      Skeletal aging is characterized by low bone turnover and marrow fat accumulation. However, the underlying mechanism for this imbalance is unclear. Here, we show that during aging in rats and mice proinflammatory and senescent subtypes of immune cells, including macrophages and neutrophils, accumulate in the bone marrow and secrete abundant grancalcin. The injection of recombinant grancalcin into young mice was sufficient to induce premature skeletal aging. In contrast, genetic deletion of Gca in neutrophils and macrophages delayed skeletal aging. Mechanistically, we found that grancalcin binds to the plexin-b2 receptor and partially inactivates its downstream signaling pathways, thus repressing osteogenesis and promoting adipogenesis of bone marrow mesenchymal stromal cells. Heterozygous genetic deletion of Plexnb2 in skeletal stem cells abrogated the improved bone phenotype of Gca-knockout mice. Finally, we developed a grancalcin-neutralizing antibody and showed that its treatment of older mice improved bone health. Together, our data suggest that grancalcin could be a potential target for the treatment of age-related osteoporosis.
    Keywords:  bone marrow mesenchymal stromal cells; bone remodeling; grancalcin; immune cells; immunoregulation; linage fate; plexin-b2 pathway; senescence; skeletal aging
    DOI:  https://doi.org/10.1016/j.cmet.2021.08.009
  27. Cell Stem Cell. 2021 Oct 07. pii: S1934-5909(21)00382-9. [Epub ahead of print]28(10): 1708-1725
    Mesenchymal stromal cells: Putative microenvironmental modulators become cell therapy.
    Mauro Krampera, Katarina Le Blanc.
      An exceptional safety profile has been shown in a large number of cell therapy clinical trials that use mesenchymal stromal cells (MSCs). However, reliable potency assays are still lacking to predict MSC immunosuppressive efficacy in the clinical setting. Nevertheless, MSCs are approved in Japan and Europe for the treatment of graft-versus-host and Crohn's fistular diseases, but not in the United States for any clinical indication. We discuss potential mechanisms of action for the therapeutic effects of MSC transplantation, experimental models that dissect tissue modulating function of MSCs, and approaches for identifying MSC effects in vivo by integrating biomarkers of disease and MSC activity.
    DOI:  https://doi.org/10.1016/j.stem.2021.09.006
  28. Oncogene. 2021 Oct 07.
    CRISPR screens identify cholesterol biosynthesis as a therapeutic target on stemness and drug resistance of colon cancer.
    Shanshan Gao, Fraser Soares, Shiyan Wang, Chi Chun Wong, Huarong Chen, Zhenjie Yang, Weixin Liu, Minnie Y Y Go, Musaddeque Ahmed, Yong Zeng, Catherine Adell O'Brien, Joseph J Y Sung, Housheng Hansen He, Jun Yu.
      Cancer stem cells (CSCs) are responsible for tumor progression, recurrence, and drug resistance. To identify genetic vulnerabilities of colon cancer, we performed targeted CRISPR dropout screens comprising 657 Drugbank targets and 317 epigenetic regulators on two patient-derived colon CSC-enriched spheroids. Next-generation sequencing of pooled genomic DNAs isolated from surviving cells yielded therapeutic candidates. We unraveled 44 essential genes for colon CSC-enriched spheroids propagation, including key cholesterol biosynthetic genes (HMGCR, FDPS, and GGPS1). Cholesterol biosynthesis was induced in colon cancer tissues, especially CSC-enriched spheroids. The genetic and pharmacological inhibition of HMGCR/FDPS impaired self-renewal capacity and tumorigenic potential of the spheroid models in vitro and in vivo. Mechanistically, HMGCR or FDPS depletion impaired cancer stemness characteristics by activating TGF-β signaling, which in turn downregulated expression of inhibitors of differentiation (ID) proteins, key regulators of cancer stemness. Cholesterol and geranylgeranyl diphosphate (GGPP) rescued the growth inhibitory and signaling effect of HMGCR/FDPS blockade, implying a direct role of these metabolites in modulating stemness. Finally, cholesterol biosynthesis inhibitors and 5-FU demonstrated antitumor synergy in colon CSC-enriched spheroids, tumor organoids, and xenografts. Taken together, our study unravels novel genetic vulnerabilities of colon CSC-enriched spheroids and suggests cholesterol biosynthesis as a potential target in conjunction with traditional chemotherapy for colon cancer treatment.
    DOI:  https://doi.org/10.1038/s41388-021-01882-7
  29. Cell Rep. 2021 Oct 05. pii: S2211-1247(21)01221-3. [Epub ahead of print]37(1): 109767
    PHDs/CPT1B/VDAC1 axis regulates long-chain fatty acid oxidation in cardiomyocytes.
    Aude Angelini, Pradip K Saha, Antrix Jain, Sung Yun Jung, Randall L Mynatt, Xinchun Pi, Liang Xie.
      Cardiac metabolism is a high-oxygen-consuming process, showing a preference for long-chain fatty acid (LCFA) as the fuel source under physiological conditions. However, a metabolic switch (favoring glucose instead of LCFA) is commonly reported in ischemic or late-stage failing hearts. The mechanism regulating this metabolic switch remains poorly understood. Here, we report that loss of PHD2/3, the cellular oxygen sensors, blocks LCFA mitochondria uptake and β-oxidation in cardiomyocytes. In high-fat-fed mice, PHD2/3 deficiency improves glucose metabolism but exacerbates the cardiac defects. Mechanistically, we find that PHD2/3 bind to CPT1B, a key enzyme of mitochondrial LCFA uptake, promoting CPT1B-P295 hydroxylation. Further, we show that CPT1B-P295 hydroxylation is indispensable for its interaction with VDAC1 and LCFA β-oxidation. Finally, we demonstrate that a CPT1B-P295A mutant constitutively binds to VDAC1 and rescues LCFA metabolism in PHD2/3-deficient cardiomyocytes. Together, our data identify an oxygen-sensitive regulatory axis involved in cardiac metabolism.
    Keywords:  cardiac metabolism switch; cardiomyocyte; carnitine O-palmitoyltransferase 1b; heart failure; hypoxia; long-chain fatty acid; myocardial infarction; prolyl hydroxylase domain protein; voltage-dependent anion channel
    DOI:  https://doi.org/10.1016/j.celrep.2021.109767
  30. Lancet Haematol. 2021 Oct 05. pii: S2352-3026(21)00231-3. [Epub ahead of print]
    Haematopoietic stem-cell transplantation in older adults: geriatric assessment, donor considerations, and optimisation of care.
    Vanessa E Kennedy, Rebecca L Olin.
      Haematopoietic stem-cell transplantation (HSCT) has seen substantial growth among older adults. Chronological age is no longer viewed as an absolute barrier to HSCT, and alternative methods for assessing pre-transplantation fitness are increasingly used. In this Series paper, we summarise the metrics for pre-transplantation risk assessment in older adults, including both traditional metrics and geriatric assessment, and the ability of these metrics to predict post-transplantation outcomes. We also discuss strategies to broaden the utility of geriatric assessment, including in chronologically younger HSCT candidates and to guide individualised pre-transplantation interventions. Finally, we discuss donor considerations in older adults, including use of older sibling donors, haploidentical donors, and emerging data for donor-associated clonal haematopoiesis of indeterminate potential.
    DOI:  https://doi.org/10.1016/S2352-3026(21)00231-3
  31. Front Cardiovasc Med. 2021 ;8 728228
    Cardiovascular Aging and Physical Activity: Insights From Metabolomics.
    Ryan Mao Heng Lim, Angela S Koh.
      The purpose of this review is to explore how metabolomics can help uncover mechanisms through which physical activity may influence the progression of cardiovascular aging. Cardiovascular aging is a process of functional and structural changes in older adults which can progress to cardiovascular disease. Metabolomics profiling is an investigative tool that can track the diverse changes which occur in human biochemistry with physical activity and aging. This mini review will summarize published investigations in metabolomics and physical activity, with a specific focus on the metabolic pathways that connect physical activity with cardiovascular aging.
    Keywords:  aging; cardiovascular disease; cardiovascular trial; metabolomics; musculoskeletal function; physical activity
    DOI:  https://doi.org/10.3389/fcvm.2021.728228
  32. CMAJ. 2021 Oct 04. 193(39): E1525-E1533
    Optimizing care for critically ill older adults.
    Olivia Geen, Bram Rochwerg, Xuyi Mimi Wang.
      
    DOI:  https://doi.org/10.1503/cmaj.210652
  33. Nat Commun. 2021 Oct 04. 12(1): 5797
    Orchestrating and sharing large multimodal data for transparent and reproducible research.
    Massive Analysis Quality Control (MAQC) Society Board of Directors
      Reproducibility is essential to open science, as there is limited relevance for findings that can not be reproduced by independent research groups, regardless of its validity. It is therefore crucial for scientists to describe their experiments in sufficient detail so they can be reproduced, scrutinized, challenged, and built upon. However, the intrinsic complexity and continuous growth of biomedical data makes it increasingly difficult to process, analyze, and share with the community in a FAIR (findable, accessible, interoperable, and reusable) manner. To overcome these issues, we created a cloud-based platform called ORCESTRA ( orcestra.ca ), which provides a flexible framework for the reproducible processing of multimodal biomedical data. It enables processing of clinical, genomic and perturbation profiles of cancer samples through automated processing pipelines that are user-customizable. ORCESTRA creates integrated and fully documented data objects with persistent identifiers (DOI) and manages multiple dataset versions, which can be shared for future studies.
    DOI:  https://doi.org/10.1038/s41467-021-25974-w
  34. Front Nutr. 2021 ;8 679312
    Therapeutic Potential of Nutraceuticals and Dietary Supplements in the Prevention of Viral Diseases: A Review.
    Saumya Singh, Prithwish Kola, Dalveer Kaur, Gisha Singla, Vibhu Mishra, Parmjit S Panesar, Kumar Mallikarjunan, Meena Krishania.
      Nowadays, despite enormous scientific advances, viral diseases remain the leading cause of morbidity worldwide, and their potential to spread is escalating, eventually turning into pandemics. Nutrition can play a major role in supporting the immune system of the body and for the optimal functioning of the cells of the immune system. A healthy diet encompassing vitamins, multi-nutrient supplements, functional foods, nutraceuticals, and probiotics can play a pivotal role in combating several viral invasions in addition to strengthening the immune system. This review provides comprehensive information on diet-based scientific recommendations, evidence, and worldwide case studies in light of the current pandemic and also with a particular focus on virus-induced respiratory tract infections. After reviewing the immune potential of nutraceuticals based on the lab studies and on human studies, it was concluded that bioactive compounds such as nutraceuticals, vitamins, and functional foods (honey, berries, etc.) with proven antiviral efficacy, in addition to pharmaceutical medication or alone as dietary supplements, can prove instrumental in treating a range of virus-induced infections in addition to strengthening the immune system. Milk proteins and peptides can also act as adjuvants for the design of more potent novel antiviral drugs.
    Keywords:  coronavirus; dietary supplements; functional foods; immunity; nutraceuticals; viral diseases
    DOI:  https://doi.org/10.3389/fnut.2021.679312
  35. Geroscience. 2021 Oct 04.
    Oklahoma Nathan Shock Aging Center - assessing the basic biology of aging from genetics to protein and function.
    Holly Van Remmen, Willard M Freeman, Benjamin F Miller, Michael Kinter, Jonathan D Wren, Ann Chiao, Rheal A Towner, Timothy A Snider, William E Sonntag, Arlan Richardson.
      The Oklahoma Shock Nathan Shock Center is designed to deliver unique, innovative services that are not currently available at most institutions. The focus of the Center is on geroscience and the development of careers of young investigators. Pilot grants are provided through the Research Development Core to junior investigators studying aging/geroscience throughout the USA. However, the services of our Center are available to the entire research community studying aging and geroscience. The Oklahoma Nathan Shock Center provides researchers with unique services through four research cores. The Multiplexing Protein Analysis Core uses the latest mass spectrometry technology to simultaneously measure the levels, synthesis, and turnover of hundreds of proteins associated with pathways of importance to aging, e.g., metabolism, antioxidant defense system, proteostasis, and mitochondria function. The Genomic Sciences Core uses novel next-generation sequencing that allows investigators to study the effect of age, or anti-aging manipulations, on DNA methylation, mitochondrial genome heteroplasmy, and the transcriptome of single cells. The Geroscience Redox Biology Core provides investigators with a comprehensive state-of-the-art assessment of the oxidative stress status of a cell, e.g., measures of oxidative damage and redox couples, which are important in aging as well as many major age-related diseases as well as assays of mitochondrial function. The GeroInformatics Core provides investigators assistance with data analysis, which includes both statistical support as well as analysis of large datasets. The Core also has developed number of unique software packages to help with interpretation of results and discovery of new leads relevant to aging. In addition, the Geropathology Research Resource in the Program Enhancement Core provides investigators with pathological assessments of mice using the recently developed Geropathology Grading Platform.
    Keywords:  Genomic Sciences Core; Geropathology Grading Platform; Geroscience
    DOI:  https://doi.org/10.1007/s11357-021-00454-7
  36. Front Nutr. 2021 ;8 760720
    Editorial: Coronavirus Disease (COVID-19): Diet, Inflammation and Nutritional Status.
    Ioannis Zabetakis, Christophe Matthys, Alexandros Tsoupras.
      
    Keywords:  COVID-19; Mediterranean diet (MD); chronic disease; inflammation; nutrition; obesity
    DOI:  https://doi.org/10.3389/fnut.2021.760720
  37. Lancet Diabetes Endocrinol. 2021 Oct 04. pii: S2213-8587(21)00244-8. [Epub ahead of print]
    COVID-19 and metabolic disease: mechanisms and clinical management.
    Charlotte Steenblock, Peter E H Schwarz, Barbara Ludwig, Andreas Linkermann, Paul Zimmet, Konstantin Kulebyakin, Vsevolod A Tkachuk, Alexander G Markov, Hendrik Lehnert, Martin Hrabě de Angelis, Hannes Rietzsch, Roman N Rodionov, Kamlesh Khunti, David Hopkins, Andreas L Birkenfeld, Bernhard Boehm, Richard I G Holt, Jay S Skyler, J Hans DeVries, Eric Renard, Robert H Eckel, K George M M Alberti, Bruno Geloneze, Juliana C Chan, Jean Claude Mbanya, Henry C Onyegbutulem, Ambady Ramachandran, Abdul Basit, Mohamed Hassanein, Gavin Bewick, Giatgen A Spinas, Felix Beuschlein, Rüdiger Landgraf, Francesco Rubino, Geltrude Mingrone, Stefan R Bornstein.
      Up to 50% of the people who have died from COVID-19 had metabolic and vascular disorders. Notably, there are many direct links between COVID-19 and the metabolic and endocrine systems. Thus, not only are patients with metabolic dysfunction (eg, obesity, hypertension, non-alcoholic fatty liver disease, and diabetes) at an increased risk of developing severe COVID-19 but also infection with SARS-CoV-2 might lead to new-onset diabetes or aggravation of pre-existing metabolic disorders. In this Review, we provide an update on the mechanisms of how metabolic and endocrine disorders might predispose patients to develop severe COVID-19. Additionally, we update the practical recommendations and management of patients with COVID-19 and post-pandemic. Furthermore, we summarise new treatment options for patients with both COVID-19 and diabetes, and highlight current challenges in clinical management.
    DOI:  https://doi.org/10.1016/S2213-8587(21)00244-8
  38. Rev Invest Clin. 2021 ;73(5): 321-325
    THE PRESENT AND FUTURE OF PERSONALIZED NUTRITION.
    Nimbe Torres, Armando R Tovar.
      In recent decades, there has been an increase in the presence of metabolic disorders associated with obesity. Central in the treatment of these conditions, including abnormalities in glucose and lipid metabolism, dietary strategies play an important role. However, dietary recommendations are based on the generalization of nutrient or food intake response for all individuals, which not necessarily impacts the health of all individuals. The concept of personalized nutrition or precision nutrition has been recently developed, which states that diet is not the only factor accountable for metabolic responses such as postprandial glucose peaks, but that other factors are also involved, one of the most important of which is the gut microbiota. Therefore, the future of nutritional interventions is to generate algorithms based on the type of food consumed, biochemical parameters, physical activity, genetic variability, and especially the gut microbiota to predict the type of diet a person requires according to his or her metabolic alterations.
    Keywords:  Microbiota and nutrition; Nutrigenomics; Personalized nutrition; Precision nutrition
    DOI:  https://doi.org/10.24875/RIC.21000346
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