bims-minfam Biomed News
on Inflammation and metabolism in ageing and cancer
Issue of 2021–09–12
28 papers selected by
Ayesh Seneviratne, University of Toronto
  1. Gata2 haploinsufficiency promotes proliferation and functional decline of HSCs with myeloid bias during aging.
  2. RNA m6A Modification Plays a Key Role in Maintaining Stem Cell Function in Normal and Malignant Hematopoiesis.
  3. Glycosylation and Aging.
  4. Cell plasticity, senescence, and quiescence in cancer stem cells: Biological and therapeutic implications.
  5. Extending human healthspan and longevity: a symposium report.
  6. Exogenous mitochondrial transfer and endogenous mitochondrial fission facilitate AML resistance to OxPhos inhibition.
  7. Inflammatory Molecular Mediators and Pathways Involved in Vascular Aging and Stroke: A Comprehensive Review.
  8. Calorie intake rather than food quantity consumed is the key factor for the anti-aging effect of calorie restriction.
  9. NAD+ supplementation reduces neuroinflammation and cell senescence in a transgenic mouse model of Alzheimer's disease via cGAS-STING.
  10. Macroautophagy and aging: The impact of cellular recycling on health and longevity.
  11. Bridging geriatric medicine, clinical pharmacology and ageing biology to understand and improve outcomes of medicines in old age and frailty.
  12. Surviving Covid-19 with Heparin?
  13. Long term follow-up of frontline Dasatinib in older patients with chronic myeloid leukemia in chronic phase treated outside clinical trials: a real-life cohort observational study.
  14. Intermittent Versus Continuous Energy Restriction for Weight Loss and Metabolic Improvement: A Meta-Analysis and Systematic Review.
  15. Glutamine promotes escape from therapy-induced senescence in tumor cells.
  16. Anti-aging: senolytics or gerostatics (unconventional view).
  17. A Feasibility Study of Primary Care Liaisons: Linking Older Adults to Community Resources.
  18. Role of Copper on Mitochondrial Function and Metabolism.
  19. [Metabolites for frailty biomarkers].
  20. Lifestyle Adjustments in Long-COVID Management: Potential Benefits of Plant-Based Diets.
  21. Perspectives on the dynamic implications of cellular senescence and immunosenescence on macrophage aging biology.
  22. Improving SIRT1 by trehalose supplementation reduces oxidative stress, inflammation, and histopathological scores in the kidney of aged rats.
  23. Stress and cancer: mechanisms, significance and future directions.
  24. Serial frailty assessments following allogeneic stem cell transplant in older adults: A pilot study.
  25. Mesenchymal stromal cells: what have we learned so far about their therapeutic potential and mechanisms of action?
  26. Hospitalisation among vaccine breakthrough COVID-19 infections.
  27. Preliminary Findings of mRNA Covid-19 Vaccine Safety in Pregnant Persons.
  28. What's the evidence for COVID-19 booster shots?
  1. Blood Adv. 2021 Sep 08. pii: bloodadvances.2021004726. [Epub ahead of print]
    Gata2 haploinsufficiency promotes proliferation and functional decline of HSCs with myeloid bias during aging.
    Ali Mahmoud Abdelfattah, Antonia Hughes-Davies, Liam Daniel Clayfield, Juan Bautista Menendez-Gonzalez, Alhomidi Almotiri, Badi Alotaibi, Alex Tonks, Neil P Rodrigues.
      During aging, hematopoietic stem cell (HSC) function wanes with important biological and clinical implications for benign and malignant hematology, and other co-morbidities, such as cardiovascular disease. However, the molecular mechanisms regulating HSC aging remain incompletely defined. GATA2 haploinsufficiency driven clinical syndromes initially result in primary immunodeficiencies and routinely evolve into hematologic malignancies on acquisition of further epigenetic mutations in both young and older patients. Using a conditional mouse model of Gata2 haploinsufficiency, we discover that during aging Gata2 promotes HSC proliferation, monocytosis, and loss of the common lymphoid progenitor. Aging of Gata2 haploinsufficient mice also offsets enhanced HSC apoptosis and decreased granulocyte-macrophage progenitor number normally observed in young Gata2 haploinsufficient mice. Transplantation of elderly Gata2 haploinsufficient HSCs impairs HSC function with evidence of myeloid bias. Our data demonstrate that Gata2 regulates HSC aging and suggest the mechanisms by which Gata2 mediated HSC aging has an impact on the evolution of malignancies in GATA2 haploinsufficiency syndromes.
    DOI:  https://doi.org/10.1182/bloodadvances.2021004726
  2. Front Cell Dev Biol. 2021 ;9 710964
    RNA m6A Modification Plays a Key Role in Maintaining Stem Cell Function in Normal and Malignant Hematopoiesis.
    Peipei Wang, Mengdie Feng, Guoqiang Han, Rong Yin, Yashu Li, Shuxin Yao, Pengbo Lu, Yuhua Wang, Haojian Zhang.
      N6-methyladenosine (m6A) is a commonly modification of mammalian mRNAs and plays key roles in various cellular processes. Emerging evidence reveals the importance of RNA m6A modification in maintaining stem cell function in normal hematopoiesis and leukemogenesis. In this review, we first briefly summarize the latest advances in RNA m6A biology, and further highlight the roles of m6A writers, readers and erasers in normal hematopoiesis and acute myeloid leukemia. Moreover, we also discuss the mechanisms of these m6A modifiers in preserving the function of hematopoietic stem cells (HSCs) and leukemia stem cells (LSCs), as well as potential strategies for targeting m6A modification related pathways. Overall, we provide a comprehensive summary and our insights into the field of RNA m6A in normal hematopoiesis and leukemia pathogenesis.
    Keywords:  RNA m6A; hematopoiesis; hematopoietic stem cells; leukemia stem cells; myeloid leukemia
    DOI:  https://doi.org/10.3389/fcell.2021.710964
  3. Adv Exp Med Biol. 2021 ;1325 341-373
    Glycosylation and Aging.
    Ana Cindrić, Jasminka Krištić, Marina Martinić Kavur, Marija Pezer.
      Human lifespan has increased significantly in the last 200 years, emphasizing our need to age healthily. Insights into molecular mechanisms of aging might allow us to slow down its rate or even revert it. Similar to aging, glycosylation is regulated by an intricate interplay of genetic and environmental factors. The dynamics of glycopattern variation during aging has been mostly explored for plasma/serum and immunoglobulin G (IgG) N-glycome, as we describe thoroughly in this chapter. In addition, we discuss the potential functional role of agalactosylated IgG glycans in aging, through modulation of inflammation level, as proposed by the concept of inflammaging. We also comment on the potential to use the plasma/serum and IgG N-glycome as a biomarker of healthy aging and on the interventions that modulate the IgG glycopattern. Finally, we discuss the current knowledge about animal models for human plasma/serum and IgG glycosylation and mention other, less explored, instances of glycopattern changes during organismal aging and cellular senescence.
    Keywords:  Aging; Biological age; Glycosylation; IgG N-glycome; Inflammaging; Plasma N-glycome
    DOI:  https://doi.org/10.1007/978-3-030-70115-4_17
  4. Pharmacol Ther. 2021 Sep 01. pii: S0163-7258(21)00187-X. [Epub ahead of print] 107985
    Cell plasticity, senescence, and quiescence in cancer stem cells: Biological and therapeutic implications.
    Ritama Paul, Jay F Dorsey, Yi Fan.
      Cancer stem cells (CSCs) are a distinct population of cells within tumors with capabilities of self-renewal and tumorigenicity. CSCs play a privotal role in cancer progression, metastasis, and relapse and tumor resistance to cytotoxic therapy. Emerging scientific evidence indicates that CSCs adopt several mechanisms, driven by cellular plasticity, senescence and quiescence, to maintain their self-renewal capability and to resist tumor microenvironmental stress and treatments. This poses major hindrances for CSC-targeting anti-cancer therapies: cell plasticity maintains stemness in CSCs and renders tumor cells to acquire stem-like phenotypes, contributing to tumor heterogeneity and CSC generation; cellular senescence induces genetic reprogramming and stemness activation, leading to CSC-mediated tumor progression and metastasis; cell quienscence facilitates CSC to overcome their intrinsic vulnerabilities and therapeutic stress, inducing tumor relapse and therapy resistance. These mechanisms are subjected to spatiotemporal regulation by hypoxia, CSC niche, and extracellular matrix in the tumor microenvironment. Here we integrate the recent advances and current knowledge to elucidate the mechanisms involved in the regulation of plasticity, senescence and quiescence of CSCs and the potential therapeutic implications for the future.
    Keywords:  Cancer stem cells; Plasticity; Quiescence; Senescence; Therapy resistance; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.pharmthera.2021.107985
  5. Ann N Y Acad Sci. 2021 Sep 08.
    Extending human healthspan and longevity: a symposium report.
    Loren M DeVito, Nir Barzilai, Ana Maria Cuervo, Laura J Niedernhofer, Sofiya Milman, Morgan Levine, Daniel Promislow, Luigi Ferrucci, George A Kuchel, Joan Mannick, Jamie Justice, Mitzi M Gonzales, James L Kirkland, Pinchas Cohen, Judith Campisi.
      For many years, it was believed that the aging process was inevitable and that age-related diseases could not be prevented or reversed. The geroscience hypothesis, however, posits that aging is, in fact, malleable and, by targeting the hallmarks of biological aging, it is indeed possible to alleviate age-related diseases and dysfunction and extend longevity. This field of geroscience thus aims to prevent the development of multiple disorders with age, thereby extending healthspan, with the reduction of morbidity toward the end of life. Experts in the field have made remarkable advancements in understanding the mechanisms underlying biological aging and identified ways to target aging pathways using both novel agents and repurposed therapies. While geroscience researchers currently face significant barriers in bringing therapies through clinical development, proof-of-concept studies, as well as early-stage clinical trials, are underway to assess the feasibility of drug evaluation and lay a regulatory foundation for future FDA approvals in the future.
    Keywords:  biological aging; geroscience; hallmarks of aging; healthspan; longevity
    DOI:  https://doi.org/10.1111/nyas.14681
  6. Blood Adv. 2021 Sep 10. pii: bloodadvances.2020003661. [Epub ahead of print]
    Exogenous mitochondrial transfer and endogenous mitochondrial fission facilitate AML resistance to OxPhos inhibition.
    Kaori Saito, Qi Zhang, Haeun Yang, Kotoko Yamatani, Tomohiko Ai, Vivian Ruvolo, Natalia Baran, Tianyu Cai, Helen Ma, Rodrigo Jacamo, Vinitha Mary Kuruvilla, Junichi Imoto, Sonoko Kinjo, Kazuho Ikeo, Kaori Moriya, Koya Suzuki, Takashi Miida, Yong-Mi Kim, Christopher P Vellano, Michael Andreeff, Joseph R Marszalek, Yoko Tabe, Marina Y Konopleva.
      Acute myeloid leukemia (AML) cells are highly dependent on oxidative phosphorylation (OxPhos) for survival and continually adapt to fluctuations in nutrient and oxygen availability in the bone marrow (BM) microenvironment. We investigated how the BM microenvironment affects the response to OxPhos inhibition in AML by using a novel complex I OxPhos inhibitor, IACS-010759. Cellular adhesion, growth, and apoptosis assays, along with measurements of mtDNA expression and mitochondrial reactive oxygen species generation, indicated that direct interactions with BM stromal cells triggered compensatory activation of mitochondrial respiration and resistance to OxPhos inhibition in AML cells. Mechanistically, OxPhos inhibition induced (1) transfer of mesenchymal stem cell (MSC)-derived mitochondria to AML cells via tunneling nanotubes under direct-contact coculture conditions, and (2) mitochondrial fission with an increase in functional mitochondria and mitophagy in AML cells. Mitochondrial fission is known to enhance cell migration, and we observed mitochondrial transport to the leading edge of protrusions of migrating AML cells toward MSCs by electron microscopy analysis. We further demonstrated that cytarabine, a commonly used antileukemia agent, increased OxPhos inhibition-triggered mitochondrial transfer from MSCs to AML cells. Our findings indicate an important role of exogenous mitochondrial trafficking from BM stromal cells to AML cells as well as endogenous mitochondrial fission and mitophagy in the compensatory adaptation of leukemia cells to energetic stress in the BM microenvironment.
    DOI:  https://doi.org/10.1182/bloodadvances.2020003661
  7. Curr Med Chem. 2021 Sep 01.
    Inflammatory Molecular Mediators and Pathways Involved in Vascular Aging and Stroke: A Comprehensive Review.
    Amro M Soliman, Srijit Das, Pasuk Mahakkanukrauh.
      There is an increase in the incidence of cardiovascular diseases with aging and it is one of the leading causes of death worldwide. The main cardiovascular pathologies include atherosclerosis, stroke, myocardial infarction, hypertension and stroke. Chronic inflammation is one of the significant contributors to the age-related vascular diseases. Therefore, it is important to understand the molecular mechanisms of the persistent inflammatory conditions occurring in the blood vessels as well as the signaling pathways involved. Herein, we performed an extant search of literature involving PubMed, ISI, WoS and Scopus databases for retrieving all relevant articles with the most recent findings illustrating the potential role of various inflammatory mediators along with their proposed activated pathways in the pathogenesis and progression of vascular aging. We also highlight the major pathways contributing to age-related vascular disorders. The outlined molecular mechanisms, pathways and mediators of vascular aging represent potential drug targets that can be utilized to inhibit and/or slow the pathogenesis and progression of vascular aging.
    Keywords:  atherosclerosis; cardiovascular; inflammation; inflammatory mediators; stroke; vascular aging
    DOI:  https://doi.org/10.2174/0929867328666210901122359
  8. Aging (Albany NY). 2021 Sep 07. 13(undefined):
    Calorie intake rather than food quantity consumed is the key factor for the anti-aging effect of calorie restriction.
    Yaru Liang, Yuqi Gao, Rui Hua, Maoyang Lu, Huiling Chen, Zhuoran Wang, Liyuan Li, Kaiqiang Hu, Yuemiao Yin, Kang Xu, Hongqi Gao, Qingfei Liu, Ying Qiu, Zhao Wang.
      Although calorie restriction has been reported to extend lifespan in several organisms, animals subjected to calorie restriction consume not only fewer calories but also smaller quantities of food. Whether it is the overall restriction of calories or the coincidental reduction in the quantity of food consumed that mediates the anti-aging effects is unclear. Here, we subjected mice to five dietary interventions. We showed that both calorie and quantity restriction could improve early survival, but no maximum lifespan extension was observed in the mice fed isocaloric diet in which food quantity was reduced. Mice fed isoquant diet with fewer calories showed maximum lifespan extension and improved health among all the groups, suggesting that calorie intake rather than food quantity consumed is the key factor for the anti-aging effect of calorie restriction. Midlife liver gene expression correlations with lifespan revealed that calorie restriction raised fatty acid biosynthesis and metabolism and biosynthesis of amino acids but inhibited carbon metabolism, indicating different effects on fatty acid metabolism and carbohydrate metabolism. Our data illustrate the effects of calories and food quantity on the lifespan extension by calorie restriction and their potential mechanisms, which will provide guidance on the application of calorie restriction to humans.
    Keywords:  calorie intake; calorie restriction; fatty acid biosynthesis; food quantity; healthspan
    DOI:  https://doi.org/10.18632/aging.203493
  9. Proc Natl Acad Sci U S A. 2021 Sep 14. pii: e2011226118. [Epub ahead of print]118(37):
    NAD+ supplementation reduces neuroinflammation and cell senescence in a transgenic mouse model of Alzheimer's disease via cGAS-STING.
    Yujun Hou, Yong Wei, Sofie Lautrup, Beimeng Yang, Yue Wang, Stephanie Cordonnier, Mark P Mattson, Deborah L Croteau, Vilhelm A Bohr.
      Alzheimer's disease (AD) is a progressive and fatal neurodegenerative disorder. Impaired neuronal bioenergetics and neuroinflammation are thought to play key roles in the progression of AD, but their interplay is not clear. Nicotinamide adenine dinucleotide (NAD+) is an important metabolite in all human cells in which it is pivotal for multiple processes including DNA repair and mitophagy, both of which are impaired in AD neurons. Here, we report that levels of NAD+ are reduced and markers of inflammation increased in the brains of APP/PS1 mutant transgenic mice with beta-amyloid pathology. Treatment of APP/PS1 mutant mice with the NAD+ precursor nicotinamide riboside (NR) for 5 mo increased brain NAD+ levels, reduced expression of proinflammatory cytokines, and decreased activation of microglia and astrocytes. NR treatment also reduced NLRP3 inflammasome expression, DNA damage, apoptosis, and cellular senescence in the AD mouse brains. Activation of cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING) are associated with DNA damage and senescence. cGAS-STING elevation was observed in the AD mice and normalized by NR treatment. Cell culture experiments using microglia suggested that the beneficial effects of NR are, in part, through a cGAS-STING-dependent pathway. Levels of ectopic (cytoplasmic) DNA were increased in APP/PS1 mutant mice and human AD fibroblasts and down-regulated by NR. NR treatment induced mitophagy and improved cognitive and synaptic functions in APP/PS1 mutant mice. Our findings suggest a role for NAD+ depletion-mediated activation of cGAS-STING in neuroinflammation and cellular senescence in AD.
    Keywords:  Alzheimer’s disease; DNA repair; NAD supplementation; inflammation; neurodegeneration
    DOI:  https://doi.org/10.1073/pnas.2011226118
  10. Mol Aspects Med. 2021 Sep 07. pii: S0098-2997(21)00080-7. [Epub ahead of print] 101020
    Macroautophagy and aging: The impact of cellular recycling on health and longevity.
    Jose L Nieto-Torres, Malene Hansen.
      Aging is associated with many deleterious changes at the cellular level, including the accumulation of potentially toxic components that can have devastating effects on health. A key protective mechanism to this end is the cellular recycling process called autophagy. During autophagy, damaged or surplus cellular components are delivered to acidic vesicles called lysosomes, that secure degradation and recycling of the components. Numerous links between autophagy and aging exist. Autophagy declines with age, and increasing evidence suggests that this reduction plays important roles in both physiological aging and the development of age-associated disorders. Studies in pharmacologically and genetically manipulated model organisms indicate that defects in autophagy promote age-related diseases, and conversely, that enhancement of autophagy has beneficial effects on both healthspan and lifespan. Here, we review our current understanding of the role of autophagy in different physiological processes and their molecular links with aging and age-related diseases. We also highlight some recent advances in the field that could accelerate the development of autophagy-based therapeutic interventions.
    Keywords:  AMPK; Aging; Autophagy; C. elegans; Healthspan; Lifespan; Neurodegeneration; mTOR
    DOI:  https://doi.org/10.1016/j.mam.2021.101020
  11. Ageing Res Rev. 2021 Sep 02. pii: S1568-1637(21)00204-X. [Epub ahead of print] 101457
    Bridging geriatric medicine, clinical pharmacology and ageing biology to understand and improve outcomes of medicines in old age and frailty.
    Sarah N Hilmer.
      
    Keywords:  Ageing; Deprescribing; Frailty; Medicines; Pharmacokinetics; Polypharmacy
    DOI:  https://doi.org/10.1016/j.arr.2021.101457
  12. N Engl J Med. 2021 Sep 09. 385(11): 1056
    Surviving Covid-19 with Heparin?
      
    DOI:  https://doi.org/10.1056/NEJMx210013
  13. Acta Oncol. 2021 Sep 09. 1-7
    Long term follow-up of frontline Dasatinib in older patients with chronic myeloid leukemia in chronic phase treated outside clinical trials: a real-life cohort observational study.
    Fabio Stagno, Massimo Breccia, Mario Annunziata, Malgorzata Monika Trawinska, Alessandra Iurlo, Nicola Sgherza, Carmen Fava, Antonella Gozzini, Luigiana Luciano, Ida Carmosino, Massimiliano Bonifacio, Federica Sorà, Sabrina Leonetti Crescenzi, Monica Crugnola, Gabriele Gugliotta, Sara Galimberti, Cristina Bucelli, Gioia Colafigli, Costanzo Feo, Mario Tiribelli, Endri Mauro, Antonella Russo Rossi, Attilio Guarini, Elisabetta Abruzzese, Gianantonio Rosti, Francesco Di Raimondo, Roberto Latagliata.
       BACKGROUND: A limited amount of data has been published in chronic-phase chronic myeloid leukemia (CP-CML) patients aged >75 years treated frontline with second-generation tyrosine kinase inhibitors.
    AIMS: To address this issue in a clinical 'real-life' setting, we retrospectively analyzed 45 CP-CML patients (pts) followed in 20 Italian Centers and treated frontline with dasatinib (DAS).
    PATIENTS AND METHODS: Median age was 78.4 years (range 75-89.2 years). DAS starting dose was 100 mg QD in 35 pts (77.7%), 80 mg QD in 1 pts (2.2%) and 50 mg QD in 9 pts (20.1%), respectively. The median follow-up was 42.6 months (IQR 20.4 - 63.3).
    RESULTS: Grade 3 and 4 side effects, both hematological and non-hematological, were detected in 6 (13.3%) and 12 (26.6%) pts, respectively. Pleural effusions of all grades occurred in 13 pts (28.8%) after a median period of DAS exposure of 14.7 months (IQR 3.0 - 33.1). The rates of DAS dose reduction and permanent drug discontinuation were 53.3% and 20.0%, respectively. As the best response, 42/45 patients (93.3%) achieved a complete cytogenetic response (CCyR), 35/45 (77.7%) a major molecular response (MMR) and 24/45 (53.3%) a deep molecular response (both MR 4.0 and MR 4.5). Only 1 patient (2.2%) progressed to the blast phase after 13 months of therapy; 8 deaths were observed (1 CML-related and 7 CML-unrelated). Cumulative event-free survival and overall survival at 36 months were 64.7% (95%, CI 49.4 - 80.0) and 82.3% (95%, CI 70.3-94.3), respectively.
    CONCLUSION: These findings, although evaluated in a limited and selected cohort of patients, suggest that DAS might be effective in older patients (aged >75 years) affected by CP-CML with acceptable toxicity.
    Keywords:  CML therapy; Chronic myeloid leukemia; dasatinib; imatinib; nilotinib; older CML patients
    DOI:  https://doi.org/10.1080/0284186X.2021.1971292
  14. Obesity (Silver Spring). 2021 Jan;29(1): 108-115
    Intermittent Versus Continuous Energy Restriction for Weight Loss and Metabolic Improvement: A Meta-Analysis and Systematic Review.
    Shasha He, Jiao Wang, Jie Zhang, Jixiong Xu.
       OBJECTIVE: This study aimed to evaluate the effects of intermittent energy restriction (IER; only for 2-3 d/wk) versus continuous energy restriction (CER) on weight loss and metabolic outcomes in adults with overweight or obesity.
    METHODS: Methods included searching databases from the last decade to December 18, 2019, for randomized controlled trials (RCTs) that assessed weight loss and metabolic outcomes in IER and CER. RevMan version 5.3 software was used for statistical analysis of the data. The effect sizes were expressed as weight mean differences and 95% CI.
    RESULTS: This review included 11 RCTs (n = 850). Meta-analysis showed that IER had greater effects on absolute weight loss, the percentage of weight loss, and improving insulin sensitivity than CER. In the subgroup analysis, short-term (2-3 months) intervention (P < 0.0001) was associated with weight loss.
    CONCLUSIONS: This systematic review shows that IER (2-3 d/wk) had greater effects on short-term weight loss than CER and that IER results in comparative metabolic improvements. Furthermore, longer RCTs are needed to validate these findings.
    DOI:  https://doi.org/10.1002/oby.23023
  15. Aging (Albany NY). 2021 Sep 07. 13(undefined):
    Glutamine promotes escape from therapy-induced senescence in tumor cells.
    Francesco Pacifico, Nadia Badolati, Stefano Mellone, Mariano Stornaiuolo, Antonio Leonardi, Elvira Crescenzi.
      Therapy-induced senescence (TIS) is a major cellular response to anticancer therapies. While induction of a persistent growth arrest would be a desirable outcome in cancer therapy, it has been shown that, unlike normal cells, cancer cells are able to evade the senescence cell cycle arrest and to resume proliferation, likely contributing to tumor relapse. Notably, cells that escape from TIS acquire a plastic, stem cell-like phenotype. The metabolic dependencies of cells that evade senescence have not been thoroughly studied. In this study, we show that glutamine depletion inhibits escape from TIS in all cell lines studied, and reduces the stem cell subpopulation. In line with a metabolic reliance on glutamine, escaped clones overexpress the glutamine transporter SLC1A5. We also demonstrate a central role of glutamine synthetase that mediates resistance to glutamine deprivation, conferring independence from exogenous glutamine. Finally, rescue experiments demonstrate that glutamine provides nitrogen for nucleotides biosynthesis in cells that escape from TIS, but also suggest a critical involvement of glutamine in other metabolic and non-metabolic pathways. On the whole, these results reveal a metabolic vulnerability of cancer stem cells that recover proliferation after exposure to anticancer therapies, which could be exploited to prevent tumor recurrence.
    Keywords:  cancer stem cells; escape; glutamine; glutamine synthetase; therapy-induced senescence
    DOI:  https://doi.org/10.18632/aging.203495
  16. Oncotarget. 2021 Aug 31. 12(18): 1821-1835
    Anti-aging: senolytics or gerostatics (unconventional view).
    Mikhail V Blagosklonny.
      Senolytics are basically anti-cancer drugs, repurposed to kill senescent cells selectively. It is even more difficult to selectively kill senescent cells than to kill cancer cells. Based on lessons of cancer therapy, here I suggest how to exploit oncogene-addiction and to combine drugs to achieve selectivity. However, even if selective senolytic combinations will be developed, there is little evidence that a few senescent cells are responsible for organismal aging. I also discuss gerostatics, such as rapamycin and other rapalogs, pan-mTOR inhibitors, dual PI3K/mTOR inhibitors, which inhibit growth- and aging-promoting pathways. Unlike senolytics, gerostatics do not kill cells but slow down cellular geroconversion to senescence. Numerous studies demonstrated that inhibition of the mTOR pathways by any means (genetic, pharmacological and dietary) extends lifespan. Currently, only two studies demonstrated that senolytics (fisetin and a combination Dasatinib plus Quercetin) extend lifespan in mice. These senolytics slightly inhibit the mTOR pathway. Thus, life extension by these senolytics can be explained by their slight rapamycin-like (gerostatic) effects.
    Keywords:  aging; geroscience; hyperfunction theory; senolytics; sirolimus
    DOI:  https://doi.org/10.18632/oncotarget.28049
  17. Am J Prev Med. 2021 Sep 05. pii: S0749-3797(21)00370-6. [Epub ahead of print]
    A Feasibility Study of Primary Care Liaisons: Linking Older Adults to Community Resources.
    Allison M Boll, Melissa R Ensey, Katherine A Bennett, Mary P O'Leary, Breanne M Wise-Swanson, Aimee M Verrall, Michael V Vitiello, Barbara B Cochrane, Elizabeth A Phelan.
       INTRODUCTION: Programs and services available through the aging services network can help community-dwelling older adults to age in place but are often not discussed in routine primary care. The primary care liaison was developed as a novel integration intervention to address this disconnect.
    METHODS: Employed by an Area Agency on Aging, primary care liaisons performed outreach to primary care with the goal of raising awareness of community-based programs, resources, and services available to older adults and their caregivers and facilitating referrals. The evaluation of the primary care liaison model, conducted from December 2015 to February 2019, used the Reach, Effectiveness, Adoption, Implementation, Maintenance framework and assessed reach (number of clinics contacted), adoption (number of referrals to the Area Agency on Aging), implementation (number of follow-up contacts with a practice), and effectiveness (proportion of referrals reached and provided relevant resources).
    RESULTS: The primary care liaisons contacted a median of 18.5 clinics per month (IQR=15-31). Primary care referrals averaged >100 per month, and referrals increased over time. Successful follow-up outreach visits had a median of 3 (IQR=2-10), and follow-up contacts had a median of 3 (IQR=1-7) per practice. Three quarters of caregivers for people with dementia reached by Area Agency on Aging staff were provided with information about relevant resources.
    CONCLUSIONS: The primary care liaison model is feasible, fosters ongoing interactions between primary care and Area Agencies on Aging, and connects older adults and their caregivers to relevant programs and services. Adoption of the primary care liaison model by other Area Agencies on Aging across the U.S. may help further the vision of optimized health and well-being of older adults.
    DOI:  https://doi.org/10.1016/j.amepre.2021.05.034
  18. Front Mol Biosci. 2021 ;8 711227
    Role of Copper on Mitochondrial Function and Metabolism.
    Lina M Ruiz, Allan Libedinsky, Alvaro A Elorza.
      Copper is essential for life processes like energy metabolism, reactive oxygen species detoxification, iron uptake, and signaling in eukaryotic organisms. Mitochondria gather copper for the assembly of cuproenzymes such as the respiratory complex IV, cytochrome c oxidase, and the antioxidant enzyme superoxide dismutase 1. In this regard, copper plays a role in mitochondrial function and signaling involving bioenergetics, dynamics, and mitophagy, which affect cell fate by means of metabolic reprogramming. In mammals, copper homeostasis is tightly regulated by the liver. However, cellular copper levels are tissue specific. Copper imbalances, either overload or deficiency, have been associated with many diseases, including anemia, neutropenia, and thrombocytopenia, as well as tumor development and cancer aggressivity. Consistently, new pharmacological developments have been addressed to reduce or exacerbate copper levels as potential cancer therapies. This review goes over the copper source, distribution, cellular uptake, and its role in mitochondrial function, metabolic reprograming, and cancer biology, linking copper metabolism with the field of regenerative medicine and cancer.
    Keywords:  ROS; cancer; copper; differentiation; hematopoietic stem cells (HSCs); metabolic reprograming; mitochondria; proliferation
    DOI:  https://doi.org/10.3389/fmolb.2021.711227
  19. Nihon Ronen Igakkai Zasshi. 2021;58(3):58(3): 333-340
    [Metabolites for frailty biomarkers].
      
    DOI:  https://doi.org/10.3143/geriatrics.58.333
  20. Curr Nutr Rep. 2021 Sep 10.
    Lifestyle Adjustments in Long-COVID Management: Potential Benefits of Plant-Based Diets.
    Maximilian Andreas Storz.
       PURPOSE OF REVIEW: The SARS-CoV-2-pandemic has caused mortality and morbidity at an unprecedented global scale. Many patients infected with SARS-CoV-2 continue to experience symptoms after the acute phase of infection and report fatigue, sleep difficulties, anxiety, and depression as well as arthralgia and muscle weakness. Summarized under the umbrella term "long-COVID," these symptoms may last weeks to months and impose a substantial burden on affected individuals. Dietary approaches to tackle these complications have received comparably little attention. Although plant-based diets in particular were shown to exert benefits on underlying conditions linked to poor COVID-19 outcomes, their role with regard to COVID-19 sequelae is yet largely unknown. Thus, this review sought to investigate whether a plant-based diet could reduce the burden of long-COVID.
    RECENT FINDINGS: The number of clinical trials investigating the role of plant-based nutrition in COVID-19 prevention and management is currently limited. Yet, there is evidence from pre-pandemic observational and clinical studies that a plant-based diet may be of general benefit with regard to several clinical conditions that can also be found in individuals with COVID-19. These include anxiety, depression, sleep disorders, and musculoskeletal pain. Adoption of a plant-based diet leads to a reduced intake in pro-inflammatory mediators and could be one accessible strategy to tackle long-COVID associated prolonged systemic inflammation. Plant-based diets may be of general benefit with regard to some of the most commonly found COVID-19 sequelae. Additional trials investigating which plant-based eating patterns confer the greatest benefit in the battle against long-COVID are urgently warranted.
    Keywords:  Economic burden; Nutrition; Plant-based diet; SARS-CoV-2; Long-COVID; Vegan
    DOI:  https://doi.org/10.1007/s13668-021-00369-x
  21. Biogerontology. 2021 Sep 06.
    Perspectives on the dynamic implications of cellular senescence and immunosenescence on macrophage aging biology.
    Rohit Sharma.
      An intricate relationship between impaired immune functions and the age-related accumulation of tissue senescent cells is rapidly emerging. The immune system is unique as it undergoes mutually inclusive and deleterious processes of immunosenescence and cellular senescence with advancing age. While factors inducing immunosenescence and cellular senescence may be shared, however, both these processes are fundamentally different which holistically influence the aging immune system. Our understanding of the biological impact of immunosenescence is relatively well-understood, but such knowledge regarding cellular senescence in immune cells, especially in the innate immune cells such as macrophages, is only beginning to be elucidated. Tissue-resident macrophages are long-lived, and while functioning in tissue-specific and niche-specific microenvironments, senescence in macrophages can be directly influenced by senescent host cells which may impact organismal aging. In addition, evidence of age-associated immunometabolic changes as drivers of altered macrophage phenotype and functions such as inflamm-aging is also emerging. The present review describes the emerging impact of cellular senescence vis-à-vis immunosenescence in aging macrophages, its biological relevance with other senescent non-immune cells, and known immunometabolic regulators. Gaps in our present knowledge, as well as strategies aimed at understanding cellular senescence and its therapeutics in the context of macrophages, have been reviewed.
    Keywords:  Aging; Immunometabolism; Immunosenescence; Macrophages; Senescence
    DOI:  https://doi.org/10.1007/s10522-021-09936-9
  22. J Food Biochem. 2021 Sep 08. e13931
    Improving SIRT1 by trehalose supplementation reduces oxidative stress, inflammation, and histopathological scores in the kidney of aged rats.
    Faegheh Bahri, Mohammad Khaksari, Sajjadeh Movahedinia, Bentolhoda Shafiei, Mohammad Amin Rajizadeh, Mahdieh Nazari-Robati.
      The aging process leads to progressive loss of kidney function. Sirtuin1 (SIRT1) exerts renoprotective effects by conferring resistance to cellular stresses. Trehalose potentially displayed various beneficial effects to promote health span. In this study, we investigated the effects of trehalose on renal SIRT1 and kidney function in senescent rats. Trehalose (2% w/v) was administrated in drinking water for 1 month to male aged rats (24 months). Then, the level of SIRT1 mRNA and protein, malondialdehyde, total antioxidant capacity, tumor necrosis factor α as well as parameters related to the function and histology of the kidneys were evaluated. Trehalose supplementation increased the level of SIRT1, whereas alleviated the level of oxidative stress, inflammation, and histopathology scores in senescent tissues. However, trehalose administration did not alter kidney function indices in old rats. Collectively, these findings suggested that trehalose was an effective intervention to ameliorate some aspects of age-associated injury in the old kidneys. PRACTICAL APPLICATIONS: Aging is associated with impairment in renal structure and function. Trehalose is a natural disaccharide, which is widely distributed in many organisms. The consumption of trehalose as a dietary supplement is increasing worldwide. This study showed that trehalose administration to aged rats had renoprotective effects through reducing oxidative stress and inflammation, which was mediated by SIRT1. Our results provide useful information for individuals using this sugar as a supplement.
    Keywords:  SIRT1; aging; inflammation; oxidative stress; trehalose
    DOI:  https://doi.org/10.1111/jfbc.13931
  23. Nat Rev Cancer. 2021 Sep 10.
    Stress and cancer: mechanisms, significance and future directions.
    Anabel Eckerling, Itay Ricon-Becker, Liat Sorski, Elad Sandbank, Shamgar Ben-Eliyahu.
      The notion that stress and cancer are interlinked has dominated lay discourse for decades. More recent animal studies indicate that stress can substantially facilitate cancer progression through modulating most hallmarks of cancer, and molecular and systemic mechanisms mediating these effects have been elucidated. However, available clinical evidence for such deleterious effects is inconsistent, as epidemiological and stress-reducing clinical interventions have yielded mixed effects on cancer mortality. In this Review, we describe and discuss specific mediating mechanisms identified by preclinical research, and parallel clinical findings. We explain the discrepancy between preclinical and clinical outcomes, through pointing to experimental strengths leveraged by animal studies and through discussing methodological and conceptual obstacles that prevent clinical studies from reflecting the impacts of stress. We suggest approaches to circumvent such obstacles, based on targeting critical phases of cancer progression that are more likely to be stress-sensitive; pharmacologically limiting adrenergic-inflammatory responses triggered by medical procedures; and focusing on more vulnerable populations, employing personalized pharmacological and psychosocial approaches. Recent clinical trials support our hypothesis that psychological and/or pharmacological inhibition of excess adrenergic and/or inflammatory stress signalling, especially alongside cancer treatments, could save lives.
    DOI:  https://doi.org/10.1038/s41568-021-00395-5
  24. J Geriatr Oncol. 2021 Sep 04. pii: S1879-4068(21)00182-X. [Epub ahead of print]
    Serial frailty assessments following allogeneic stem cell transplant in older adults: A pilot study.
    Rachel Ombres, Jude K A des Bordes, Uday R Popat, Sriram Yennu, Richard E Champlin, Supriya G Mohile, Partow Kebriaei, Holly M Holmes.
       INTRODUCTION: Increasing numbers of older adults undergo allogeneic stem cell transplantation (SCT) as the only chance of meaningful survival for hematologic malignancies. However, toxicities in vulnerable patients may offset the benefits of SCT. Frailty and abnormal geriatric assessment (GA) prior to SCT have been associated with decreased overall survival in persons aged 60 and older. The purpose of this pilot study was to determine the prevalence of baseline GA deficits and frailty, the prevalence of frailty or death at three and six months after allogeneic SCT, and associations between baseline assessments and the presence of frailty or death post-SCT.
    METHODS: We enrolled 50 patients aged 60 years and older and completed a baseline GA including comorbidity, polypharmacy, nutrition, physical performance, functional status, social support, depression and anxiety, and cognition. Frailty was defined as three or more abnormalities of gait speed, grip strength, weight loss, physical activity, and exhaustion, and was assessed at baseline, three months, and six months after SCT. A composite outcome of frailty or death at three months and six months was analyzed.
    RESULTS: Frailty was present in 11/50 (22%) of patients at baseline. Ten patients did not complete three- month follow-up, and twelve patients did not complete six-month follow-up. Of those with follow-up data, 22 patients (55%) were frail or deceased three months after SCT, and 27 patients (71%) were frail or deceased six months after SCT. Frailty at baseline was not significantly associated with frailty or death at three or six months after SCT. However, the study's small enrollment limits conclusions on these associations.
    CONCLUSION: GA deficits and frailty are prevalent in older adult SCT recipients at baseline and after transplant. Future studies should aim for larger enrollment in order to validate associations between these deficits and outcomes, especially survival, functional status, and quality of life following SCT.
    Keywords:  Elderly; Frail; Geriatric assessment; Hematopoietic stem cell transplantation
    DOI:  https://doi.org/10.1016/j.jgo.2021.08.008
  25. Emerg Top Life Sci. 2021 Sep 08. pii: ETLS20210013. [Epub ahead of print]
    Mesenchymal stromal cells: what have we learned so far about their therapeutic potential and mechanisms of action?
    Francesco Amadeo, Katherine Trivino Cepeda, James Littlewood, Bettina Wilm, Arthur Taylor, Patricia Murray.
      Mesenchymal stromal cells (MSCs) have been found to be safe and effective in a wide range of animal models of human disease. MSCs have been tested in thousands of clinical trials, but results show that while these cells appear to be safe, they tend to lack efficacy. This has raised questions about whether animal models are useful for predicting efficacy in patients. However, a problem with animal studies is that there is a lack of standardisation in the models and MSC therapy regimes used; there appears to be publication bias towards studies reporting positive outcomes; and the reproducibility of results from animal experiments tends not to be confirmed prior to clinical translation. A further problem is that while some progress has been made towards investigating the mechanisms of action (MoA) of MSCs, we still fail to understand how they work. To make progress, it is important to ensure that prior to clinical translation, the beneficial effects of MSCs in animal studies are real and can be repeated by independent research groups. We also need to understand the MoA of MSCs to assess whether their effects are likely to be beneficial across different species. In this review, we give an overview of the current clinical picture of MSC therapies and discuss what we have learned from animal studies. We also give a comprehensive update of what we know about the MoA of MSCs, particularly in relation to their role in immunomodulation.
    Keywords:  MSC clinical trials; MSCs; animal models; extracellular vesicles; mesenchymal stromal cells
    DOI:  https://doi.org/10.1042/ETLS20210013
  26. Lancet Infect Dis. 2021 Sep 07. pii: S1473-3099(21)00558-2. [Epub ahead of print]
    Hospitalisation among vaccine breakthrough COVID-19 infections.
    Prerak V Juthani, Akash Gupta, Kelly A Borges, Christina C Price, Alfred I Lee, Christine H Won, Hyung J Chun.
      
    DOI:  https://doi.org/10.1016/S1473-3099(21)00558-2
  27. N Engl J Med. 2021 Sep 08.
    Preliminary Findings of mRNA Covid-19 Vaccine Safety in Pregnant Persons.
      
    DOI:  https://doi.org/10.1056/NEJMx210016
  28. CMAJ. 2021 09 07. 193(35): E1400-E1401
    What's the evidence for COVID-19 booster shots?
    Lauren Vogel, Diana Duong.
      
    DOI:  https://doi.org/10.1503/cmaj.1095959
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