bims-minfam Biomed News
on Inflammation and metabolism in ageing and cancer
Issue of 2022–03–27
twenty-two papers selected by
Ayesh Seneviratne, University of Toronto
  1. The central moTOR of metabolism.
  2. A relationship among the blood serum levels of interleukin-6, albumin, and 25-hydroxyvitamin D and frailty in elderly patients with chronic coronary syndrome.
  3. Intermittent and periodic fasting, longevity and disease.
  4. As predicted by hyperfunction theory, rapamycin treatment during development extends lifespan.
  5. Aldehyde Dehydrogenase Enzyme Functions in Acute Leukemia Stem Cells.
  6. Antioxidant and Antiaging Properties of a Novel Synergistic Nutraceutical Complex: Readouts from an In Cellulo Study and an In Vivo Prospective, Randomized Trial.
  7. Synergy of Venetoclax and 8-Chloro-Adenosine in AML: The Interplay of rRNA Inhibition and Fatty Acid Metabolism.
  8. The Association of Nutrition Quality with Frailty Syndrome among the Elderly.
  9. Guava Fruit and Acacia pennata Vegetable Intake Association with Frailty of Older Adults in Northern Thailand.
  10. NAD+ centric mechanisms and molecular determinants of skeletal muscle disease and aging.
  11. Functional Decline in the Cancer Patient: A Review.
  12. Mice eat less and explore more after intake of certain amino acids.
  13. Venetoclax-Resistant MV4-11 Leukemic Cells Activate PI3K/AKT Pathway for Metabolic Reprogramming and Redox Adaptation for Survival.
  14. Geriatric emergency medicine-a model for frailty friendly healthcare.
  15. Telomere length and vitamin B12.
  16. An Imaging System for Monitoring C. elegans Behavior and Aging.
  17. The Reconstitution Dynamics of Cultivated Hematopoietic Stem Cells and Progenitors Is Independent of Age.
  18. Amino Acid Signaling for TOR in Eukaryotes: Sensors, Transducers, and a Sustainable Agricultural fuTORe.
  19. Searching for the link between inflammaging and sarcopenia.
  20. Preprint Highlight: ER-lysosome lipid transfer protein VPS13C/PARK23 prevents aberrant mtDNA- dependent STING signaling.
  21. Anti-Inflammatory and Active Biological Properties of the Plant-Derived Bioactive Compounds Luteolin and Luteolin 7-Glucoside.
  22. Genistein, a tool for geroscience.
  1. Dev Cell. 2022 Mar 15. pii: S1534-5807(22)00126-5. [Epub ahead of print]
    The central moTOR of metabolism.
    Judith Simcox, Dudley W Lamming.
      The protein kinase mechanistic target of rapamycin (mTOR) functions as a central regulator of metabolism, integrating diverse nutritional and hormonal cues to control anabolic processes, organismal physiology, and even aging. This review discusses the current state of knowledge regarding the regulation of mTOR signaling and the metabolic regulation of the four macromolecular building blocks of the cell: carbohydrate, nucleic acid, lipid, and protein by mTOR. We review the role of mTOR in the control of organismal physiology and aging through its action in key tissues and discuss the potential for clinical translation of mTOR inhibition for the treatment and prevention of diseases of aging.
    Keywords:  amino acids; lipids; mTOR; mTORC1; mTORC2; metabolism; protein; rapamycin
    DOI:  https://doi.org/10.1016/j.devcel.2022.02.024
  2. Aging Med (Milton). 2022 Mar;5(1): 17-29
    A relationship among the blood serum levels of interleukin-6, albumin, and 25-hydroxyvitamin D and frailty in elderly patients with chronic coronary syndrome.
    Jing-Rong Dai, Jie Li, Xu He, Hong Huang, Yan Li.
       Background: With the aggravation of the aging of the world population, frailty has become one of the common complications in elderly people. Its diagnosis is not objective, the pathogenesis is not clear, and interventions are not sound, thus intensifying the problem. Furthermore, frailty is closely associated with the occurrence and poor prognosis of coronary atherosclerotic heart disease. Moreover, few studies report on the prevalence of frailty in elderly patients with the chronic coronary syndrome (CCS).
    Objective: We aimed to investigate the prevalence of frailty in elderly patients with CCS. We analyzed the correlation between the blood serum levels of interleukin-6 (IL-6), albumin (Alb), and 25-hydroxyvitamin D (25(OH)D) with frailty in elderly patients with CCS. We have also provided recommendations for helping the objective diagnosis as well as proposed new intervention methods in the future.
    Methods: Two hundred eight-eight inpatients (≥60 years) with the chronic coronary syndrome were recruited at the Department of Geriatrics, the First People's Hospital of Yunnan Province, China. General information and laboratory examination data were collected. The comprehensive geriatric assessment was conducted via an internet-based platform of the Comprehensive Geriatric Assessment (inpatient version) developed by us, among which frailty was assessed by the Chinese version of Fried Frailty Phenotype, a component of the assessment scale.
    Results: Among the total number of old patients with CCS, 87 (30.2%) had no frailty, 93 (32.3%) had early frailty, and 108 (37.5%) had frailty. According to the multivariate logistic regression analysis, after adjusting for confounding factors, IL-6 (OR = 1.066, 95% CI 1.012-1.127), Alb (OR = 0.740, 95% CI 0.560-0.978), and 25(OH)D (OR = 0.798, 95% CI 0.670-0.949) were independently associated with frailty in the three groups of models.
    Conclusion: IL-6 proved to be a risk factor for frailty in elderly patients with CCS, while Alb and 25(OH)D were protective factors, which make the potential targets for predicting and intervening frailty in elderly patients with CCS.
    Keywords:  25‐hydroxyvitamin D, albumin, chronic coronary syndrome, comprehensive geriatric assessment, coronary artery disease, elderly people, frailty, interleukin‐6
    DOI:  https://doi.org/10.1002/agm2.12201
  3. Nat Aging. 2021 Jan;1(1): 47-59
    Intermittent and periodic fasting, longevity and disease.
    Valter D Longo, Maira Di Tano, Mark P Mattson, Novella Guidi.
      Intermittent and periodic fasting (IF and PF, respectively) are emerging as safe strategies to affect longevity and healthspan by acting on cellular aging and disease risk factors, while causing no or minor side effects. IF lasting from 12 to 48 hours and repeated every 1 to 7 days and PF lasting 2 to 7 days and repeated once per month or less have the potential to prevent and treat disease, but their effect on cellular aging and the molecular mechanisms involved are only beginning to be unraveled. Here, we describe the different fasting methods and their effect on longevity in organisms ranging from yeast to humans, linking them to the major nutrient-sensing signaling pathways and focusing on the benefits of the fasting and the refeeding periods. We also discuss both the therapeutic potential and side effects of IF and PF with a focus on cancer, autoimmunity, neurodegeneration and metabolic and cardiovascular disease.
    DOI:  https://doi.org/10.1038/s43587-020-00013-3
  4. Aging (Albany NY). 2022 Mar 05. 14(5): 2020-2024
    As predicted by hyperfunction theory, rapamycin treatment during development extends lifespan.
    Mikhail V Blagosklonny.
      
    Keywords:  growth; mTOR; quasi-programmed aging; reprogramming; sirolimus
    DOI:  https://doi.org/10.18632/aging.203937
  5. Front Biosci (Schol Ed). 2022 Mar 08. 14(1): 8
    Aldehyde Dehydrogenase Enzyme Functions in Acute Leukemia Stem Cells.
    Garrett M Dancik, Ioannis F Voutsas, Spiros Vlahopoulos.
      The enzymes that belong to the aldehyde dehydrogenase family are expressed in a variety of cells; yet activity of their main members characterizes stem cells, both normal and malignant. Several members of this family perform critical functions in stem cells, in general, and a few have been shown to have key roles in malignant tumors and their recurrence. In particular, ALDH1A1, which localizes to the cytosol and the nucleus, is an enzyme critical in cancer stem cells. In acute myeloid leukemia (AML), ALDH1A1 protects leukemia-initiating cells from a number of antineoplastic agents, and proves vital for the establishment of human AML xenografts in mice. ALDH2, which is located in mitochondria, has a major role in alcohol metabolism by clearing ethanol-derived acetaldehyde. Haematopoietic stem cells require ALDH2 for protection against acetaldehyde, which can cause damage to DNA, leading to insertions, deletions, chromosomal rearrangements, and translocations. Mutations compromise stem cell function, and thereby threaten blood homeostasis. We review here the potential of targeting the enzymatic activity of aldehyde dehydrogenases in acute leukemia.
    Keywords:  acute; aldehyde dehydrogenase; biomarker; drug resistance; gene expression; immunosuppression; leukemia; myeloid; neoplastic stem cells
    DOI:  https://doi.org/10.31083/j.fbs1401008
  6. Antioxidants (Basel). 2022 Feb 26. pii: 468. [Epub ahead of print]11(3):
    Antioxidant and Antiaging Properties of a Novel Synergistic Nutraceutical Complex: Readouts from an In Cellulo Study and an In Vivo Prospective, Randomized Trial.
    Sophia Athanasopoulou, Marianna Kapetanou, Michel Georges Magouritsas, Nikoletta Mougkolia, Polykseni Taouxidou, Michael Papacharalambous, Fotios Sakellaridis, Efstathios Gonos.
      Aging is a dynamic procedure that is developed in multiple layers and characterized by distinct hallmarks. The use of biomarkers that target different hallmarks of aging is substantial in predicting adverse outcomes during the aging process, implementing specifically designed antiaging interventions and monitoring responses to these interventions. The present study aimed to develop a novel composition of plant extracts, comprising identified active ingredients that synergistically target different hallmarks of aging in cellulo and in vivo. The selected single extracts and the developed composition were tested through a powerful set of biomarkers that we have previously identified and studied. The composition of selected extracts simultaneously increased cellular lifespan, reduced the cellular oxidative load and enhanced antioxidant defense mechanisms by increasing proteasome activity and content. In addition, the combination prevented telomere attrition and preserved optimum DNA methylation levels. Remarkably, biomarker profiling of healthy volunteers who received the identified combination in the form of a nutritional supplement within the frame of a prospective, randomized, controlled 3-month trial revealed an unprecedented antioxidant capacity in humans. In conclusion, our results support the notion that interventions with specifically designed combinations of natural compounds targeting multiple hallmarks of aging represent an effective way to improve healthspan and well-being.
    Keywords:  antioxidant defense; dietary supplements; nutraceuticals; proteostasis; well-being
    DOI:  https://doi.org/10.3390/antiox11030468
  7. Cancers (Basel). 2022 Mar 11. pii: 1446. [Epub ahead of print]14(6):
    Synergy of Venetoclax and 8-Chloro-Adenosine in AML: The Interplay of rRNA Inhibition and Fatty Acid Metabolism.
    Dinh Hoa Hoang, Corey Morales, Ivan Rodriguez Rodriguez, Melissa Valerio, Jiamin Guo, Min-Hsuan Chen, Xiwei Wu, David Horne, Varsha Gandhi, Lisa S Chen, Bin Zhang, Vinod Pullarkat, Steven T Rosen, Guido Marcucci, Ralf Buettner, Le Xuan Truong Nguyen.
      It is known that 8-chloro-adenosine (8-Cl-Ado) is a novel RNA-directed nucleoside analog that targets leukemic stem cells (LSCs). In a phase I clinical trial with 8-Cl-Ado in patients with refractory or relapsed (R/R) AML, we observed encouraging but short-lived clinical responses, likely due to intrinsic mechanisms of LSC resistance. LSC homeostasis depends on amino acid-driven and/or fatty acid oxidation (FAO)-driven oxidative phosphorylation (OXPHOS) for survival. We recently reported that 8-Cl-Ado and the BCL-2-selective inhibitor venetoclax (VEN) synergistically inhibit FAO and OXPHOS in LSCs, thereby suppressing acute myeloid leukemia (AML) growth in vitro and in vivo. Herein, we report that 8-Cl-Ado inhibits ribosomal RNA (rRNA) synthesis through the downregulation of transcription initiation factor TIF-IA that is associated with increasing levels of p53. Paradoxically, 8-Cl-Ado-induced p53 increased FAO and OXPHOS, thereby self-limiting the activity of 8-Cl-Ado on LSCs. Since VEN inhibits amino acid-driven OXPHOS, the addition of VEN significantly enhanced the activity of 8-Cl-Ado by counteracting the self-limiting effect of p53 on FAO and OXPHOS. Overall, our results indicate that VEN and 8-Cl-Ado can cooperate in targeting rRNA synthesis and OXPHOS and in decreasing the survival of the LSC-enriched cell population, suggesting the VEN/8-Cl-Ado regimen as a promising therapeutic approach for patients with R/R AML.
    Keywords:  8-chloro-adenosine; acute myeloid leukemia; metabolism; rRNA synthesis; venetoclax
    DOI:  https://doi.org/10.3390/cancers14061446
  8. Int J Environ Res Public Health. 2022 Mar 13. pii: 3379. [Epub ahead of print]19(6):
    The Association of Nutrition Quality with Frailty Syndrome among the Elderly.
    Katarzyna Rolf, Aurelia Santoro, Morena Martucci, Barbara Pietruszka.
      Low diet quality among the elderly may be correlated with some diseases, including Frailty Syndrome (FS). This decline in function restricts the activity of older people, resulting in higher assistance costs. The aim of this study was to increase knowledge of diet quality predictors. Dietary intake was assessed among 196 individuals aged 60+ years using the three-day record method and FS by Fried's criteria. Based on the compliance with the intake recommendation (% of EAR/AI), we distinguished three clusters that were homogeneous in terms of the nutritional quality of the diet, using Kohonen's neural networks. The prevalence of frailty in the entire group was 3.1%, pre-frailty 38.8%, and non-frailty 58.1%. Cluster 1 (91 people with the lowest diet quality) was composed of a statistically significant higher number of the elderly attending day care centers (20.7%), frail (6.9%), pre-frail (51.7%), very low vitamin D intake (23.8% of AI), using sun cream during the summer months (always 19.8% or often 39.6%), having diabetes (20.7%), having leg pain when walking (43.1%), and deteriorating health during the last year (53.5%). The study suggests the need to take initiatives leading to the improvement of the diet of the elderly, especially in day care senior centers, where there are more frail individuals, including nutritional education for the elderly and their caregivers.
    Keywords:  day care senior centers; diet; elderly; frailty; vitamin D
    DOI:  https://doi.org/10.3390/ijerph19063379
  9. Nutrients. 2022 Mar 11. pii: 1192. [Epub ahead of print]14(6):
    Guava Fruit and Acacia pennata Vegetable Intake Association with Frailty of Older Adults in Northern Thailand.
    Jetsada Ruangsuriya, Rawiwan Wongpoomchai, Somdet Srichairatanakool, Wachiranun Sirikul, Nida Buawangpong, Penprapa Siviroj.
      As Thailand moves toward an aging society, frailty has become a concern amongst northern Thai elderly. The causes of frailty are multifactorial and include genetic, environmental, and socio-economic factors; diet is of particular interest. A cross-sectional study was conducted from September to October 2017 to investigate what kind of diets normally consumed by 350 Thai elders were associated with frailty using a questionnaire and frailty determination by Fried's phenotype followed by phytochemical analyses of the diets. The multivariable logistic regression analysis demonstrated a significant positive association between certain foods and lower frailty. Guava fruit and Acacia pennata vegetable consumption had lower odds of frailty, which were 0.52 times (95% CI 0.28-0.96, p = 0.037) and 0.42 times (95% CI 0.21-0.83, p = 0.012) when adjusted for the potential confounders. The phytochemical analyses of guava fruit showed a significantly higher amount of total flavonoids (p < 0.001), total phenolic compounds (p = 0.002), and antioxidant capacity, including DPPH (p < 0.001), ABTS (p < 0.001), and FRAP (p = 0.002) when compared to those of banana. Acacia pennata vegetable contained a significantly higher amount of total phenolic compounds (p = 0.012) when compared to those of lettuce. These findings may assist in health promotion programs of frailty prevention by encouraging an increase in consumption of either guava fruit or Acacia pennata vegetable among Thai elderly.
    Keywords:  Acacia pennata; Thailand; dietary consumption; frailty; fruits; guava fruit; older adults; vegetables
    DOI:  https://doi.org/10.3390/nu14061192
  10. Mol Cell Biochem. 2022 Mar 25.
    NAD+ centric mechanisms and molecular determinants of skeletal muscle disease and aging.
    Sabrina Wagner, Ravikumar Manickam, Marco Brotto, Srinivas M Tipparaju.
      The nicotinamide adenine dinucleotide (NAD+) is an essential redox cofactor, involved in various physiological and molecular processes, including energy metabolism, epigenetics, aging, and metabolic diseases. NAD+ repletion ameliorates muscular dystrophy and improves the mitochondrial and muscle stem cell function and thereby increase lifespan in mice. Accordingly, NAD+ is considered as an anti-oxidant and anti-aging molecule. NAD+ plays a central role in energy metabolism and the energy produced is used for movements, thermoregulation, and defense against foreign bodies. The dietary precursors of NAD+ synthesis is targeted to improve NAD+ biosynthesis; however, studies have revealed conflicting results regarding skeletal muscle-specific effects. Recent advances in the activation of nicotinamide phosphoribosyltransferase in the NAD+ salvage pathway and supplementation of NAD+ precursors have led to beneficial effects in skeletal muscle pathophysiology and function during aging and associated metabolic diseases. NAD+ is also involved in the epigenetic regulation and post-translational modifications of proteins that are involved in various cellular processes to maintain tissue homeostasis. This review provides detailed insights into the roles of NAD+ along with molecular mechanisms during aging and disease conditions, such as the impacts of age-related NAD+ deficiencies on NAD+-dependent enzymes, including poly (ADP-ribose) polymerase (PARPs), CD38, and sirtuins within skeletal muscle, and the most recent studies on the potential of nutritional supplementation and distinct modes of exercise to replenish the NAD+ pool.
    Keywords:  Aging; Diabetes; Epigenetics; Muscle diseases; NAD+; Redox
    DOI:  https://doi.org/10.1007/s11010-022-04408-1
  11. Cancers (Basel). 2022 Mar 08. pii: 1368. [Epub ahead of print]14(6):
    Functional Decline in the Cancer Patient: A Review.
    Jaidyn Muhandiramge, Suzanne G Orchard, Erica T Warner, Gijsberta J van Londen, John R Zalcberg.
      A decline in functional status, an individual's ability to perform the normal activities required to maintain adequate health and meet basic needs, is part of normal ageing. Functional decline, however, appears to be accelerated in older patients with cancer. Such decline can occur as a result of a cancer itself, cancer treatment-related factors, or a combination of the two. The accelerated decline in function seen in older patients with cancer can be slowed, or even partly mitigated through routine assessments of functional status and timely interventions where appropriate. This is particularly important given the link between functional decline and impaired quality of life, increased mortality, comorbidity burden, and carer dependency. However, a routine assessment of and the use of interventions for functional decline do not typically feature in the long-term care of cancer survivors. This review outlines the link between cancer and subsequent functional decline, as well as potential underlying mechanisms, the tools that can be used to assess functional status, and strategies for its prevention and management in older patients with cancer.
    Keywords:  ageing; cancer; elderly; frailty; functional decline; functional status
    DOI:  https://doi.org/10.3390/cancers14061368
  12. Nature. 2022 Mar 21.
    Mice eat less and explore more after intake of certain amino acids.
      
    Keywords:  Neuroscience
    DOI:  https://doi.org/10.1038/d41586-022-00830-z
  13. Antioxidants (Basel). 2022 Feb 25. pii: 461. [Epub ahead of print]11(3):
    Venetoclax-Resistant MV4-11 Leukemic Cells Activate PI3K/AKT Pathway for Metabolic Reprogramming and Redox Adaptation for Survival.
    Hind A Alkhatabi, Samir F Zohny, Mohammed Razeeth Shait Mohammed, Hani Choudhry, Mohd Rehan, Aamir Ahmad, Farid Ahmed, Mohammad Imran Khan.
      Venetoclax (ABT199) is a selective B-cell lymphoma 2 (BCL-2) inhibitor. The US FDA recently approved it to be used in combination with low-dose cytarabine or hypomethylating agents in acute myeloid leukemia (AML) or elderly patients non-eligible for chemotherapy. However, acquiring resistance to venetoclax in AML patients is the primary cause of treatment failure. To understand the molecular mechanisms inherent in the resistance to BCL-2 inhibitors, we generated a venetoclax-resistant cell line model and assessed the consequences of this resistance on its metabolic pathways. Untargeted metabolomics data displayed a notable impact of resistance on the PI3K/AKT pathway, the Warburg effect, glycolysis, the TCA cycle, and redox metabolism. The resistant cells showed increased NADPH and reduced glutathione levels, switching their energy metabolism towards glycolysis. PI3K/AKT pathway inhibition shifted resistant cells towards oxidative phosphorylation (OXPHOS). Our results provide a metabolic map of resistant cells that can be used to design novel metabolic targets to challenge venetoclax resistance in AML.
    Keywords:  MV4-11; OXPHOS; PI3K/AKT pathway; acute myeloid leukemia; glycolysis; metabolomics; redox metabolism; venetoclax; venetoclax resistance model
    DOI:  https://doi.org/10.3390/antiox11030461
  14. Age Ageing. 2022 Mar 01. pii: afab280. [Epub ahead of print]51(3):
    Geriatric emergency medicine-a model for frailty friendly healthcare.
    Simon P Mooijaart, Christopher R Carpenter, Simon P Conroy.
      As the world's population continues to age over the decades ahead, medical educators and researchers in every adult medical and surgical specialty will need to 'geriatricise' their clinical science. Many have already engaged with geriatrics. Here we describe the progress that has been made and the opportunities ahead in the field of Geriatric Emergency Medicine (GEM), a field that has taken large steps in integrating holistic care. Future opportunities exist in the three domains of evidence-based medicine: including patient preferences and needs, generating scientific evidence, and improving physician knowledge and expertise. Implementation requires new innovations also in the organisation of care. Similar strategies may be useful in other fields of medicine, in making holistic care the standard for older people.
    Keywords:  emergency medicine; evidence-based medicine; frailty; older people
    DOI:  https://doi.org/10.1093/ageing/afab280
  15. Vitam Horm. 2022 ;pii: S0083-6729(22)00014-0. [Epub ahead of print]119 299-324
    Telomere length and vitamin B12.
    Guruvaiah Praveen, Mudili Sivaprasad, G Bhanuprakash Reddy.
      Telomeres are non-coding nucleoprotein structures consisting of a highly conserved tandem repeat DNA sequence that caps the ends of chromosomes in eukaryotes. Telomeres confer chromosomal stability, protect the genome from nucleolytic degradation, avoid aberrant recombination and improper repair, and prevent random fusion of chromosomes. The end-replication problem results in telomere shortening with every cell division, eventually leading to cellular senescence and aging. Telomere length (TL) is thereby an ideal candidate for "biological aging." Telomeres possess guanine-rich repeats, which are highly susceptible to oxidative stress. Epidemiological studies have indicated the association of telomere attrition with mortality and various age-related diseases. Micronutrients comprising vitamins and minerals act as potential modulators of stress and can influence TL. Research has indicated that vitamin B12 (B12) regulates oxidative stress and maintains genomic stability, thereby influencing telomere integrity and cellular aging. The deficiency of B12 leads to elevated levels of homocysteine, which reduces the methylation potential and increases oxidative stress, thereby compromising the TL. Telomere shortening and mitochondrial dysfunction are independently linked to aging. However, they are connected through telomerase reverse transcriptase activity, which regulates mitochondrial biogenesis. Further, experimental evidence indicated the positive association of B12 with relative TL and mitochondrial DNA copy number, an indirect index of mitochondrial biogenesis. The present chapter provides some insights into the role of B12 in influencing TL. Exploring their association might open new avenues to understand the pathophysiology of aging and age-related diseases.
    Keywords:  8-Oxo-G; Aging; Homocysteine; Methylation; Mitochondrial DNA copy number oxidative stress; Telomerase; Telomere length; Vitamin B12
    DOI:  https://doi.org/10.1016/bs.vh.2022.01.014
  16. Methods Mol Biol. 2022 ;2468 329-338
    An Imaging System for Monitoring C. elegans Behavior and Aging.
    Matthew A Churgin, Christopher Fang-Yen.
      Many experiments in C. elegans neurobiology rely on imaging its behavior. Here we describe procedures for building a flexible and inexpensive imaging system using standard optical and mechanical components.
    Keywords:  Aging; Behavior; C. elegans; Imaging
    DOI:  https://doi.org/10.1007/978-1-0716-2181-3_18
  17. Int J Mol Sci. 2022 Mar 15. pii: 3160. [Epub ahead of print]23(6):
    The Reconstitution Dynamics of Cultivated Hematopoietic Stem Cells and Progenitors Is Independent of Age.
    Frauke Gotzhein, Tim Aranyossy, Lars Thielecke, Tanja Sonntag, Vanessa Thaden, Boris Fehse, Ingo Müller, Ingmar Glauche, Kerstin Cornils.
      Hematopoietic stem cell transplantation (HSCT) represents the only curative treatment option for numerous hematologic malignancies. While the influence of donor age and the composition of the graft have already been examined in clinical and preclinical studies, little information is available on the extent to which different hematological subpopulations contribute to the dynamics of the reconstitution process and on whether and how these contributions are altered with age. In a murine model of HSCT, we therefore simultaneously tracked different cultivated and transduced hematopoietic stem and progenitor cell (HSPC) populations using a multicolor-coded barcode system (BC32). We studied a series of age-matched and age-mismatched transplantations and compared the influence of age on the reconstitution dynamics. We show that reconstitution from these cultured and assembled grafts was substantially driven by hematopoietic stem cells (HSCs) and multipotent progenitors (MPPs) independent of age. The reconstitution patterns were polyclonal and stable in all age groups independently of the variability between individual animals, with higher output rates from MPPs than from HSCs. Our experiments suggest that the dynamics of reconstitution and the contribution of cultured and individually transduced HSPC subpopulations are largely independent of age. Our findings support ongoing efforts to expand the application of HSCT in older individuals as a promising strategy to combat hematological diseases, including gene therapy applications.
    Keywords:  aging; clonality; genetic barcoding; hematopoietic progenitor cells; hematopoietic stem cells; stem cell transplantation
    DOI:  https://doi.org/10.3390/ijms23063160
  18. Biomolecules. 2022 Mar 02. pii: 387. [Epub ahead of print]12(3):
    Amino Acid Signaling for TOR in Eukaryotes: Sensors, Transducers, and a Sustainable Agricultural fuTORe.
    Nanticha Lutt, Jacob O Brunkard.
      Eukaryotic cells monitor and regulate metabolism through the atypical protein kinase target of rapamycin (TOR) regulatory hub. TOR is activated by amino acids in animals and fungi through molecular signaling pathways that have been extensively defined in the past ten years. Very recently, several studies revealed that TOR is also acutely responsive to amino acid metabolism in plants, but the mechanisms of amino acid sensing are not yet established. In this review, we summarize these discoveries, emphasizing the diversity of amino acid sensors in human cells and highlighting pathways that are indirectly sensitive to amino acids, i.e., how TOR monitors changes in amino acid availability without a bona fide amino acid sensor. We then discuss the relevance of these model discoveries to plant biology. As plants can synthesize all proteinogenic amino acids from inorganic precursors, we focus on the possibility that TOR senses both organic metabolites and inorganic nutrients. We conclude that an evolutionary perspective on nutrient sensing by TOR benefits both agricultural and biomedical science, contributing to ongoing efforts to generate crops for a sustainable agricultural future.
    Keywords:  Arabidopsis thaliana; Castor1; GATOR; GCN2; Ragulator; Sestrin2; amino acid signaling; mTOR; metabolism; target of rapamycin
    DOI:  https://doi.org/10.3390/biom12030387
  19. Ageing Res Rev. 2022 Mar 17. pii: S1568-1637(22)00053-8. [Epub ahead of print]77 101611
    Searching for the link between inflammaging and sarcopenia.
    Tiantian Wang.
      
    Keywords:  Adipokines; Inflammaging; Inflammatory cytokines; Myokines; Sarcopenia
    DOI:  https://doi.org/10.1016/j.arr.2022.101611
  20. Mol Biol Cell. 2022 Apr 01. 33(4): mbcP22021003
    Preprint Highlight: ER-lysosome lipid transfer protein VPS13C/PARK23 prevents aberrant mtDNA- dependent STING signaling.
    Luis Bonet-Ponce.
      
    DOI:  https://doi.org/10.1091/mbc.P22-02-1003
  21. Nutrients. 2022 Mar 09. pii: 1155. [Epub ahead of print]14(6):
    Anti-Inflammatory and Active Biological Properties of the Plant-Derived Bioactive Compounds Luteolin and Luteolin 7-Glucoside.
    Sabrina Caporali, Alessandro De Stefano, Cinzia Calabrese, Alfredo Giovannelli, Massimo Pieri, Isabella Savini, Manfredi Tesauro, Sergio Bernardini, Marilena Minieri, Alessandro Terrinoni.
      Flavonoids are interesting molecules synthetized by plants. They can be found abundantly in seeds and fruits, determining the color, flavor, and other organoleptic characteristics, as well as contributing to important nutritional aspects. Beyond these characteristics, due to their biochemical properties and characteristics, they can be considered bioactive compounds. Several interesting studies have demonstrated their biological activity in different cellular and physiological processes in high-order organisms including humans. The flavonoid molecular structure confers the capability of reacting with and neutralizing reactive oxygen species (ROS), behaving as scavengers in all processes generating this class of molecules, such as UV irradiation, a process widely present in plant physiology. Importantly, the recent scientific literature has demonstrated that flavonoids, in human physiology, are active compounds acting not only as scavengers but also with the important role of counteracting the inflammation process. Among the wide variety of flavonoid molecules, significant results have been shown by investigating the role of the flavones luteolin and luteolin-7-O-glucoside (LUT-7G). For these compounds, experimental results demonstrated an interesting anti-inflammatory action, both in vitro and in vivo, in the interaction with JAK/STAT3, NF-κB, and other pathways described in this review. We also describe the effects in metabolic pathways connected with inflammation, such as cellular glycolysis, diabetes, lipid peroxidation, and effects in cancer cells. Moreover, the inhibition of inflammatory pathway in endothelial tissue, as well as the NLRP3 inflammasome assembly, demonstrates a key role in the progression of such phenomena. Since these micronutrient molecules can be obtained from food, their biochemical properties open new perspectives with respect to the long-term health status of healthy individuals, as well as their use as a coadjutant treatment in specific diseases.
    Keywords:  endothelial inflammation; flavones; flavonoids; glucose metabolism; inflammation; luteolin; luteolin-7-O-glucoside (LUT-7G)
    DOI:  https://doi.org/10.3390/nu14061155
  22. Mech Ageing Dev. 2022 Mar 17. pii: S0047-6374(22)00047-1. [Epub ahead of print]204 111665
    Genistein, a tool for geroscience.
    Cristina Mas- Bargues, Consuelo Borrás, José Viña.
      Geroprotection is defined as protection from the adverse effects of aging. The need for geroprotection implies changes towards individually tailored interventions that preserve an individual's independence, physical function, and cognition. Genistein, a phytoestrogen obtained from soya, has been reported to have beneficial properties on age-related diseases such as neurodegenerative and cardiovascular diseases or cancer. Indeed, genistein is a multimodal agent: it acts as a cancer protective agent, promoting apoptosis and cell cycle arrest, and inhibiting angiogenesis and metastasis, but it also acts as an antioxidant, anti-inflammatory, and anti-amyloid-β and autophagy promoter. Altogether, these properties make genistein a possible treatment for the specific aspects of age-related diseases such as hypertension, metabolic diseases, Alzheimer's disease, and osteoporosis.
    Keywords:  Age-related diseases; Aging; Genistein; Geroprotection
    DOI:  https://doi.org/10.1016/j.mad.2022.111665
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