bims-minfam 2021-08-29 papers

bims-minfam

Biomed News

on Inflammation and metabolism in ageing and cancer

Issue of 2021‒08‒29
thirty-two papers selected by
Ayesh Seneviratne
University of Toronto

Inflammation and Aging of Hematopoietic Stem Cells in Their Niche.
Emerging Role of Acquired Mutations and Clonal Hematopoiesis in Atherosclerosis　- Beyond Conventional Cardiovascular Risk Factors.
Aspartate availability limits hematopoietic stem cell function during hematopoietic regeneration.
Understanding the role of host metabolites in the induction of immunesenescence: future strategies for keeping the ageing population healthy.
The aryl hydrocarbon receptor modulates murine hematopoietic stem cell homeostasis and influences lineage-biased stem and progenitor cells.
Epigenetic age is associated with baseline and 3-year change in frailty in the Canadian Longitudinal Study on Aging.
FDA-Approved Drug Screening for Compounds That Facilitate Hematopoietic Stem and Progenitor Cells (HSPCs) Expansion in Zebrafish.
Longitudinal evidence for immunosenescence and inflammaging in free-living great tits.
Lipid metabolism and mitochondria: Cross talk in cancer.
Dynamic Changes of the Bone Marrow Niche: Mesenchymal Stromal Cells and Their Progeny During Aging and Leukemia.
Precision nutrition for gut microbiome and diabetes research: Application of nutritional n-of-1 clinical trials.
Dietary Control of Inflammation and Resolution.
Involvement of Extracellular vesicles in aging process and their beneficial effects in alleviating aging-associated symptoms.
Whole-Grain Intake in the Mediterranean Diet and a Low Protein to Carbohydrates Ratio Can Help to Reduce Mortality from Cardiovascular Disease, Slow Down the Progression of Aging, and to Improve Lifespan: A Review.
Nutrients with anabolic/anticatabolic, antioxidant, and anti-inflammatory properties: Targeting the biological mechanisms of aging to support musculoskeletal health.
Accelerated Epigenetic Aging in Peripheral Blood Does not Predict Dementia Risk.
Talking about frailty: The role of stigma and precarity in older peoples' constructions of frailty.
Incidence and severity of G6PI-induced arthritis are not increased in genetically distinct mouse strains upon aging.
The Triglyceride-glucose index as an adiposity marker and a predictor of fat loss induced by a low-calorie diet.
SCD1, autophagy and cancer: implications for therapy.
5-Azacytidine depletes hematopoietic stem cells and synergizes with an anti-CD117 antibody to augment donor engraftment in immunocompetent mice.
Targeting aging cells improves survival.
Mechano-energetic aspects of Barth Syndrome.
Biological Aspects of Selected Myokines in Skeletal Muscle: Focus on Aging.
Anti-Inflammatory Properties of Diet: Role in Healthy Aging.
The Mediterranean diet and health: a comprehensive overview.
Germs, geriatrics, and grandpa: Generations of gaps, goals, and goodness.
Retracted: P0981ANTIDIABETIC AND RENOPROTECTIVE ROLE OF METFORMIN ON METABOLIC PARAMETERS IN KIDNEY OF DIABETIC AGING RATS.
CD7-deleted hematopoietic stem cells can restore immunity after CAR T cell therapy.
Supplemental Ferulic Acid Inhibits Total Body Irradiation-Mediated Bone Marrow Damage, Bone Mass Loss, Stem Cell Senescence, and Hematopoietic Defect in Mice by Enhancing Antioxidant Defense Systems.
Dietary AGEs as Exogenous Boosters of Inflammation.
Hematopoietic Dysfunction during Graft-Versus-Host Disease: A Self-Destructive Process?

Cells. 2021 Jul 21. pii: 1849. [Epub ahead of print]10(8):

Inflammation and Aging of Hematopoietic Stem Cells in Their Niche.

Daozheng Yang, Gerald de Haan.

  Hematopoietic stem cells (HSCs) sustain the lifelong production of all blood cell lineages. The functioning of aged HSCs is impaired, including a declined repopulation capacity and myeloid and platelet-restricted differentiation. Both cell-intrinsic and microenvironmental extrinsic factors contribute to HSC aging. Recent studies highlight the emerging role of inflammation in contributing to HSC aging. In this review, we summarize the recent finding of age-associated changes of HSCs and the bone marrow niche in which they lodge, and discuss how inflammation may drive HSC aging.

Keywords:  aging; hematopoietic stem cells; heterogeneity; inflammation; niche

DOI:  https://doi.org/10.3390/cells10081849
Circ J. 2021 Aug 25.

Emerging Role of Acquired Mutations and Clonal Hematopoiesis in Atherosclerosis　- Beyond Conventional Cardiovascular Risk Factors.

María A Zuriaga, José J Fuster.

  Accumulating evidence suggests that conventional cardiovascular risk factors are incompletely predictive of cardiovascular disease, as a substantial risk remains even when these factors are apparently managed well. In this context, clonal hematopoiesis has emerged as a new and potent risk factor for atherosclerotic cardiovascular disease and other cardiometabolic conditions. Clonal hematopoiesis typically arises from somatic mutations that confer a competitive advantage to a mutant hematopoietic stem cell, leading to its clonal expansion in the stem cell population and its progeny of blood leukocytes. Human sequencing studies and experiments in mice suggest that clonal hematopoiesis, at least when driven by certain mutations, contributes to accelerated atherosclerosis development. However, the epidemiology, biology and clinical implications of this phenomenon remain incompletely understood. Here, we review the current understanding of the connection between clonal hematopoiesis and atherosclerosis, and highlight knowledge gaps in this area of research.

Keywords:  Aging; Atherosclerosis; CHIP; Inflammation; TET2

DOI:  https://doi.org/10.1253/circj.CJ-21-0505
Cell Stem Cell. 2021 Aug 21. pii: S1934-5909(21)00296-4. [Epub ahead of print]

Aspartate availability limits hematopoietic stem cell function during hematopoietic regeneration.

Le Qi, Misty S Martin-Sandoval, Salma Merchant, Wen Gu, Matthias Eckhardt, Thomas P Mathews, Zhiyu Zhao, Michalis Agathocleous, Sean J Morrison.

  The electron transport chain promotes aspartate synthesis, which is required for cancer cell proliferation. However, it is unclear whether aspartate is limiting in normal stem cells. We found that mouse hematopoietic stem cells (HSCs) depend entirely on cell-autonomous aspartate synthesis, which increases upon HSC activation. Overexpression of the glutamate/aspartate transporter, Glast, or deletion of glutamic-oxaloacetic transaminase 1 (Got1) each increased aspartate levels in HSCs/progenitor cells and increased the function of HSCs but not colony-forming progenitors. Conversely, deletion of Got2 reduced aspartate levels and the function of HSCs but not colony-forming progenitors. Deletion of Got1 and Got2 eliminated HSCs. Isotope tracing showed aspartate was used to synthesize asparagine and purines. Both contributed to increased HSC function as deletion of asparagine synthetase or treatment with 6-mercaptopurine attenuated the increased function of GLAST-overexpressing HSCs. HSC function is thus limited by aspartate, purine, and asparagine availability during hematopoietic regeneration.

Keywords:  asparagine; aspartate; electron transport chain; hematopoietic stem cell; metabolism; mitochondria; purine; regeneration

DOI:  https://doi.org/10.1016/j.stem.2021.07.011
Br J Pharmacol. 2021 Aug 26.

Understanding the role of host metabolites in the induction of immunesenescence: future strategies for keeping the ageing population healthy.

Jessica Conway, Michelangelo Certo, Janet M Lord, Claudio Mauro, Niharika A Duggal.

Advancing age is accompanied by significant remodelling of the immune system, termed immunesenescence, and increased systemic inflammation, termed inflammaging, both of which contribute towards an increased risk of developing chronic diseases in old age. Age-associated alterations in metabolic homeostasis have been linked with changes in a range of physiological functions, but their impact on immunesenescence remains poorly understood. In this article, we review the recent literature to formulate hypotheses as to how an age-associated dysfunctional metabolism, driven by an accumulation of key host metabolites (saturated fatty acids, cholesterol, ceramides, lactate) and loss of other metabolites (glutamine, tryptophan, short chain fatty acids), might play a role in driving immunesenescence and inflammaging, ultimately leading to diseases of old age. We also highlight the potential use of metabolic immunotherapeutic strategies targeting these processes in counteracting immunesenescence and restoring immune homeostasis in older adults.

DOI: https://doi.org/10.1111/bph.15671
Stem Cells Dev. 2021 Aug 24.

The aryl hydrocarbon receptor modulates murine hematopoietic stem cell homeostasis and influences lineage-biased stem and progenitor cells.

Keegan L Vaughan, Anthony M Franchini, Harrison G Kern, B Paige Lawrence.

The core function of hematopoietic stem and progenitor cells (HSPCs) is to provide lifelong production of all lineages of the blood and immune cells. The mechanisms that modulate HSPC homeostasis and lineage-biasing are not fully understood. Growing evidence implicates the aryl hydrocarbon receptor (AHR), an environment sensing transcription factor, as a regulator of hematopoiesis. AHR ligands modulate the frequency of mature hematopoietic cells in the bone marrow and periphery, while HSPCs from mice lacking AHR (AHR KO) have increased proliferation. Yet, whether AHR modulates HSPC lineage potential and directs differentiation towards specific lineage-biased progenitors is not well understood. Our current study revealed that AHR-KO mice have an increased proportion of myeloid-biased HSCs and myeloid-biased multipotent progenitors (MPP3) cells. Utilizing inducible AHR knockout mice (iAHR-KO), it was discovered that acute deletion of AHR doubled the number of MPP3 cells and altered the composition of downstream lineage-committed progenitors, such as increased frequency of pre-granulocyte/monocyte committed progenitors. Furthermore, in-vivo antagonism of the AHR led to a 2.5-fold increase in the number of MPP3 cells and promoted myeloid-biased differentiation. Using hematopoietic-specific conditional AHR knockout mice (AHRVav1) revealed that increased frequency of myeloid-biased HSCs and myeloid-biased progenitors are driven by AHR signaling that is intrinsic to the hematopoietic compartment. These findings demonstrate that the AHR plays a pivotal role in regulating steady-state hematopoiesis, influencing HSPC homeostasis and lineage potential. Additionally, the data presented provide potential insight into how deliberate modulation of AHR signaling could help with the treatment of a broad ranges of diseases that require the hematopoietic compartment.

DOI: https://doi.org/10.1089/scd.2021.0096
Clin Epigenetics. 2021 Aug 23. 13(1): 163

Epigenetic age is associated with baseline and 3-year change in frailty in the Canadian Longitudinal Study on Aging.

Chris P Verschoor, David T S Lin, Michael S Kobor, Oxana Mian, Jinhui Ma, Guillaume Pare, Gustavo Ybazeta.

  BACKGROUND: The trajectory of frailty in older adults is important to public health; therefore, markers that may help predict this and other important outcomes could be beneficial. Epigenetic clocks have been developed and are associated with various health-related outcomes and sociodemographic factors, but associations with frailty are poorly described. Further, it is uncertain whether newer generations of epigenetic clocks, trained on variables other than chronological age, would be more strongly associated with frailty than earlier developed clocks. Using data from the Canadian Longitudinal Study on Aging (CLSA), we tested the hypothesis that clocks trained on phenotypic markers of health or mortality (i.e., Dunedin PoAm, GrimAge, PhenoAge and Zhang in Nat Commun 8:14617, 2017) would best predict changes in a 76-item frailty index (FI) over a 3-year interval, as compared to clocks trained on chronological age (i.e., Hannum in Mol Cell 49:359-367, 2013, Horvath in Genome Biol 14:R115, 2013, Lin in Aging 8:394-401, 2016, and Yang Genome Biol 17:205, 2016).RESULTS: We show that in 1446 participants, phenotype/mortality-trained clocks outperformed age-trained clocks with regard to the association with baseline frailty (mean = 0.141, SD = 0.075), the greatest of which is GrimAge, where a 1-SD increase in ΔGrimAge (i.e., the difference from chronological age) was associated with a 0.020 increase in frailty (95% CI 0.016, 0.024), or ~ 27% relative to the SD in frailty. Only GrimAge and Hannum (Mol Cell 49:359-367, 2013) were significantly associated with change in frailty over time, where a 1-SD increase in ΔGrimAge and ΔHannum 2013 was associated with a 0.0030 (95% CI 0.0007, 0.0050) and 0.0028 (95% CI 0.0007, 0.0050) increase over 3 years, respectively, or ~ 7% relative to the SD in frailty change.
CONCLUSION: Both prevalence and change in frailty are associated with increased epigenetic age. However, not all clocks are equally sensitive to these outcomes and depend on their underlying relationship with chronological age, healthspan and lifespan. Certain clocks were significantly associated with relatively short-term changes in frailty, thereby supporting their utility in initiatives and interventions to promote healthy aging.

Keywords:  CLSA; DNA methylation; Epigenetic clock; Frailty

DOI:  https://doi.org/10.1186/s13148-021-01150-1
Cells. 2021 Aug 20. pii: 2149. [Epub ahead of print]10(8):

FDA-Approved Drug Screening for Compounds That Facilitate Hematopoietic Stem and Progenitor Cells (HSPCs) Expansion in Zebrafish.

Zhi Feng, Chenyu Lin, Limei Tu, Ming Su, Chunyu Song, Shengnan Liu, Michael Edbert Suryanto, Chung-Der Hsiao, Li Li.

  Hematopoietic stem cells (HSCs) are a specialized subset of cells with self-renewal and multilineage differentiation potency, which are essential for their function in bone marrow or umbilical cord blood transplantation to treat blood disorders. Expanding the hematopoietic stem and progenitor cells (HSPCs) ex vivo is essential to understand the HSPCs-based therapies potency. Here, we established a screening system in zebrafish by adopting an FDA-approved drug library to identify candidates that could facilitate HSPC expansion. To date, we have screened 171 drugs of 7 categories, including antibacterial, antineoplastic, glucocorticoid, NSAIDS, vitamins, antidepressant, and antipsychotic drugs. We found 21 drugs that contributed to HSPCs expansion, 32 drugs' administration caused HSPCs diminishment and 118 drugs' treatment elicited no effect on HSPCs amplification. Among these drugs, we further investigated the vitamin drugs ergocalciferol and panthenol, taking advantage of their acceptability, limited side-effects, and easy delivery. These two drugs, in particular, efficiently expanded the HSPCs pool in a dose-dependent manner. Their application even mitigated the compromised hematopoiesis in an ikzf1-/- mutant. Taken together, our study implied that the larval zebrafish is a suitable model for drug repurposing of effective molecules (especially those already approved for clinical use) that can facilitate HSPCs expansion.

Keywords:  HSPCs expansion; drug screening; vitamins; zebrafish

DOI:  https://doi.org/10.3390/cells10082149
Exp Gerontol. 2021 Aug 21. pii: S0531-5565(21)00309-0. [Epub ahead of print] 111527

Longitudinal evidence for immunosenescence and inflammaging in free-living great tits.

Martin Těšický, Tereza Krajzingrová, Zuzana Świderská, Kamila Syslová, Barbora Bílková, Jiří Eliáš, Hana Velová, Jana Svobodová, Petra Bauerová, Tomáš Albrecht, Michal Vinkler.

  The first-line effector mechanisms of immune defence, including inflammation and oxidative burst, contribute significantly to host-pathogen resistance. Whether these immune responses undergo age-related changes in birds remains unknown. Here, we tracked selected inflammatory parameters in 54 free-living great tits (Parus major) of known age, captured repeatedly over three consecutive years, with the aims to investigate long-term repeatability and age-dependent changes in cellular oxidative burst responsiveness upon in vitro stimulation with bacterial lipopolysaccharide (LPS), and to identify its relationships with leukotriene B4 (LTB4) levels and haematological traits. In addition, we linked these immunological traits to selected physiological markers (antioxidants and oxidative stress markers). LTB4 levels increased with age and we have shown a similar non-significant tendency also for absolute granulocyte counts, indicating propagating chronic inflammation over the bird's lifetime, consistent with the inflammaging hypothesis. In contrast, cellular oxidative burst followed a quadratic trend of dependency on age with a peak in midlife individuals, in line with the immunosenescence hypothesis. Interestingly, LTB4 levels were positively associated with general oxidative damage, but negatively with antioxidant glutathione peroxidase activity, indicating links to redox balance. This longitudinal study demonstrates the contrasting patterns of age-related changes in background and acute markers of pro-inflammatory immunity contributing to immunosenescence in birds and thus provides basis for interpretation of the tested inflammatory markers in cross-cohort datasets.

Keywords:  Ageing; Aging; Avian inflammaging; Birds; Ecoimmunology; Haematology; Immunosenescence; Inflammation; Innate immunity senescence; Oxidative burst; Oxidative damage; Oxidative stress; Passerines; Redox balance; Respiratory burst; Testosterone; Wild

DOI:  https://doi.org/10.1016/j.exger.2021.111527
Curr Drug Targets. 2021 Aug 24.

Lipid metabolism and mitochondria: Cross talk in cancer.

Anubhav Srivastava, Pransu Srivastava, Shashank Mathur, Sabiya Abbas, Neeraj Rai, Swasti Tiwari, Meenakshi Tiwari, Lokendra Sharma.

  Metabolic reprogramming is considered a major event in cancer initiation, progression and metastasis. The metabolic signature of cancer cells includes alterations in glycolysis, mitochondrial respiration, fatty acid/lipid and amino acid metabolism. Being at a junction of various metabolic pathways, mitochondria play a key role in fueling cancer growth through regulating bioenergetics, metabolism and cell death. Increasing evidence suggests that alteration in lipid metabolism is a common feature of metastatic progression, including fatty acid synthesis as well as fatty acid oxidation. However, the interplay between lipid metabolism and mitochondria in carcinogenesis remains obscure. The present review focuses on key lipid metabolic pathways associated with mitochondrial regulation that drive cancer phenotype and metastasis. We also review potential targets of lipid metabolism and mitochondria to improve the therapeutic regime in cancer patients. This review aims to improve our current understanding of the intricate relation of lipids with mitochondria and provides insights into new therapeutic approaches.

Keywords:  Apoptosis; Bioenergetics; Cancer; Cardiolipin; Chemo-therapeutics; Drug Targets; Fatty acid oxidation; Lipid metabolism; Metastasis; Mitochondria

DOI:  https://doi.org/10.2174/1389450122666210824144907
Front Cell Dev Biol. 2021 ;9 714716

Dynamic Changes of the Bone Marrow Niche: Mesenchymal Stromal Cells and Their Progeny During Aging and Leukemia.

Kevin Woods, Borhane Guezguez.

  Mesenchymal stromal cells (MSCs) are a heterogenous cell population found in a wide range of tissues in the body, known for their nutrient-producing and immunomodulatory functions. In the bone marrow (BM), these MSCs are critical for the regulation of hematopoietic stem cells (HSC) that are responsible for daily blood production and functional immunity throughout an entire organism's lifespan. Alongside other stromal cells, MSCs form a specialized microenvironment BM tissue called "niche" that tightly controls HSC self-renewal and differentiation. In addition, MSCs are crucial players in maintaining bone integrity and supply of hormonal nutrients due to their capacity to differentiate into osteoblasts and adipocytes which also contribute to cellular composition of the BM niche. However, MSCs are known to encompass a large heterogenous cell population that remains elusive and poorly defined. In this review, we focus on deciphering the BM-MSC biology through recent advances in single-cell identification of hierarchical subsets with distinct functionalities and transcriptional profiles. We also discuss the contribution of MSCs and their osteo-adipo progeny in modulating the complex direct cell-to-cell or indirect soluble factors-mediated interactions of the BM HSC niche during homeostasis, aging and myeloid malignancies. Lastly, we examine the therapeutic potential of MSCs for rejuvenation and anti-tumor remedy in clinical settings.

Keywords:  adipocyte; aging; bone marrow niche; leukemia; mesenchymal stromal cells; osteoblast

DOI:  https://doi.org/10.3389/fcell.2021.714716
J Diabetes. 2021 Aug 28.

Precision nutrition for gut microbiome and diabetes research: Application of nutritional n-of-1 clinical trials.

Ju-Sheng Zheng, José M Ordovás.

DOI: https://doi.org/10.1111/1753-0407.13220
Front Nutr. 2021 ;8 709435

Dietary Control of Inflammation and Resolution.

Barry Sears, Asish K Saha.

  The healing of any injury requires a dynamic balance of initiation and resolution of inflammation. This hypothesis-generating review presents an overview of the various nutrients that can act as signaling agents to modify the metabolic responses essential for the optimal healing of injury-induced inflammation. In this hypothesis-generating review, we describe a defined nutritional program consisting of an integrated interaction of a calorie-restricted anti-inflammatory diet coupled with adequate levels of omega-3 fatty acids and sufficient levels of dietary polyphenols that can be used in clinical trials to treat conditions associated with insulin resistance. Each dietary intervention works in an orchestrated systems-based approach to reduce, resolve, and repair the tissue damage caused by any inflammation-inducing injury. The orchestration of these specific nutrients and their signaling metabolites to facilitate healing is termed the Resolution Response. The final stage of the Resolution Response is the activation of intracellular 5' adenosine monophosphate-activated protein kinase (AMPK), which is necessary to repair tissue damaged by the initial injury-induced inflammation. The dietary optimization of the Resolution Response can be personalized to the individual by using standard blood markers. Once each of those markers is in their appropriate ranges, activation of intracellular AMPK will be facilitated. Finally, we outline how the resulting activation of AMPK will affect a diverse number of other intercellular signaling systems leading to an extended healthspan.

Keywords:  5' adenosine monophosphate-activated protein kinase; SPMs; anti-inflammatory diet; calorie-restriction; inflammation; omega-3 fatty acids; polyphenols; resolution response

DOI:  https://doi.org/10.3389/fnut.2021.709435
Cell Biol Int. 2021 Aug 24.

Involvement of Extracellular vesicles in aging process and their beneficial effects in alleviating aging-associated symptoms.

Madhurima Das, Vaijayanti Kale.

  Aging is a gradual and unavoidable physiological phenomenon that manifests in the natural maturation process and continues to progress from infanthood to adulthood. Many elderly people suffer from aging-associated hematological and non-hematological disorders. Recent advances in regenerative medicine have shown new revolutionary paths of treating such diseases using stem cells; however, aging also affects the quality and competence of stem and progenitor cells themselves and ultimately directs their death or apoptosis and senescence a decline in their regenerative potential. Recent research works show that extracellular vesicles (EVs) isolated from different types of stem cells may provide a safe treatment for aging-associated disorders. The cargo of EVs comprises packets of information in the form of various macromolecules that can modify the fate of the target cells. To harness the true potential of EVs in regenerative medicine, it is necessary to understand how this cargo contributes to the rejuvenation of aged stem and progenitor populations and to identify the aging-associated changes in the macromolecular profile of the EVs themselves. In this review, we endeavor to summarize the current knowledge on the involvement of EVs in the aging process and delineate the role of EVs in the reversal of aging-associated phenotypes. We have also analyzed the involvement of the molecular cargo of EVs in the generation of aging-associated disorders. This knowledge could not only help us in understanding the mechanism of the aging process. Still, it could also facilitate the development of new cell-free biologics to treat aging-related disorders in the future. This article is protected by copyright. All rights reserved.

Keywords:  Aging; Extracellular Vesicles (EVs); Mesenchymal Stem Cells (MSCs); Rejuvenation; Stem Cells

DOI:  https://doi.org/10.1002/cbin.11691
Nutrients. 2021 Jul 25. pii: 2540. [Epub ahead of print]13(8):

Whole-Grain Intake in the Mediterranean Diet and a Low Protein to Carbohydrates Ratio Can Help to Reduce Mortality from Cardiovascular Disease, Slow Down the Progression of Aging, and to Improve Lifespan: A Review.

Cristiano Capurso.

  Increase in the aging population is a phenomenon all over the world. Maintaining good functional ability, good mental health, and cognitive function in the absence of severe disease and physical disability define successful aging. A healthy lifestyle in middle age predisposes successful aging. Longevity is the result of a multifactorial phenomenon, which involves feeding. Diets that emphasize fruit and vegetables, whole grains rather than refined grains, low-fat dairy, lean meats, fish, legumes, and nuts are inversely associated with mortality or to a lower risk of becoming frail among elderly subjects. A regular physical activity and a regular intake of whole grain derivatives together with the optimization of the protein/carbohydrate ratio in the diet, where the ratio is significantly less than 1 such as in the Mediterranean diet and the Okinawan diet, reduces the risk of developing aging-related diseases and increases healthy life expectancy. The purpose of our review was to analyze cohort and case-control studies that investigated the effects of cereals in the diet, especially whole grains and derivatives as well as the effects of a diet with a low protein-carbohydrate ratio on the progression of aging, mortality, and lifespan.

Keywords:  aging; carbohydrates; diet; frailty; lifespan; protein; whole grain

DOI:  https://doi.org/10.3390/nu13082540
Exp Gerontol. 2021 Aug 21. pii: S0531-5565(21)00303-X. [Epub ahead of print]154 111521

Nutrients with anabolic/anticatabolic, antioxidant, and anti-inflammatory properties: Targeting the biological mechanisms of aging to support musculoskeletal health.

Jatupol Kositsawat, Gustavo Duque, Ben Kirk.

  Old age is associated with declines in bone density and muscle mass and function, which predisposes to mobility disability, falls, and fractures. Poor nutritional status, a risk factor for several age-related pathologies, becomes prevalent in old age and contributes to the structural and functional changes of the musculoskeletal system that increases the risk of osteoporosis, sarcopenia, osteosarcopenia, and physical frailty. The biological mechanisms underpinning these pathologies often overlap and include loss of proteostasis, impaired redox functioning, and chronic low-grade inflammation. Thus, provision of nutrients with anabolic/anticatabolic, antioxidant, and anti-inflammatory properties may be an effective strategy to offset these age-related pathologies. We searched PUBMED for pre-clinical and clinical work examining the effects of nutrients with a combined effect on muscle and bone. This review summarizes recent evidence on the mechanisms of action and potential clinical use of nutrients that concomitantly improve muscle and bone health in older persons.

Keywords:  Anabolics; Geroscience; Inflammaging; Osteosarcopenia; Oxidative stress

DOI:  https://doi.org/10.1016/j.exger.2021.111521
Curr Alzheimer Res. 2021 Aug 22.

Accelerated Epigenetic Aging in Peripheral Blood Does not Predict Dementia Risk.

P D Fransquet, P Lacaze, R Saffery, R C Shah, R Vryer, A Murray, R L Woods, J Ryan.

  BACKGROUND: There is strong evidence that epigenetic age acceleration is associated with increased risk of later-life diseases and all-cause mortality. However, there is currently limited evidence that suggests accelerated epigenetic age is associated with dementia risk.OBJECTIVE: This study aims to clarify whether epigenetic biomarkers of accelerated aging can pre- dict dementia risk, which is an important consideration as aging is the greatest risk factor for the disease.
METHODS: DNA methylation was measured in peripheral blood samples provided by 160 partici- pants from the ASPirin in Reducing Events in the Elderly study, including 73 pre-symptomatic de- mentia cases and 87 controls matched for age, sex, and smoking and education status. Epigenetic age was calculated using Horvath, Hannum, GrimAge and PhenoAge DNA methylation clocks, and age acceleration (the disparity between chronological age and epigenetic age) was determined.
RESULTS: There was no difference in age acceleration between dementia cases and controls. In males, only Hannum's intrinsic epigenetic age acceleration was increased in pre-symptomatic de- mentia cases compared to controls (Δ +1.8 years, p = 0.03).
CONCLUSION: These findings provide no strong evidence that accelerated epigenetic aging measured in peripheral blood can predict dementia risk.

Keywords:  Accelerated Aging; DNA Methylation; GrimAge; Hannum; Horvath; PhenoAge; dementia; epigenetic clock

DOI:  https://doi.org/10.2174/1567205018666210823100721
J Aging Stud. 2021 Sep;pii: S0890-4065(21)00041-4. [Epub ahead of print]58 100951

Talking about frailty: The role of stigma and precarity in older peoples' constructions of frailty.

Victoria Cluley, Graham Martin, Zoe Radnor, Jay Banerjee.

  The clinical identification of frailty is increasingly thought to be important in countries with ageing populations. Understanding how older people labelled as frail make sense of this categorisation is therefore important. A number of recent studies have reported negative perceptions of the term among older people themselves. Building on this, we focus on how and why those assessed to be frail make sense of frailty as they do. We draw on 26a discourse analysis of situated interviews with 30 older people accessing emergency care in an English NHS hospital. Three interpretive repertoire pairs (Frailty is 26a bodily issue/frailty is about mind-set; Frailty is 26a negative experience/frailty is an inevitable experience; I'm not frail/I feel frail), identified across the participants' talk, are outlined and discussed in relation to discourses of the fourth age and precarity. We conclude that frailty is often seen in terms what others have referred to as 'real' old age and is linked to discourses of dependence and precarity.

Keywords:  Frailty; Older peoples' perspectives; Precarity; Resistance; Stigma

DOI:  https://doi.org/10.1016/j.jaging.2021.100951
Arthritis Res Ther. 2021 Aug 24. 23(1): 222

Incidence and severity of G6PI-induced arthritis are not increased in genetically distinct mouse strains upon aging.

Nico Andreas, Sylvia Müller, Nicole Templin, Paul M Jordan, Harald Schuhwerk, Michael Müller, Jana Gerstmeier, Laura Miek, Saskia Andreas, Oliver Werz, Thomas Kamradt.

  BACKGROUND: The incidence of rheumatoid arthritis is correlated with age. In this study, we analyzed the association of the incidence and severity of glucose-6-phosphate isomerase (G6PI)-induced arthritis with age in two different mouse strains.METHODS: Young and very old mice from two different arthritis-susceptible wild-type mouse strains were analyzed after a single subcutaneous injection of G6PI s.c. The metabolism and the function of synoviocytes were analyzed in vitro, the production of bioactive lipid mediators by myeloid cells and synoviocytes was assessed in vitro and ex vivo by UPLC-MS-MS, and flow cytometry was used to verify age-related changes of immune cell composition and function.
RESULTS: While the severity of arthritis was independent from age, the onset was delayed in old mice. Old mice showed common signs of immune aging like thymic atrophy associated with decreased CD4+ effector T cell numbers. Despite its decrease, the effector T helper (Th) cell compartment in old mice was reactive and functionally intact, and their Tregs exhibited unaltered suppressive capacities. In homeostasis, macrophages and synoviocytes from old mice produced higher amounts of pro-inflammatory cyclooxygenase (COX)-derived products. However, this functional difference did not remain upon challenge in vitro nor upon arthritis reactions ex vivo.
CONCLUSION: While old mice show a higher baseline of inflammatory functions, this does not result in increased reaction towards self-antigens in arthritis-susceptible mouse strains. Together, our data from two different mouse strains show that the susceptibility for G6PI-induced arthritis is not age-dependent.

Keywords:  Age; Arthritis; FLS; G6PI; SPM; T cells

DOI:  https://doi.org/10.1186/s13075-021-02596-7
Eur J Clin Invest. 2021 Aug 28. e13674

The Triglyceride-glucose index as an adiposity marker and a predictor of fat loss induced by a low-calorie diet.

Fernando Vidal-Ostos, Omar Ramos-Lopez, Ellen E Blaak, Arne Astrup, J Alfredo Martinez.

  BACKGROUND: This study aimed to investigate the putative role of the Triglyceride-glucose index (TyG index) computed as ln[TG (mg/dL) × glucose (mg/dL)/2] and derived proxies as predictors of adiposity and weight loss changes after a low calorie diet (LCD) intervention.METHODS: A total of 744 adult participants from the multicenter DIOGenes intervention study were prescribed a LCD (800 kcal/day) during 8 weeks. Body composition and fat content at baseline and after 8 weeks were estimated by DEXA/BIA. A multivariate analysis approach was used to estimate the difference in ∆Weight1-2 (kg), ∆BMI1-2 (kg/m2 ) or ∆Fat1-2 (%) between the basal value (point 1) and after 8 weeks following a LCD (point 2), respectively. The TyG index at baseline (TyG1 ), after following the LCD for 8 weeks (TyG2 ), or the TyG index differences between both time points (∆TyG1-2 ) were analyzed as predictors of weight and fat changes.
RESULTS: TyG1 was associated with ∆Weight1-2 (kg) and ∆BMI1-2 (kg/m2 ), with β=0.812 (p=0.017) and β=0.265 (p=0.018), respectively. Also, TyG2 values were inversely related to ∆Fat1-2 (%), β=-1.473 (p=0.015). Moreover, ∆TyG1-2 was associated with ∆Weight1-2 (kg) and ∆Fat1-2 (%), β= 0.689 (p=0.045) and β=1.764 (p=0.002), respectively. Furthermore, an association between TyG2 and resistance to fat loss was found (p=0.015).
CONCLUSION: TyG1 index is a good predictor of weight loss induced by LCD. Moreover, TyG2 was closely related to resistance to fat loss, while ∆TyG1-2 values were positively associated with body fat changes. Therefore, TyG index and derived estimations could be used as markers of individualized responses to energy restriction and a surrogate of body composition outcomes in clinical/epidemiological settings in obesity conditions.

Keywords:  TyG index; fat loss; precision medicine; statistical predictors; weight loss

DOI:  https://doi.org/10.1111/eci.13674
J Exp Clin Cancer Res. 2021 Aug 24. 40(1): 265

SCD1, autophagy and cancer: implications for therapy.

Francesca Ascenzi, Claudia De Vitis, Marcello Maugeri-Saccà, Christian Napoli, Gennaro Ciliberto, Rita Mancini.

  BACKGROUND: Autophagy is an intracellular degradation system that removes unnecessary or dysfunctional components and recycles them for other cellular functions. Over the years, a mutual regulation between lipid metabolism and autophagy has been uncovered.METHODS: This is a narrative review discussing the connection between SCD1 and the autophagic process, along with the modality through which this crosstalk can be exploited for therapeutic purposes.
RESULTS: Fatty acids, depending on the species, can have either activating or inhibitory roles on autophagy. In turn, autophagy regulates the mobilization of fat from cellular deposits, such as lipid droplets, and removes unnecessary lipids to prevent cellular lipotoxicity. This review describes the regulation of autophagy by lipid metabolism in cancer cells, focusing on the role of stearoyl-CoA desaturase 1 (SCD1), the key enzyme involved in the synthesis of monounsaturated fatty acids. SCD1 plays an important role in cancer, promoting cell proliferation and metastasis. The role of autophagy in cancer is more complex since it can act either by protecting against the onset of cancer or by promoting tumor growth. Mounting evidence indicates that autophagy and lipid metabolism are tightly interconnected.
CONCLUSION: Here, we discuss controversial findings of SCD1 as an autophagy inducer or inhibitor in cancer, highlighting how these activities may result in cancer promotion or inhibition depending upon the degree of cancer heterogeneity and plasticity.

Keywords:  Autophagy; Lipid metabolism; cancer

DOI:  https://doi.org/10.1186/s13046-021-02067-6
Blood Adv. 2021 Aug 27. pii: bloodadvances.2020003841. [Epub ahead of print]

5-Azacytidine depletes hematopoietic stem cells and synergizes with an anti-CD117 antibody to augment donor engraftment in immunocompetent mice.

Andriyana K Bankova, Wendy Pang, Brenda Josefina Velasco, Janel R Long-Boyle, Judith A Shizuru.

Depletion of hematopoietic stem cells (HSC) is used therapeutically in many malignant and non-malignant blood disorders in the setting of a hematopoietic cell transplantation (HCT) to eradicate diseased HSC allowing donor HSC to engraft. Current treatments to achieve HSC elimination rely on modalities that cause DNA strand breakage (i.e., alkylators, radiation) resulting in multiple short-term and long-term toxicities, and sometimes even death. These risks have severely limited HCT utilization to patients with few to no co-morbidities, and excluded many others with diseases curable by HCT. 5-Azacytidine (AZA) is a widely used hypomethylating agent that is thought to preferentially target leukemic cells in myeloid malignancies. Here, we reveal a previously unknown effect of AZA on HSC. We show that AZA induces early HSC proliferation in vivo and exerts a direct cytotoxic effect on proliferating HSC in vitro. When used to pretreat recipient mice for transplant, AZA permitted low level donor HSC engraftment. Moreover, by combining AZA with a monoclonal antibody (mAb), targeting CD117 (c-Kit), a molecule expressed on HSC, more robust HSC-depletion and substantially higher levels of multilineage donor cell engraftment was achieved in immunocompetent mice. The enhanced effectiveness of this combined regimen correlated with increased apoptotic cell death in HSPC. Together, these findings highlight a previously unknown therapeutic mechanism for AZA which may broaden its utilization in clinical practice. Moreover, the synergy we show between AZA and anti-CD117 mAb is a novel strategy to eradicate abnormal HSC which can be rapidly tested in the clinical setting.

DOI: https://doi.org/10.1182/bloodadvances.2020003841
Science. 2021 Jul 16. 373(6552): 281-282

Targeting aging cells improves survival.

Lynne S Cox, Janet M Lord.

DOI: https://doi.org/10.1126/science.abi4474
J Inherit Metab Dis. 2021 Aug 23.

Mechano-energetic aspects of Barth Syndrome.

Jan Dudek, Christoph Maack.

Energy-demanding organs like the heart are strongly dependent on oxidative phosphorylation in mitochondria. Oxidative phosphorylation is governed by the respiratory chain located in the inner mitochondrial membrane. The inner mitochondrial membrane is the only cellular membrane with significant amounts of the phospholipid cardiolipin, and cardiolipin was found to directly interact with a number of essential protein complexes, including respiratory chain complexes I to V. An inherited defect in the biogenesis of cardiolipin causes Barth syndrome, which is associated with cardiomyopathy, skeletal myopathy, neutropenia and growth retardation. Energy conversion is dependent on reducing equivalents, which are replenished by oxidative metabolism in the Krebs cycle. Cardiolipin deficiency in Barth syndrome also affects Krebs cycle activity, metabolite transport and mitochondrial morphology. During excitation-contraction coupling, calcium (Ca2+ ) released from the sarcoplasmic reticulum drives sarcomeric contraction. At the same time, Ca2+ influx into mitochondria drives the activation of Krebs cycle dehydrogenases and the regeneration of reducing equivalents. Reducing equivalents are essential not only for energy conversion, but also for maintaining a redox buffer, which is required to detoxify reactive oxygen species (ROS). Defects in CL may also affect Ca2+ uptake into mitochondria and thereby hamper energy supply and demand matching, but also detoxification of ROS. Here, we review the impact of cardiolipin deficiency on mitochondrial function in Barth syndrome and discuss potential therapeutic strategies. This article is protected by copyright. All rights reserved.

DOI: https://doi.org/10.1002/jimd.12427
Int J Mol Sci. 2021 Aug 07. pii: 8520. [Epub ahead of print]22(16):

Biological Aspects of Selected Myokines in Skeletal Muscle: Focus on Aging.

Rosa Mancinelli, Franco Checcaglini, Francesco Coscia, Paola Gigliotti, Stefania Fulle, Giorgio Fanò-Illic.

  In the last decade, clear evidence has emerged that the cellular components of skeletal muscle are important sites for the release of proteins and peptides called "myokines", suggesting that skeletal muscle plays the role of a secretory organ. After their secretion by muscles, these factors serve many biological functions, including the exertion of complex autocrine, paracrine and/or endocrine effects. In sum, myokines affect complex multi-organ processes, such as skeletal muscle trophism, metabolism, angiogenesis and immunological response to different physiological (physical activity, aging, etc.) or pathological states (cachexia, dysmetabolic conditions, chronic inflammation, etc.). The aim of this review is to describe in detail a number of myokines that are, to varying degrees, involved in skeletal muscle aging processes and belong to the group of proteins present in the functional environment surrounding the muscle cell known as the "Niche". The particular myokines described are those that, acting both from within the cell and in an autocrine manner, have a defined relationship with the modulation of oxidative stress in muscle cells (mature or stem) involved in the regulatory (metabolic or regenerative) processes of muscle aging. Myostatin, IGF-1, NGF, S100 and irisin are examples of specific myokines that have peculiar features in their mechanisms of action. In particular, the potential role of one of the most recently characterized myokines-irisin, directly linked to an active lifestyle-in reducing if not reversing senescence-induced oxidative damage is discussed in terms of its possible application as an agent able to counteract the deleterious effects of muscle aging.

Keywords:  niche; oxidative stress; physical activity; sarcopenia; satellite cells; skeletal muscle secretome

DOI:  https://doi.org/10.3390/ijms22168520
Biomedicines. 2021 Jul 30. pii: 922. [Epub ahead of print]9(8):

Anti-Inflammatory Properties of Diet: Role in Healthy Aging.

Kristine Stromsnes, Angela G Correas, Jenny Lehmann, Juan Gambini, Gloria Olaso-Gonzalez.

  Inflammation is a physiological process involved in the defenses of the body and the repair of tissues. It is acutely activated by infections, trauma, toxins, or allergic reactions. However, if it becomes chronic, inflammation can end up stimulating the development of diseases such as cardiovascular disease, autoimmune disease, neurological disease, or cancer. Additionally, during aging, inflammation becomes increasingly more chronic. Furthermore, we found that certain foods, such as saturated fats, have pro-inflammatory activity. Taking this into account, in this review we have discussed different diets with possible anti-inflammatory activity, the commonly ingested components of each diet and their active compounds. In addition, we have proposed some dietary guidelines, as well as a list of compounds present in foods with anti-inflammatory activity, outlining how to combine them to achieve optimal anti-inflammatory effects. Therefore, we can conclude that the compounds in our diet with anti-inflammatory activity could help alleviate the inflammatory processes derived from diseases and unhealthy diets, and thereby promote healthy aging.

Keywords:  aging; anti-inflammatory; diet; healthy aging; inflammaging; inflammation; nutraceutics; nutrition; polyphenol

DOI:  https://doi.org/10.3390/biomedicines9080922
J Intern Med. 2021 Aug 23.

The Mediterranean diet and health: a comprehensive overview.

M Guasch-Ferré, W C Willett.

  The Mediterranean diet (MedDiet), one of the most studied and well-known dietary patterns worldwide, has been associated with a wide range of benefits for health. In the present narrative review, we aimed to provide a comprehensive overview of the current knowledge on the relation of the MedDiet to important health outcomes, considering both observational and intervention studies with both risk factors and clinical diseases as outcomes. In addition, we considered the clinical and public health impacts of the MedDiet on both human and planetary health. Earlier research confirmed by recent studies has provided strong evidence for the benefits of the MedDiet on cardiovascular health, including reduction in the incidence of cardiovascular outcomes as well as risk factors including obesity, hypertension, metabolic syndrome, and dyslipidaemia. There is also evidence that MedDiet is associated with lower rates of incident diabetes, and better glycaemic control in diabetic patients compared to control diets. In prospective studies, adherence to the MedDiet reduced mortality, especially cardiovascular mortality, hence increased longevity. In addition, it has been associated with less age-related cognitive dysfunction and lower incidence of neurodegenerative disorders, particularly Alzheimer's disease. Furthermore, the relatively low environmental impacts (water, nitrogen and carbon footprint) of the MedDiet is an additional positive aspect of the Mediterranean dietary model. It is likely that the combination of a healthy diet with social behaviours and the way of life of Mediterranean regions makes the MedDiet a sustainable lifestyle model that could likely be followed in other regions with country-specific and culturally appropriate variations.

Keywords:  cancer; cardiovascular disease; chronic diseases; health; mediterranean diet; neurodegenerative diseases

DOI:  https://doi.org/10.1111/joim.13333
J Am Geriatr Soc. 2021 Aug 28.

Germs, geriatrics, and grandpa: Generations of gaps, goals, and goodness.

Thomas Yoshikawa.

DOI: https://doi.org/10.1111/jgs.17364
Nephrol Dial Transplant. 2020 Jun 01. pii: gfaa142.P0981. [Epub ahead of print]35(Supplement_3):

Retracted: P0981ANTIDIABETIC AND RENOPROTECTIVE ROLE OF METFORMIN ON METABOLIC PARAMETERS IN KIDNEY OF DIABETIC AGING RATS.

Pardeep Kumar, Najma Baquer.

DOI: https://doi.org/10.1093/ndt/gfaa142.P0981
JCI Insight. 2021 Aug 23. pii: 149819. [Epub ahead of print]6(16):

CD7-deleted hematopoietic stem cells can restore immunity after CAR T cell therapy.

Miriam Y Kim, Matthew L Cooper, Miriam T Jacobs, Julie K Ritchey, Julia Hollaway, Todd A Fehniger, John F DiPersio.

  Targeting T cell malignancies with universal CD7-targeting chimeric antigen receptor T cells (UCART7) can lead to profound immune deficiency due to loss of normal T and NK cells. While a small population of endogenous CD7- T cells exists, these cells are unlikely to be able to repopulate the entire immune repertoire after UCART7 treatment, as they are limited in number and proliferative capacity. To rescue T and NK cells after UCART7, we created hematopoietic stem cells genetically deleted for CD7 (CD7-KO HSCs). CD7-KO HSCs were able to engraft immunodeficient mice and differentiate into T and NK cells lacking CD7 expression. CD7-KO T and NK cells could perform effector functions as robustly as control T and NK cells. Furthermore, CD7-KO T cells were phenotypically and functionally distinct from endogenous CD7- T cells, indicating that CD7-KO T cells can supplement immune functions lacking in CD7- T cells. Mice engrafted with CD7-KO HSCs maintained T and NK cell numbers after UCART7 treatment, while these were significantly decreased in control mice. These studies support the development of CD7-KO HSCs to augment host immunity in patients with T cell malignancies after UCART7 treatment.

Keywords:  Cancer immunotherapy; Gene therapy; Hematopoietic stem cells; Immunology; Oncology

DOI:  https://doi.org/10.1172/jci.insight.149819
Antioxidants (Basel). 2021 Jul 28. pii: 1209. [Epub ahead of print]10(8):

Supplemental Ferulic Acid Inhibits Total Body Irradiation-Mediated Bone Marrow Damage, Bone Mass Loss, Stem Cell Senescence, and Hematopoietic Defect in Mice by Enhancing Antioxidant Defense Systems.

Sajeev Wagle, Hyun-Jaung Sim, Govinda Bhattarai, Ki-Choon Choi, Sung-Ho Kook, Jeong-Chae Lee, Young-Mi Jeon.

  While total body irradiation (TBI) is an everlasting curative therapy, the irradiation can cause long-term bone marrow (BM) injuries, along with senescence of hematopoietic stem cells (HSCs) and mesenchymal stem cells (MSCs) via reactive oxygen species (ROS)-induced oxidative damages. Thus, ameliorating or preventing ROS accumulation and oxidative stress is necessary for TBI-requiring clinical treatments. Here, we explored whether administration of ferulic acid, a dietary antioxidant, protects against TBI-mediated systemic damages, and examined the possible mechanisms therein. Sublethal TBI (5 Gy) decreased body growth, lifespan, and production of circulating blood cells in mice, together with ROS accumulation, and senescence induction of BM-conserved HSCs and MSCs. TBI also impaired BM microenvironment and bone mass accrual, which was accompanied by downregulated osteogenesis and by osteoclastogenic and adipogenic activation in BM. Long-term intraperitoneal injection of ferulic acid (50 mg/kg body weight, once per day for 37 consecutive days) protected mice from TBI-mediated mortality, stem cell senescence, and bone mass loss by restoring TBI-stimulated disorders in osteogenic, osteoclastic, and adipogenic activation in BM. In vitro experiments using BM stromal cells supported radioprotective effects of ferulic acid on TBI-mediated defects in proliferation and osteogenic differentiation. Overall, treatment with ferulic acid prevented TBI-mediated liver damage and enhanced endogenous antioxidant defense systems in the liver and BM. Collectively, these results support an efficient protection of TBI-mediated systemic defects by supplemental ferulic acid, indicating its clinical usefulness for TBI-required patients.

Keywords:  antioxidant defense system; bone marrow injury; bone marrow microenvironment; ferulic acid; reactive oxygen species; stem cell senescence; total body irradiation

DOI:  https://doi.org/10.3390/antiox10081209
Nutrients. 2021 Aug 16. pii: 2802. [Epub ahead of print]13(8):

Dietary AGEs as Exogenous Boosters of Inflammation.

Ma Eugenia Garay-Sevilla, Armando Rojas, Manuel Portero-Otin, Jaime Uribarri.

  Most chronic modern non-transmissible diseases seem to begin as the result of low-grade inflammation extending over prolonged periods of time. The importance of diet as a source of many pro-inflammatory compounds that could create and sustain such a low-grade inflammatory state cannot be ignored, particularly since we are constantly exposed to them during the day. The focus of this review is on specific components of the diet associated with inflammation, specifically advanced glycation end products (AGEs) that form during thermal processing of food. AGEs are also generated in the body in normal physiology and are widely recognized as increased in diabetes, but many people are unaware of the potential importance of exogenous AGEs ingested in food. We review experimental models, epidemiologic data, and small clinical trials that suggest an important association between dietary intake of these compounds and development of an inflammatory and pro-oxidative state that is conducive to chronic diseases. We compare dietary intake of AGEs with other widely known dietary patterns, such as the Mediterranean and the Dietary Approaches to Stop Hypertension (DASH) diets, as well as the Dietary Inflammation Index (DII). Finally, we delineate in detail the pathophysiological mechanisms induced by dietary AGEs, both direct (i.e., non-receptor-mediated) and indirect (receptor-mediated).

Keywords:  DASH diet; Mediterranean diet; RAGE; dietary inflammatory index (DII); inflammatory diet; low AGE diet; low-grade inflammation; matrix glycation

DOI:  https://doi.org/10.3390/nu13082802
Cells. 2021 Aug 10. pii: 2051. [Epub ahead of print]10(8):

Hematopoietic Dysfunction during Graft-Versus-Host Disease: A Self-Destructive Process?

Konradin F Müskens, Caroline A Lindemans, Mirjam E Belderbos.

  Graft-versus-host disease (GvHD) is a major complication of allogeneic hematopoietic (stem) cell transplantation (HCT). Clinically, GvHD is associated with severe and long-lasting hematopoietic dysfunction, which may contribute to the high mortality of GvHD after HCT. During GvHD, excessive immune activation damages both hematopoietic stem and progenitor cells and their surrounding bone marrow niche, leading to a reduction in cell number and functionality of both compartments. Hematopoietic dysfunction can be further aggravated by the occurrence-and treatment-of HCT-associated complications. These include immune suppressive therapy, coinciding infections and their treatment, and changes in the microbiome. In this review, we provide a structured overview of GvHD-mediated hematopoietic dysfunction, including the targets in the bone marrow, the mechanisms of action and the effect of GvHD-related complications and their treatment. This information may aid in the identification of treatment options to improve hematopoietic function in patients, during and after GvHD.

Keywords:  bone marrow niche; cytopenia; graft failure; graft-versus-host disease; hematopoiesis; hematopoietic stem cell transplantation; poor graft function

DOI:  https://doi.org/10.3390/cells10082051