bims-minfam Biomed News
on Inflammation and metabolism in ageing and cancer
Issue of 2021‒01‒24
thirty papers selected by
Ayesh Seneviratne
University of Toronto

  1. J Biol Chem. 2020 Dec 02. pii: S0021-9258(20)00116-7. [Epub ahead of print]296 100125
    Enriquez-Hesles E, Smith DL, Maqani N, Wierman MB, Sutcliffe MD, Fine RD, Kalita A, Santos SM, Muehlbauer MJ, Bain JR, Janes KA, Hartman JL, Hirschey MD, Smith JS.
      Caloric restriction (CR) improves health span and life span of organisms ranging from yeast to mammals. Understanding the mechanisms involved will uncover future interventions for aging-associated diseases. In budding yeast, Saccharomyces cerevisiae, CR is commonly defined by reduced glucose in the growth medium, which extends both replicative and chronological life span (CLS). We found that conditioned media collected from stationary-phase CR cultures extended CLS when supplemented into nonrestricted (NR) cultures, suggesting a potential cell-nonautonomous mechanism of CR-induced life span regulation. Chromatography and untargeted metabolomics of the conditioned media, as well as transcriptional responses associated with the longevity effect, pointed to specific amino acids enriched in the CR conditioned media (CRCM) as functional molecules, with L-serine being a particularly strong candidate. Indeed, supplementing L-serine into NR cultures extended CLS through a mechanism dependent on the one-carbon metabolism pathway, thus implicating this conserved and central metabolic hub in life span regulation.
    Keywords:  Saccharomyces cerevisiae; aging; amino acids; caloric restriction; cell-nonautonomous; chronological life span; one-carbon metabolism; serine
  2. Blood Cancer Discov. 2021 Jan 01. 2(1): 32-53
    Xie SZ, Kaufmann KB, Wang W, Chan-Seng-Yue M, Gan OI, Laurenti E, Garcia-Prat L, Takayanagi SI, Ng SWK, Xu C, Zeng AGX, Jin L, McLeod J, Wagenblast E, Mitchell A, Kennedy JA, Liu Q, Boutzen H, Kleinau M, Jargstorf J, Holmes G, Zhang Y, Voisin V, Bader GD, Wang JCY, Hannun YA, Luberto C, Schroeder T, Minden MD, Dick JE.
      Acute myeloid leukemia (AML) is a caricature of normal hematopoiesis, driven from leukemia stem cells (LSC) that share some hematopoietic stem cell (HSC) programs including responsiveness to inflammatory signaling. Although inflammation dysregulates mature myeloid cells and influences stemness programs and lineage determination in HSC by activating stress myelopoiesis, such roles in LSC are poorly understood. Here, we show that S1PR3, a receptor for the bioactive lipid sphingosine-1-phosphate, is a central regulator which drives myeloid differentiation and activates inflammatory programs in both HSC and LSC. S1PR3-mediated inflammatory signatures varied in a continuum from primitive to mature myeloid states across AML patient cohorts, each with distinct phenotypic and clinical properties. S1PR3 was high in LSC and blasts of mature myeloid samples with linkages to chemosensitivity, while S1PR3 activation in primitive samples promoted LSC differentiation leading to eradication. Our studies open new avenues for therapeutic target identification specific for each AML subset.
    Keywords:  Acute myeloid leukemia; S1PR3; TNFα via NF-κB; hematopoietic stem cells; myeloid differentiation
  3. Cancer. 2021 Jan 20.
    Oran B, Saliba RM, Mehta RS, Alousi AM, Marin D, Valdez BC, Chen J, Bashir Q, Ciurea SO, Olson AL, Hosing C, Kebriaei P, Rezvani K, Shpall EJ, Champlin RE, Andersson BS, Popat UR.
      BACKGROUND: A myeloablative conditioning regimen can be safely given to older patients and those with comorbidities without increasing nonrelapse mortality (NRM) by fractionating the dose of intravenous busulfan. How this approach compares in efficacy with traditional, nonfractionated, lower dose regimens is unknown.METHODS: Outcomes were compared in patients with acute myeloid leukemia (AML) or myelodysplastic syndrome who received either myeloablative, fractionated busulfan (f-Bu) dosed to achieve an area under the curve of 20,000 μmol per minute (f-Bu20K) over 2 weeks (n = 84) or a standard, nonfractionated, lower busulfan dose regimen of 16,000 μmol per minute (Bu16K) over 4 days (n = 78). Both groups also received fludarabine 40 mg/m2 intravenously for 4 days. Graft-versus-host disease prophylaxis was tacrolimus and methotrexate. Patients in the Bu16K group who had unrelated donors also received antithymocyte globulin. The primary endpoint was progression-free survival.
    RESULTS: Roughly one-half of the patients were aged >65 years, approximately 40% had poor-risk cytogenetics, approximately 40% of those with AML were not in complete remission, and approximately 40% had a comorbidity index >3. At 2 years, progression-free survival was significantly improved in the f-Bu20K group compared with the Bu16K group (45% vs 24%, respectively; hazard ratio [HR], 0.6; 95% CI, 0.4-0.8; P = .004). This was because of a significant reduction in progression (34% vs 59%, respectively; HR, 0.5; 95% CI, 0.3-0.8; P = .003) without any increase in NRM (21% vs 15%, respectively; HR, 1.4; 95% CI, 0.7-3; P = .3), which resulted in improved overall survival (51% vs 31%, respectively; HR, 0.6; 95% CI, 0.3-0.9; P = .01).
    CONCLUSIONS: A myeloablative, fractionated busulfan regimen reduces relapse and improves survival without increasing NRM in older patients with AML and myelodysplastic syndrome.
    Keywords:  acute myeloid leukemia (AML); busulfan; fractionated; myeloablative; myelodysplastic syndrome (MDS)
  4. Cells. 2021 Jan 16. pii: E174. [Epub ahead of print]10(1):
    Schank M, Zhao J, Moorman JP, Yao ZQ.
      According to the WHO, 38 million individuals were living with human immunodeficiency virus (HIV), 25.4 million of which were using antiretroviral therapy (ART) at the end of 2019. Despite ART-mediated suppression of viral replication, ART is not a cure and is associated with viral persistence, residual inflammation, and metabolic disturbances. Indeed, due to the presence of viral reservoirs, lifelong ART therapy is required to control viremia and prevent disease progression into acquired immune deficiency syndrome (AIDS). Successful ART treatment allows people living with HIV (PLHIV) to achieve a similar life expectancy to uninfected individuals. However, recent studies have illustrated the presence of increased comorbidities, such as accelerated, premature immune aging, in ART-controlled PLHIV compared to uninfected individuals. Studies suggest that both HIV-infection and ART-treatment lead to mitochondrial dysfunction, ultimately resulting in cellular exhaustion, senescence, and apoptosis. Since mitochondria are essential cellular organelles for energy homeostasis and cellular metabolism, their compromise leads to decreased oxidative phosphorylation (OXPHOS), ATP synthesis, gluconeogenesis, and beta-oxidation, abnormal cell homeostasis, increased oxidative stress, depolarization of the mitochondrial membrane potential, and upregulation of mitochondrial DNA mutations and cellular apoptosis. The progressive mitochondrial damage induced by HIV-infection and ART-treatment likely contributes to accelerated aging, senescence, and cellular dysfunction in PLHIV. This review discusses the connections between mitochondrial compromise and cellular dysfunction associated with HIV- and ART-induced toxicities, providing new insights into how HIV and current ART directly impact mitochondrial functions and contribute to cellular senescence and aging in PLHIV. Identifying this nexus and potential mechanisms may be beneficial in developing improved therapeutics for treating PLHIV.
    Keywords:  ART; HIV; ROS; cellular dysfunction; mitochondria; mtDNA
  5. Nature. 2021 Jan 20.
    Minhas PS, Latif-Hernandez A, McReynolds MR, Durairaj AS, Wang Q, Rubin A, Joshi AU, He JQ, Gauba E, Liu L, Wang C, Linde M, Sugiura Y, Moon PK, Majeti R, Suematsu M, Mochly-Rosen D, Weissman IL, Longo FM, Rabinowitz JD, Andreasson KI.
      Ageing is characterized by the development of persistent pro-inflammatory responses that contribute to atherosclerosis, metabolic syndrome, cancer and frailty1-3. The ageing brain is also vulnerable to inflammation, as demonstrated by the high prevalence of age-associated cognitive decline and Alzheimer's disease4-6. Systemically, circulating pro-inflammatory factors can promote cognitive decline7,8, and in the brain, microglia lose the ability to clear misfolded proteins that are associated with neurodegeneration9,10. However, the underlying mechanisms that initiate and sustain maladaptive inflammation with ageing are not well defined. Here we show that in ageing mice myeloid cell bioenergetics are suppressed in response to increased signalling by the lipid messenger prostaglandin E2 (PGE2), a major modulator of inflammation11. In ageing macrophages and microglia, PGE2 signalling through its EP2 receptor promotes the sequestration of glucose into glycogen, reducing glucose flux and mitochondrial respiration. This energy-deficient state, which drives maladaptive pro-inflammatory responses, is further augmented by a dependence of aged myeloid cells on glucose as a principal fuel source. In aged mice, inhibition of myeloid EP2 signalling rejuvenates cellular bioenergetics, systemic and brain inflammatory states, hippocampal synaptic plasticity and spatial memory. Moreover, blockade of peripheral myeloid EP2 signalling is sufficient to restore cognition in aged mice. Our study suggests that cognitive ageing is not a static or irrevocable condition but can be reversed by reprogramming myeloid glucose metabolism to restore youthful immune functions.
  6. Aging (Albany NY). 2021 Jan 20. 13
    Barbé-Tuana FM, Grun LK, Pierdoná V, Parisi MM, Friedrich F, Guma FTCR, Pinto LA, Stein RT, Pitrez PMC, Jones MH.
      Severe therapy-resistant asthma (STRA) is closely associated with distinct clinical and inflammatory pheno-endotypes, which may contribute to the development of age-related comorbidities. Evidence has demonstrated a contribution of accelerated telomere shortening on the poor prognosis of respiratory diseases in adults. Eotaxin-1 (CCL11) is an important chemokine for eosinophilic recruitment and the progression of asthma. In the last years has also been proposed as an age-promoting factor. This study aimed to investigate the association of relative telomere length (rTL) and eotaxin-1 in asthmatic children. Children aged 8-14 years (n=267) were classified as healthy control (HC, n=126), mild asthma (MA, n=124) or severe therapy-resistant asthma (STRA, n=17). rTL was performed by qPCR from peripheral blood. Eotaxin-1 was quantified by ELISA from fresh-frozen plasma. STRA had shorter telomeres compared to HC (p=0.02) and MA (p=0.006). Eotaxin-1 levels were up-regulated in STRA [median; IQR25-75)] [(1,190 pg/mL; 108-2,510)] compared to MA [(638 pg/mL; 134-1,460)] (p=0.03) or HC [(627 pg/mL; 108-1,750)] (p<0.01). Additionally, shorter telomeres were inversely correlated with eotaxin-1 levels in STRA (r=-0.6, p=0.013). Our results suggest that short telomeres and up-regulated eotaxin-1, features of accelerated aging, could prematurely contribute to a senescent phenotype increasing the risk for early development of age-related diseases in asthma.
    Keywords:  CCL11; inflammaging; senescence; severe asthma; telomere length
  7. Pituitary. 2021 Jan 18.
    Duran-Ortiz S, List EO, Basu R, Kopchick JJ.
      Progress made in the years of aging research have allowed the opportunity to explore potential interventions to slow aging and extend healthy lifespan. Studies performed in yeast, worms, flies and mice subjected to genetic and pharmacological interventions have given insight into the cellular and molecular mechanisms associated with longevity. Furthermore, it is now possible to effectively modulate pathways that slow aging at different stages of life (early life or at an adult age). Interestingly, interventions that extend longevity in adult mice have had sex-specific success, suggesting a potential link between particular pathways that modulate aging and sex. For example, reduction of the growth hormone (GH)/insulin-like growth factor-1 (IGF-1) axis at an adult age extends lifespan preferentially in females. Moreover, several postnatal dietary interventions tested by the 'Intervention Testing Program (ITP)' from the National Institute of Aging (NIA) have shown that while pharmacological interventions like rapamycin affect the IGF-1/insulin pathway and preferentially extend lifespan in females; dietary compounds that target other cellular pathways are effective only in male mice-indicating mutually exclusive sex-specific pathways. Therefore, a combination of interventions that target non-overlapping aging-related pathways appears to be an effective approach to further extend healthy lifespan in both sexes. Here, we review the germline and postnatal mouse lines that target the GH/IGF-1 axis as a mechanism to extend longevity as well as the dietary compounds that tested positive in the NIA program to increase lifespan. We believe that the interventions reviewed in this paper could constitute feasible combinations for an extended healthy lifespan in both male and female mice.
    Keywords:  Aging; GHRKO mice; Growth hormone; IGF-I; Intervention testing program; Longevity
  8. Aging (Albany NY). 2021 Jan 20. 13
    Qi Z, Ji H, Le M, Li H, Wieland A, Bauer S, Liu L, Wink M, Herr I.
      The broccoli-derived isothiocyanate sulforaphane inhibits inflammation, oxidative stress and cancer, but its effect on healthspan and longevity are unclear. We used the C. elegans nematode model and fed the wildtype and 9 mutant strains ±sulforaphane. The lifespan, phenotype, pharyngeal pumping, mobility, lipofuscin accumulation, and RNA and protein expression of the nematodes were assessed by using Kaplan-Meier survival analysis, in vivo live imaging, fluorescence microscopy, and qRT-PCR. Sulforaphane increased the lifespan and promoted a health-related phenotype by increasing mobility, appetite and food intake and reducing lipofuscin accumulation. Mechanistically, sulforaphane inhibited DAF-2-mediated insulin/insulin-like growth factor signaling and its downstream targets AGE-1, AKT-1/AKT-2. This was associated with increased nuclear translocation of the FOXO transcription factor homolog DAF-16. In turn, the target genes sod-3, mtl-1 and gst-4, known to enhance stress resistance and lifespan, were upregulated. These results indicate that sulforaphane prolongs the lifespan and healthspan of C. elegans through insulin/IGF-1 signaling. Our results provide the basis for a nutritional sulforaphane-enriched strategy for the promotion of healthy aging and disease prevention.
    Keywords:  Caenorhabditis elegans; DAF-16; aging; insulin; sulforaphane
  9. Life (Basel). 2021 Jan 15. pii: E60. [Epub ahead of print]11(1):
    Izzo C, Vitillo P, Di Pietro P, Visco V, Strianese A, Virtuoso N, Ciccarelli M, Galasso G, Carrizzo A, Vecchione C.
      Aging can be seen as process characterized by accumulation of oxidative stress induced damage. Oxidative stress derives from different endogenous and exogenous processes, all of which ultimately lead to progressive loss in tissue and organ structure and functions. The oxidative stress theory of aging expresses itself in age-related diseases. Aging is in fact a primary risk factor for many diseases and in particular for cardiovascular diseases and its derived morbidity and mortality. Here we highlight the role of oxidative stress in age-related cardiovascular aging and diseases. We take into consideration the molecular mechanisms, the structural and functional alterations, and the diseases accompanied to the cardiovascular aging process.
    Keywords:  aging; cardiovascular diseases; molecular mechanisms; oxidative stress
  10. Elife. 2021 Jan 19. pii: e59399. [Epub ahead of print]10
    Lyu Y, Weaver KJ, Shaukat HA, Plumoff ML, Tjilos M, Promislow DE, Pletcher SD.
      It has been recognized for nearly a century that diet modulates aging. Despite early experiments suggesting that reduced caloric intake augmented lifespan, accumulating evidence indicates that other characteristics of the diet may be equally or more influential in modulating aging. We demonstrate that behavior, metabolism, and lifespan in Drosophila are affected by whether flies are provided a choice of different nutrients or a single, complete medium, largely independent of the amount of nutrients that are consumed. Meal choice elicits a rapid metabolic reprogramming that indicates a potentiation of TCA cycle and amino acid metabolism, which requires serotonin 2A receptor. Knockdown of glutamate dehydrogenase, a key TCA pathway component, abrogates the effect of dietary choice on lifespan. Our results reveal a mechanism of aging that applies in natural conditions, including our own, in which organisms continuously perceive and evaluate nutrient availability to promote fitness and well-being.
    Keywords:  D. melanogaster; genetics; genomics
  11. Semin Cancer Biol. 2021 Jan 18. pii: S1044-579X(20)30276-5. [Epub ahead of print]
    Ji Y, Kumar R, Ghokale A, Chao HP, Rycaj K, Chen X, Li Q, Tang DG.
      LRIG1, leucine-rich repeats and immunoglobulin-like domains protein 1, was discovered more than 20 years ago and has been shown to be downregulated or lost, and to function as a tumor suppressor in several cancers. Another well-reported biological function of LRIG1 is to regulate and help enforce the quiescence of adult stem cells (SCs). In both contexts, LRIG1 regulates SC quiescence and represses tumor growth via, primarily, antagonizing the expression and activities of ERBB and other receptor tyrosine kinases (RTKs). We have recently reported that in treatment-naïve human prostate cancer (PCa), LRIG1 is primarily regulated by androgen receptor (AR) and is prominently overexpressed. In castration-resistant PCa (CRPC), both LRIG1 and AR expression becomes heterogeneous and, frequently, discordant. Importantly, in both androgen-dependent PCa and CRPC models, LRIG1 exhibits tumor-suppressive functions. Moreover, LRIG1 induction inhibits the growth of pre-established AR+ and AR- PCa. Here, upon a brief introduction of the LRIG1 and the LRIG family, we provide an updated overview on LRIG1 functions in regulating SC quiescence and repressing tumor development. We further highlight the expression, regulation and functions of LRIG1 in treatment-naïve PCa and CRPC. We conclude by offering the perspectives of identifying novel cancer-specific LRIG1-interacting signaling partners and developing LRIG1-based anti-cancer therapeutics and diagnostic/prognostic biomarkers.
    Keywords:  Cancer stem cells; LRIG1; Prostate cancer; Stem cells; Tumor suppressor
  12. Nutr Res. 2020 Dec 04. pii: S0271-5317(20)30585-6. [Epub ahead of print]85 119-134
    Balakrishnan J, Kannan S, Govindasamy A.
      Docosahexaenoic acid (DHA) is one of the most important fatty acids that plays a critical role in maintaining proper brain function and cognitive development. Deficiency of DHA leads to several neurodegenerative disorders and, therefore, dietary supplementations of these fatty acids are essential to maintain cognitive health. However, the complete picture of how DHA is incorporated into the brain is yet to be explored. In general, the de novo synthesis of DHA is poor, and targeting the brain with specific phospholipid carriers provides novel insights into the process of reduction of disease progression. Recent studies have suggested that compared to triacylglycerol form of DHA, esterified form of DHA (i.e., lysophosphatidylcholine [lysoPC]) is better incorporated into the brain. Free DHA is transported across the outer membrane leaflet of the blood-brain barrier via APOE4 receptors, whereas DHA-lysoPC is transported across the inner membrane leaflet of the blood-brain barrier via a specific protein called Mfsd2a. Dietary supplementation of this lysoPC specific form of DHA is a novel therapy and is used to decrease the risk of various neurodegenerative disorders. Currently, structured glycerides of DHA - novel nutraceutical agents - are being widely used for the prevention and treatment of various neurological diseases. However, it is important to fully understand their metabolic regulation and mechanism of transportation to the brain. This article comprehensively reviews various studies that have evaluated the bioavailability of DHA, mechanisms of DHA transport, and role of DHA in preventing neurodegenerative disorders, which provides better insight into the pathophysiology of these disorders and use of structured DHA in improving neurological health.
    Keywords:  DHA; brain; phospholipids; triacylglycerol; β-amyloid
  13. Obes Rev. 2021 Jan 20. e13197
    Monnard CR, Dulloo AG.
      It is now recognized that the amount and type of dietary fat consumed play an important role in metabolic health. In humans, high intake of polyunsaturated fatty acids (PUFAs) has been associated with reductions in cardiovascular disease risk, improvements in glucose homeostasis, and changes in body composition that involve reductions in central adiposity and, more recently, increases in lean body mass. There is also emerging evidence, which suggests that high intakes of the plant-based essential fatty acids (ePUFAs)-n-6 linoleic acid (LA) and n-3 α-linolenic acid (ALA)-have a greater impact on body composition (fat mass and lean mass) and on glucose homeostasis than the marine-derived long-chain n-3 PUFA-eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). In addition, high intake of both ePUFAs (LA and ALA) may also have anti-inflammatory effects in humans. The purpose of this review is to highlight the emerging evidence, from both epidemiological prospective studies and clinical intervention trials, of a role for PUFA, in particular ePUFA, in the long-term regulation of body weight and body composition, and their impact on cardiometabolic health. It also discusses current notions about the mechanisms by which PUFAs modulate fat mass and lean mass through altered control of energy intake, thermogenesis, or lean-fat partitioning.
    Keywords:  cachexia; catch-up growth; diabetes; fat-free mass; obesity; sarcopenia; thermogenesis
  14. Aging Cell. 2021 Jan 20. e13297
    Cheng Y, Pitoniak A, Wang J, Bohmann D.
      The progressively increasing frailty, morbidity and mortality of aging organisms coincides with, and may be causally related to, their waning ability to adapt to environmental perturbations. Transcriptional responses to challenges, such as oxidative stress or pathogens, diminish with age. This effect is manifest in the declining function of the stress responsive transcription factor Nrf2. Protective gene expression programs that are controlled by the Drosophila Nrf2 homolog, CncC, support homeostasis and longevity. Age-associated chromatin changes make these genes inaccessible to CncC binding and render them inert to signal-dependent transcriptional activation in old animals. In a previous paper, we have reported that overexpression of the CncC dimerization partner Maf-S counteracts this degenerative effect and preserves organism fitness. Building on this work, we show here that Maf-S overexpression prevents loss of chromatin accessibility and maintains gene responsiveness. Moreover, the same outcome, along with an extension of lifespan, can be achieved by inducing CncC target gene expression pharmacologically throughout adult life. Thus, pharmacological or dietary interventions that can preserve stress responsive gene expression may be feasible anti-aging strategies.
    Keywords:  Nrf2; aging; chromatin; drosophila; oxidative stress; transcription
  15. Trends Endocrinol Metab. 2021 Jan 08. pii: S1043-2760(21)00001-1. [Epub ahead of print]
    Sohrabi Y, Reinecke H, Godfrey R.
      Recent data have revealed that fructose-rich diet triggers inflammation and lipid synthesis. Furthermore, lipid metabolism, cholesterol synthesis and sterol regulatory element binding protein-2 (SREBP-2) activation correlates with coronavirus disease 2019 (COVID-19)-induced cytokine storm. High fructose consumption result in SREBPs activation, altered cholesterol and lipid synthesis and may establish an innate immune memory in the cells, leading to severe COVID-19 in patients with obesity.
    Keywords:  COVID-19; cholesterol synthesis; cytokine storm; lipid synthesis; obesity
  16. Diabetes Metab Res Rev. 2020 Sep 10. e3405
    Weaver JR, Odanga JJ, Breathwaite EK, Treadwell ML, Murchinson AC, Walters G, Fuentes DP, Lee JB.
      AIMS: Type 2 diabetes (T2D) is a global health problem that will be diagnosed in almost 300 million people by 2025 according to the World Health Organization. Before being diagnosed with T2D, individuals may have glucose levels above normal but below the diabetic range. This condition is known as prediabetes. Studies showed that people with prediabetes had an increase in several pro-inflammatory cytokines in their serum and in their fasting glucose levels. The answer remains unclear when inflammation begins in the pancreas and islets, and what is the extent of this inflammation.METHODS: Subjects with haemoglobin A1c levels from 5.7% to 6.4% were classified as pre-diabetic. Sections of pancreas and isolated islets from normal donors and donors with prediabetes were tested for markers of inflammation and glucose-stimulated insulin secretion (GSIS).
    RESULTS: Gene and protein expression of the inflammatory markers resistin, interleukin-1 beta, tumour necrosis factor-alpha, interleukin-6, and monocyte chemoattractant protein-1 increased in donors with prediabetes compared to normal donors. GSIS response was significantly decreased in pre-diabetic islets compared to normal islets. Donors with prediabetes also had decreased expression of CD163+ cells but not CD68+ cells.
    CONCLUSIONS: Based on our findings, inflammation and islet dysfunction may be more significant than originally thought in people with prediabetes. Rather than being in a normal state before diabetes occurs, it appears that subjects are already in an early diabetic condition resembling more closely T2D.
    Keywords:  cytokines; inflammation; insulin; islets; macrophages; prediabetes
  17. Aging Cell. 2021 Jan 20. e13296
    Ogrodnik M, Evans SA, Fielder E, Victorelli S, Kruger P, Salmonowicz H, Weigand BM, Patel AD, Pirtskhalava T, Inman CL, Johnson KO, Dickinson SL, Rocha A, Schafer MJ, Zhu Y, Allison DB, von Zglinicki T, LeBrasseur NK, Tchkonia T, Neretti N, Passos JF, Kirkland JL, Jurk D.
      Cellular senescence is characterized by an irreversible cell cycle arrest and a pro-inflammatory senescence-associated secretory phenotype (SASP), which is a major contributor to aging and age-related diseases. Clearance of senescent cells has been shown to improve brain function in mouse models of neurodegenerative diseases. However, it is still unknown whether senescent cell clearance alleviates cognitive dysfunction during the aging process. To investigate this, we first conducted single-nuclei and single-cell RNA-seq in the hippocampus from young and aged mice. We observed an age-dependent increase in p16Ink4a senescent cells, which was more pronounced in microglia and oligodendrocyte progenitor cells and characterized by a SASP. We then aged INK-ATTAC mice, in which p16Ink4a -positive senescent cells can be genetically eliminated upon treatment with the drug AP20187 and treated them either with AP20187 or with the senolytic cocktail Dasatinib and Quercetin. We observed that both strategies resulted in a decrease in p16Ink4a exclusively in the microglial population, resulting in reduced microglial activation and reduced expression of SASP factors. Importantly, both approaches significantly improved cognitive function in aged mice. Our data provide proof-of-concept for senolytic interventions' being a potential therapeutic avenue for alleviating age-associated cognitive impairment.
    Keywords:  SASP; aging; brain; cognition; memory; neurodegeneration; senescence; senolytic; telomeres
  18. Cells. 2021 Jan 15. pii: E167. [Epub ahead of print]10(1):
    Sorriento D, Rusciano MR, Visco V, Fiordelisi A, Cerasuolo FA, Poggio P, Ciccarelli M, Iaccarino G.
      Insulin resistance (IRES) is a pathophysiological condition characterized by the reduced response to insulin of several tissues, including myocardial and skeletal muscle. IRES is associated with obesity, glucose intolerance, dyslipidemia, and hypertension, evolves toward type 2 diabetes, and increases the risk of developing cardiovascular diseases. Several studies designed to explore the mechanisms involved in IRES allowed the identification of a multitude of potential molecular targets. Among the most promising, G Protein Coupled Receptor Kinase type 2 (GRK2) appears to be a suitable one given its functional implications in many cellular processes. In this review, we will discuss the metabolic role of GRK2 in those conditions that are characterized by insulin resistance (diabetes, hypertension, heart failure), and the potentiality of its inhibition as a therapeutic strategy to revert both insulin resistance and its associated phenotypes.
    Keywords:  GRK2; diabetes; heart failure; hypertension; insulin resistance
  19. Transfus Apher Sci. 2021 Jan 11. pii: S1473-0502(21)00016-1. [Epub ahead of print] 103066
    Mukherjee S, Reddy O, Panch S, Stroncek D.
      Cell processing laboratories are an important part of cancer treatment centers. Cell processing laboratories began by supporting hematopoietic stem cell (HSC) transplantation programs. These laboratories adapted closed bag systems, centrifuges, sterile connecting devices and other equipment used in transfusion services/blood banks to remove red blood cells and plasma from marrow and peripheral blood stem cells products. The success of cellular cancer immunotherapies such as Chimeric Antigen Receptor (CAR) T-cells has increased the importance of cell processing laboratories. Since many of the diseases successfully treated by CAR T-cell therapy are also treated by HSC transplantation and since HSC transplantation teams are well suited to manage patients treated with CAR T-cells, many cell processing laboratories have begun to produce CAR T-cells. The methods that have been used to process HSCs have been modified for T-cell enrichment, culture, stimulation, transduction and expansion for CAR T-cell production. While processing laboratories are well suited to manufacture CAR T-cells and other cellular therapies, producing these therapies is challenging. The manufacture of cellular therapies requires specialized facilities which are costly to build and maintain. The supplies and reagents, especially vectors, can also be expensive. Finally, highly skilled staff are required. The use of automated equipment for cell production may reduce labor requirements and the cost of facilities. The steps used to produce CAR T-cells are reviewed, as well as various strategies for establishing a laboratory to manufacture these cells.
    Keywords:  Cancer immunotherapy; Cell processing; Cellular therapy; Chimeric antigen receptor T-cells; Hematopoietic stem cell transplantation
  20. J Inflamm Res. 2021 ;14 75-84
    Chekol Abebe E, Asmamaw Dejenie T, Mengie Ayele T, Dagnew Baye N, Agegnehu Teshome A, Tilahun Muche Z.
      Equivalent to regulatory T cells, a novel B cell populace, called regulatory B cells (Bregs), has been found to exert a negative immune regulatory role. These subsets of cells account for 0.5% of human B cells from the periphery that expand after activation upon certain stimuli depending on the nature of the microenvironment and provide a variety of Breg cell phenotypes. The increasing number of suppressive mechanisms attributed to Bregs suggests that these immune cells play many roles in immune regulation. Bregs have been confirmed to play a role in host defense mechanisms of healthy individuals as well as they play pathologic and protective roles in diseases or other conditions. Accumulating evidence reported that Bregs have a role in autoimmune and infectious diseases to lower inflammation, and in cancer to attenuate antitumor immune responses, thereby to promote cancer growth and metastasis. More recently, Bregs are also found to be involved in conditions like transplantation for transplant tolerance, during pregnancy to create an immune-privileged uterine environment and during early neonate life. Herein, the review summarizes recent findings aimed to provide understanding on the Breg cells, in the hope to gain insight on the general overview, development, mechanism of activation, and action of Bregs as well as their potential roles in health and diseases.
    Keywords:  disease; health; immune regulation; regulatory B cells
  21. J Clin Invest. 2021 Jan 19. pii: 145966. [Epub ahead of print]131(2):
    Farese RV, Walther TC.
  22. Autoimmun Rev. 2021 Jan 18. pii: S1568-9972(21)00024-0. [Epub ahead of print] 102765
    Katz-Agranov N, Zandman-Goddard G.
      BACKGROUND AND AIMS: Many forms of immune dysregulation, which lead to inflammaging and senescence, have been demonstrated in patients with systemic lupus erythematosus (SLE; lupus) and in the aging population. The discovery of the microbiome and its association with human health and pathology has led it to be the center of investigation as a major contributor to the pathogenesis of immunosenescence in both populations. Similar alterations to the microbiome in the form of dysbiosis, that are demonstrated in both aging and in lupus patients, may help explain the significant overlap in clinical manifestations seen in these groups.METHODS: We performed an extensive literature review, utilizing the Pubmed search engine and Google Scholar for studies evaluating the microbiome in two groups, elderly populations and lupus patients (both murine and human models), between the years 2000-2019. We searched for the terms: microbiome, dysbiosis, lupus, elderly, aging and inflammaging, which yielded hundreds of articles, of which 114 were used for preparation of this paper. We compared the similarities between the populations.
    RESULTS: We found that the similar processes of immune dysregulation, in both aging populations and lupus patients, extend to the microbiome, in the form of dysbiosis. Some of these similarities include loss of microbiota biodiversity, increased representation of microbes that are associated with inflammation and disease (i.e Proteobacteria, Bacteroidetes), a relative decrease in protective microbes with "anti-inflammatory" properties (i.e Firmicutes) and a subsequent compromise to the intestinal barrier, leading to leakage of proinflammatory microbial components in both groups.
    CONCLUSIONS: We conclude that there are several similar alterations in the composition and function of the microbiome of lupus patients and aging individuals, leading to immunosenescence, which may also be a contributing mechanism in lupus. It seems in fact that the microbiome of SLE may actually be analogous to immunosenescence. This knowledge may help the continuous efforts in finding a solution for both conditions.
    Keywords:  Aging; Dysbiosis; Inflammaging; Lupus; Microbiome; SLE; Senescence
  23. Life (Basel). 2021 Jan 19. pii: E69. [Epub ahead of print]11(1):
    Choi I, Son H, Baek JH.
      The tricarboxylic acid cycle (TCA) is a series of chemical reactions used in aerobic organisms to generate energy via the oxidation of acetylcoenzyme A (CoA) derived from carbohydrates, fatty acids and proteins. In the eukaryotic system, the TCA cycle occurs completely in mitochondria, while the intermediates of the TCA cycle are retained inside mitochondria due to their polarity and hydrophilicity. Under cell stress conditions, mitochondria can become disrupted and release their contents, which act as danger signals in the cytosol. Of note, the TCA cycle intermediates may also leak from dysfunctioning mitochondria and regulate cellular processes. Increasing evidence shows that the metabolites of the TCA cycle are substantially involved in the regulation of immune responses. In this review, we aimed to provide a comprehensive systematic overview of the molecular mechanisms of each TCA cycle intermediate that may play key roles in regulating cellular immunity in cell stress and discuss its implication for immune activation and suppression.
    Keywords:  Krebs cycle; cellular immunity; immunometabolism; tricarboxylic acid cycle
  24. J Clin Invest. 2021 Jan 19. pii: 145962. [Epub ahead of print]131(2):
    Abel ED.
  25. J Lipid Res. 2020 Dec;pii: S0022-2275(20)60021-9. [Epub ahead of print]61(12): 1589-1604
    Zou Y, Wang YN, Ma H, He ZH, Tang Y, Guo L, Liu Y, Ding M, Qian SW, Tang QQ.
      Beiging of white adipose tissue (WAT) has beneficial effects on metabolism. Although it is known that beige adipocytes are active in lipid catabolism and thermogenesis, how they are regulated deserves more explorations. In this study, we demonstrate that stearoyl-CoA desaturase 1 (SCD1) in subcutaneous WAT (scWAT) responded to cold stimulation and was able to promote mobilization of triacylglycerol [TAG (triglyceride)]. In vitro studies showed that SCD1 promoted lipolysis in C3H10T1/2 white adipocytes. The lipolytic effect was contributed by one of SCD1's products, oleic acid (OA). OA upregulated adipose TAG lipase and hormone-sensitive lipase expression. When SCD1 was overexpressed in the scWAT of mice, lipolysis was enhanced, and oxygen consumption and heat generation were increased. These effects were also demonstrated by the SCD1 knockdown experiments in mice. In conclusion, our study suggests that SCD1, known as an enzyme for lipid synthesis, plays a role in upregulating lipid mobilization through its desaturation product, OA.
    Keywords:  adipocytes; lipolysis; lipophagy; oleic acid; stearoyl-CoA desaturase-1; thermogenesis; triacylglycerol
  26. Cell Rep. 2021 Jan 19. pii: S2211-1247(20)31649-1. [Epub ahead of print]34(3): 108660
    Romani M, Sorrentino V, Oh CM, Li H, de Lima TI, Zhang H, Shong M, Auwerx J.
      Aging is characterized by loss of proteostasis and mitochondrial homeostasis. Here, we provide bioinformatic evidence of dysregulation of mitochondrial and proteostasis pathways in muscle aging and diseases. Moreover, we show accumulation of amyloid-like deposits and mitochondrial dysfunction during natural aging in the body wall muscle of C. elegans, in human primary myotubes, and in mouse skeletal muscle, partially phenocopying inclusion body myositis (IBM). Importantly, NAD+ homeostasis is critical to control age-associated muscle amyloidosis. Treatment of either aged N2 worms, a nematode model of amyloid-beta muscle proteotoxicity, human aged myotubes, or old mice with the NAD+ boosters nicotinamide riboside (NR) and olaparib (AZD) increases mitochondrial function and muscle homeostasis while attenuating amyloid accumulation. Hence, our data reveal that age-related amyloidosis is a contributing factor to mitochondrial dysfunction and that both are features of the aging muscle that can be ameliorated by NAD+ metabolism-enhancing approaches, warranting further clinical studies.
    Keywords:  NAD(+); aging; amyloid-beta; amyloidosis; inclusion body myositis; mitochondria; nicotinamide riboside; olaparib; proteostasis; skeletal muscle
  27. J Mol Cell Cardiol. 2021 Jan 15. pii: S0022-2828(21)00003-1. [Epub ahead of print]
    Rigaud VOC, Khan M.
    Keywords:  Cardiac regeneration; Cardiomyocyte proliferation; Cell cycle; Developmental signaling; Myocardial infarction
  28. Aging Ment Health. 2021 Jan 18. 1-9
    Greenfield L, Mathews S, Toukhsati SR.
      OBJECTIVES: Depression is common in older adults and is linked to morbidity and mortality. The aim of this study was to investigate whether specific symptoms of depression (dysphoria, anhedonia and anergia) predicted mortality in older Australian Aged Care residents.METHODS: Eighty older adults (M = 83.16 ± 7.14) without cognitive impairment residing in 14 Residential Aged Care facilities located in Melbourne, Australia, completed the 15-item Geriatric Depression Scale-Short Form (GDS-15) and the Standardized Mini Mental State Examination. Residential Aged Care facilities provided the primary end-point of all-cause mortality at follow-up (M = 5.4 years ± 0.1).
    RESULTS: Univariate Kaplan-Meier survival curves and Cox Proportional Hazards regression analyses were used to evaluate whether symptoms of depression predicted all-cause mortality, with known prognostic factors controlled. The results indicated that anhedonia (Hazard Ratio = 2.931 [95% CI 1.278-6.722], p = .011) and anergia (Hazard Ratio = 2.783 [95% CI 1.065-7.276], p = .037) were associated with almost a threefold increased risk of mortality in older adults living in RAC in adjusted analyses. Dysphoria did not predict mortality.
    CONCLUSIONS: These findings advance understanding of the mortality risks of anhedonia and anergia in an understudied population. Symptoms of anhedonia and anergia should be targeted for screening in older adults living in Aged Care to increase the detection and potential for referral to treatment for depressive presentation.
    Keywords:  Depression; anergia; anhedonia; dysphoria; mortality; older adults; residential aged care
  29. Clin Transl Sci. 2020 Aug 16.
    Chen K, Sinelnikov MY, Reshetov IV, Timashev P, Gu Y, Mu L, Lu P, Zhang Y.
      Upper limb lymphedema is one of the most common complications after breast cancer surgery and radiotherapy. Despite various physical therapy and surgical options available, the impaired lymph fluid drainage may be progressive due to lymphatic vascular insufficiency making treatment more difficulty. Stem cell therapy provides a promising alternative in the treatment of various chronic diseases. The wide applicability of cell therapy has been reviewed throughout literature. This review provides an overview of recent progress in the therapeutic effect of adult stem cells for primary and secondary lymphedema after breast surgery in preclinical studies and clinical cases. We start with a brief introduction about the pathophysiological mechanisms of postmastectomy lymphedema. Regarding existing treatments, we systematically summarize the benefits and limitations of recent progress. Because of their multidirectional differentiation potential and growth factor secretion, stem cell therapy shows promising results in the management of light to severe lymphedema. Increasing evidences have demonstrated a noticeable reduction in postmastectomy lymphedema and increased lymph-angiogenesis after specific stem cell therapy. Current data suggests that stem cell therapy in lymphedema treatment provides reversal of pathological reorganization associated with lymphedema progression. Finally, we propose potential strategies for overcoming the challenges in the development of multipotent progenitor cells for the treatment and prevention of lymphedema in clinical practice.