bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2023–06–18
sixteen papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research
  1. Metabolism along the life journey of T cells.
  2. Activated protein C modulates T-cell metabolism and epigenetic FOXP3 induction via α-Ketoglutarate.
  3. Lipid metabolism reprogramming of CD8+ T cell and therapeutic implications in cancer.
  4. Reactive oxygen species formation and its effect on CD4+ T cell-mediated inflammation.
  5. Crosstalk between trace elements and T-cell immunity during early-life health in pigs.
  6. Time-resolved proteomic analyses of senescence highlight metabolic rewiring of mitochondria.
  7. Drugs Targeting Mechanisms of Aging to Delay Age-Related Disease and Promote Healthspan: Proceedings of a National Institute on Aging Workshop.
  8. Recovery of intracellular glucose uptake in T cells during partial remission of type 1 diabetes.
  9. SWI/SNF chromatin remodeling complexes as key regulators of CD8+ T cell fate.
  10. PD-1/CTLA-4 Blockade Leads to Expansion of CD8+PD-1int TILs and Results in Tumor Remission in Experimental Liver Cancer.
  11. Transcriptomics reveals a distinct metabolic profile in T cells from severe allergic asthmatic patients.
  12. Mitochondria: at the crossroads between mechanobiology and cell metabolism.
  13. Canonical BAF complex activity shapes the enhancer landscape that licenses CD8+ T cell effector and memory fates.
  14. Gut microbiota and anti-aging: Focusing on spermidine.
  15. Supplementation with Nicotinamide riboside attenuates T cell exhaustion and improves survival in sepsis.
  16. The SWI/SNF chromatin remodeling complexes BAF and PBAF differentially regulate epigenetic transitions in exhausted CD8+ T cells.
  1. Life Metab. 2023 Feb;pii: load002. [Epub ahead of print]2(1):
    Metabolism along the life journey of T cells.
    Min Peng, Ming O Li.
      T cells are one of few cell types in adult mammals that can proliferate extensively and differentiate diversely upon stimulation, which serves as an excellent example to dissect the metabolic basis of cell fate decisions. During the last decade, there has been an explosion of research into the metabolic control of T-cell responses. The roles of common metabolic pathways, including glycolysis, lipid metabolism, and mitochondrial oxidative phosphorylation, in T-cell responses have been well characterized, and their mechanisms of action are starting to emerge. In this review, we present several considerations for T-cell metabolism-focused research, while providing an overview of the metabolic control of T-cell fate decisions during their life journey. We try to synthesize principles that explain the causal relationship between cellular metabolism and T-cell fate decision. We also discuss key unresolved questions and challenges in targeting T-cell metabolism to treat disease.
    Keywords:  FAO; OXPHOS; T cells; acetyl-CoA; glycolysis; immunometabolism
    DOI:  https://doi.org/10.1093/lifemeta/load002
  2. Blood Adv. 2023 Jun 14. pii: bloodadvances.2023010083. [Epub ahead of print]
    Activated protein C modulates T-cell metabolism and epigenetic FOXP3 induction via α-Ketoglutarate.
    Dheerendra Gupta, Ahmed Elwakiel, Satish Ranjan, Manish Kumar Pandey, Shruthi Krishnan, Saira Ambreen, Reinhard Henschler, Rajiv Rana, Maria Keller, Uta Ceglarek, Khurrum Shahzad, Shrey Kohli, Berend Isermann.
      A direct regulation of adaptive immunity by the coagulation protease activated protein C (aPC) has recently been established. T-cell pre-incubation with aPC for 1 hour prior to transplantation increases FOXP3+ Tregs and reduces acute graft versus host disease (aGvHD) in mice, but the underlying mechanism remains unknown. As cellular metabolism modulates epigenetic gene regulation and plasticity in T-cells, we hypothesized that aPC promotes FOXP3+ expression by altering T-cell metabolism. To this end, T-cell differentiation was assessed in vitro using mixed lymphocyte reaction or plate-bound α-CD3/CD28 stimulation and ex vivo using T-cells isolated from aGvHD mice without and with aPC preincubation or analyses of mice with high plasma aPC levels. In stimulated CD4+CD25- cells, aPC induces FOXP3 expression while reducing expression of Th1-cell markers. Increased FOXP3 expression is associated with altered epigenetic markers (reduced 5-methylcytosine and H3K27me3) and reduced Foxp3 promoter methylation and activity These changes are linked to metabolic quiescence, decreased glucose and glutamine uptake, decreased mitochondrial metabolism (reduced TCA metabolites and mitochondrial membrane potential), and decreased intracellular glutamine and α-ketoglutarate levels. In mice with high aPC plasma levels, T-cell subpopulations in the thymus are not altered, reflecting normal T-cell development, while FOXP3 expression in splenic T-cells is reduced. Glutamine and α-ketoglutarate substitution reverse aPC-mediated FOXP3+ induction and abolish aPC-mediated suppression of allogeneic T-cell stimulation. These findings show that aPC modulates cellular metabolism in T-cells, reducing glutamine and α-ketoglutarate levels, which results in altered epigenetic marks, Foxp3 promoter demethylation and induction of FOXP3 expression, thus favoring a Treg-like phenotype.
    DOI:  https://doi.org/10.1182/bloodadvances.2023010083
  3. Cancer Lett. 2023 Jun 12. pii: S0304-3835(23)00218-5. [Epub ahead of print] 216267
    Lipid metabolism reprogramming of CD8+ T cell and therapeutic implications in cancer.
    Runxian Wang, Zhenya Liu, Zhiyao Fan, Hanxiang Zhan.
      Effector, memory and exhaustion are three phenotypes of CD8+ T cell. In tumor microenvironment (TME), metabolism dysfunction of the three should take the blame for immune escape. Against background of CD8+ T cell in normal development, multiple determinants in TME, including nutrition competition, PD-1 signals and other cancer- CD8+ T cell interaction, cause metabolism reprograming, including failure in energy metabolism and other abnormal lipid metabolism. Further, incompatibility of different CD8+ T cell metabolism pattern results in unresponsiveness of immune checkpoint blockade (ICB). Therefore, combination of ICB and drugs aiming at abnormal lipid metabolism provides promising direction to improve cancer therapy.
    Keywords:  Cholesterol; Energy metabolism; Immune checkpoint blockade; Lipid peroxidation; Metabolism regulating drug; Mitochondria
    DOI:  https://doi.org/10.1016/j.canlet.2023.216267
  4. Front Immunol. 2023 ;14 1199233
    Reactive oxygen species formation and its effect on CD4+ T cell-mediated inflammation.
    Panyin Shu, Hantian Liang, Jianan Zhang, Yubin Lin, Wenjing Chen, Dunfang Zhang.
      Reactive oxygen species (ROS) are produced both enzymatically and non-enzymatically in vivo. Physiological concentrations of ROS act as signaling molecules that participate in various physiological and pathophysiological activities and play an important role in basic metabolic functions. Diseases related to metabolic disorders may be affected by changes in redox balance. This review details the common generation pathways of intracellular ROS and discusses the damage to physiological functions when the ROS concentration is too high to reach an oxidative stress state. We also summarize the main features and energy metabolism of CD4+ T-cell activation and differentiation and the effects of ROS produced during the oxidative metabolism of CD4+ T cells. Because the current treatment for autoimmune diseases damages other immune responses and functional cells in the body, inhibiting the activation and differentiation of autoreactive T cells by targeting oxidative metabolism or ROS production without damaging systemic immune function is a promising treatment option. Therefore, exploring the relationship between T-cell energy metabolism and ROS and the T-cell differentiation process provides theoretical support for discovering effective treatments for T cell-mediated autoimmune diseases.
    Keywords:  CD4+ T cells; Th17 cells; Treg cells; effector T cells (Teffs); inflammation; reactive oxygen species
    DOI:  https://doi.org/10.3389/fimmu.2023.1199233
  5. Sci China Life Sci. 2023 Jun 06.
    Crosstalk between trace elements and T-cell immunity during early-life health in pigs.
    Shunshun Jin, Liuqin He, Chenbo Yang, Xinmiao He, Heshu Chen, Yanzhong Feng, Wenjie Tang, Jianzhong Li, Di Liu, Tiejun Li.
      With gradual ban on the use of antibiotics, the deficiency and excessive use of trace elements in intestinal health is gaining attention. In mammals, trace elements are essential for the development of the immune system, specifically T-cell proliferation, and differentiation. However, there remain significant gaps in our understanding of the effects of certain trace elements on T-cell immune phenotypes and functions in pigs. In this review, we summarize the specificity, development, subpopulations, and responses to pathogens of porcine T cells and the effects of functional trace elements (e.g., iron, copper, zinc, and selenium) on intestinal T-cell immunity during early-life health in pigs. Furthermore, we discuss the current trends of research on the crosstalk mechanisms between trace elements and T-cell immunity. The present review expands our knowledge of the association between trace elements and T-cell immunity and provides an opportunity to utilize the metabolism of trace elements as a target to treat various diseases.
    Keywords:  T cells; gut; immunity; pig; trace elements
    DOI:  https://doi.org/10.1007/s11427-022-2339-0
  6. Life Sci Alliance. 2023 Sep;pii: e202302127. [Epub ahead of print]6(9):
    Time-resolved proteomic analyses of senescence highlight metabolic rewiring of mitochondria.
    Jun Yong Kim, Ilian Atanassov, Frederik Dethloff, Lara Kroczek, Thomas Langer.
      Mitochondrial dysfunction and cellular senescence are hallmarks of aging. However, the relationship between these two phenomena remains incompletely understood. In this study, we investigated the rewiring of mitochondria upon development of the senescent state in human IMR90 fibroblasts. Determining the bioenergetic activities and abundance of mitochondria, we demonstrate that senescent cells accumulate mitochondria with reduced OXPHOS activity, resulting in an overall increase of mitochondrial activities in senescent cells. Time-resolved proteomic analyses revealed extensive reprogramming of the mitochondrial proteome upon senescence development and allowed the identification of metabolic pathways that are rewired with different kinetics upon establishment of the senescent state. Among the early responding pathways, the degradation of branched-chain amino acid was increased, whereas the one carbon folate metabolism was decreased. Late-responding pathways include lipid metabolism and mitochondrial translation. These signatures were confirmed by metabolic flux analyses, highlighting metabolic rewiring as a central feature of mitochondria in cellular senescence. Together, our data provide a comprehensive view on the changes in mitochondrial proteome in senescent cells and reveal how the mitochondrial metabolism is rewired in senescent cells.
    DOI:  https://doi.org/10.26508/lsa.202302127
  7. J Gerontol A Biol Sci Med Sci. 2023 Jun 16. 78(Supplement_1): 53-60
    Drugs Targeting Mechanisms of Aging to Delay Age-Related Disease and Promote Healthspan: Proceedings of a National Institute on Aging Workshop.
    Sara E Espinoza, Sundeep Khosla, Joseph A Baur, Rafael de Cabo, Nicolas Musi.
      The geroscience hypothesis posits that by targeting key hallmarks of aging we may simultaneously prevent or delay several age-related diseases and thereby increase healthspan, or life span spent free of significant disease and disability. Studies are underway to examine several possible pharmacological interventions for this purpose. As part of a National Institute on Aging workshop on the development of function-promoting therapies, scientific content experts provided literature reviews and state-of-the-field assessments for the studies of senolytics, nicotinamide adenine dinucleotide (NAD+) boosters, and metformin. Cellular senescence increases with age, and preclinical studies demonstrate that the use of senolytic drugs improves healthspan in rodents. Human studies using senolytics are in progress. NAD+ and its phosphorylated form, NADP+, play vital roles in metabolism and cellular signaling. Increasing NAD+ by supplementation with precursors including nicotinamide riboside and nicotinamide mononucleotide appears to extend healthspan in model organisms, but human studies are limited and results are mixed. Metformin is a biguanide widely used for glucose lowering, which is believed to have pleiotropic effects targeting several hallmarks of aging. Preclinical studies suggest it improves life span and healthspan, and observational studies suggest benefits for the prevention of several age-related diseases. Clinical trials are underway to examine metformin for healthspan and frailty prevention. Preclinical and emerging clinical studies suggest there is potential to improve healthspan through the use of pharmacologic agents reviewed. However, much further research is needed to demonstrate benefits and general safety for wider use, the appropriate target populations, and longer-term outcomes.
    Keywords:  Aging; Cellular senescence; Geroscience; Healthspan; Metformin; Nicotinamide riboside
    DOI:  https://doi.org/10.1093/gerona/glad034
  8. Diabetologia. 2023 Jun 10.
    Recovery of intracellular glucose uptake in T cells during partial remission of type 1 diabetes.
    Rong Tang, Ting Zhong, Kang Lei, Xiaoxi Lin, Xia Li.
       AIMS/HYPOTHESIS: Notwithstanding the irreversible beta cell failure seen in type 1 diabetes, some individuals may experience a special phase named 'partial remission' or 'the honeymoon period', in which there is a transient recovery of beta cell function. Importantly, this stage of partial remission shows spontaneous immune downregulation, although the exact mechanisms are unclear. Intracellular energy metabolism is crucial for the differentiation and function of T cells, and provides promising targets for immunometabolic intervention strategies, but its role during partial remission is unknown. In this study, we aim to investigate the association between T cell intracellular glucose and fatty acid metabolism and the partial remission phase.
    METHODS: This is a cross-sectional study with a follow-up component. Intracellular uptake of glucose and fatty acids by T cells was detected in participants with either new-onset type 1 diabetes or type 1 diabetes that was already in partial remission, and compared with heathy individuals and participants with type 2 diabetes. Subsequently, the participants with new-onset type 1 diabetes were followed up to determine whether they experienced a partial remission (remitters) or not (non-remitters). The trajectory of changes in T cell glucose metabolism was observed in remitters and non-remitters. Expression of programmed cell death-1 (PD-1) was also analysed to investigate possible mechanisms driving altered glucose metabolism. Partial remission was defined when patients had convalescent fasting or 2 h postprandial C-peptide >300 pmol/l after insulin treatment.
    RESULTS: Compared with participants with new-onset type 1 diabetes, intracellular glucose uptake by T cells decreased significantly in individuals with partial remission. The trajectory of these changes during follow-up showed that intracelluar glucose uptake in T cells fluctuated during different disease stages, with a decreased uptake during partial remission that rebounded after remission. This dynamic in T cell glucose uptake was only detected in remitters and not in non-remitters. Further analysis demonstrated that changes of intracellular glucose uptake were found in subsets of CD4+ and CD8+ T cells, including Th17, Th1, CD8+ naive T cells (Tn) and CD8+ terminally differentiated effector memory T cells (Temra). Moreover, glucose uptake in CD8+ T cells was negatively related to PD-1 expression. The intracellular metabolism of fatty acids was not found to be different between new-onset participants and those in partial remission.
    CONCLUSIONS/INTERPRETATION: Intracellular glucose uptake in T cells was specifically decreased during partial remission in type 1 diabetes and may be related to PD-1 upregulation, which may be involved in the down-modulation of immune responses during partial remission. This study suggests that altered immune metabolism could be a target for interventions at the point of diagnosis of type 1 diabetes.
    Keywords:  Glucose uptake; Intracellular metabolism; Partial remission; T cell; Type 1 diabetes
    DOI:  https://doi.org/10.1007/s00125-023-05938-z
  9. Immunity. 2023 Jun 13. pii: S1074-7613(23)00235-2. [Epub ahead of print]56(6): 1162-1164
    SWI/SNF chromatin remodeling complexes as key regulators of CD8+ T cell fate.
    Lisa Rausch, Axel Kallies.
      CD8+ T cell fate is tightly regulated by epigenetic modification. In this issue of Immunity, McDonald et al. and Baxter et al. demonstrate that the chromatin remodeling complexes cBAF and PBAF control proliferation, differentiation, and function of cytotoxic T cells in response to infection as well as cancer.
    DOI:  https://doi.org/10.1016/j.immuni.2023.05.018
  10. Liver Cancer. 2023 Jun;12(2): 129-144
    PD-1/CTLA-4 Blockade Leads to Expansion of CD8+PD-1int TILs and Results in Tumor Remission in Experimental Liver Cancer.
    Sandra Bufe, Artur Zimmermann, Sarina Ravens, Immo Prinz, Laura Elisa Buitrago-Molina, Robert Geffers, Norman Woller, Florian Kühnel, Steven R Talbot, Fatih Noyan, Michael Peter Manns, Heiner Wedemeyer, Matthias Hardtke-Wolenski, Elmar Jaeckel, Ana C Davalos-Misslitz.
       Background: Checkpoint inhibitors act on exhausted CD8+ T cells and restore their effector function in chronic infections and cancer. The underlying mechanisms of action appear to differ between different types of cancer and are not yet fully understood.
    Methods: Here, we established a new orthotopic HCC model to study the effects of checkpoint blockade on exhausted CD8+ tumor-infiltrating lymphocytes (TILs). The tumors expressed endogenous levels of HA, which allowed the study of tumor-specific T cells.
    Results: The induced tumors developed an immune-resistant TME in which few T cells were found. The few recovered CD8+ TILs were mostly terminally exhausted and expressed high levels of PD-1. PD-1/CTLA-4 blockade resulted in a strong increase in the number of CD8+ TILs expressing intermediate amounts of PD-1, also called progenitor-exhausted CD8+ TILs, while terminally exhausted CD8+ TILs were almost absent in the tumors of treated mice. Although transferred naïve tumor-specific T cells did not expand in the tumors of untreated mice, they expanded strongly after treatment and generated progenitor-exhausted but not terminally exhausted CD8+ TILs. Unexpectedly, progenitor-exhausted CD8+ TILs mediated the antitumor response after treatment with minimal changes in their transcriptional profile.
    Conclusion: In our model, few doses of checkpoint inhibitors during the priming of transferred CD8+ tumor-specific T cells were sufficient to induce tumor remission. Therefore, PD-1/CTLA-4 blockade has an ameliorative effect on the expansion of recently primed CD8+ T cells while preventing their development into terminally exhausted CD8+ TILs in the TME. This finding could have important implications for future T-cell therapies.
    Keywords:  Adoptive T-cell therapy; Checkpoint blockade; Liver cancer; T-cell exclusion; T-cell exhaustion
    DOI:  https://doi.org/10.1159/000526899
  11. Front Allergy. 2023 ;4 1129248
    Transcriptomics reveals a distinct metabolic profile in T cells from severe allergic asthmatic patients.
    Carmela Pablo-Torres, Carlota Garcia-Escribano, Martina Romeo, Cristina Gomez-Casado, Ricardo Arroyo Solera, José Luis Bueno-Cabrera, M Del Mar Reaño Martos, Alfredo Iglesias-Cadarso, Carlos Tarín, Ioana Agache, Tomás Chivato, Domingo Barber, María M Escribese, Elena Izquierdo.
      The reasons behind the onset and continuation of chronic inflammation in individuals with severe allergies are still not understood. Earlier findings indicated that there is a connection between severe allergic inflammation, systemic metabolic alterations and impairment of regulatory functions. Here, we aimed to identify transcriptomic alterations in T cells associated with the degree of severity in allergic asthmatic patients. T cells were isolated from severe (n = 7) and mild (n = 9) allergic asthmatic patients, and control (non-allergic, non-asthmatic healthy) subjects (n = 8) to perform RNA analysis by Affymetrix gene expression. Compromised biological pathways in the severe phenotype were identified using significant transcripts. T cells' transcriptome of severe allergic asthmatic patients was distinct from that of mild and control subjects. A higher count of differentially expressed genes (DEGs) was observed in the group of individuals with severe allergic asthma vs. control (4,924 genes) and vs. mild (4,232 genes) groups. Mild group also had 1,102 DEGs vs. controls. Pathway analysis revealed alterations in metabolism and immune response in the severe phenotype. Severe allergic asthmatic patients presented downregulation in genes related to oxidative phosphorylation, fatty acid oxidation and glycolysis together with increased expression of genes coding inflammatory cytokines (e.g. IL-19, IL-23A and IL-31). Moreover, the downregulation of genes involved in TGFβ pathway together with a decreased tendency on the percentage of T regulatory cell (CD4 + CD25+), suggest a compromised regulatory function in severe allergic asthmatic patients. This study demonstrates a transcriptional downregulation of metabolic and cell signalling pathways in T cells of severe allergic asthmatic patients associated with diminished regulatory T cell function. These findings support a link between energy metabolism of T cells and allergic asthmatic inflammation.
    Keywords:  CD3+cells; Tregs; allergy; inflammation; metabolism; severe phenotype; t cells; transcriptomics
    DOI:  https://doi.org/10.3389/falgy.2023.1129248
  12. Biol Cell. 2023 Jun 16.
    Mitochondria: at the crossroads between mechanobiology and cell metabolism.
    Émilie Su, Catherine Villard, Jean-Baptiste Manneville.
      Metabolism and mechanics are two key facets of structural and functional processes in cells, such as growth, proliferation, homeostasis and regeneration. Their reciprocal regulation has been increasingly acknowledged in recent years: external physical and mechanical cues entail metabolic changes, which in return regulate cell mechanosensing and mechanotransduction. Since mitochondria are pivotal regulators of metabolism, we review here the reciprocal links between mitochondrial morphodynamics, mechanics and metabolism. Mitochondria are highly dynamic organelles which sense and integrate mechanical, physical and metabolic cues to adapt their morphology, the organization of their network and their metabolic functions. While some of the links between mitochondrial morphodynamics, mechanics and metabolism are already well established, others are still poorly documented and open new fields of research. First, cell metabolism is known to correlate with mitochondrial morphodynamics. For instance, mitochondrial fission, fusion and cristae remodeling allow the cell to fine-tune its energy production through the contribution of mitochondrial oxidative phosphorylation and cytosolic glycolysis. Second, mechanical cues and alterations in mitochondrial mechanical properties reshape and reorganize the mitochondrial network. Mitochondrial membrane tension emerges as a decisive physical property which regulates mitochondrial morphodynamics. However, the converse link hypothesizing a contribution of morphodynamics to mitochondria mechanics and/or mechanosensitivity has not yet been demonstrated. Third, we highlight that mitochondrial mechanics and metabolism are reciprocally regulated, although little is known about the mechanical adaptation of mitochondria in response to metabolic cues. Deciphering the links between mitochondrial morphodynamics, mechanics and metabolism still presents significant technical and conceptual challenges but is crucial both for a better understanding of mechanobiology and for potential novel therapeutic approaches in diseases such as cancer. This article is protected by copyright. All rights reserved.
    Keywords:  Mitochondrial morphodynamics; cancer; cytoskeleton; glycolysis; mechanotransduction; membrane tension; oxidative phosphorylation
    DOI:  https://doi.org/10.1111/boc.202300010
  13. Immunity. 2023 Jun 13. pii: S1074-7613(23)00222-4. [Epub ahead of print]56(6): 1303-1319.e5
    Canonical BAF complex activity shapes the enhancer landscape that licenses CD8+ T cell effector and memory fates.
    Bryan McDonald, Brent Y Chick, Nasiha S Ahmed, Mannix Burns, Shixin Ma, Eduardo Casillas, Dan Chen, Thomas H Mann, Carolyn O'Connor, Nasun Hah, Diana C Hargreaves, Susan M Kaech.
      CD8+ T cells provide host protection against pathogens by differentiating into distinct effector and memory cell subsets, but how chromatin is site-specifically remodeled during their differentiation is unclear. Due to its critical role in regulating chromatin and enhancer accessibility through its nucleosome remodeling activities, we investigated the role of the canonical BAF (cBAF) chromatin remodeling complex in antiviral CD8+ T cells during infection. ARID1A, a subunit of cBAF, was recruited early after activation and established de novo open chromatin regions (OCRs) at enhancers. Arid1a deficiency impaired the opening of thousands of activation-induced enhancers, leading to loss of TF binding, dysregulated proliferation and gene expression, and failure to undergo terminal effector differentiation. Although Arid1a was dispensable for circulating memory cell formation, tissue-resident memory (Trm) formation was strongly impaired. Thus, cBAF governs the enhancer landscape of activated CD8+ T cells that orchestrates TF recruitment and activity and the acquisition of specific effector and memory differentiation states.
    Keywords:  ARID1A; BAF complex; CD8(+) T cells; antiviral immunity; chromatin remodeling; effector T cell; epigenetics; immunotherapy; memory T cell
    DOI:  https://doi.org/10.1016/j.immuni.2023.05.005
  14. Crit Rev Food Sci Nutr. 2023 Jun 16. 1-19
    Gut microbiota and anti-aging: Focusing on spermidine.
    Leilei Yu, Jiani Pan, Min Guo, Hui Duan, Hao Zhang, Arjan Narbad, Qixiao Zhai, Fengwei Tian, Wei Chen.
      The human gut microbiota plays numerous roles in regulating host growth, the immune system, and metabolism. Age-related changes in the gut environment lead to chronic inflammation, metabolic dysfunction, and illness, which in turn affect aging and increase the risk of neurodegenerative disorders. Local immunity is also affected by changes in the gut environment. Polyamines are crucial for cell development, proliferation, and tissue regeneration. They regulate enzyme activity, bind to and stabilize DNA and RNA, have antioxidative properties, and are necessary for the control of translation. All living organisms contain the natural polyamine spermidine, which has anti-inflammatory and antioxidant properties. It can regulate protein expression, prolong life, and improve mitochondrial metabolic activity and respiration. Spermidine levels experience an age-related decrease, and the development of age-related diseases is correlated with decreased endogenous spermidine concentrations. As more than just a consequence, this review explores the connection between polyamine metabolism and aging and identifies advantageous bacteria for anti-aging and metabolites they produce. Further research is being conducted on probiotics and prebiotics that support the uptake and ingestion of spermidine from food extracts or stimulate the production of polyamines by gut microbiota. This provides a successful strategy to increase spermidine levels.
    Keywords:  Polyamines; aging; gut microbiota; probiotics; spermidine
    DOI:  https://doi.org/10.1080/10408398.2023.2224867
  15. Shock. 2023 Jun 15.
    Supplementation with Nicotinamide riboside attenuates T cell exhaustion and improves survival in sepsis.
    Guang-Ju Zhao, Xi-Yu Yang, Chen Zhang, Wei Dong, Fu-Bo Dong, Jie Zhang, Xiao-Yan Chen, Ren-Qi Yao, Zhong Xiao, Long-Wang Chen, Yong-Ming Yao, Zhong-Qiu Lu.
       ABSTRACT: T cell exhaustion is the main cause of sepsis-induced immunosuppression, and is associated with the poor prognosis. Nicotinamide adenine dinucleotide (NAD+) is well known for its anti-aging effect, but its role in sepsis-induced T cell exhaustion remains to be elucidated. In the present study, using a classic septic animal model, we found that the levels of NAD+ and its downstream molecule-sirtuins 1 (SIRT1) in T cells in sepsis were decreased. Supplementation with Nicotinamide ribose (NR), the precursor of NAD+, right after cecal ligation and puncture significantly increased the levels of NAD+ and SIRT1. Supplementation with NR alleviated the depletion of mononuclear cells and T lymphocytes in spleen in sepsis, and increased the levels of CD3+CD4+ and CD3+CD8+T cells. Interestingly, both Th1 and Th2 cells were expanded after NR treatment, but the balance of Th1/Th2 was partly restored. NR also inhibited the regulatory T cells expansion and PD-1 expression in CD4+T cells in sepsis. Additionally, the bacteria load, organ damage (lung, heart, liver and kidney) and the mortality of septic mice were reduced after NR supplementation. In summary, these results demonstrate the beneficial effect of NR on sepsis and T cell exhaustion, which is associated with NAD+/SIRT1 pathway.
    DOI:  https://doi.org/10.1097/SHK.0000000000002153
  16. Immunity. 2023 Jun 13. pii: S1074-7613(23)00225-X. [Epub ahead of print]56(6): 1320-1340.e10
    The SWI/SNF chromatin remodeling complexes BAF and PBAF differentially regulate epigenetic transitions in exhausted CD8+ T cells.
    Amy E Baxter, Hua Huang, Josephine R Giles, Zeyu Chen, Jennifer E Wu, Sydney Drury, Katherine Dalton, Simone L Park, Leonel Torres, Brandon W Simone, Max Klapholz, Shin Foong Ngiow, Elizabeth Freilich, Sasikanth Manne, Victor Alcalde, Viktoriya Ekshyyan, Shelley L Berger, Junwei Shi, Martha S Jordan, E John Wherry.
      CD8+ T cell exhaustion (Tex) limits disease control during chronic viral infections and cancer. Here, we investigated the epigenetic factors mediating major chromatin-remodeling events in Tex-cell development. A protein-domain-focused in vivo CRISPR screen identified distinct functions for two versions of the SWI/SNF chromatin-remodeling complex in Tex-cell differentiation. Depletion of the canonical SWI/SNF form, BAF, impaired initial CD8+ T cell responses in acute and chronic infection. In contrast, disruption of PBAF enhanced Tex-cell proliferation and survival. Mechanistically, PBAF regulated the epigenetic and transcriptional transition from TCF-1+ progenitor Tex cells to more differentiated TCF-1- Tex subsets. Whereas PBAF acted to preserve Tex progenitor biology, BAF was required to generate effector-like Tex cells, suggesting that the balance of these factors coordinates Tex-cell subset differentiation. Targeting PBAF improved tumor control both alone and in combination with anti-PD-L1 immunotherapy. Thus, PBAF may present a therapeutic target in cancer immunotherapy.
    Keywords:  BAF; CRISPR-Cas9 screen; PBAF; SWI/SNF; T cell exhaustion; T cell memory; chromatin remodelling complexes; epigenetics; immunotherapy
    DOI:  https://doi.org/10.1016/j.immuni.2023.05.008
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